Clinical trial NCT02618577
Conditions: Atrial High Rate Episodes
Keywords: Anticoagulation Atrial High Rate Episodes Atrial Fibrillation VKA NOAC
Sponsor: Atrial Fibrillation Network
Start date: 2016-02-01; Completion date: 2022-12-31
Enrollment: 2608 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
NOAH is an investigator-initiated, prospective, parallel-group, double-blind, randomised, multi-centre trial. The objective of the trial is to demonstrate that oral anticoagulation using the NOAC edoxaban is superior to current therapy to pre-vent stroke, systemic embolism, or cardiovascular death in patients with AHRE and at least two stroke risk factors but without AF. The trial will be conducted in several European countries.

Detailed description:
Atrial fibrillation (AF) is a common cause of stroke, especially ischemic stroke. So far, all available data that demonstrate a beneficial effect of oral anticoagulation for stroke prevention have been collected in populations with AF documented by conventional ECG recordings. It is well established that a large proportion of AF episodes remain undiagnosed ("silent AF"), and many of these patients present with a stroke as the first clinical sign of AF. Earlier initiation of anticoagulation could prevent such events. Continuous monitoring of atrial rhythm by implanted devices could close this diagnostic gap. Pacemakers, defibrillators, and cardiac resynchronisation devices already provide automated algorithms alerting to the occurrence of highly organised atrial tachyarrhythmia episodes, also called "subclinical atrial fibrillation" or, more commonly, "atrial high rate episodes" (AHRE). Data from large prospectively followed patient cohorts demonstrated that stroke rate is increased in patients with AHRE. A sizeable portion of these patients develops clinically detected AF over time. In these patients, AHRE can be considered as an early manifestation of paroxysmal AF. A few AHRE patients do not develop clinically overt AF, and the absolute stroke rates are lower in patients with AHRE when compared to stroke rates in patients with clinically diagnosed AF. In light of the bleeding complications associated with oral anticoagulant therapy, there is thus uncertainty about the optimal antithrombotic therapy in patients with AHREs.

The Non-vitamin K antagonist Oral anticoagulants (NOACs) provide similar or slightly better stroke prevention, and appear slightly safer compared to vitamin K antagonists (VKAs). In addition, no individual therapy adjustment of NOACs has to be performed. Edoxaban, a newly introduced NOAC, at a dose regime of 60 mg once daily (OD) has a favourable profile compared to dose-adjusted VKA therapy: In the ENGAGE-TIMI 48 trial, edoxaban prevented strokes at least as effectively as VKA therapy but caused less major bleeding events than VKA therapy.

Arms: arm 1: Edoxaban will be applied in NOAH at the therapeutic dose approved for stroke prevention in non-valvular AF, i.e. 60 mg OD with a reduction of dose to 30 mg OD in patients with one of the following characteristics:

Impaired renal function (CrCl 15-50 ml/min), or low body weight (≤60 kg), or patients receiving the glycoprotein-P inhibitors cyclosporin, dronedarone, erythromycin, or ketoconazole. arm 2: Either one tablet of ASA 100 mg plus one placebo tablet matching in colour, form and size to edoxaban 60 mg or one placebo tablet matching in colour, weight, form and size to ASA 100 mg plus one placebo tablet matching in colour, form and size to edoxaban 60 mg will be administered per day depending on the indication for use of antiplatelet therapy as assessed by the responsible investigator
Interventions: intervention 1: Edoxaban intervention 2: ASA
Intervention descriptions: intervention 1: Edoxaban will be applied at the therapeutic dose approved for stroke prevention in non-valvular AF intervention 2: ASA 100 mg tablets or Placebo, based on accepted indication for the latter, including peripheral or coronary artery disease, a prior myocardial infarction, or a prior stroke.

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL TRIAL PROTOCOL 
 
NOAH - AFNET 6 
Non-vitamin K antagonist Oral anticoagulants 
in patients with Atrial High rate episodes 
 
 
 
 
An Investigator-driven, Prospective, Parallel-group, Randomised, Double-blind, Multi-centre Trial 
initiated by the European Society of Cardiology and AFNET  
 
 
 
 
EudraCT number: 2015-003997-33 
NCT number: NCT02618577 
ISRCTN number: ISRCTN17309850 
 
 
 
Responsible Sponsor: 
Kompetenznetz Vorhofflimmern e.V. (AFNET) 
[Atrial Fibrillation NETwork] 
Mendelstraße 11 
48149 Münster, Germany  
 
 
 
 
Version control: 
No. 1.0 dated 2016-05-06, (dated 2016-10-10 (valid in France, only)) 
No. 2.0 dated 2017-12-01  
No. 3.0 dated 2018-04-27 
No. 4.0 dated 2018-11-06 
 No. 5.0 dated 2019-12-01 
No. 5.1 dated 2020-10-01 
 


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INTERNATIONAL CHIEF INVESTIGATOR 
Professor Paulus Kirchhof, Hamburg and Münster, Germany 
The University Medical Center Hamburg – Eppendorf  
University Heart & Vascular Center, Department of Cardiology 
Martinistraße 52 
20251 Hamburg, Germany  
Email: 
p.kirchhof@uke.de 
Phone 
+49 407 410 524 38 
Fax: 
+49 407 410 558 62 
 
 
SPONSOR 
Kompetenznetz Vorhofflimmern e.V. (AFNET) 
[Atrial Fibrillation NETwork] 
Represented by Professor Andreas Götte, member of the board of directors 
Mendelstraße 11 
48149 Münster, Germany 
Email: 
info@kompetenznetz-vorhofflimmern.de  
Phone: 
+49 251 980 1340 
Fax: 
+49 251 980 1349 
http://www.kompetenznetz-vorhofflimmern.de/english 
 
 
CONTRACT RESEARCH ORGANISATION (CRO) 
CRI – The Clinical Research Institute GmbH 
Arnulfstr. 19 
80335 München, Germany 
Email: 
noah@cri-muc.eu 
Phone: 
+49 89 990 1649-963 
Fax: 
+49 89 990 1649-863 
 
 
 
 
All information in this study protocol including attachments provided to you as investigator, potential investi-
gator, sub-investigator or committee member must be treated confidentially. The right to use this information 
is limited to you, your staff, members of the relevant committees or entitled authorities. The objectives and 
the content of this study, as well as its results, must be treated confidentially and may not be made available 
to third parties at any time before, during and after the study without written approval of the sponsor except 
to the extent necessary to get informed consent from patients. This applies to investigators and all support-
ing staff involved in the study. Transmission, duplication or use for publication is permitted only with the writ-
ten agreement of the sponsor. 
This protocol has been written in accordance with current applicable guidelines (ICH-GCP and EU-Directive 
2001/20/EC) as well as all other relevant additional references, medical and legal ones. 
 
Prepared by Elisabeth Freund, MSc (CRI), Thomas Fetsch, MD (CRI), Paulus Kirchhof, and the NOAH – 
AFNET 6 nucleus group 
 
 


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Table of Contents 
1. 
Summary ..................................................................................................................................................... 7 
2. 
Abbreviations ............................................................................................................................................ 10 
3. 
Introduction ............................................................................................................................................... 12 
3.1 
Background Information.................................................................................................................. 12 
3.2 
Study Rationale .............................................................................................................................. 12 
3.3 
Benefit-risk Assessment ................................................................................................................. 13 
4. 
Study Objectives ....................................................................................................................................... 14 
4.1 
Primary Outcome Parameters ........................................................................................................ 15 
4.2 
Secondary Outcome Parameters ................................................................................................... 15 
5. 
Study Design ............................................................................................................................................. 15 
5.1 
Flow Chart ...................................................................................................................................... 16 
6. 
Selection of Patients ................................................................................................................................. 16 
6.1 
Informed Consent ........................................................................................................................... 16 
6.2 
Study Population ............................................................................................................................. 17 
6.2.1 
Number of patients .................................................................................................................. 17 
6.2.2 
Inclusion criteria ...................................................................................................................... 17 
6.2.3 
Exclusion criteria ..................................................................................................................... 18 
6.2.4 
Adequate detection of AHRE .................................................................................................. 18 
6.2.5 
Randomisation ........................................................................................................................ 19 
7. 
Therapy ..................................................................................................................................................... 19 
7.1 
Study Drugs / Investigational Medicinal Products .......................................................................... 20 
7.1.1 
Description of edoxaban ......................................................................................................... 20 
7.1.2 
Description of acetylsalicylic acid (ASA) ................................................................................. 21 
7.1.3 
Description of placebo ............................................................................................................ 21 
7.1.4 
Identification of study drugs .................................................................................................... 21 
7.1.5 
Storage condition .................................................................................................................... 21 
7.2 
Non-investigational Products .......................................................................................................... 21 
7.3 
Compliance with Study Drugs, Dispensing and Return .................................................................. 22 
7.4 
Blinding/Unblinding ......................................................................................................................... 23 
7.5 
Temporary or Permanent Discontinuation of Study Drugs ............................................................. 23 
7.6 
Concomitant Medication ................................................................................................................. 25 
7.7 
Post-study Treatment ..................................................................................................................... 25 
8. 
Adverse Event Reporting .......................................................................................................................... 25 
8.1 
Adverse Events ............................................................................................................................... 25 


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8.2 
Adverse Drug Reactions ................................................................................................................. 26 
8.3 
Serious Adverse Events ................................................................................................................. 26 
8.4 
Recording and Reporting Serious Adverse Events ........................................................................ 27 
8.4.1 
Definition of intensity ............................................................................................................... 27 
8.4.2 
Definition of causality .............................................................................................................. 28 
8.5 
Adverse Event Follow-up Procedures ............................................................................................ 28 
8.6 
Handling of Expedited Safety Reports ............................................................................................ 28 
9. 
Study Schedule ......................................................................................................................................... 28 
9.1 
Visit Schedule ................................................................................................................................. 28 
9.2 
Baseline Visit .................................................................................................................................. 30 
9.2.1 
Documentation of the qualifying AHRE .................................................................................. 30 
9.3 
Follow-up ........................................................................................................................................ 31 
9.3.1 
Clinical visits (Months 12, 24, and 36) .................................................................................... 31 
9.3.2 
Drug/device visits (Months 6, 18, and 30 or longer if required) .............................................. 31 
9.3.3 
Triggered visit „Discontinuation of study drug“ ....................................................................... 32 
9.3.4 
Final visit (at global end of study) ........................................................................................... 32 
9.4 
Patient withdrawal from the study ................................................................................................... 33 
9.5 
Electrocardiogram ........................................................................................................................... 33 
9.6 
Blood Samples ................................................................................................................................ 33 
9.7 
Quality of Life, Experience, Symptoms and Cognitive Function..................................................... 34 
9.7.1 
Patient Reported Outcomes: quality of life, experience and symptoms ................................. 34 
9.8 
Clinical Assessment of Performance Status and Cognitive Function ............................................ 34 
9.9 
Measures to be taken in case of a Pandemic ................................................................................ 35 
10. Duration of Study Participation ................................................................................................................. 36 
10.1 Overall Duration of the Study ......................................................................................................... 36 
10.2 Duration of Study Participation for Individual Patients ................................................................... 36 
11. Stopping and Discontinuation Criteria....................................................................................................... 36 
11.1 Discontinuation Criteria for the Study and Study Sites ................................................................... 36 
11.2 Discontinuation Criteria for Patients ............................................................................................... 36 
12. Statistics .................................................................................................................................................... 37 
12.1 Statistical Methods .......................................................................................................................... 37 
12.1.1 
Analysis of the primary outcome ............................................................................................. 37 
12.1.2 
Analysis of the secondary outcome ........................................................................................ 37 
12.1.3 
Continuous secondary endpoints will be analysed as change from baseline using the 
baseline adjusted analysis of covariance (ANCOVA). Safety analysis .................................. 38 
12.1.4 
Subgroup analysis .................................................................................................................. 38 
12.2 Sample Size and Power Calculations ............................................................................................. 38 


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12.3 Interim Analysis and reassessment of the Sample Size ................................................................ 40 
12.4 Patient Selection for Analyses ........................................................................................................ 40 
13. Access to Source Data / Documents ........................................................................................................ 41 
13.1 Source Data .................................................................................................................................... 41 
13.2 Source Documents ......................................................................................................................... 41 
13.3 Direct Access .................................................................................................................................. 41 
14. Quality Control and Quality Assurance ..................................................................................................... 41 
14.1 Quality Control ................................................................................................................................ 41 
14.2 Initiation Visit ................................................................................................................................... 41 
14.3 Study Monitoring ............................................................................................................................. 42 
14.4 Close Out Visit ................................................................................................................................ 42 
14.5 Quality Assurance ........................................................................................................................... 42 
14.5.1 
Inspections .............................................................................................................................. 42 
14.5.2 
Audits ...................................................................................................................................... 42 
15. Ethical and Legal Consideration ............................................................................................................... 43 
15.1 Ethical Consideration ...................................................................................................................... 43 
15.1.1 
Institutional Review Board / Independent Ethics Committee .................................................. 43 
15.1.2 
Steering Committee ................................................................................................................ 43 
15.1.3 
Endpoint Review Committee ................................................................................................... 43 
15.1.4 
Data and Safety Monitoring Board .......................................................................................... 44 
15.1.5 
National coordinators .............................................................................................................. 44 
15.2 Legal Consideration ........................................................................................................................ 44 
15.3 Modification of Protocol .................................................................................................................. 44 
15.4 Financing and Insurance ................................................................................................................ 44 
15.5 Investigators’ Information on IMP ................................................................................................... 45 
15.6 Personal Data and Data Protection ................................................................................................ 45 
15.7 Data Handling and Record Keeping ............................................................................................... 45 
15.7.1 
Completion of case report forms ............................................................................................. 45 
15.7.2 
Archiving ................................................................................................................................. 45 
15.8 Confidentiality ................................................................................................................................. 45 
15.9 Responsibilities ............................................................................................................................... 46 
16. Final Report and Publication Policy, Property Rights ............................................................................... 46 
17. Definitions and Classification .................................................................................................................... 46 
17.1 Protocol Violation ............................................................................................................................ 46 
17.2 Major Protocol Violation .................................................................................................................. 46 
18. References ................................................................................................................................................ 47 


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19. Signatures ................................................................................................................................................. 52 
Appendix I: Members of the Steering Committee ............................................................................................. 53 
Appendix II: Time Schedule .............................................................................................................................. 55 
Appendix III: Definition of primary outcome events .......................................................................................... 58 
Appendix IV: International Society on Thrombosis and Haemostasis (ISTH) Bleeding Definitions ................. 60 
Appendix V: Definition of overt AF .................................................................................................................... 61 
Appendix VI: Change management of anticoagulants at discontinuation of study drug .................................. 62 
Appendix VII: ESC guidelines 2010 .................................................................................................................. 63 
Appendix VIII: Suggestions for optimal programming of devices for adequate detection of AHRE ................. 64 
Appendix IX: Declaration of Helsinki (Version Fortaleza, October 2013) ......................................................... 65 
 
 


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1. Summary 
TITLE 
Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High rate 
episodes (NOAH - AFNET 6) 
INTERNATIONAL 
CHIEF INVESTIGATOR 
Professor Paulus Kirchhof, Hamburg and Münster, Germany 
SPONSOR 
Kompetenznetz Vorhofflimmern e.V. (AFNET) 
[Atrial Fibrillation NETwork] 
BACKGROUND AND 
RATIONALE 
Atrial fibrillation (AF) is a common cause of stroke, especially ischemic stroke. 
So far, all available data that demonstrate a beneficial effect of oral anti-
coagulation for stroke prevention have been collected in populations with AF 
documented by conventional ECG recordings. It is well established that a large 
proportion of AF episodes remain undiagnosed (“silent AF”), and many of 
these patients present with a stroke as the first clinical sign of AF. Earlier 
initiation of anticoagulation could prevent such events. Continuous monitoring 
of atrial rhythm by implanted devices could close this diagnostic gap. Pace-
makers, defibrillators, cardiac resynchronisation devices, and insertable 
cardiac monitors already provide automated algorithms alerting to the 
occurrence of highly organised atrial tachyarrhythmia episodes, also called 
“subclinical atrial fibrillation” or, more commonly, “atrial high rate episodes” 
(AHRE). Data from large prospectively followed patient cohorts demonstrated 
that stroke rate is increased in patients with AHRE. A sizeable portion of these 
patients develops clinically detected AF over time. In these patients, AHRE can 
be considered as an early manifestation of paroxysmal AF. A few AHRE 
patients do not develop clinically overt AF, and the absolute stroke rates are 
lower in patients with AHRE when compared to stroke rates in patients with 
clinically diagnosed AF. In light of the bleeding complications associated with 
oral anticoagulant therapy, there is thus uncertainty about the optimal 
antithrombotic therapy in patients with AHRE. 
The Non-vitamin K antagonist Oral anticoagulants (NOACs) provide similar or 
slightly better stroke prevention, and appear slightly safer compared to vitamin 
K antagonists (VKAs). In addition, no individual therapy adjustment of NOACs 
has to be performed. Edoxaban, a newly introduced NOAC, at a dose regime 
of 60 mg once daily (OD) has a favourable profile compared to dose-adjusted 
VKA therapy: In the ENGAGE-TIMI 48 trial, edoxaban prevented strokes at 
least as effectively as VKA therapy but caused less major bleeding events than 
VKA therapy. 
STUDY OBJECTIVE(S) 
To demonstrate that oral anticoagulation with the NOAC edoxaban is superior 
to current therapy (antiplatelet therapy or no therapy depending on cardio-
vascular risk) to prevent stroke, systemic embolism, or cardiovascular death in 
patients with AHRE but without overt AF and at least two stroke risk factors 
leading to a modified CHA2DS2VASc score of 2 or more. 
STUDY DESIGN 
Investigator-initiated, prospective, parallel-group, randomised, double-blind, 
multi-centre trial. Although it can be argued that the indication tested is within 
the registered label of edoxaban, NOAH – AFNET 6 will be conducted as a 
phase IIIb study. 
STUDY POPULATION 
Medical condition /  
Main selection criteria 
The following main criteria must be present for eligibility into the study: 
 
Pacemaker, defibrillator or insertable cardiac monitor implanted for any 
reason with feature of detection of AHRE, implanted at least 2 months prior 


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to randomisation 
 
AHRE (≥ 170 bpm atrial rate and ≥ 6 min duration) documented by the 
implanted device  
 
Age ≥ 65 years 
 
In addition, at least one of the following cardiovascular conditions leading 
to a modified CHA2DS2VASc score of 2 or more: 
 Age ≥ 75 years, 
 heart failure (clinically overt or LVEF < 45%), 
 arterial hypertension (chronic treatment for hypertension, esti-
mated need for continuous antihypertensive therapy or resting 
blood pressure > 145/90 mmHg), 
 diabetes mellitus, 
 prior stroke or transient ischemic attack (TIA), 
 vascular disease (previous myocardial infarction, peripheral, ca-
rotid/cerebral, or aortic plaques on transesophageal echocardio-
gram [TEE]). 
Patients with history of overt AF or atrial flutter, patients with a clear 
contraindication for oral anticoagulation, patients with a clear need for oral 
anticoagulation, and patients with indication for long-term antiplatelet therapy 
other than acetylsalicylic acid (ASA) or a need for treatment with any 
antiplatelet agent in addition to edoxaban, especially dual antiplatelet therapy 
(DAPT) are not suitable for NOAH - AFNET 6. 
Number of patients 
NOAH - AFNET 6 is an event-driven trial with a planned number of randomised 
and treated patients of n=2,538 and an anticipated number of primary 
endpoints of n=220. Patient recruitment is expected to be completed after 71 
months. 
Expected number of 
sites 
Approximately 200 to 250 sites in Europe with adequate experience in follow-
up of implanted pacemakers, defibrillators or insertable cardiac monitors in 
clinical routine. 
INVESTIGATIONAL 
INTERVENTIONS 
Investigational medicinal product 
(IMP) being tested: 
edoxaban 
IMP used as a comparator: 
acetylsalicylic acid or placebo (depending 
on the indication for use of antiplatelet 
therapy) 
Edoxaban will be used in NOAH - AFNET 6 at the therapeutic dose approved 
for stroke prevention in non-valvular AF, i.e. 60 mg OD with a reduction of dose 
to 30 mg OD in patients with one of the following characteristics: 
 Impaired renal function (CrCl 15-50 ml/min), or 
 low body weight (≤60 kg), or  
 patients receiving the p-glycoprotein inhibitors cyclosporin, 
dronedarone, erythromycin, or ketoconazole. 
PRIMARY OUTCOME 
PARAMETERS 
Time from randomisation to the first occurrence of stroke, systemic embolism, 
or cardiovascular death. A detailed definition of these outcome events is 
provided in Appendix III. 
SECONDARY 
OUTCOME 
 
Components of the primary outcome 
 
Major Adverse Cardiac Events (MACEs: cardiovascular death, myocardial 


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PARAMETERS 
infarction, acute coronary syndrome (ACS), PCI, CABG) 
 
Stroke or systemic arterial embolism 
 
All-cause death 
 
Major bleeding events according to the ISTH definitions 
 
Quality of life changes at 12 and 24 months compared to baseline 
 
Patient satisfaction at 12 and 24 months compared to baseline 
 
Cost effectiveness and health resource utilisation 
 
Patient autonomy changes at 12 and 24 months compared to baseline 
including chronic consequences of stroke (aphasia, hemianopia (“mild 
stroke”)) 
 
Cognitive function at 12 and 24 months compared to baseline 
ASSESSMENT 
SCHEDULE 
1. Enrolment and randomisation 
2. Scheduled clinical follow-up at months 12, 24 and 36 after randomisation 
3. “Drug/device visits” for dispensing of study drug and upload of device inter-
rogations derived from the implanted device at months 6, 18, and 30 (con-
tinued in 6 months intervals after 36-months visit, if necessary) 
4. Final end of study visit after the required number of primary outcome 
events has been accrued and verified 
STATISTICAL 
CONSIDERATIONS 
The main aim of the proposed study is to test the null hypothesis that the 
hazard rate, which is assumed to be constant during the study period, is 
identical in the two groups (usual care and NOAC). 
Based on the stroke and death rates of published trials (MOST, ASSERT, 
Medtronic AT500 data set, SOS), an annualised rate of stroke, systemic 
embolism, or cardiovascular death of 5.3% in the control group is expected. 
The primary analysis is in the modified intention-to-treat population, consisting 
of all randomised patients with a qualifying AHRE and intake of at least one 
dose of study drug. Patients who develop overt AF during the trial period will 
be censored at that point in time but followed according to protocol until the 
global end of the trial. All other patients who will not reach the endpoint by the 
end of the study will be censored at that time point. Cumulative incidence 
curves and corresponding p-values from competing risk analysis as well as 
tables with estimated (cause-specific) hazard ratios, confidence intervals, and 
corresponding p-values will be provided. The Cox-proportional hazards model 
will be used to estimate the (cause-specific) hazard ratio of edoxaban versus 
usual care. 
Safety analysis will be performed with all patients enrolled. 
DURATION OF STUDY 
PERIOD 
 
Duration per patient: Mean expected follow-up time of 42 months with a 
minimum follow-up time of 12 months and an expected maximum follow-up 
time of presumably 83 months. Every patient will be followed-up until global 
end of study. The exact duration of follow-up will be determined by the accrual 
of events (event-driven trial). 
The trial will be terminated after 220 evaluable primary outcomes have 
occurred. The total study duration of 90 months (around 7.5 years) was 
adapted based on an interim analysis. 
 
 
 


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2. Abbreviations 
ACS 
Acute coronary syndrome 
AE 
adverse event 
AF 
atrial fibrillation 
AFNET 
Atrial Fibrillation NETwork  
AHRE 
atrial high rate episodes 
ALT 
alanine transaminase 
ASA 
Acetylsalicylic acid 
aPCC 
activated prothrombin complex concentrate 
aPTT 
activated Partial Thromboplastin Time 
AST 
aspartate transaminase 
CABG 
coronary artery bypass graft surgery 
CrCl 
creatinine clearance 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CV 
Curriculum Vitae 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
DAPT 
dual antiplatelet therapy 
ECG 
electrocardiography 
e-CRF 
electronic case report form 
EHRA 
European Heart Rhythm Association 
EQ-5D 
Euroquol 5D questionnaire 
ERC 
Endpoint Review Committee 
FU 
follow-up 
GCP 
Good Clinical Practice 
HF 
heart failure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IIT 
Investigator Initiated Trial 
INR 
International Normalised Ratio 
IRB 
Institutional Review Board 
ISTH 
International Society on Thrombosis and Haemostasis 
ITT 
intention-to-treat 
LVEF 
left ventricular ejection fraction 


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MACES 
Major Adverse Cardiovascular Events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MoCA 
Montreal cognitive assessment 
mITT 
modified intention-to-treat 
NIHSS 
National Institutes of Health Stroke Scale 
NOAC 
Non-vitamin K antagonist oral anticoagulants 
NYHA 
New York Heart Association 
OD 
once daily 
PACT-Q 
Perception of AntiCoagulant Treatment Questionnaire 
PCC 
Prothrombin complex concentrate 
PCI 
percutaneous coronary intervention 
PE 
physical examination 
PI 
principal investigator 
QoL 
Quality-of-life 
RBSMP 
Risk Based Study Monitoring Plan 
SAE 
serious adverse event 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse event 
TEE 
transesophageal echocardiogram 
TIA 
transient ischemic attack 
VKA 
vitamin K antagonist 
 
The terms “trial” and “study” as well as “study drug” and “study medication” are being used interchangeably 
throughout this protocol. 
 
 


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3. Introduction 
3.1 
Background Information 
Atrial fibrillation (AF) is a common cause of stroke, especially ischemic stroke. Unlike strokes of other aetiol-
ogy, which can be prevented by antiplatelet therapy, strokes in patients with AF require oral anticoagulation 
for adequate stroke prevention (1). Recently, four new, non-vitamin K antagonist oral anticoagulants (NO-
ACs) have been introduced into clinical practice that provide alternatives to vitamin K antagonist (VKA) ther-
apy (2-6). Edoxaban is one of these NOACs. The NOACs including edoxaban provide similar or slightly bet-
ter stroke prevention, and appear slightly safer compared to VKAs (7), but seem easier to use than VKAs. 
The NOAH - AFNET 6 trial will only commence in countries where edoxaban has been approved for stroke 
prevention in atrial fibrillation. 
So far, all available data that demonstrate a beneficial effect of oral anticoagulation for stroke prevention 
have been collected in populations with AF documented by conventional ECG recordings (8). Studies in 
other populations in the absence of AF, e.g. heart failure, had outcomes whereby slight reductions in stroke 
were counterbalanced by increased bleeding (9). This illustrates the need to target anticoagulant therapy to 
patients at high risk for stroke events related to AF. 
It is well established that many AF episodes remain undiagnosed (“silent AF”; 1). Often, a potentially pre-
ventable stroke is the first clinical manifestation of AF in patients with undiagnosed silent AF. Therefore, bet-
ter techniques to detect silent AF are needed. Published and ongoing studies suggest that systematic inter-
mittent ECG screening, using patient-operated devices (10, 11), “opportunistic screening” (1, 12), or Holter 
ECG recordings, e.g. in survivors of a stroke (3, 14), are capable of detecting additional patients with hitherto 
undiagnosed, silent AF. Although these non-invasive techniques increase the diagnostic yield of patients 
with silent AF, they will still miss many patients (15). 
Continuous monitoring of atrial rhythm by implanted devices could close this diagnostic gap (15). While dedi-
cated implanted rhythm monitoring devices are currently evaluated, most modern pacemakers, defibrillators, 
cardiac resynchronisation devices, and insertable cardiac monitors already provide automated algorithms 
alerting to the occurrence of highly organised atrial tachyarrhythmia episodes, also called “subclinical atrial 
fibrillation” or, more commonly, “atrial high rate episodes” (AHRE; 16, 18, 19). Data from large prospectively 
followed patient cohorts demonstrated that stroke rate is increased in patients with AHRE (16, 17). Indeed, a 
sizeable portion of these patients develops clinically detected AF over time, but often only after the first 
stroke (16, 42). Thus, AHRE can be assumed an early manifestation of paroxysmal AF. 
On the other hand, the absolute stroke rates are lower in patients with AHRE when compared to stroke rates 
in patients with clinically diagnosed AF, and automated detection algorithms of AHRE by implanted devices 
have a good sensitivity, but not a sufficient specificity to distinguish AF from other arrhythmias or artefacts 
when compared to Holter ECG recordings analysed by specialists (18). In light of the bleeding complications 
associated with oral anticoagulant therapy, there is thus uncertainty about the optimal antithrombotic therapy 
in patients with AHRE, and more studies are needed to determine whether oral anticoagulation should be 
recommended for these patients (1, 19). 
3.2 
Study Rationale 
The NOACs provide similar or slightly better stroke prevention, and appear slightly safer compared to VKAs 
(7, 45). Edoxaban at a dose regime of 60 mg once daily (OD) with a planned dose reduction to 30 mg OD in 
patients with reduced edoxaban elimination as outlined in the edoxaban Summary of Product Characteristics 
[SmPC] has a favourable profile compared to dose-adjusted VKA therapy: In the ENGAGE-TIMI 48 trial (6), 
edoxaban prevented strokes at least as effectively as VKA therapy (hazard ratio 0.8 (0.63 – 0.99), p<0.0001 
for non-inferiority; (6)). Furthermore, importantly for the design of NOAH - AFNET 6, an edoxaban dose re-
gime of 60 mg OD caused less major bleeding events than VKA therapy in the ENGAGE trial (hazard ratio 
0.8 [0.71 – 0.91], p<0.0001). Thus, an edoxaban 60 mg OD therapy regimen provides an intervention that is 
safer than VKA (20% less major bleeding events, CI 9% – 37%), and at least as effective in preventing 


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strokes in non valvular AF patients. This intervention is expected to prevent clinical and subclinical strokes 
and thereby improve quality of life, and maintain cognitive function. 
This randomised trial, therefore, tests the hypothesis that oral anticoagulation with the NOAC edoxaban used 
in a 60 mg OD dose regime is superior to antiplatelet therapy (or no therapy depending on cardiovascular 
risk) to prevent stroke, systemic embolism, or cardiovascular death in patients with AHRE, but without AF, 
and with at least two stroke risk factors. 
If combined with another similarly sized trial (ARTESIA, NCT01938248), the data are likely to change clinical 
practice in this patient group, with benefits for a large number of patients with AHRE. The NOAH - AFNET 6 
Steering Committee plans combined analyses of the results of these two trials. The results of NOAH - 
AFNET 6 may also inform future guidance on the management of patients with atrial arrhythmias detected by 
implantable ECG monitors. 
3.3 
Benefit-risk Assessment 
General risk assessment of the NOAH - AFNET 6 trial: All study drugs are market approved for prevention of 
stroke in patients with non-valvular AF. Although AHRE are presently not considered equal to AF document-
ed by conventional ECG recordings, VKA and NOACs are currently used for patients with AHRE in clinical 
routine (off-label use), and the documentation of short-lasting arrhythmias that resemble atrial fibrillation is 
considered “non valvular AF” by many clinicians, although data supporting the use of anticoagulants in gen-
eral are lacking in this population. Other clinicians will strive to document AF in the usual way in AHRE pa-
tients. Thus, there is true clinical equipoise for the use of anticoagulation in patients with AHRE. In view of 
the potential benefits for stroke prevention in this population, this is a clinically important issue that calls for 
resolution in a controlled clinical trial.  
The other patient characteristics of the NOAH – AFNET 6 population and the use of edoxaban in the trial 
mirror the European label of edoxaban to ensure that the use of edoxaban is limited to patients in whom 
safety information exists from the completed phase III programme leading to the market authorisation of 
edoxaban in Europe (6). The sponsor of NOAH – AFNET 6 and the scientific partner, the European Society 
of Cardiology, have carefully considered how to define the phase of this investigator-initiated trial, also in 
view of the fact that edoxaban has been evaluated in a large clinical trial program in patients with very similar 
characteristics compared to those to be enrolled in NOAH – AFNET 6, and in view of the conduct of a similar 
trial (ARTESIA, NCT01938248) as phase IV. Reflecting the equipoise of anticoagulation and the uncertainty 
whether AHRE represent an early form of AF, NOAH – AFNET 6 will be conducted as a phase IIIb study. 
All concomitant study procedures are standard care procedures according to applicable medical guidelines 
used within the recommended indications. All participating study sites have to document sufficient experi-
ence in the management of patients with implanted pacemakers, defibrillators, cardiac resynchronisation 
devices or insertable cardiac monitors and of patients with AF.  
Thus, the overall risk level of the NOAH – AFNET 6 trial is expected to be low. 
Assessment of the individual risk of study patients: The risk of therapy within NOAH - AFNET 6 seems ac-
ceptable in view of the favourable safety profile of an edoxaban 60 mg OD regime in the ENGAGE-TIMI 48 
trial compared to warfarin. In light of existing data for apixaban and warfarin, the bleeding risk on edoxaban 
may only slightly exceed that of acetylsalicylic acid therapy (3, 23). Thus, the individual risk of study patients 
in the group randomised to treatment with NOAC will not differ from the risk of therapy in clinical routine 
treatment for prevention of stroke in patients with non-valvular AF. Patients randomised to treatment with 
NOAC have an increased risk for bleeding events compared to patients randomised to the group that under-
goes usual care. Event rates for AHRE patients do not exist and will be generated in NOAH - AFNET 6. 
Based on the observed baseline stroke rates in AHRE patients (refer to section 12), similar effect differences 
are expected for NOAH - AFNET 6. 


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Figure 1: Major efficacy and safety event rates for AF patients randomised to an edoxaban 60 mg OD regime 
in the ENGAGE-TIMI 48 trial compared to event rates reported in patients randomised to acetylsal-
icylic acid in the AVERROES and BAFTA trials (3, 6, 23). All events are given as annualised rates 
in percent. This figure is replicated in the sample size estimation section.  
General benefit of study patients: All patients participating in NOAH - AFNET 6 will have the added benefit of 
careful standardised monitoring of their anticoagulant treatment by their study physicians as well as of addi-
tional quality management by the CRO, the sponsor, the independent Data and Safety Monitoring Board and 
the Steering Committee. 
Individual benefit of study patients: Patients randomised to edoxaban will receive a treatment that has been 
shown to be safer with a reduced annualized rate of major bleedings (hazard ratio 0.80) compared to VKA 
and slightly more effective to prevent stroke or systemic embolism than VKA with reduced annualized rates 
of these events (hazard ratio 0.79) in general AF populations (6). VKA therapy in general AF patients itself 
was demonstrated to be three times more effective in preventing stroke or systemic embolism compared to 
antiplatelet therapy (22). Based on the existing literature, it is likely that a similar benefit will be conveyed by 
edoxaban in patients with AHRE detected by pacemaker. By participating in the NOAH - AFNET 6 trial, pa-
tients will receive this safe anticoagulant earlier than in usual care, i.e. when atrial arrhythmias are docu-
mented by the implanted device rather than by the ordinary ECG, with the potential for added stroke preven-
tion. 
4. Study Objectives 
To demonstrate that oral anticoagulation with the NOAC edoxaban is superior to current therapy (antiplatelet 
therapy or no therapy depending on cardiovascular risk) to prevent stroke, systemic embolism, or cardiovas-
cular death in patients with AHRE but without overt AF (Appendix I) and at least two stroke risk factors lead-
ing to a modified CHA2DS2VASc score of 2 or more. 
0
2
4
6
8
10
12
ENGAGE edoxaban 60 mg OD
AVERROES aspirin
BAFTA aspirin
Major event rates on edoxaban and aspirin 
all extracranial hemorrhage
fatal bleeding
hemorrhagic stroke plus other ICH
stroke, systemic embolism, or cardiovascular death


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4.1 
Primary Outcome Parameters 
The primary outcome parameter of NOAH - AFNET 6 is defined as the time from randomisation to the first 
occurrence of stroke, systemic embolism or cardiovascular death. A detailed definition of these outcome 
events is provided in Appendix III. 
4.2 
Secondary Outcome Parameters 
The secondary outcome parameters are defined as 
 
 
components of the primary outcome, 
 
Major Adverse Cardiac Events (MACEs: cardiovascular death, myocardial infarction, acute coronary 
syndrome (ACS); PCI, CABG), 
 
stroke or systemic arterial embolism 
 
all-cause death, 
 
major bleeding events according to the International Society on Thrombosis and Haemostasis (ISTH) 
definitions (60, 61), (Appendix IV) 
 
quality of life changes at 12 and 24 months compared to baseline (assessed by EQ-5D including its vis-
ual-analogue scale and by the Karnofsky scale), 
 
patient satisfaction at 12 and 24 months compared to baseline (assessed by modified EHRA score (36) 
and PACT-Q (43)) 
 
cost effectiveness and health resource utilisation estimated by quantification of relevant events, interven-
tions, nights spent in hospital and cardiovascular therapies, 
 
changes of autonomy status only in patients with stroke during study participation, potentially assessed 
at each clinical follow-up visit by modified Rankin scale; a maximum of 2 subsequent assessments in fol-
low-up per patient with stroke should be performed, 
 
cognitive function (MoCA) at 12 and 24 months compared to baseline. 
5. Study Design 
NOAH - AFNET 6 is an investigator-initiated, prospective, parallel-group, double-blind, randomised, multi-
centre trial. The trial tests whether oral anticoagulation using the NOAC edoxaban is superior to current ther-
apy to prevent stroke, systemic embolism, or cardiovascular death in patients with AHRE. The trial will be 
conducted in several European countries (details of study sites are provided in a separate document). 
NOAH - AFNET 6 is an event-driven trial with a planned number of randomised and treated patients of 
n=2,538 and an anticipated number of primary endpoints of n=220. The total duration of the trial is an esti-
mate based on observed outcome rates in other large trials with similar populations. The total number of 
events in the trial is depending on the observed hazard rates and on the time at risk, which is the follow-up 
time of all patients. In practice, the event-driven design may result in slight variation of the expected trial 
duration and of the total number of patients enrolled if observed event rates do not exactly match the as-
sumed rates. All patients will be followed until the global end of the trial. 


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5.1 
Flow Chart 
 
Figure 2: Study flow chart 
6. Selection of Patients 
6.1 
Informed Consent 
A signed, ethics committee (EC) /institutional review board (IRB) approved informed consent form, written in 
accordance with country-specific applicable data privacy acts, the Declaration of Helsinki (Appendix IX) and 
the applicable laws for research using medical devices and drugs, will be obtained from every patient prior to 
any study-related procedure. All clinical data needed to evaluate the potential eligibility of a patient before 
study inclusion, e. g. recent laboratory results, ECG recordings or other technical parameters, are considered 
to be performed during clinical routine and are therefore not considered to be part of study related proce-
dures. Participants will be advised that their quality of life and satisfaction data are collected for research 
purposes and will not be used to guide clinical care. 
The investigator or responsible medical staff will explain the nature, purpose and risks of the study and pro-
vide the patient with a copy of the patient information sheet. The patient will be given sufficient time to con-
sider the study's implications before deciding whether to participate. 
Should there be any modifications to the protocol, such that this would directly affect the patient’s participa-
tion in the study, e.g. a change in any procedure, an addendum to the informed consent form specifying the 
modification must be compiled and the patients must agree to sign this addendum indicating that they re-
consent to further participate in the modified study. 
A signed copy of the patient’s informed consent form must be maintained in the study file on site. The pa-
tient’s permanent medical records should indicate the patient's study participation. A patient information 
sheet will be handed out to the patient unless declined by him/her. 
 
 


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6.2 
Study Population 
The intended population for this study consists of patients who have documented AHRE but no history of 
overt AF at the time of randomisation and a risk for stroke fulfilling the inclusion criteria as listed below, i.e. 
approximating a modified CHA2DS2VASc score of 2 or more. This population has a clinical risk profile that 
would make patients with ECG-documented AF eligible for oral anticoagulation. In view of the uncertainty 
around event rates in patients with documented AHRE, a blind assessment of event rates is planned during 
the trial. It will be considered to adjust the trial population should event rates be lower than anticipated (see 
below for details). Patients will be recruited by contracted study sites only. The aim is to activate approxi-
mately 200 to 250 sites in Europe with adequate experience in follow-up of implanted pacemakers, defibrilla-
tors or insertable cardiac monitors in clinical routine and in treatment of patients with AF. Patient recruitment 
is expected to be completed after 71 months. 
6.2.1 
Number of patients 
A total of 2,538 patients will be randomised and treated throughout Europe. Patients who develop overt AF 
during the trial period will be censored at that time point but followed according to protocol until the global 
end of the trial. The hazard of developing overt AF is assumed to remain constant and it is estimated at 
0.287. The sample size may be adapted once in a blinded manner as described in the statistics section (re-
fer to section 12). 
6.2.2 
Inclusion criteria 
I1. 
Pacemaker ,defibrillator or insertable cardiac monitor implanted for any reason with feature of detection 
of AHRE, implanted at least 2 months prior to randomisation. 
I2. 
AHRE detection feature activated for adequate detection of AHRE (refer to Appendix XIII). 
I3. 
AHRE (≥ 170 bpm atrial rate and ≥ 6 min duration) documented by the implanted device.  
Any AHRE episode recorded is potentially eligible, but AHRE episodes detected in the first 2 months 
after implantation of a new device involving placement or repositioning of atrial electrodes are not 
eligible. AHRE episodes recorded in the first two months after a simple “box change” operation, i.e. 
exchange of a pacemaker or defibrillator device without exchange or repositioning of atrial electrodes, 
are eligible. 
I4. 
Age ≥ 65 years. 
I5. 
In addition, at least one of the following cardiovascular conditions leading to a modified CHA2DS2VASc 
score of 2 or more: 
 
Age ≥ 75 years; 
 
Heart failure (clinically overt or LVEF < 45%); 
 
Arterial hypertension (chronic treatment for hypertension, estimated need for continuous antihyper-
tensive therapy or resting blood pressure > 145/90 mmHg); 
 
Diabetes mellitus; 
 
Prior stroke or transient ischemic attack (TIA); 
 
Vascular disease (previous myocardial infarction, peripheral, carotid/cerebral, or aortic plaques on 
transesophageal echocardiogram [TEE]). 
I6. 
Provision of signed informed consent. 
 
 


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6.2.3 
Exclusion criteria 
General exclusion criteria 
E1. Any disease that limits life expectancy to less than 1 year. 
E2. Participation in another controlled clinical trial, either within the past two months or still ongoing. 
E3. Previous participation in the present trial NOAH - AFNET 6. 
E4. Drug abuse or clinically manifest alcohol abuse. 
Exclusion criteria related to a cardiac condition 
E5. Any history of overt AF or atrial flutter. 
E6. Indication for oral anticoagulation (e.g. deep venous thrombosis). 
E7. Contraindication for oral anticoagulation in general. 
E8. Contraindication for edoxaban as stated in the current SmPC. 
E9. Indication for long-term antiplatelet therapy other than acetylsalicylic acid or a need for treatment with 
any antiplatelet agent in addition to edoxaban, especially dual antiplatelet therapy (DAPT). Patients 
with a transient requirement for DAPT (e.g. after receiving a stent) will be eligible when the need for 
DAPT is no longer present. 
E10. Acute coronary syndrome, coronary revascularisation (PCI or bypass surgery), or overt stroke within 30 
days prior to randomisation. 
Exclusion criteria based on laboratory abnormalities 
E11. 
End stage renal disease (creatinine clearance (CrCl) < 15 ml/min as calculated by the Cock-
croft-Gault method, refer to 7.1.1.). 
Legal exclusion criterion (applicable in countries where legally required) 
E.12. All persons exempt from participation in a clinical trial by law. 
6.2.4 
Adequate detection of AHRE 
An adequate detection of AHRE by the implanted device is essential for screening of eligible patients to be 
included in NOAH - AFNET 6. Device interrogations derived from the implanted device containing the index 
AHRE episode that led to inclusion will be digitally uploaded for central review by an independent core 
analysis centre. The results of review will not lead to post-hoc exclusion of the patients if criteria of AHRE are 
not met but will detect protocol violations relevant for stability measures of final analysis and will lead to 
training of corresponding study sites to prevent future violations and therefore assure a standard quality of 
adequate AHRE detection. 
The following paragraph outlines adequate settings of devices for adequate identification of AHRE episodes 
in patients who are potentially eligible for NOAH - AFNET 6: 
 
The intracardiac electrogram (IEGM) storage should be activated while the atrial tachycardia detection 
rate should be set to 170 bpm. Episodes at lower atrial rates are not qualifying episodes for NOAH - 
AFNET 6. Higher rate thresholds are acceptable, but may miss some episodes that would make patients 
eligible for NOAH - AFNET 6. Although false atrial tachyarrhythmia detection due to repetitive non-re-
entrant ventriculo-atrial synchrony is rare for episodes greater than 6 minutes in duration, this phenome-
non can be diagnosed by checking the stored IEGMs and can be eliminated by avoiding very long pro-
grammed AV delays and/or by increasing the post-ventricular atrial refractory period.  
 
For pacemakers and implantable cardioverter-defibrillators (ICDs) with programmable atrial electrogram 
configuration, the latter should be programmed Atip-Aring, in order to avoid noise detection and the use 
of short tip-to-ring spacing atrial leads (<10 mm) is strongly recommended.  


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 
Finally the devices should be optimally programmed according to the individual patient and to the most 
recent practice guidelines (25, 26, 27), ensuring as far as possible optimum hemodynamic and avoiding 
unnecessary ventricular pacing. 
Cardiac rhythm management device manufacturers use different detection algorithms and settings for the 
most accurate device diagnostics and EGM recordings. Detailed information will be provided in a separate 
instruction document “Appendix VIII: Suggestions for optimal programming of devices for adequate detection 
of AHRE” (see Appendix VIII).  
6.2.5 
Randomisation 
Study patients will be randomised to one of two parallel groups in a 1:1 design, designated as “NOAC” and 
“Usual Care”. Randomisation will be stratified by indication for use of antiplatelet therapy as assessed by the 
responsible investigator at the time of randomisation. 
Randomisation will be done per study site in blocks of variable size to allow minimising potential confounders 
related to different healthcare practice. A randomisation list will be created by the responsible study statisti-
cian before study start, and imported into the randomisation server of the e-trial management system. During 
the trial, randomisation will be performed by each site personnel within the e-CRF of the e-trial management 
system according to the imported randomisation list. The investigator has to document several clinical items 
prior to randomisation to verify eligibility of the patient for randomisation and to determine the stratum. The e-
trial management system displays the medication number to be used, not the random group, and asks for 
confirmation by authorised study personnel. The account ID of the person performing the randomisation in 
the e-trial management system and the corresponding time stamp will automatically be documented in an 
electronic audit trail. 
7. Therapy 
NOAH - AFNET 6 is a double-blind trial designed to evaluate the safety and efficacy of the NOAC edoxaban 
in comparison to usual care consisting of either ASA or no antithrombotic therapy depending on the indica-
tion for use of antiplatelet therapy. Patients will receive study medication OD for oral intake depending on the 
random group throughout the whole study duration. 
Patients of the “NOAC” group will receive anticoagulation therapy with edoxaban. Patients in the “Usual 
Care” group will receive either acetylsalicylic acid (ASA) or no antithrombotic therapy depending on the indi-
cation for use of antiplatelet therapy (stratification at the time of randomisation). All patients will receive iden-
tical number and form of study medication using the “double-dummy” technique:  
 
In the “NOAC” group one edoxaban tablet plus one placebo tablet matching in colour, weight, form and 
size to ASA 100 mg will be administered per day irrespective of stratum according to indication for use of 
antiplatelet therapy. The use of edoxaban eliminates the necessity of parallel intake of ASA 100 mg in 
case of an indication for use of antiplatelet therapy. 
 
In the “Usual Care” group either one tablet of ASA 100 mg plus one placebo tablet matching in colour, 
form and size to edoxaban 60 mg or one placebo tablet matching in colour, weight, form and size to ASA 
100 mg plus one placebo tablet matching in colour, form and size to edoxaban 60 mg will be adminis-
tered per day depending on the indication for use of antiplatelet therapy as assessed by the responsible 
investigator. 
 
A documented change of indication for use of antiplatelet therapy in follow-up will lead to blinded ex-
change of double-dummy study drug according to actual indication. In case of a new indication for treat-
ment with any antiplatelet agent in addition to edoxaban, especially dual antiplatelet therapy (DAPT), 
blind treatment with study drugs has to be terminated and adequate treatment according to medical 
guidelines has to be provided by the treating physician. The patient will remain in regular study follow-up 
until the global end of the trial. 


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7.1 
Study Drugs / Investigational Medicinal Products 
An investigational medicinal product is defined as follows by the European Commission (The rules governing 
medicinal products in the European Union, Volume 10, Clinical Trials, 2006): 
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical 
study, including products already with a marketed authorisation but used or assembled (formulated or pack-
aged) in a way different from the authorised form, or when used for an unauthorised indication, or when used 
to gain further information about the authorised form. 
In this protocol, investigational products are: 
 
edoxaban 60 mg tablets, 
 
edoxaban 30 mg tablets, 
 
ASA 100 mg tablets, and 
 
matching placebo tablets. 
 
Figure 3: Drug supply schema. 
The usual care group is divided into antiplatelet and placebo therapy defined (stratified) by indica-
tion of antiplatelet therapy existing at inclusion into NOAH - AFNET 6. 
7.1.1 
Description of edoxaban 
Edoxaban has been tested in large trials and will be applied in NOAH - AFNET 6 at the therapeutic dose 
approved for stroke prevention in non-valvular AF, i.e. 60 mg OD with a reduction of dose to 30 mg OD in 
patients with one of the following characteristics: 
1. Impaired renal function (CrCl 15-50 ml/min*), or 
2. Low body weight (≤60 kg), or  
3. Patients receiving the p-glycoprotein inhibitors ketoconazole, ciclosporin, erythromycin, or droneda-
rone.  
If conditions for reduced dosage of edoxaban are not anymore fulfilled during the study, dosage of edoxaban 
should be increased as stated in the SmPC. 
The e-trial management system will automatically identify those conditions if adequately documented by the 
study site personnel and supply an appropriate medication box containing either 60 mg or 30 mg tablets in 
patients randomised to edoxaban. However, the investigator finally needs either to confirm the calculated 
dosage or adjust the dosage according to his medical decision and provide a reason for doing so. 
* calculated by the Cockcroft-Gault method: 
For male: ((140 - age [years])/ Serum creatinine value [mg/dl])* (weight[Kg] / 72) 
For female 0.85 * ((140 - age [years])/ Serum creatinine value [mg/dl])* (weight[Kg] / 72) 


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7.1.2 
Description of acetylsalicylic acid (ASA) 
ASA has been used for decades as standard therapeutic agent for antithrombotic therapy according to cor-
responding medical guidelines. Within NOAH - AFNET 6 either tablets of 100 mg ASA will be applied or 
matching placebo tablets. The e-trial management system will automatically identify the indication for use of 
antiplatelet therapy as assessed by the responsible investigator, if adequately documented, and supply an 
appropriate medication bottle. 
7.1.3 
Description of placebo 
Matching placebo tablets will be applied which are comparable in size, weight, shape and colour to  
 
edoxaban 60 mg tablets, 
 
edoxaban 30 mg tablets, 
 
ASA 100 mg tablets. 
7.1.4 
Identification of study drugs 
The following investigational medicinal products will be provided by the manufacturer of edoxaban: 
Product 
Potency 
Edoxaban tablets + matching placebo 
60 mg 
Edoxaban tablets + matching placebo 
30 mg 
ASA tablets  + matching placebo 
100 mg 
Table 1: Investigational medicinal products 
All study drugs will be packed in study-specific blisters. The sponsor will assure that adequate labelling, stor-
age, and distribution including import of study drugs to study sites on demand is provided by drug suppliers. 
All quality management requests related to manufacturing, labelling, storage, distribution and reporting de-
fined in applicable international and national standards will be followed by the drug suppliers subcontracted 
by the sponsor. 
7.1.5 
Storage condition 
Due to the double-blind design, the different storage conditions for edoxaban, ASS or placebo cannot be 
followed individually but the most restrictive has to be considered. Thus, all study drugs have to be stored 
continuously between 2 and 25° C. Temperature has to be controlled and documented, e.g. by means of 
temperature logger provided by the sponsor. Detailed instructions for handling of temperature logging will be 
provided. In case of exceedance (<2°C or > 25°C) the investigator has to inform the CRO and report the 
duration of the exceedance and the peak temperature. The CRO will subsequently inform the sponsor who 
will give advice on actions to be taken in cooperation with the manufacturer of the study drugs. 
7.2 
Non-investigational Products 
Other medications used in the study as support or escape medication for preventative, diagnostic, or thera-
peutic reasons, as components of the standard of care for a given diagnosis, are considered non-
investigational products. 


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7.3 
Compliance with Study Drugs, Dispensing and Return 
The study drugs will be supplied to the study sites in sufficient quantity according to local needs, e. g. ex-
pected recruitment rate. The respective time of drug supply will be determined by the CRO but supply itself 
will be provided by the Drug Supplier. 
The logistics of study drug distribution will be managed and tracked centrally in the e-trial management sys-
tem. Each study medication unit will be supplied with a unique medication number together with a corre-
sponding unique verifier printed on study specific labels. A list of all unique medication numbers together 
with the corresponding unique verifiers of the provided study medication will be hosted in the materials tool 
of the e-trial management system.  
Labelling follows requirements as specified in Volume 4, EU Guidelines to Good Manufacturing Practice, 
Annex 13, Investigational Medicinal Products. National requirements will be taken into consideration. The 
Drug Supplier responsible for labelling and delivery of study drug to study sites receives automated supply 
orders via e-mail from the e-trial management system as soon as a pre-defined minimal number of study 
drugs in stock at the study site is reached. Triggers for supply orders are individually defined for the different 
types of study drugs. Tracking of study drugs to be sent to study sites will be performed in the e-trial man-
agement system revealing information on medication numbers and verifiers, date of shipment and recipient 
by study site. Receipt of study drug has to be tracked in the e-trial management system by the receiving site 
staff by entering the verifier printed on each label. 
When a patient is randomised, the e-trial management system displays the medication numbers to be used. 
Site staff has to confirm dispense of the pre-defined study drugs to the patient by entering in the e-trial man-
agement system the corresponding verifiers printed on each label of the study drugs. By doing so, the inves-
tigator documents each dispensing of study medication to a patient with the patient’s ID, study site ID and 
the date of dispensing (automatically allocated by the e-trial management system). Comparable procedures 
will be performed at each drug/device visit in follow-up. 
Patients will be asked to bring all unused or partly used medication at each visit in follow-up. The investigator 
will assess patients’ compliance with study drug by asking the patient about medication intake and by pill 
count during every clinical visit and at the end of follow-up. In case the patient did not take the assigned 
study drugs for a period of more than 7 consecutive days the date, duration and reason for interruption has 
to be documented. 
Compliance with study drug is defined as following (percentages refer to the period between the last docu-
mented follow-up visit and the next, ideally 6 months): 
 
Intake of study drugs < 80% of the number of pills calculated for the corresponding time period:  
non-compliance. 
 
Intake of study drugs 80% to < 90% of the number of pills calculated for the corresponding time period: 
acceptable compliance. 
 
Intake of study drugs 90% or more of the number of pills calculated for the corresponding time period: 
good compliance. 
In case of non-compliance the investigator has to instruct the patient about importance of regular drug in-
take. 
Any unused or partly used study medication has to be returned to the drug supplier periodically or latest at 
the end of the trial in the corresponding study site, depending on the amount of such medication in local 
stock. Returned study medication will be tracked by the investigator in the e-trial management system in a 
way comparable to the procedures at study medication dispense. The shipment of returned or unused study 
medication to the drug supplier will be managed by the CRO but performed by the investigator. 


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7.4 
Blinding/Unblinding 
To maintain blinding of study treatment, all study drugs will be prepared in tablets matching edoxaban and 
ASA tablets in form, size and colour. Patients, investigators and staff of study sites, committee members, 
and the sponsor’s and CRO’s staff conducting the study, will not have access to individual patient treatment 
assignments. The members of the Data and Safety Monitoring Board (DSMB) will have access to such as-
signments on demand. 
Blinding is critical to the integrity of this clinical trial. However, the patient’s treatment may be revealed by the 
investigator in a medical emergency, in which knowledge of the investigational product would be instrumen-
tal for further treatment decisions. A newly occurring indication for change of dosage of the study drugs or for 
initiation or termination of antiplatelet therapy is not a valid reason for unblinding since procedures for blind-
ed change of dosage and antiplatelet therapy are offered. Before breaking the blind of an individual patient’s 
blinded treatment, the investigator should have determined that the information is necessary, i.e., that it will 
alter the patient’s immediate management. In many cases, particularly when the emergency is clearly not 
study drug-related, the situation may be managed by assuming that the patient is receiving active product 
without unblinding. 
Every patient will be provided with an alert card. The alert card: 
 
indicates that the patient is participating in a double-blind clinical trial, 
 
provides the trial number and acronym, 
 
will note that the patient may be receiving either edoxaban or ASA or placebo, and 
 
includes the investigator’s name and phone number for providing information to emergency medical per-
sonnel. 
Unblinding: In a medical emergency and if knowledge of the patient’s randomised treatment assignment 
would have a meaningful impact on individual management, the patient’s treatment assignment can be un-
blinded. However, whenever possible, the need to break the blind should first be discussed with the CRO’s 
medical advisor or project director. 
Information regarding patient’s treatment assignment should be provided only to those who are caring for the 
patient and as few other people as possible. Thus, bias will be minimised by assuring that the Endpoint Re-
view Committee (ERC) remains blinded to treatment assignment, even if the investigator has been unblind-
ed. 
Unblinding of a patient’s treatment will be managed and tracked centrally in the e-trial management system. 
The investigator who is breaking the blind has to document date and reason for code break in the e-CRF and 
in the patient’s medical records. The CRO will receive an automated email containing all necessary infor-
mation on the code break (however without information regarding treatment) at the same time of the data 
being documented in the e-CRF. In case the e-CRF system is not reachable the investigator has to contact 
the CRO’s hotline to induce unblinding. 
7.5 
Temporary or Permanent Discontinuation of Study Drugs 
In case of newly occurring 
 
clinical indication for oral anticoagulation (such as new diagnosis of overt AF), or  
 
contraindications as given in the current SmPC of edoxaban or of ASA, or  
 
clinical indication for long term treatment (> 6 months) with any antiplatelet agent in addition to study 
medication, especially dual antiplatelet (DAPT) therapy, or 
 
contraindications for oral anticoagulation in general, or  
 
patient’s request of permanent study drug discontinuation,  


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therapy with blinded study medication should be stopped permanently and other adequate, open-label ther-
apy should be started according to applicable medical guidelines.  
In case of clinical indication for temporary treatment with antiplatelet agent in addition to study medication (≤ 
6 months duration), study medication should not be stopped permanently but discontinued temporarily, only, 
for the duration of prescription of any antiplatelet agent in addition to study medication. 
 
Date and reason of discontinuation of study drugs have to be documented (refer to section 9.3.3). Be aware 
of the fact that overt AF can only reliably be diagnosed by external ECG recordings according to ESC guide-
lines 2010, (Appendix VII). 
The initiation of oral anticoagulation should follow local clinical practice in patients who develop overt AF or 
another indication for oral anticoagulation. The study medication should be stopped just prior to initiation of 
effective oral anticoagulation. Compared to usual care, where the patient is not anticoagulated prior to AF 
detection, this will provide the same timing and effectiveness of oral anticoagulation in patients randomised 
to usual care (ASA or no therapy), and a better anticoagulation (edoxaban) until initiation of oral anticoagula-
tion in the patients randomised to edoxaban. This regime applies to all patients. For details refer to Appendix 
VI. 
If anticoagulation must be temporarily discontinued for medical reasons, e.g. in case of bleeding or to reduce 
the risk of bleeding during surgical or other procedures, study medication should be stopped as soon as 
possible and preferably at least 24 hours before the procedure.  
In case of non-life-threatening bleeding time is the most important antidote of the NOACs in view of the rela-
tively short elimination half-lives. After cessation of treatment, restoration of haemostasis is to be expected 
within 12–24 h after the last taken dose, given plasma half-life of around 12 h for edoxaban. In addition, 
standard supportive measurements (such as mechanical compression, surgical haemostasis, fluid replace-
ment, and other haemodynamic support) should be provided. 
In case of life-threatening bleeding the administration of prothrombin complex concentrate (PCC) or activat-
ed prothrombin complex concentrate (aPCC) can be considered in a patient with life-threatening bleeding if 
immediate haemostatic support is required. Clinical trials and registry data with NOACs have shown that this 
is rarely needed. The choice between PCC and aPCC may depend on their availability and the experience of 
the treatment centre. However, the efficacy of PCC or aPCC in patients who are actively bleeding has not 
been firmly established and one has to balance the potential prothrombotic effects against the potential anti-
coagulant benefits. 
For details on adequate therapy in case of bleeding please refer to chapter 9, page 20 ff. of the Updated 
European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants 
in patients with non-valvular atrial fibrillation attached as Appendix VI. 
Date, duration and reason for interruption have to be documented in the corresponding AE or SAE form of 
the e-CRF. In deciding whether a procedure should be delayed until 24 hours after the last dose of study 
medication, the potentially increased risk of bleeding should be weighed against the urgency of the interven-
tion. Study medication should be restarted after the surgical or other procedures as soon as adequate hae-
mostasis has been established. If oral medicinal products cannot be taken during or after surgical interven-
tion, consider administering a parenteral anticoagulant and then switch to oral study medication. 
If the patient did not take the assigned study drugs for any other reason (intended or unintended) this has to 
be documented in the e-CRF as part of the compliance measure at each follow-up visit (refer to section 7.3). 
Discontinuation of study drug, temporary or permanent, will not result in termination of study participation 
(intention-to-treat principle). In any case of discontinuation of study drug the patient will be followed accord-
ing to study protocol until the global end of the trial. 


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7.6 
Concomitant Medication 
The concomitant use of antiplatelet agents is discouraged in all study patients, because the concomitant use 
of an oral anticoagulant and antiplatelet agents increases the risk of bleeding without known benefits. Pa-
tients who require treatment with any antiplatelet agent in addition to edoxaban, especially dual antiplatelet 
therapy, at the start of the trial are not eligible for NOAH - AFNET 6 (refer to 6.2.3, exclusion criteria). If the 
indication for treatment with any antiplatelet agent in addition to edoxaban, especially dual antiplatelet thera-
py, appears after inclusion into the trial therapy with blinded study drugs should be stopped permanently and 
other adequate, open-label therapy should be started according to applicable medical guidelines (refer to 
7.5, temporary or permanent discontinuation of study drugs). All other concomitant medication can be used 
within the NOAH - AFNET 6 trial if in line with the contraindications given in the current SmPC of edoxaban. 
In the e-CRF, all concomitant drugs will be documented by generic name and dosage administered. 
7.7 
Post-study Treatment 
It is at the discretion of the treating physician which kind of therapy will be prescribed to the patient once their 
participation in the study has ended (global study end or premature study discontinuation). It is recommend-
ed to strictly follow the applicable medical guidelines and the market authorisation of the intended drugs. 
8. Adverse Event Reporting 
As all study treatments in NOAH - AFNET 6 are marketed and in-line with clinical practice, even knowing that 
the administration of edoxaban in AHRE patients without overt non-valvular AF is not in-line with the ap-
proved label, adverse events are expected to occur in similar clinical manifestations and at a comparable 
rate as the known adverse events of the approved therapies applied in the trial (i.e. “low risk trial”). 
8.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject ad-
ministered a pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
A newly diagnosed concomitant disease is also considered an AE. However, onset of ECG-documented AF 
and subsequently confirmed diagnosis of AF after randomisation is not considered an AE and does not re-
quire documentation in an AE form in the e-CRF unless any criterion for seriousness is met. Onset of AF has 
to be documented in a special “AF onset form”. 
Following the patient’s randomisation in the study, all AEs, whether related or not related to study drug, must 
be collected. However, within the context of the NOAH – AFNET 6 trial, no specific AEs and/or laboratory 
abnormalities are being considered as critical to safety evaluations. Thus, reporting of AEs not fulfilling any 
criteria of seriousness (refer to section 8.3) is not time critical. 
All AEs will be documented by study site personnel in the relevant section of the e-CRF specifying: 
 
the type of AE 
 
the diagnosis of the underlying illness or disorder rather than its individual symptoms. 
 
the date of onset,  
 
the date of resolution, 
 
the outcome, 
 
the intensity, 


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 
the causal relationship to study drug, and if related, the suspected study drug, and 
 
the action taken with regard to study drugs. 
8.2 
Adverse Drug Reactions 
According to Directive 2001/20/EC, Adverse Drug Reactions (ADRs) are all untoward and unintended re-
sponses to an investigational medicinal product related to any dose administered, irrespective of its degree 
of seriousness. Events associated with placebo will usually not satisfy the criteria for a serious adverse drug 
reaction. For all ADRs an assessment of “expectedness” will be performed by the sponsor or its responsible 
subcontractors. 
8.3 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that 
 
results in death or, 
 
is life-threatening 
(defined as an event in which the patient was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more severe) or, 
 
requires inpatient hospitalisation or prolongation of existing hospitalisation  
(defined as inpatient care of more than one calendar day [= at least one overnight stay]; see also NOTE 
below) or, 
 
results in persistent or significant disability/ incapacity or, 
 
is a congenital anomaly / birth defect, or 
 
is a medically important event 
(defined as a medical event(s) that may not be immediately life-threatening or result in death or hospital-
isation but, based upon appropriate medical and scientific judgment, may jeopardize the patient or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious outcomes listed in the 
definition above. Examples of such events include, but are not limited to, intensive treatment in an emer-
gency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalisation).  
More than one of the above criteria can be applicable to each event. 
These characteristics/consequences have to be considered at the time of the event. For example, regarding 
a life-threatening event, this refers to an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more severe. 
 
NOTE: The following hospitalisations are not considered SAEs: 
 
A visit to any hospital department or emergency room which does not result in an overnight stay (unless 
considered an “important medical event” or an immediate life-threatening event). 
 
Any non-emergency medical or surgical admission planned before signing consent. 
 
Routine health assessment requiring admission for baseline/trending of health status (e.g. routine colon-
oscopy). 
 
Any overnight hospital stay required only for overnight diagnostic procedure (e.g. sleep laboratory). 
 
Admission encountered for another life circumstance that carries no bearing on health status and re-
quires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver respite, 
family circumstances, administrative). 


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8.4 
Recording and Reporting Serious Adverse Events 
Following the patient’s written consent to participate in the study, all SAEs, whether related or not related to 
study drug, must be collected. 
The investigator should specify and report in the e-CRF the nature of the sign or symptom leading to the 
SAE, the date of onset of the sign or symptom, the date of resolution (duration) of the specific event (not of 
the underlying disease), the intensity, interventions performed (if any), the relationship to study treatment, 
and the outcome. 
All SAEs, whether related or unrelated to study drug, must be reported expeditiously to the CRO through the 
SAE section of the e-CRF within 24 hours of becoming aware of the event. An SAE form within the e-CRF 
should be completed for any event where doubt exists regarding its status of seriousness. As a minimum, 
the investigator has to fill out the following items of the internet-based SAE form: 
 
type of event, 
 
description, 
 
date of onset, 
 
criteria for seriousness, 
 
causal relationship to study drug, and if related, the suspected study drug. 
As soon as further information regarding the event is available (e.g. discharge letter), the investigator should 
complete the documentation in the e-CRF and sign it electronically. Copies of the discharge letter, of all re-
ports regarding examinations carried out and/or diagnostic findings should be faxed to the CRO. For labora-
tory results, the laboratory normal ranges should be included. All documents should be sent to the CRO after 
adequate blinding of patient identifiers, only. 
Follow-up of any SAE that is fatal or life threatening should be provided within one additional calendar week. 
Any SAE reporting (initial reporting and follow-up information on e.g. changes of an ongoing SAE’s intensity 
or relationship to the investigational product or outcome) is done through the SAE section of the e-CRF and 
an automated email notification system within the e-trial management system, i.e. no extra SAE form needs 
to be faxed but the CRO will receive an automated email containing all necessary information on the SAE at 
the same time of the data being documented or changes of relevant SAE data being made in the e-CRF. 
The sponsor will via contracted CRO forward all SAEs immediately after awareness to the pharmacovigi-
lance department of the edoxaban manufacturer for inclusion in their global safety database. The relevant 
SAE data will be retrieved from data documented by the investigator within the e-CRF and sent to the edox-
aban manufacturer digitally. Changes of relevant SAE data (including deletion of SAEs if relevant criteria are 
not met) will also be forwarded to the pharmacovigilance department of the edoxaban manufacturer. Patient 
identifying data will consist of patient ID number, year of birth, gender and site ID number, only. 
According to legal requirements and international standards, annual safety reports will be prepared by the 
sponsor or its responsible subcontractors and forwarded to responsible authorities of all participating coun-
tries and to all corresponding ECs / IRBs. 
8.4.1 
Definition of intensity 
Intensity 
Definition 
Mild 
Patient is aware of signs and symptoms but they are easily tolerated 
Moderate 
Signs/symptoms cause sufficient discomfort to interfere with usual activities 
Severe 
Patient is incapable to work or perform usual activities 
Very severe 
Signs/symptoms are debilitating, significantly incapacitate patient despite 
symptomatic therapy 


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8.4.2 
Definition of causality 
In accordance with Council of International Organisations of Medical Sciences (CIOMS), causality of an 
event will be assessed as: 
not related: 
No causal relationship exists between the study treatment and the event but an obvious alter-
native cause exists, e.g. the patient's underlying medical condition or concomitant therapy. 
or 
related: 
There is a reasonable / plausible possibility that the event may have been caused by the 
study treatment (e.g. the event cannot be explained by concomitant disease(s) or other 
drugs/treatments). 
8.5 
Adverse Event Follow-up Procedures 
The investigator should take all appropriate measures to ensure the safety of the patients, notably he / she 
should follow-up the outcome of any AE or SAE (clinical signs, laboratory values or other, etc.) until the re-
turn to normal or consolidation of the patient’s condition. 
In case of any SAE, the patient must be followed until clinical recovery is completed and laboratory results 
have returned to normal, or until progression has been stabilized. This may imply that follow-up will continue 
after termination of the trial, and that additional investigation may be requested by the CRO team. 
8.6 
Handling of Expedited Safety Reports 
This applies to any SAE that is considered related to study drug and the nature or severity is not consistent 
with the applicable product information (suspected unexpected serious adverse event; SUSAR). The expect-
edness of an adverse reaction will be determined by the sponsor or its responsible subcontractors according 
to the Reference Safety Information (RSI) document of each study drug. The RSI will be clearly identified 
before global start of the trial and is the same in all participating countries. 
The sponsor will act in strict compliance with all applicable laws and regulations and will ensure that any 
delegate strictly abides by the same. The sponsor or its responsible subcontractors will notify the competent 
authorities, corresponding ECs / IRBs and all principal investigators concerned of any SUSAR in-line with 
applicable regulatory requirements. In addition, the sponsor or its responsible subcontractors will inform the 
marketing authorisation holder of the study drug of the previous notification to the competent authorities. 
Before notification of a SUSAR to the competent authorities and corresponding ECs / IRBs, unblinding for 
this patient must be performed by the sponsor or its responsible subcontractors, however blinding should be 
maintained for the investigator and for the biostatisticians responsible for data analysis and interpretation. 
Unblinding of a patient’s treatment will be managed and tracked centrally in the e-trial management system. 
The person performing code break has to document date and reason in the e-CRF. 
9. Study Schedule 
All data and assessments described in the following sections have to be documented as defined in the e-
CRF, even if not described in detail in the study protocol. 
9.1 
Visit Schedule 
The expected timing and assessment of the study are outlined in the following table: 
 


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Assessment 
Baseline 
Visit 
Day 0 
Drug/Device 
Visit* 
Month 6 
Clinical 
Visit* 
Month 12 
Drug/Device 
Visit* 
Month 18 
Clinical 
Visit* 
Month 24 
Drug/Device 
Visit* 
Month 30** 
Clinical 
Visit* 
Month 36 
Final 
  Visit*** 
 
Signed ICF (medical informed consent) 
X 
 
 
 
 
 
 
 
Check inclusion & exclusion criteria 
X 
 
 
 
 
 
 
 
Physical examination (PE) / medical history 
X 
 
X 
 
X 
 
X 
 
Karnofsky score 
X 
 
X 
 
X 
 
 
 
Modified Rankin scale 
 
 
X 1 
 
X 1 
 
X 1 
 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
Number of AHRE, upload of device interrogations 
from implanted device 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory parameters (blood sample) 
X 2 
 
X 3 
 
 
 
 
 
Cognitive function test (MoCA) 
X 
 
X 
 
X 
 
 
 
Quality-of-Life questionnaire (EQ-5D)4 
X 
 
X 
 
X 
 
 
 
Patient ’s satisfaction and symptom severity ques-
tionnaire4 (mEHRA score, PACT-Q)  
X 
 
X 
 
X 
 
 
 
Supply of study drug 
X 
X 
X 
X 
X 
X 
X 
 
Return of study drug 
 
X 
X 
X 
X 
X 
X 
X 
Adverse event (AE) /serious adverse event (SAE) 
 
X 
X 
X 
X 
X 
X 
X 
Table 2: Study visit schedules 
* Time window +/-  2 weeks 
** or longer if required 
*** within 3 months after confirmation that the required number of adjudicated endpoints has been reached (will be announced by CRO) 
1 Assessment of modified Rankin scale only in pts. with stroke during study participation; a maximum of 2 subsequent assessments in follow-up per patient with stroke should be performed 
2 Blood sample not older than 28 days at the date of randomisation (full blood cell count, serum creatinine, AST, ALT, bilirubin, aPTT, and INR) + extra blood sample for central analyses 
3 Extra blood sample for central analyses, only 
4 All Quality-of-Life measures and satisfaction questionnaires should ideally be completed prior to the clinical consultation.


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9.2 
Baseline Visit 
A patient meets eligibility criteria of the study if all inclusion and exclusion criteria are fulfilled as described in 
the sections above. Prior to any trial related procedure a signed informed consent form has to be obtained 
from every patient to be included in NOAH – AFNET 6 and kept on file locally. 
At the baseline visit, the investigator or designee will: 
 
Obtain patients' informed consent; 
 
Document all inclusion and exclusion criteria (refer to section 9.2.1 for qualifying AHRE); 
 
Assess patients' medical history; 
 
Assess quality-of-life (EQ-5D questionnaire) prior to the main clinical consultation (refer to section 9.7); 
 
Assess patient’ s satisfaction and symptom severity (PACT-Q questionnaire and modified EHRA score) 
prior to the main clinical consultation (refer to section 9.7); 
 
Obtain a 12-lead ECG and digitally upload the ECG to a provided system (refer to section 9.5); 
 
Perform a physical examination including actual weight; 
 
Assess function of implanted device and AHRE detection settings, number of AHRE; 
 
Upload interrogations derived from the implanted device according to upload instructions (will be given 
as a separate instruction document); 
 
Obtain blood samples for laboratory assessments (refer to section 9.6); 
 
Collect a blood sample for storage in the central laboratory (separate informed consent required; refer to 
section 9.6); 
 
Assess cognitive function (MoCA test; refer to section 9.8); 
 
Assess performance status (Karnofsky score; refer to section 9.8); 
 
Initiate study therapy. 
9.2.1 
Documentation of the qualifying AHRE  
Presence of AHRE is an essential inclusion criterion for NOAH - AFNET 6. Documentation of the qualifying 
AHRE is essential to monitor inclusion criteria. To allow meaningful assessment of the qualifying AHRE, a 
digital upload onto a provided system is mandatory to perform a central review. Description of events without 
documentation of the episode is not sufficient for documentation of the qualifying AHRE. The results of re-
view will not lead to post-hoc exclusion of the patients if criteria of AHRE are not met but will detect protocol 
violations relevant for stability measures of final analysis and will lead to training of corresponding study sites 
to prevent future violations and therefore assure a standard quality of adequate AHRE detection. 
If AHRE has not been confirmed (i.e. index condition for NOAH - AFNET 6 is not fulfilled),  
 
and no study medication has been administered, the patient will not remain in the study (refer to section 
11.2); 
 
and at least one dose of study medication has been administered, the patient will remain in the study 
(principle of intention-to-treat) and has to be followed according to protocol until the end of the trial. 
 
 


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9.3 
Follow-up 
NOAH - AFNET 6 is an event-driven trial. All patients will be followed until the global end of the trial. Sample 
size has been estimated based on a minimal follow-up time of 12 months after the end of enrolment and 
assuming an enrolment time of 71 months. 
Clinical follow-up visits will be performed at months 12, 24, and 36. Starting at month 6 and subsequently 
alternating to clinical follow-up visits, patients will come to the study site for dispensing study drug and up-
load of device interrogations derived from the implanted device (“drug/device visit”). After month 36, no more 
scheduled clinical visits will take place but “drug/device visits” in 6-monthly intervals until end of study, only. 
All patients will be followed for outcome and safety until global end of the trial. After the required number of 
primary outcome events has been accrued and verified, all patients will be seen for a final end of study visit. 
For all scheduled follow-up visits, a time window of +/- 2 weeks is allowed.  
9.3.1 
Clinical visits (Months 12, 24, and 36) 
At each visit, the investigator or designee will 
 
Assess the AHRE detection settings in the implanted device; 
 
Assess overall heart rhythm, number of AHRE, and history of AF since preceding visit; 
 
Upload device interrogations derived from the implanted device according to upload instructions (will be 
given as a separate instruction document); 
 
Perform a physical examination including actual weight; 
 
Obtain a 12-lead ECG and digitally upload the ECG to a provided system (refer to section 9.5); 
 
Assess for clinical events, AEs, SAEs, and contraindications for edoxaban or oral anticoagulation that 
occurred since the preceding visit / contact; 
 
Assess modified Rankin scale in patients with stroke during study participation; a maximum of 2 subse-
quent assessments in follow-up per patient with stroke should be performed 
 
Assess and document adherence to study therapy by asking the patient and by pill count; 
 
Dispense new study medication as far as required and collect remaining study medication. 
At month 12 and 24 the investigator or designee will in addition: 
 
Assess quality-of-life (EQ-5D questionnaire) prior to the clinical consultation (refer to section 9.7); 
 
Assess performance status (Karnofsky score; refer to section 9.8); 
 
Assess patient’ s satisfaction and symptom severity (PACT-Q questionnaire and modified EHRA score) 
prior to the main clinical consultation (refer to section 9.7); 
 
Assess cognitive function (MoCA test; refer to section 9.8). 
At month 12 the investigator or designee will in addition: 
 
Obtain blood sample for central analyses (refer to section 9.6). 
9.3.2 
Drug/device visits (Months 6, 18, and 30 or longer if required) 
At each drug/device visit, the investigator or designee will 
 
Record patients weight, dispense new study medication as far as required and collect used/empty study 
medication; 
 
Assess and document adherence to study therapy by asking the patient and by pill count; 


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 
Obtain a 12-lead ECG and digitally upload the ECG to a provided system (refer to section 9.5); 
 
Upload device interrogations derived from the implanted device according to upload instructions (will be 
given as a separate instruction document); 
 
Assess for clinical events, AEs and SAEs that occurred since the preceding visit / contact. 
9.3.3 
Triggered visit „Discontinuation of study drug“ 
If the study drug needs to be discontinued for medical reasons (e.g. in case of clinical indication for antico-
agulation or antithrombotic therapy such as new diagnosis of AF or in case of contraindications given in the 
current SmPC of edoxaban or for oral anticoagulation in general) or the patient’s request of study drug dis-
continuation (refer to section 7.5) this has to be documented in the e-CRF and the investigator or his design-
ee will 
 
Assess the AHRE detection settings in the implanted device; 
 
Assess overall heart rhythm, number of AHRE, and history of AF since preceding visit; 
 
Upload device interrogations derived from the implanted device according to upload instructions (will be 
given as a separate instruction document); 
 
In case of new diagnosis of AF as reason for discontinuation of study drug, upload first ECG available 
with documentation of AF; 
 
Assess for clinical events, AEs and SAEs that occurred since the preceding visit / contact; 
 
Document date and reason for discontinuation of study drug; 
 
Assess and document previous adherence to study drug by asking the patient and by pill count; 
 
Collect all study medication. 
Although having discontinued study drug, these patients will be followed according to study protocol until 
global end of study (intention-to-treat). 
9.3.4 
Final visit (at global end of study) 
The global end of study will be announced by the CRO after all necessary primary endpoints have been 
reached. All regular scheduled follow-up visits have to be cancelled after this point in time, but a final in per-
son visit has to be scheduled for all patients still in follow-up at the time of global end of study. It is expected 
that this visit will be scheduled, performed and documented within 3 months after announcement by the 
CRO. At that visit, the investigator or his designee will 
 
Assess overall heart rhythm, number of AHRE, and history of AF since preceding visit; 
 
Upload device interrogations derived from the implanted device according to upload instructions (will be 
given as a separate instruction document); 
 
Obtain a 12-lead ECG and digitally upload the ECG to a provided system (refer to section 9.5); 
 
Assess for clinical events, AEs and SAEs that occurred since the preceding visit / contact; 
 
Assess and document previous adherence to study drug by asking the patient and by pill count; 
 
Terminate study medication intake and collect all remaining study medication; 
 
Document and start change management to therapy after end of study in each patient. 
In patients with premature termination of study drug before global end of study the final visit might be per-
formed as final phone call assessing for clinical events, AEs and SAEs, only. 


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After termination of study treatment it is at the discretion of the treating physician which kind of therapy will 
be prescribed to the patient. It is recommended to strictly follow the applicable medical guidelines and the 
market authorisation of the intended drugs. 
9.4 
Patient withdrawal from the study 
Termination of treatment with study medication for any reason does not necessarily mean premature study 
withdrawal or termination of study procedures. Individual study participation is only terminated in case of 
death or patient’s explicit wish. It is expected that a large proportion of patients wishing to withdraw consent 
for further study participation wish to avoid the time and effort of study-specific visits at the study site rather 
than completely withdrawing from study participation. All study patients wear an implanted device with the 
need of personal visits for periodic device checks in clinical routine. Patients expressing the wish to withdraw 
from the study will therefore be asked to maintain consent for minimal effort follow-up, allowing to use their 
clinical data achieved at the clinically indicated visits within the NOAH - AFNET 6 trial (modification of con-
sent). All study patients wearing an implanted device with home monitoring capacity should be asked to con-
sent for a follow-up allowing using their device data achieved by remote monitoring. 
If a patient completely withdraws consent to any further study participation, the investigator should contact 
the patient and 
 
Assess overall heart rhythm, number of AHRE, and history of AF since preceding visit; 
 
Upload device interrogations derived from the implanted device according to upload instructions; 
 
Assess for clinical events, AEs and SAEs that occurred since the preceding visit / contact; 
 
Assess and document adherence to study therapy by asking the patient and by pill count; 
 
Collect all study medication 
These data will be documented in the e-CRF in a withdrawal visit. 
9.5 
Electrocardiogram 
All patients will undergo 12-lead ECG at baseline and as part of the clinical follow-up visits. Operators re-
cording ECGs should ensure that chest leads are placed in the proper position and electrodes make good 
skin contact to minimize noise and artefacts. The reversal of limb leads and the switching of precordial leads 
are known to cause important alterations in ECGs. 
All ECGs will be uploaded digitally onto a central server. This requires an ECG machine capable of exporting 
an adequate digital format that can then be uploaded. Details regarding upload of ECGs are described in a 
separate ECG upload manual. 
The ECG recording should be digitally annotated with the date of recording, patient study ID and gender, 
only. No patient identifying annotations (e. g. last name, first name, date of birth) must be documented. 
In case an ECG is only available as paper version, a copy has to be faxed or mailed to the CRO for further 
analyses to be performed by a central evaluation centre. 
9.6 
Blood Samples 
Routine laboratory parameters obtained within clinical routine procedures are part of the standard work-up of 
the patient’s status before study participation in order to verify the enrolment criteria and therefore not con-
sidered to be part of study related procedures. If these parameters can be assessed from a blood sample not 
older than 28 days at the date of inclusion, blood sampling and analysis do not have to be repeated within 
the study baseline visit. Parameters include a full blood cell count, serum creatinine, AST, ALT, bilirubin, 
aPTT, and INR. All blood parameters will be determined at the local laboratory of the study sites provided 


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their analytical laboratories are certified. The e-CRF will collect laboratory values and information whether 
the value is normal or abnormal. 
At baseline and at clinical visit month 12, a study-specific blood sample will be collected (20 ml whole blood) 
and sent to a central laboratory for archiving for later analysis (analyses of factors and mechanisms of AF, 
stroke, and bleeding, including genetic markers) which will be performed either in the central laboratory of 
the trial or within scientific collaborations. All analyses will be supervised by the Steering Committee. Patients 
will provide a separate signed informed consent to obtain this extra blood sample. Details regarding handling 
and shipment of these blood samples are described in a separate manual. 
9.7 
Quality of Life, Experience, Symptoms and Cognitive Function 
All patients will be requested to complete quality-of-life, symptom and experience questionnaires and under-
go cognitive function testing at baseline, 12 and 24 months. It is hypothesised that the intervention will lead 
to improved quality-of-life, reduce symptoms, improve patient experience and maintain cognitive function. 
This hypothesis is based on the observation that AF, including “asymptomatic” forms, is associated with re-
duced quality of life (44). Observational data suggest that small cerebral emboli are common in patients with 
short AF episodes (51, 55) and can contribute to reduced quality of life (56, 57). Based on the assumption 
that AHRE are a very early form of AF conveying a risk of stroke including silent brain lesions, it is expected 
that quality of life and cognitive function in AHRE patients will also be reduced. Furthermore, the collection of 
EQ-5D information will provide a valid basis to compare the intervention tested in NOAH - AFNET 6 to other 
interventions in terms of utility and cost effectiveness. This will inform payers and providers of health care 
services and allow to put the findings of NOAH - AFNET 6 into a broader health care perspective (58, 59). 
Significant benefits should be observed within 12 months of treatment and be maintained thereafter. All as-
sessments will be conducted in accordance with the QOL Site Training Manual (will be given as a separate 
instruction manual) prior to the main clinical consultation. 
9.7.1 
Patient Reported Outcomes: quality of life, experience and symptoms 
Quality of life will be assessed using the EuroQoL EQ-5D L questionnaire. The EQ-5D is a self-administered, 
validated, generic preference-based measure of health status that comprises a 5-question multi-attribute 
questionnaire and a visual analogue self-rating scale (46, 47, 48). Patients are asked to rate severity of their 
current problems according to 5 levels (no problems, slight problems, moderate problems, severe problems, 
and extreme problems). Patients can therefore be classified into 3,125 possible health states which can be 
converted into an EQ-5D index score. On the visual analogue scale patients are asked to rate their own 
health state relative to full health (score=100) or worst imaginable health state (score=0). 
Patients’ expectations of, and satisfaction with their anticoagulant treatment will be assessed using the Per-
ception AntiCoagulant Treatment Questionnaire (PACT-Q). This is a validated tool which takes around 10 
minutes to complete (49, 50). 
Patient perception of the severity of their symptoms will be assessed using the modified EHRA score (36). 
9.8 
Clinical Assessment of Performance Status and Cognitive Function 
Performance status will be assessed using the Karnofsky Performance Status Scale (52, 53). The Karnofsky 
score runs from 100 to 0, where 100 is "perfect" health and 0 is death, and has previously been used in AF 
patients (54): 
100% – normal, no complaints, no signs of disease 
90% – capable of normal activity, few symptoms or signs of disease 
80% – normal activity with some difficulty, some symptoms or signs 
70% – caring for self, not capable of normal activity or work 
60% – requiring some help, can take care of most personal requirements 
50% – requires help often, requires frequent medical care 


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40% – disabled, requires special care and help 
30% – severely disabled, hospital admission indicated but no risk of death 
20% – very ill, urgently requiring admission, requires supportive measures or treatment 
10% – moribund, rapidly progressive fatal disease processes 
0% – death 
Cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA; 62); a rapid screening 
instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentra-
tion, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and 
orientation. Time to administer the MoCA is approximately 10 minutes. The total possible score is 30 points; 
a score of 26 or above is considered normal. 
9.9 
Measures to be taken in case of a Pandemic 
In case of a pandemic, actions should be taken by the study sites in order to support the safe continuation of 
the NOAH - AFNET 6 study and to protect the study population from harm. The goal is to keep as many pa-
tients as possible in the study without endangering their safety or health in order to allow a meaningful con-
tinuation of the study and not to jeopardize the quality of the study data. Measures will be taken by the spon-
sor to warrant the continued supply of study medication and medical care during study participation. Based 
on local requirements, the study team shall perform a risk assessment to determine whether the actions 
described below and potentially additional actions will be implemented at its site to assure the patients’ safe-
ty.  
 
In case an increased risk due to progressive pandemic is foreseeable, patients should be invited to the 
study site early, regardless of the calculated visit date, to assure medication supply for the next 6 
months. 
 
Study patients should be contacted by phone before a FU-visit, in order to clarify whether their state of 
health allows them to visit the study site without an increased risk to themselves or others.  
If a personal FU-visit at the study site is possible: 
 
Examinations which are not relevant for the safety of the patient may be omitted to shorten the duration 
of the patient’s stay at the site. 
 
To reduce the number of examinations, study medication may be dispensed based on patient records, 
consultation with the general practitioner or an interview with the patient.  
 
The study team shall adhere to local requirements and polices related to infection control for the pan-
demic. 
In case of a lockdown or (self-)quarantine of study patients: 
 
FU-visits should be performed by phone with the focus on evaluation of any new adverse events as well 
as information necessary to determine safety aspects with regard to supply of the study drug. 
 
Study medication may be sent by taxi or courier after a FU-visit by phone. Date and time of dispatch as 
well as delivery to the patient has to be documented. 
 
Study patients with an implanted device with home monitoring capacity should be monitored remotely. 
 
Remote enrolment of study patients may be performed based on patient records and an interview with 
the patient. To reduce the number of assessments, examinations may be limited to those that are rele-
vant for the patient’s safety and the assignment of study medication. 
Each action, especially deviations from the study protocol, needs to be documented for every patient affect-
ed. 
 


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10. Duration of Study Participation 
10.1 Overall Duration of the Study 
Screening and enrolment of patients is expected to be accomplished after 71 months. Based on the sample 
size estimation, it is expected that the required number of adjudicated / verified primary outcome events will 
be reached 12 months after enrolment of the last patient. Due to the time required to obtain follow-up infor-
mation and to adjudicate events (about 3 months to perform a final study visit in all patients still in the trial 
plus 4 months for receiving SAE documents and adjudication by ERC to confirm that the required number of 
adjudicated endpoints have been reached), a total study duration of 71 + 12 + 3 + 4 = 90 months is ex-
pected. The total study duration of 90 months (about 7.5 years) was adapted based on an interim analysis. 
Global end of study (EOS) is defined in Appendix II as the last Final Visit performed in a study patient. This 
date will be approved by the sponsor and announced by the CRO. 
10.2 Duration of Study Participation for Individual Patients 
Based on the sample size estimation, the expected mean follow-up time will be about 42 months per patient 
with a minimum follow-up time of 12 months and a maximum follow-up time of presumably 83 months until 
end of final visit after required number of endpoints has been reached. Every patient will be followed-up until 
global end of study. The exact duration of follow-up will be determined by the accrual of events (event-driven 
study). 
11. Stopping and Discontinuation Criteria 
When the study is terminated, the nature of termination will be documented (scheduled end/discontinuation 
with justification). Discontinuation of the study will be communicated in writing according to the legal re-
quirement. The decision to stop the study will be reached jointly by the sponsor and the SC. 
11.1 Discontinuation Criteria for the Study and Study Sites 
Following a recommendation of the Data and Safety Monitoring Board (DSMB), the SC may decide discon-
tinuation of the study due to efficacy criteria or adverse reactions in either study group. Discontinuation of the 
study can also be decided if patients cannot be recruited in sufficient numbers within a certain time period. 
Detailed criteria for a premature stopping of the entire trial based on safety concerns will be defined in the 
DSMB and SC charters. 
Furthermore, the sponsor in collaboration with the international chief investigator has the right to close local 
study sites for enrolment of further patients if a major protocol violation occurs, if the site does not comply 
with the study protocol or decisions of the committees or the international chief investigator or if the site re-
mains inactive for several months. Such decisions will always be taken on a case-by-case basis, but may be 
taken e.g. if the study procedures and study therapy is not delivered according to protocol and after remind-
ers to adhere to the protocol from the study team. 
11.2 Discontinuation Criteria for Patients 
The investigator is not able to decide about the discontinuation of study participation of any patient. The in-
vestigator has only the option to discontinue study medication for compelling medical reasons. In this case, 
however, the patient will continue to be followed-up according to study protocol.  
If a patient has been randomised but discontinued study participation prior to exposure to study medication, 
that patient will not be followed. Such patients will be replaced by enrolling other, additional patients. 


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Once a patient has been randomised and at least one dose of study medication was taken, but he/she dis-
continued study drug, the patient has to be followed according to study protocol (intention-to-treat) until glob-
al end of study. 
The patients will be advised in the informed consent forms that they have the right to withdraw from study 
participation at any time without statement of reasons. However, the investigator should try to find out the 
reason for patient’s withdrawal of consent and document these in the e-CRF. 
In case, a protocol violation is noticed, the patient will remain in the intention-to-treat group and will be fol-
lowed according to protocol. 
Patients will be followed according to the study protocol irrespective of whether they experience any out-
come event. 
Reasonable effort should be made to contact any patient lost to follow-up during the course of the study in 
order to complete assessments and retrieve any outstanding data. The responsible investigator will take all 
acceptable measures to retrieve information on vital status of all patients enrolled in the trial. 
12. Statistics 
The main aim of the proposed study is to test the null hypothesis that the hazard rate, which is assumed to 
be constant during the study period, is identical in the two groups (usual care and NOAC). 
Based on the stroke and death rates of published trials (MOST, ASSERT, Medtronic AT500 data set, SOS), 
an annualised rate of stroke, systemic embolism, or cardiovascular death of 5.3% in the control group is 
expected (details given in section 12.2). 
12.1 Statistical Methods 
The null hypothesis will be tested in a two-arm randomised trial in which patients are entered and then fol-
lowed if either (a) a primary endpoint is observed or (b) the patient develops overt AF or (c) the observation 
period ends. Based on the sample size estimate, it is expected that patients will be accrued in a period of 71 
months and followed up for the whole duration of study patient recruitment plus at least 12 months until the 
end of regular follow-up. The exact study duration will depend on the number of adjudicated primary out-
come events. 
12.1.1 Analysis of the primary outcome 
The primary endpoint is the time from randomisation to the first occurrence of stroke, systemic embolism or 
cardiovascular death. Patients who develop overt AF during the trial period will be censored at that point in 
time but followed according to protocol until the global end of the trial. All other patients who will not reach 
the primary endpoint by the global end of the study will be censored at that time point. All randomised pa-
tients will be included in the analysis on a modified intention-to-treat-basis.  
Cumulative incidence curves and corresponding p-values from competing risk analysis as well as tables with 
estimated (cause-specific) hazard ratios, confidence intervals, and corresponding p-values will be provided. 
The Cox-proportional hazards model will be used to estimate the (cause-specific) hazard ratio of edoxaban 
versus usual care. 
12.1.2 Analysis of the secondary outcome 
 
The following secondary endpoints will be analysed in the same way as the primary endpoint: time to com-
ponents of primary outcome, time to major adverse cardiac events (MACEs), time to stroke or arterial embo-
lism, time to major bleeding events.  


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Time to all-cause death will be analysed using Kaplan-Meier curves and corresponding p-values from the 
log-rank test as well as tables with estimated hazard ratios, confidence intervals, and corresponding p-values 
from a Cox-proportional hazards model. 
12.1.3 Continuous secondary endpoints will be analysed as change from baseline using the baseline ad-
justed analysis of covariance (ANCOVA). Safety analysis 
Safety data include adverse events as defined in section 8.1, primary safety endpoints, and data for other 
safety evaluations. Safety data will be collected on all enrolled patients (i.e. all patients that signed informed 
consent) in this study. 
The primary safety outcome in this study is a composite of cardiovascular death, stroke, and systemic embo-
lism which will be analysed using time-to-event methodology as described in section 12.1.1. Similar analyses 
and summary statistics will be provided for the components of this safety composite endpoint. 
SAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary in its actual 
version at the start of the study by Lowest Level Terms (LLT). Treatment related SAEs will be summarized 
under each treatment group, by system organ class (SOC) and preferred term (PT). Comparisons between 
treatment groups will be made using Fisher’s exact tests for the proportion of subjects with an AE (grouped 
under one preferred term). SAEs will be summarized by severity and relation to study treatment received. 
12.1.4 Subgroup analysis 
A list of subgroup criteria will be pre-specified in the statistical analysis plan. 
12.2 Sample Size and Power Calculations 
Estimation of stroke rates in the NOAH - AFNET 6 population. The table below gives the estimated an-
nual event rates based on recently published trials. Taken together, this information forms the basis for the 
sample size estimation and for the risk assessment for individual patients enrolled into NOAH - AFNET 6. 
 
Stroke 
Cardiovascular death 
Sum 
ASSERT (16), 261 pts, 2.5 yrs. FU 
1.7 
2.9 
4.45 
MOST (17), 160 pts, 2.25 yrs. FU 
5 
4.2 
9.2 
AT500 (28), 725 pts, 1.833 yrs. FU 
3.6 
 
 
Botto et al (31), 223 pts., 1 yr. FU 
3.2 
 
 
AVERROES ASA arm (3), 2791 pts, 1.1 yrs. FU 
3.4 
3.1 
6.4 
AVERROES and ACTIVE ASA arms pAF (37), 1576 
pts, 1.1 yrs. FU 
2.1 
3.1 
5.2 
ROCKET-AF pAF patients (38), 2514 pts, 2.4 yrs. 
FU 
1.7 
3.5 
4.9 
SOS (32), 4287 pts, 2.17 yrs. FU 
1.2 
 
 
Estimated event rate control (weighed by patient-
years FU) 
1.9 
3.3 
5.3 
Table 3: Published annual stroke and cardiovascular death event rates in patients with documented AHRE. 
Event rates are split by stroke and cardiovascular death. The sum of these two components deter-
mines the estimate for the primary outcome. All events are rounded to one decimal after calcula-
tion. 
Estimation of the safety of edoxaban in the NOAH - AFNET 6 population. The safety assessment for the 
NOAH - AFNET 6 trial participants is based on the favourable bleeding profile of a edoxaban 60 mg OD re-


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gime compared to warfarin in the ENGAGE-TIMI 48 trial, combined with the observations made in BAFTA 
and AVERROES that acetylsalicylic acid does not cause more severe bleeding events or therapy discontin-
uation than warfarin (3, 6, 23). Thus, the risk for patients randomised to edoxaban seems very small. The 
safety assessment is in line with the observed small bleeding rates in the ENGAGE-TIMI 48 trial (Table 4). 
Development of overt, diagnosed AF in patients with AHRE. Some patients with AHRE will develop 
overt, diagnosed AF during the follow-up time. As diagnosis of overt AF constitutes an indication for oral 
anticoagulation, these patients will be censored at the time of developing overt AF. In addition to expected 
event rates and the potential for event reduction, the sample size estimate recognises that these patients will 
be censored at this moment. Most of these patients will be additional to the expected attrition rate in this 
double blind randomised trial. Based on data published in the ASSERT study and in a small portion of the 
MOST trial population, 13-16% of patients with AHRE will develop overt AF over a follow up time of 2.5 years 
(16, 17). Based on the increased use of clinical ECG monitoring, e.g. by Holter ECGs, it is expected that this 
rate will be higher in the NOAH - AFNET 6 population. 
 
Figure 4 
 
stroke, systemic em-
bolism, or cardiovas-
cular death 
fatal bleed-
ing 
hemorrhagic 
stroke plus 
other ICH 
Major extra-
cranial hem-
orrhage 
ENGAGE edoxaban 60 mg 
OD dosing regime 
3.85 
0.20 
0.39 
2.65 
AVERROES aspirin 
6.40 
0.20 
0.50 
1.2* 
BAFTA aspirin 
8.10 
0.10 
0.50 
2.00 
Table 4 
Figure 4 and corresponding Table 4 
Major efficacy and safety annual event rates for patients randomised to edoxaban 60 mg OD in the EN-
GAGE-TIMI 48 trial compared to event rates reported in patients randomised to acetylsalicylic acid in the 
AVERROES and BAFTA trials (3, 6, 23). All events are given as annualised rates in percent. 
*For the AVERROES acetylsalicylic acid group, only the AVERROES major bleeds are reported, although 
some of the “clinically relevant non-major bleeds” in AVERROES would have been classified as “major” in 
BAFTA and ENGAGE.  
0
2
4
6
8
10
12
ENGAGE edoxaban 60 mg OD
AVERROES aspirin
BAFTA aspirin
Major event rates on edoxaban and aspirin 
all extracranial hemorrhage
fatal bleeding
hemorrhagic stroke plus other ICH
stroke, systemic embolism, or cardiovascular death


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Estimation of the benefit of edoxaban in the NOAH - AFNET 6 population. Patients randomised to 
edoxaban will have a reduction in stroke or TIA rates by 2/3 (67%), (3, 39), and a 10% reduction in cardio-
vascular death. The effect estimate for stroke prevention is based on the effect size observed for stroke pre-
vention with VKAs vs. acetylsalicylic acid, assuming that edoxaban is at least as effective as dose-adjusted 
warfarin in preventing strokes in AHRE patients (1, 33). This assumption discounts the fact that NOAH - 
AFNET 6 will compare the potentially more effective agent edoxaban to a control therapy that will consist of 
acetylsalicylic acid or placebo. The effect size for reduction in cardiovascular death is the point estimate of 
reduction in cardiovascular deaths observed in the four NOAC trials compared to warfarin. This conservative 
estimate is thus based on the assumption that the mortality benefit of edoxaban vs. usual care in NOAH - 
AFNET 6 is not bigger than the mortality benefit of edoxaban compared to dose-adjusted warfarin observed 
in ENGAGE-TIMI 48 and in the other three NOAC trials (34). These assumptions result in an estimated event 
rate of 0.64% per year for stroke and a 3% event rate for cardiovascular death. The event rate in the edoxa-
ban group in NOAH - AFNET 6 (3.64% per year) is very similar to the observed event rate in patients en-
rolled in ENGAGE and randomised to edoxaban that match the NOAH - AFNET 6 inclusion criteria (3.45% 
per year, unpublished data provided by Daiichi Sankyo based on analysis of the ENGAGE data base). 
Sample size. Based on these assumptions, computation of sample size is based on a hazard ratio of 0.68, 
accrual period of 71 months and minimal follow-up of 12 months. Specifically, it assumes annual hazard 
rates of 5.3% for the standard treatment group versus 3.64% for the NOAC group. This is equivalent to me-
dian event-free survival of 13 years for the standard treatment group versus 19 years for the NOAC group. 
This effect size is considered realistic, in the sense that an effect of this order of magnitude can be reasona-
bly anticipated in this field of research. 
The criterion for significance (alpha) is set at two tailed 5% and for power (1-beta) at 80%. Thus, if the true 
population hazard ratio of control to treated patients is 0.68 then at least 220 events are expected to be ob-
served. Assuming that the competing event of non-cardiac death has a hazard rate of 0.02 for both groups 
then at least 865 patients per group are needed to have a power of 80% to detect as significant that differ-
ence at the two-sided 5% level of significance. Patients who develop overt AF during the trial period will be 
censored at that time point. The hazard of developing overt AF or of dropping out of the trial for other rea-
sons (e.g. withdrawal of consent) is assumed to be at 0.287 throughout the trial. This 0.287 hazard is equiva-
lent to 25% first year development of overt AF or of dropping out of the trial for other reasons, and goes up to 
57% by the end of the third year. Taking this into account, the number of patients per group becomes 1,269 
(63, 64, 65). This estimate is based on the assumption that 5% patients per year will decide to stop the study 
during the follow-up. In addition, it is expected that 16% of the patients will develop overt AF, and thus re-
quire oral anticoagulation outside of the trial, over a follow-up period of 2.5 years (based on ASSERT, 41/261 
patients over 2.5 year follow-up) (16, 17). Thus, 2,538 patients have to be randomised and treated.  
12.3 Interim Analysis and reassessment of the Sample Size 
The Steering Committee assessed pooled event rates after about 1,000 patient-years of observation in the 
entire study population (without knowledge of study group assignment or study treatment). The event rate 
was 4.61% (95%‐confidence interval: 3.46%, 6.16 %). This event rate is not significantly different to the as-
sumed event rate of 4.4% per year (p=0.748). In this respect, the number of required events does not 
change. However, since the recruitment rate was lower than expected, the required accrual period changes 
from 54 to 71 months.  
12.4 Patient Selection for Analyses 
Under the mITT principle, all randomised patients with a qualifying AHRE (refer to section 6.2.4) and intake 
of at least one dose of study drug will be included in the primary analysis and censoring mechanism will be 
applied to those patients without event at the end of the study follow-up. Patients without an event at the end 
of follow-up will have their efficacy measure censored at the end of follow-up. Patients without an event and 
who are lost to follow-up will be censored on the day of last contact with the patient. In addition, a sensitivity 


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(robustness) analysis will be conducted using per-protocol population (i.e., among those without major proto-
col violations). 
Patients who develop overt AF during the trial period will be censored at that time point. The hazard of de-
veloping overt AF is assumed to remain constant and it is estimated at 0.287. 
Safety analysis will be performed on all enrolled patients (i.e. all patients that signed informed consent) in 
this study. 
13. Access to Source Data / Documents 
13.1 Source Data 
Source data are defined as all information in original records and certified copies of original records of clini-
cal findings, observations or other activities in a clinical study necessary for the reconstruction and evalua-
tion of the study. Source data are contained in source documents. 
13.2 Source Documents 
Source documents are defined as original documents, data and records (e.g. hospital records, clinical and 
office charts, electronic patient records, laboratory notes, memoranda, patient diaries or evaluation check 
lists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, patient files, records kept at phar-
macy, at the laboratories and at medico technical departments) involved in this clinical study. 
In case of data that are result of patient reporting and will not be documented in clinical routine, the e-CRF is 
the source document, if the patients answer is documented there without prior documentation on paper. 
13.3 Direct Access 
Direct access is defined as the permission to examine, analyse, verify and reproduce any records and re-
ports that are important to evaluation of a clinical study. Any party with direct access should take all reason-
able precautions within the constraints of the applicable regulatory requirements to maintain the confidentiali-
ty of patient identities and sponsor proprietary information. 
The investigator agrees that representatives or the designees of the sponsor such as monitors and auditors, 
and appropriate Regulatory Agencies will be given direct access to the regular clinical files of the patient. 
14. Quality Control and Quality Assurance 
14.1 Quality Control 
Quality Control is defined as the operational techniques and activities, such as monitoring, undertaken within 
the quality assurance system to verify that the requirements for quality of the study related activities have 
been fulfilled. 
Quality Control should be applied to each stage of data handling to ensure that all data are reliable and have 
been processed correctly. 
14.2 Initiation Visit 
At each site an initiation visit will be performed by a representative of the CRO before enrolment of the first 
patient at this site. 


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14.3 Study Monitoring 
A Risk Based Study Monitoring Plan (RBSMP) will establish the guidelines for conducting quality manage-
ment (e. g. on-site monitoring visits, off-site central monitoring, and other tasks of quality control). The 
RBSMP will identify the requirement to perform an ongoing review of any e-CRF item (automated, by means 
of statistics and by research professionals, e. g. manual queries), the amount of source data verification and 
review, the frequency of on-site monitoring visits and actions to be taken based on the result of central and 
on-site monitoring. Thus, frequency of on-site visits and amount of source data verification is dynamic and 
dependent on performance and quality of each study site. Authorised, qualified representatives of the desig-
nated CRO will accomplish the monitoring of the study sites during the trial. 
It is important that the investigator and relevant personnel are available during the monitoring visits and that 
an appropriate location and sufficient amount of time is devoted to the process. During the monitoring visit a 
PC with internet connection should be available to the monitor for direct connection to the internet database 
of the study and to all the data of the patients if stored in the data system of the hospital or catheter lab. 
The main duty of the monitor is to help the sponsor and the investigator to maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the trial. At regular intervals during the study, the 
local site will be contacted through monitoring visits, letters/ emails or telephone calls by a monitor to review 
the progress of the study. 
14.4 Close Out Visit 
Independent close out visits will be performed, primarily to collect study drugs. The close out visit may be 
combined with the last monitoring visit. 
14.5 Quality Assurance 
Quality Assurance is defined as the planned and systematic actions that are established to ensure that the 
study is performed and the data are generated, documented (recorded) and reported in compliance with 
Good Clinical Practice (GCP) and the applicable regulatory requirements. 
The investigator should permit auditing by or on behalf of the sponsor and inspection by applicable regulato-
ry authorities. The investigator shall take appropriate measures required by the sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.5.1 Inspections 
An Inspection is defined as the act by a regulatory authority of conducting an official review of documents, 
facilities, records and any other resources that are deemed by the authorities to be related to the clinical 
study and that may be located at the site of the study, or at the Sponsors and/or clinical research organisa-
tion facilities or at any other establishments deemed appropriate by the regulatory authorities. 
14.5.2 Audits 
An audit is a systematic and independent review of study related activities and documents to determine 
whether the validated study related activities were conducted and the data were recorded, analysed and 
accurately reported according to the protocol, designated Standard Operating Procedure (SOP), Good Clini-
cal Practice (GCP) and the applicable regulatory requirements. An independent audit at the study site may 
take place at any time during or after the study. 


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15. Ethical and Legal Consideration 
This is an investigator initiated (IIT), phase IIIb trial which meets all relevant ethical and regulatory standards 
(ICH-GCP). The trial will be conducted in accordance with the principles laid down in the Declaration of Hel-
sinki in its version of October 2013 (Fortaleza) (Appendix IX). 
Before initiating the study in each country, approval of the corresponding regulatory authority and Institution-
al Review Board/ Independent Ethics Committee (IRB / IEC) will be obtained. 
15.1 Ethical Consideration 
15.1.1 Institutional Review Board / Independent Ethics Committee 
Provided this is not contradictory to national law, the local investigator is responsible for submitting an appli-
cation to the appropriate IRB / IEC. Furthermore the local investigator is required to forward to the sponsor a 
copy of the written and dated approval or favourable opinion of the local IRB/ IEC signed by the chairman 
and including information on the composition of the IRB / IEC. The trial (study number, clinical trial protocol 
title and version number), the documents reviewed (clinical trial protocol, informed consent form, investiga-
tor’s CV, etc.) and the date of the review should be clearly stated on the written IRB/ IEC approval/ favoura-
ble opinion. The corresponding national coordinator together with the CRO will provide substantial support 
for any IRB / IEC submission. The sponsor is responsible to assure that approval of the local IRB / IEC in 
each country is obtained prior to study start in the respective study site or country in accordance with local 
requirements.  
During the trial, any substantial modification to the clinical trial protocol will be submitted to the IRB / IEC. It 
will also be informed of any event likely to affect the safety of patients or the continued conduct of the trial, in 
particular of any change in safety. 
If requested, a progress report is sent to the IRB / IEC annually and a summary of the trial's outcome at the 
end of the study. 
15.1.2 Steering Committee 
The trial Steering Committee (SC) will consist of a small group of expert cardiologists, a neurologist, and an 
expert biostatistician (refer to Appendix I). The functions of the SC are the following: 
 
Overall responsibility for the execution and scientific reporting of the trial. 
 
Advice on the scientific and clinical aspects of the study protocol and related documents. 
 
Responsibility for the conduct of the study according to the guidelines of good clinical practice (GCP) 
including the monitoring of patient recruitment. 
 
Reassessment of the sample size based on the blind review of the biostatistician. 
 
Reassessment of benefit/ risk ratio following the recommendations of the DSMB. 
 
Decisions on continuation or termination of the study based on the recommendations of the DSMB. 
A SC charter providing operating procedures and responsibilities will be discussed and enacted at the latest 
during the second meeting. Meeting frequency will be defined by the committee and may vary depending on 
tasks. Meetings may be conference calls or face-to-face meetings. Minutes of each meeting will be provided. 
15.1.3 Endpoint Review Committee 
The Endpoint Review Committee (ERC) will consist of four experts in cardiology and stroke neurology. The 
committee will centrally adjudicate all primary outcome events as well as any hospitalisation for other reason 
and any other SAE. Adjudication will primarily be performed as a continuous online-process within the e-trial 
management system, depending on the number of documented and cleaned SAEs. If needed, additional 


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meetings may be performed, either face-to-face or conference calls. Minutes of each meeting will be provid-
ed. 
An ERC charter providing operating procedures and responsibilities will be discussed and enacted latest at 
the kick-off meeting prior to start of adjudication.  
15.1.4 Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) is an independent group of experts that advises the SC and 
study investigators. It will consist of one statistician and two clinicians with expertise in clinical trials and in 
the management of patients in the scope of the study. The members of the DSMB serve in an individual 
capacity and provide their expertise and recommendations. They regularly monitor the recruitment and con-
duct of trial, data quality and timeliness, the distribution of therapies within the study groups, the SAEs and 
further AEs selected to their discretion during the course of the trial. DSMB will perform unblinded interim 
analyses following a plan set out in the DSMB charter, and give recommendations to the SC to continue or 
stop the trial. The Haybittle-Peto boundary (40, 41) will be implemented as stopping rule guidance for the 
DSMB. 
A DSMB charter providing operating procedures and responsibilities will be kept as a separate document 
and discussed and enacted latest at the second meeting. Meeting frequency will be defined by the commit-
tee and may vary depending on tasks. Meetings may be conference calls or face-to-face meetings and may 
have an open part with guests and a closed part. Minutes of each meeting will be provided. After each meet-
ing, recommendations will be given to the SC in a written form. 
15.1.5 National coordinators 
National coordinators are selected experts that support submission to the competent authorities and IRB/IEC 
in their individual countries. The national coordinators provide their expertise regarding regulatory affairs in 
their countries. The national coordinators supervise and monitor the patient recruitment, and support re-
cruitment measures on a national level. A national coordinator can also be a member of the SC. 
15.2 Legal Consideration 
The study will be notified to the competent authority of each participating country and approval obtained prior 
to study start in the respective country. Submission to relevant regulatory authorities in all participating coun-
tries lies within the sponsor’s responsibility (if not required otherwise according to country specific require-
ments). The corresponding national coordinator will provide substantial support for any submission process. 
The study will be performed in accordance with the respective national legislation in each country. 
15.3 Modification of Protocol 
Any substantial modification to the clinical trial protocol requires written approval/favourable opinion by the 
IRB / IEC prior to its implementation, unless there are overriding safety reasons that require immediate ac-
tion. In some instances, a modification may require a change to the informed consent form. In this case, the 
investigator must receive an IRB /IEC approval/favourable opinion concerning the revised informed consent 
form prior to implementation of the change. 
Substantial modifications will be notified to the competent authorities too. 
15.4 Financing and Insurance 
The costs necessary to perform the study will be agreed upon with each investigator and will be documented 
in a separate financial agreement which will be signed by the investigator and the CRO on behalf of the 
sponsor, prior to the study commencing. 


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A patient insurance has been effected by the sponsor of the trial. Country specific requirements will be taken 
into account. 
The insurance certificate as well as the insurance conditions will be handed out to all investigators. On de-
mand, the insurance conditions have to be provided to the patients. 
15.5 Investigators’ Information on IMP 
Edoxaban as well as acetylsalicylic acid are authority approved and marketed in all European countries. The 
respective summary of product characteristics is publicly available in the internet. 
15.6 Personal Data and Data Protection 
All data obtained in the context of the clinical trial are subject to data protection. This applies to patients' data 
as well as to investigators' personal data which may be included in any database of the sponsor or the CRO. 
The investigating physicians shall take care that patient documents (e.g. copies of reports on special find-
ings) transmitted to the CRO or the sponsor contain no names, but only the year of birth and a relevant pa-
tient number. The storage of data for statistical analysis shall likewise be performed only under the patient’s 
random/study number. 
15.7 Data Handling and Record Keeping 
15.7.1 Completion of case report forms 
All medical data in this trial are to be recorded directly in the e-CRFs. Documentation on paper will be re-
stricted to exceptional circumstances only. 
The investigator must ensure the accuracy, completeness and timeliness (and legibility in case of documen-
tation on paper) of data. 
15.7.2 Archiving 
The investigator must maintain confidential all study documentation, and take measures to prevent acci-
dental or premature destruction of these documents. The investigator has to retain the study documents (i.e. 
investigator site file) after the completion or discontinuation of the study for the time period as required by 
national legislation. This especially applies to patients' signed informed consent forms and the patient identi-
fication list. 
The investigator must notify the sponsor prior to destroying any essential study documents within the speci-
fied period following completion or discontinuation of the trial. 
15.8 Confidentiality 
All information disclosed or provided by the sponsor (or any company / institution acting on his behalf), or 
produced during the trial, including, but not limited to, the clinical trial protocol, the e-CRFs and the results 
obtained during the course of the trial, is confidential. The investigator or any person under his/her authority 
agrees to undertake to keep confidential and not to disclose the information to any third party without the 
prior written approval of the sponsor. The sub-investigators shall be bound by the same obligation as the 
investigator. The investigator shall inform the sub-investigators of the confidential nature of the trial. Both, the 
investigator and the sub-investigators shall use the information solely for the purposes of the trial, to the ex-
clusion of any use for their own or for a third party's account. 


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15.9 Responsibilities 
The sponsor of this trial is responsible to health authorities for taking all reasonable steps to ensure the 
proper conduct of the trial with regard to ethical aspects, clinical trial protocol compliance, integrity and validi-
ty of the data recording. 
16. Final Report and Publication Policy, Property Rights 
The sponsor will be responsible for preparing the final study report that is to be signed by the SC. The spon-
sor will communicate the results of the trial to the investigators, authorities and IRBs/ECs. 
The SC will be primarily responsible for the creation, review and submission of publications and presenta-
tions relating to the major aspects of the study within a timely fashion after completion of the study. All anal-
yses will be the responsibility of the SC. Manuscripts for publication will be drafted by members of the SC or 
other interested investigators. All manuscripts will be subject to coordinated submission and review prior to 
submission. Coordination will be done by SC.  
NOAH - AFNET 6 is an investigator-driven trial. Interested investigators and academic initiatives will be en-
couraged and supported as appropriate if they propose additional issues that may be studied within the main 
trial. These materials must be submitted to the SC for review and comment prior to publication or public dis-
semination. All relevant measures for transparency of clinical trials, and especially the recommendations of 
the editors of the major medical journals, will be met. 
The publication rules are regulated separately and described in detail in a publication policy that is confirmed 
by the SC. 
All information and documents provided by the sponsor or its representatives are and remain the sole prop-
erty of the sponsor. The investigator shall not mention any information for any other intellectual property 
rights. 
All results, data, documents and inventions, which arise directly or indirectly from the trial in any form, shall 
be the immediate and exclusive property of the sponsor. 
17. Definitions and Classification 
17.1 Protocol Violation 
Protocol violations are any unapproved changes, deviations or departures from the study design or proce-
dures of a research project that are under the investigator’s control and that have not been reviewed and 
approved by the SC. 
17.2 Major Protocol Violation 
Major protocol violations are any unapproved changes in the research study design and/or procedures that 
are within the investigator’s control and not in accordance with the IRB- or EC-approved protocol that may 
affect the participant’s rights, safety or well-being, or the completeness, accuracy and reliability of the study 
data. Patients with major protocol violations will be excluded from the per protocol analysis. Some major 
protocol violations may be reported to regulatory authorities within defined time periods as mandated. Study 
specific definitions of major protocol violations will be given by the SC. 
 
 


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54. Kirchhof P, Fetsch T, Hanrath P, Meinertz T, Steinbeck G, Lehmacher W et al.. Targeted 
pharmacological reversal of electrical remodeling after cardioversion—rationale and design of the 
Flecainide Short-Long (Flec-SL) trial. Am Heart J 2005;150 :899 
55. Knecht S, Oelschlager C, Duning T, Lohmann H, Albers J, Stehling C, Heindel W, Breithardt G, Berger 
K, Ringelstein EB, Kirchhof P, Wersching H. Atrial fibrillation in stroke-free patients is associated with 
memory impairment and hippocampal atrophy. Eur Heart J. 2008;29(17):2125-32 
56. Vermeer SE, Longstreth WT, Jr., Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet 
Neurol. 2007;6(7):611-9. 
57. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and 
the risk of dementia and cognitive decline. N Engl J Med. 2003;348(13):1215-22. 
58. Thrall G, Lane D, Carroll D, Lip GY. Quality of life in patients with atrial fibrillation: a systematic review. 
Am J Med. 2006;119(5):448 e1-19. 
59. von Eisenhart Rothe A, Hutt F, Baumert J, Breithardt G, Goette A, Kirchhof P, Ladwig KH. Depressed 
mood amplifies heart-related symptoms in persistent and paroxysmal atrial fibrillation patients: a 
longitudinal analysis-data from the German Competence Network on Atrial Fibrillation. Europace. 2015. 
60. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and 
Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of 
major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. 
Apr 2005. J Thromb Haemost 3 (4): 692-4. 
61. Schulmann S, Angeras U, Bergqvist D, Eriksson B, Lassen M R, Fisher W and on behalf of the 
Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the 
International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medicinal products in surgical patients. Jan 2010. J Thromb Haemost 8 
(1): 202-4. 
62. Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, 
Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive 
impairment. J Am Geriatr Soc. 2005;53(4):695-9. 
63. Lachin JM, Foulkes MA. Evaluation of sample size and power for analyses of survival with allowance for 
nonuniform patient entry, losses to follow-up, noncompliance, and stratification. Biometrics. 1986 
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64. Pintilie M. Dealing with competing risks: testing covariates and calculating sample size. Statist. Med. 
2002; 21:3317–3324 
65. A. Latouche A.Porche R. Sample size calculations in the presence of competing risks. Statist. Med. 
2007; 26:5370–5380 
 
 


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19. Signatures 
The undersigned have read this protocol and agreed to conduct this study in accordance with all stipulations 
of the protocol, with the current EU regulation, with the principles of good clinical practice, and in accordance 
with the Declaration of Helsinki. 
Date 
Signature 
 
___________________ 
_____________________________________ 
 
Melanie Calvert 
 
___________________ 
_____________________________________ 
 
John Camm 
 
___________________ 
_____________________________________ 
 
Gregory Chlouverakis (study statistician) 
 
___________________ 
_____________________________________ 
 
Hans-Christoph Diener 
 
___________________ 
_____________________________________ 
 
Andreas Götte (sponsor representative) 
 
___________________ 
_____________________________________ 
 
Paulus Kirchhof (international chief investigator) 
 
___________________ 
_____________________________________ 
 
Gregory Lip 
 
___________________ 
_____________________________________ 
 
Emmanuel Simantirakis 
 
___________________ 
_____________________________________ 
 
Panos Vardas 
 
___________________ 
_____________________________________ 
 
Antonia Zapf (study statistician) 
 
___________________ 
_____________________________________ 
 
Signature principle investigator 
 
 
_____________________________________ 
 
(Name principle investigator; printed) 


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Appendix I: Members of the Steering Committee 
(in alphabetical order) 
Melanie Calvert 
PROM and patient experience expert 
Primary Care Clinical Sciences 
School of Health and Population Sciences 
College of Medical and Dental Sciences 
University of Birmingham 
Edgbaston 
Birmingham B15 2TT, United Kingdom 
Email: m.calvert@bham.ac.uk 
John Camm 
St. George's Hospital Medical School, Cranmer Terrace 
SW 17 ORE London, United Kingdom 
Email: jcamm@sgul.ac.uk 
Hans-Christoph Diener 
University Duisburg-Essen, Department of Neurology 
Hufelandstr 55  
45122 Essen, Germany 
Email: hans.diener@uk-essen.de 
Andreas Goette (sponsor representative) 
St. Vincenz Krankenhaus, Am Busdorf 2  
33098 Paderborn, Germany 
Email: andreas.goette@vincenz.de 
Paulus Kirchhof (chair) 
The University Medical Center Hamburg – Eppendorf  
University Heart & Vascular Center, Department of Cardiology 
Martinistraße 52, 20251 Hamburg, Germany  
Email: p.kirchhof@uke.de 
Gregory Lip 
Liverpool Centre for Cardiovascular Science 
University of Liverpool 
Liverpool, United Kingdom 
Email: Gregory.Lip@liverpool.ac.uk 
Emmanuel Simantirakis 
Heraklion University, Department of Cardiology 
PO Box 1352 Stavrakia 
711 10 Heraklion, Greece 
Email: esimant@hotmail.com 
Panos Vardas 
Hygeia Hospitals Group, Heart Sector 
15123 Athens, Greece 
Email: pvardas@hygeia.gr   
 
 


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Study Statisticians: 
Gregory Chlouverakis 
School of Medicine 
University of Crete 
Gallos Campus 
Rethymno, 74100, Greece 
Email: gchlouve@med.uoc.gr 
and 
Antonia Zapf  
Universitätsklinikum Hamburg-Eppendorf 
Institut für Medizinische Biometrie und Epidemiologie 
Martinistraße 52 
20246 Hamburg 
Email: a.zapf@uke.de 
 
Representative of Daiichi Sankyo (non-voting) 
Daiichi Sankyo Europe GmbH 
Zielstattstr. 48 
81379 München, Germany 


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Appendix II: Time Schedule 
FPI depends on release of study drugs; FPI estimated late in 1st quarter 2016. 
 
Tasks 
Date 
Draft study planning Draft Protocol, review and finalisation by Steering 
Committee 
December 2014 
Availability of study 
drug 
Market authorisation of edoxaban within the EU 
25.06.2015 
Final study planning Final protocol 
January 2015 
Study preparation 
Definition of study drug types and supply procedures December 2015 
Set up of the e-trial management system, 
preparation of e-CRF; preparation of all other study 
relevant documentation 
October 2015 - January 2016 
Site selection, site contacts, site evaluation 
November 2015 - November 
2020 
Initial EC and CA submission in each participating 
country 
January 2016- July 2020 
Study initiation 
Site contracting 
January 2016 - December 
2020 
Supply of the sites with study materials, initiation 
visits  
May 2016 - December 2020 
Recruitment period (FPI to LPI)  
June 2016 - April 2022 
Study duration* 
Treatment and follow-up until all necessary primary 
endpoints have been reached 
May 2022 – April 2023 
Treatment and follow-up until last patient last visit 
(global end of study) 
May 2023 – July 2023 
Mean follow-up period of all patients, assuming a 
linear patient recruitment 
42 months 
(minimum 12 months, maxi-
mum presumably 83 months) 
Interim analysis 
Assessment of pooled event rates after 1,000 pa-
tient-years of observation in the entire study popula-
tion, alternatively 24 months after enrolment of the 
first patient 
Q4 2019 
Results 
Primary EP Analysis acc. to SAP 
Q4 2023 
Submission of primary result paper for publication 
Q4 2023 


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*NOAH – AFNET 6 is an event driven trial. The total study duration may therefore be longer or shorter than 
the estimates given here. 
 


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Definition of terms 
 
Patient’s Start Of Participation (PSOP) 
 
Date informed consent signed 
 
Patient’s Start Of Study (PSOS) 
 
Date and time of randomisation. 
 
Patient’s Start Of Treatment (PSOT) 
 
Date and time of intake of first dose of study medication. 
 
Primary Endpoint Database Lock (PEDBL), global end of regular follow-up 
 
First date when the number of needed valid primary first endpoints has been verified. This date will 
be approved by sponsor. An endpoint is verified as valid primary endpoint after ERC assessment, 
only. The verification of a valid primary endpoint as first primary endpoint in a patient is performed 
by means of statistics. 
 
Last Visit, termination of study medication in each patient before global end of study 
 
Final Visit of each study patient after end of regular follow-up to be performed in all patients still in 
follow-up at the time of PEDBL. 
 
Extended Reporting Period (ERP) 
 
Period after each individual Final Visit until global EOS for reporting of AEs after termination of 
study medication. 
 
Last Patient Last Visit (LPLV), global End Of Study (EOS) 
 
LPLV is the last Final Visit performed in a study patient, equivalent to global End Of Study (EOS). 
This date will be approved by sponsor. 
 
Final Database Lock (FDBL) 
 
After EOS, final data cleaning and last ERC assessment. This date will be approved by sponsor. 
 
Notification of EOS to regulatory bodies 
 
Within 90 days after EOS this event has to be notified to all involved regulatory bodies. This date 
will be approved by sponsor. 
 
Study Closure 
 
Date of all contracts closed and all administrative procedures finished. 
 
Final Report 
 Within one year after EOS a final report according to applicable international standards has to be pro-
vided to all involved regulatory bodies. 
 
 
 


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Appendix III: Definition of primary outcome events 
Stroke comprises ischemic strokes as defined by the FDA (any stroke associated with a 4 point or greater 
increase in the NIHSS score at the time of the stroke compared to baseline) and includes ischemic infarction 
with (transient) clinical symptoms that resolve completely within 24 hours, but have a matching lesion on 
brain imaging as well as ischemic infarction interrupted by death within 24 hours. In contrast to the FDA defi-
nition, subarachnoid haemorrhage and haemorrhagic stroke are not counted as stroke in this trial but as 
major bleeding event. 
Systemic embolism will be defined as an acute vascular occlusion of an extremity or organ not occurring in 
the central nervous system, documented by means of imaging, surgery, or autopsy. 
Cardiovascular death will be defined according to the Standardized Definitions for Cardiovascular and 
Stroke End Point Events in Clinical Trials developed by the Standardized Data Collection for Cardiovascular 
Trials Initiative (35): 
Cardiovascular death includes death resulting from an acute myocardial infarction (MI), sudden cardiac 
death, death due to heart failure (HF), death due to stroke, death due to cardiovascular procedures, death 
due to cardiovascular haemorrhage, and death due to other cardiovascular causes. 
 
Death due to acute MI refers to a death by any cardiovascular mechanism (e.g., arrhythmia, sudden 
death, HF, stroke, pulmonary embolus, peripheral arterial disease) ≤ 30 days after a MI related to the 
immediate consequences of the MI, such as progressive HF or recalcitrant arrhythmia. There may be 
assessable mechanisms of cardiovascular death during this time period, but for simplicity, if the cardio-
vascular death occurs ≤ 30 days of the MI, it will be considered a death due to MI. 
 
Acute MI should be verified to the extent possible by the diagnostic criteria outlined for acute MI (24) or 
by autopsy findings showing recent MI or recent coronary thrombosis. 
 
Death resulting from a procedure to treat a MI (percutaneous coronary intervention (PCI), coronary ar-
tery bypass graft surgery (CABG)), or to treat a complication resulting from MI, should also be consid-
ered death due to acute MI. 
 
Death resulting from an elective coronary procedure to treat myocardial ischemia (i.e., chronic stable 
angina) or death due to a MI that occurs as a direct consequence of a cardiovascular investigation/ pro-
cedure/ operation should be considered as a death due to a cardiovascular procedure. 
 
Sudden cardiac death refers to a death that occurs unexpectedly, not following an acute MI, and in-
cludes the following deaths: 
 
Death witnessed and occurring without new or worsening symptoms 
 
Death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms, unless the 
symptoms suggest acute MI 
 
Death witnessed and attributed to an identified arrhythmia (e.g., captured on an electrocardio-
graphic (ECG) recording, witnessed on a monitor, or unwitnessed but found on review of record-
ings obtained by an implanted device (e.g. a defibrillator, pacemaker, or ECG recorder) 
 
Death after unsuccessful resuscitation from cardiac arrest 
 
Death after successful resuscitation from cardiac arrest and without identification of a specific car-
diac or non-cardiac aetiology 
 
Unwitnessed death in a subject seen alive and clinically stable ≤ 24 hours prior to being found 
dead without any evidence supporting a specific non-cardiovascular cause of death (information 
regarding the patient’s clinical status preceding death should be provided, if available). 
 
General considerations regarding sudden cardiac death 
Unless additional information suggests an alternate specific cause of death (e.g., death due to 


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other cardiovascular causes), if a patient is seen alive ≤ 24 hours of being found dead, sudden 
cardiac death should be recorded. For patients who were not observed alive within 24 hours of 
death, undetermined cause of death should be recorded (e.g., a subject found dead in bed, but 
who had not been seen by family for several days). 
 
Death due to HF refers to a death in association with clinically worsening symptoms and/or signs of HF 
regardless of HF aetiology. Deaths due to HF can have various aetiologies, including single or recurrent 
MIs, ischemic or non-ischemic cardiomyopathy, hypertension, or valvular disease. 
 
Death due to stroke refers to death after a stroke that is either a direct consequence of the stroke or a 
complication of the stroke. Acute stroke should be verified to the extent possible by the diagnostic criteria 
outlined for stroke. 
 
Death due to cardiovascular procedures refers to death caused by the immediate complications of a 
cardiac procedure. 
 
Death due to cardiovascular haemorrhage refers to death related to haemorrhage such as a non-stroke 
intracranial haemorrhage, non-procedural or non-traumatic vascular rupture (e.g., aortic aneurysm), or 
haemorrhage causing cardiac tamponade. 
 
Death due to other cardiovascular causes refers to a CV death not included in the above categories but 
with a specific, known cause (e.g., pulmonary embolism or peripheral arterial disease). 
 
 


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Appendix IV: International Society on Thrombosis and Haemostasis (ISTH) Bleeding Definitions 
 
Major Bleeding in Non-Surgical Patients (60) 
1. Fatal bleeding. 
and/or 
2.  Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperi-
toneal, intraarticular or pericardial, or intramuscular with compartment syndrome. 
and/or 
3.  Bleeding causing a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more, or leading to transfusion of 
two or more units of whole blood or red cells. 
 
Major Bleeding in Surgical Patients (61) 
1. Fatal bleeding. 
and/or 
2. Bleeding that is symptomatic and occurs in a critical area or organ, such as intracranial, intraspinal, in-
traocular, retroperitoneal, pericardial, in a non-operated joint, or intramuscular with compartment syn-
drome, assessed in consultation with the surgeon. 
and/or 
3. Extrasurgical site bleeding causing a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more, or leading 
to transfusion of two or more units of whole blood or red cells, with temporal association within 24–48 h 
to the bleeding. 
and/or 
4. Surgical site bleeding that requires a second intervention (open, arthroscopic, endovascular) or a hemar-
throsis of sufficient size as to interfere with rehabilitation by delaying mobilization or delayed wound heal-
ing, resulting in prolonged hospitalisation or a deep wound infection. 
and/or 
5. Surgical site bleeding that is unexpected and prolonged and/ or sufficiently large to cause hemodynamic 
instability, as assessed by the surgeon. There should be an associate fall in hemoglobin level of at least 
2 g/dL (1.24 mmol/L), or transfusion, indicated by the bleeding, of at least two units of whole blood or red 
cells, with temporal association within 24 h to the bleeding. 
6. The period for collection of these data is from start of surgery until five half-lives after the last dose of the 
drug with the longest half-life and with the longest treatment period (in case of unequal active treatment 
durations). 
7. The population is those who have received at least one dose of the study drug. 


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Appendix V: Definition of overt AF 
According to the definition as per ESC guidelines, AF is defined as a cardiac arrhythmia with the following 
characteristics: 
1. The surface ECG shows ‘absolutely’ irregular RR intervals (AF is therefore sometimes known as ar-
rhythmia absoluta), i.e. RR intervals that do not follow a repetitive pattern. 
2. There are no distinct P waves on the surface ECG. Some apparently regular atrial electrical activity may 
be seen in some ECG leads, most often in lead V1. 
3. The atrial cycle length (when visible), i.e. the interval between two atrial activations, is usually variable 
and <200 ms (>300 bpm). 
An irregular pulse should always raise the suspicion of AF, but a surface ECG recording is necessary to 
diagnose AF. Any arrhythmia that has the ECG characteristics of AF and lasts sufficiently long for a 12-lead 
ECG to be recorded, or at least 30 s on a rhythm strip, should be considered as AF. 
Within the context of NOAH - AFNET 6, an intracardiac ECG recording is not considered sufficient to prove 
occurrence of overt AF. 
 
 


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Appendix VI: Change management of anticoagulants at discontinuation of study drug 
Hein Heidbuchel, Peter Verhamme, Marco Alings, Matthias Antz, Hans-Christoph Diener, Werner Hacke, 
Jonas Oldgren, Peter Sinnaeve, A. John Camm, and Paulus Kirchhof 
Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist antico-
agulants in patients with non-valvular atrial fibrillation. Europace doi:10.1093/europace/euv309 
(separate document) 


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Appendix VII: ESC guidelines 2010 
(A. John Camm (Chairperson) (UK), Paulus Kirchhof (Germany), Gregory Y.H. Lip (UK), Ulrich Schotten 
(The Netherlands), Irene Savelieva (UK), Sabine Ernst (UK), Isabelle C. Van Gelder (The Netherlands), Na-
wwar Al-Attar (France), Gerhard Hindricks (Germany), Bernard Prendergast (UK), Hein Heidbuchel (Bel-
gium), Ottavio Alfieri (Italy), Annalisa Angelini (Italy), Dan Atar (Norway), Paolo Colonna (Italy), Raffaele De 
Caterina (Italy), Johan De Sutter (Belgium), Andreas Goette (Germany), Bulent Gorenek (Turkey), Magnus 
Heldal (Norway), Stefan H. Hohloser (Germany), Philippe Kolh (Belgium), Jean-Yves Le Heuzey (France), 
Piotr Ponikowski (Poland), Frans H. Rutten (The Netherlands). Guidelines for the management of atrial fibril-
lation. European Heart Journal (2010) 
(separate document) 


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Appendix VIII: Suggestions for optimal programming of devices for adequate detection of AHRE 
The following section outlines adequate settings of devices for correct identification of AHRE episodes in 
patients who are potentially eligible for NOAH - AFNET 6: 
 
The intracardiac electrogram (IEGM) storage should be activated while the atrial tachycardia detection 
rate must be set to 170 bpm. Episodes at lower atrial rates are not qualifying episodes for NOAH - 
AFNET 6. Higher rate thresholds are acceptable, but may miss some episodes that would make patients 
eligible for NOAH - AFNET 6. Although false atrial tachyarrhythmia detection due to repetitive non-re-
entrant ventriculo-atrial synchrony is rare for episodes greater than 6 minutes in duration, this phenome-
non can be diagnosed by checking the stored IEGMs and can be eliminated by avoiding very long pro-
grammed AV delays and/or by increasing the postventricular atrial refractory period.  
 
For pacemakers and implantable cardioverter-defibrillators (ICDs) with programmable atrial electrogram 
configuration, the later should be programmed Atip-Aring, in order to avoid noise detection and the use 
of short tip-to-ring spacing atrial leads (<10 mm) is strongly recommended.  
 
Finally the devices should be optimally programmed according to the individual patient and to the most 
recent practice guidelines (25, 26, 27), ensuring as far as possible optimum hemodynamic and avoiding 
unnecessary ventricular pacing. 
Cardiac rhythm management (CRM) device manufacturers use different detection algorithms and settings for 
the most accurate device diagnostics and EGM recordings. In general two different technologies have been 
employed: 1. Mode switch based and 2. Rate and pattern based. 
1. Mode switch (MS) based AHRE detection is very common in many pacemakers and defibrillators 
manufactured by different companies. 
a) Medtronic employs this technology for all CRM devices: In detail the nominal setting for mode 
switch is set at 185 bpm and IEGM recording is set nominally “on“ for atrial high rate and ventricular 
high rate episodes. In the case the device is programmed with mode switch “off”, the device can still 
detect and record AHRE by programming  
Data Collection Setup => AHRE => Detection Rate (Nominal 200 bpm) and Detection Duration 
(Nominal 5 sec) which can be programmed up to 60 sec. 
b) Vitatron CRM devices implanted after 2010 follow the same programming nominal values and rec-
ommendations as Medtronic (see above). 
c) St Jude Medical CRM devices also use mode switch triggered detection (nominally set at 180 bpm) 
and in the case that mode switch is turned “off” the device can use the high atrial rate setting for a 
consecutive number of cycles that the rate is exceeded. As they are both nominally “off”, they 
should be activated. The IEGM recording is nominally “off” and must be programmed “on” (AT/AF 
detection trigger). St Jude Medical defibrillators follow the same AHRE detection method, however, 
they must have mode switch “on”. 
d) Boston Scientific pacemakers and defibrillators use the same method (mode switch based) for de-
tecting AHRE. Mode switch is nominally “on” and nominal values for trigger rate is nominally set at 
170 bpm, mode switch duration at 8 cardiac cycles and entry and exit count at 8 cardiac cycles as 
well. IEGM recording is nominally “on”. 
e) Biotronik uses both mode switch and rate based detection triggers of AHRE nominally set “on” with 
cut-off rates at 160 and 200 bpm, respectively. IEGM recording is nominally “on”. 
f) 
Sorin Group CRM devices also use both mode switch and atrial burst-based detection triggers for 
AHRE detection and recording. IEGMs are always set to “on”. 
2. Rate and pattern based detection is mainly employed by Medtronic ICD devices and latest technology 
CRM devices: Both types of devices monitor the sequence of events in the atrial and ventricular channel 
and combine with exceeding a programmed threshold of atrial rate. This monitoring is nominally “on”, the 
threshold is nominally set at 171 bpm and IEGM recording is always “on”. 


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Appendix IX: Declaration of Helsinki (Version Fortaleza, October 2013) 
http://www.wma.net/en/30publications/10policies/b3/ 
 

SAP_001.pdf: 
EudraCT number: 2015-003997-33  
 
Page 1 of 37 
 
SAP 4  
 
Confidential 
NOAH // Institute of Medical Biometry and Epidemiology, Medical Center Hamburg-Eppendorf, 
Hamburg 2023 
 
Statistical Analysis Plan 
 
NOAH 
Non-vitamin K Antagonist Oral Anticoagulants in Patients with 
Atrial High Rate Episodes 
 
ClinicalTrials.gov: NCT02618577, EudraCT number: 2015-003997-33, ISRCTN 
number: ISRCTN17309850 
 
 
Version: 4 (Final Version) 
Date: 21.03.2023 
 
Author: S. Sehner, A.-K. Ozga, A. Suling 
Reviewers: B. Blank, J. Haug, P. Kirchhof, M. Wolf, A. Zapf 
Institution: Institute of Medical Biometry and Epidemiology, 
Medical Center Hamburg-Eppendorf, Hamburg 
 
 
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Page 2 of 37 
 
SAP 4  
 
Confidential 
NOAH // Institute of Medical Biometry and Epidemiology, Medical Center Hamburg-Eppendorf, 
Hamburg 2023 
Document: 
Statistical Analysis Plan for Final Analysis 
Sponsor Project Code: 
NOAH 
Study No. 
ClinicalTrials.gov: NCT02618577, EudraCT number: 2015-
003997-33, ISRCTN number: ISRCTN17309850 
Study short title: 
Non-vitamin K Antagonist Oral Anticoagulants in Patients with 
Atrial High Rate Episodes 
Version / date: 
4 / March 21, 2023 based on study protocol version 5.1, dated 
October 1, 2020 and corresponding amendment no. 4  
Author: 
S. Sehner, A.-K. Ozga 
Sponsor: 
Kompetenznetz Vorhofflimmern e.V. (AFNET) 
Statistician: 
Prof. Dr. Gregory Chlouverakis 1 and Prof. Dr. Antonia Zapf 2 
1 School of Medicine, University of Crete, Rethymno, Greece 
2 Institute of Medical Biometry and Epidemiology, University 
Medical Center Hamburg-Eppendorf, Hamburg, Germany 
 
 
Confidential 
The information contained herein is the property of Kompetenznetz Vorhofflimmern e.V. 
(AFNET) and may not be reproduced, published or disclosed to others without written 
authorization of the sponsor. The information provided in this document is strictly 
confidential and is available for review to investigators, potential investigators, health 
authorities and appropriate Ethics Committees. No disclosure should take place 
without written authorization from the sponsor except to the extent necessary to obtain 
informed consent from potential subjects. Once signed, the terms of this protocol are 
binding for all. 
 
 
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SAP 4  
 
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NOAH // Institute of Medical Biometry and Epidemiology, Medical Center Hamburg-Eppendorf, 
Hamburg 2023 
Table of Contents 
Version history....................................................................................................................... 6 
Signature Page...................................................................................................................... 7 
Abbreviations ........................................................................................................................ 8 
1 
Introduction .................................................................................................................... 9 
1.1 
Background and rationale........................................................................................ 9 
1.2 
Objectives ............................................................................................................... 9 
1.2.1 
Primary outcome .............................................................................................10 
1.2.2 
Main secondary outcomes...............................................................................10 
1.2.3 
Patient Reported Outcome (PRO) ...................................................................10 
1.2.4 
Safety outcome parameters ............................................................................10 
2 
Study Methods ..............................................................................................................11 
2.1 
Trial design ............................................................................................................11 
2.2 
Randomization and blinding ...................................................................................11 
2.3 
Sample size............................................................................................................11 
2.4 
Framework .............................................................................................................12 
2.5 
Statistical interim analyses and stopping guidance .................................................12 
2.6 
Timing of final analysis ...........................................................................................12 
3 
Statistical Principles ......................................................................................................13 
3.1 
Confidence intervals and P values .........................................................................13 
3.2 
Adherence and protocol deviations ........................................................................14 
3.3 
Analysis populations ...............................................................................................16 
3.3.1 
Modified Intention to treat Population (mITT) ...................................................16 
3.3.2 
Per Protocol population (PP) ...........................................................................16 
3.3.3 
Safety Population ............................................................................................16 
4 
Trial Population .............................................................................................................16 
4.1 
Eligibility .................................................................................................................16 
4.2 
Recruitment ............................................................................................................17 
4.3 
Withdrawal / follow-up ............................................................................................17 
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4.4 
Baseline patient characteristics (Definition of table 1) .............................................18 
5 
Analysis .........................................................................................................................18 
5.1 
Censoring and event definition ...............................................................................18 
5.1.1 
Trial specific censoring ....................................................................................18 
5.1.2 
Event definition ................................................................................................18 
5.2 
Primary endpoint analysis ......................................................................................18 
5.3 
Secondary endpoints analysis ................................................................................19 
5.3.1 
Time-to-event endpoints ..................................................................................19 
5.3.2 
Continuous endpoints ......................................................................................19 
5.3.3 
Change in autonomy status. ............................................................................20 
5.4 
Missing data analysis .............................................................................................20 
5.5 
Sensitivity analyses ................................................................................................21 
5.6 
Per protocol analyses .............................................................................................21 
5.7 
Subgroup analyses.................................................................................................21 
5.8 
Additional analyses ................................................................................................22 
5.9 
Safety analyses (SAE) ...........................................................................................22 
5.10 
Harms ....................................................................................................................23 
5.11 
Statistical software .................................................................................................23 
6 
Database Sources .........................................................................................................23 
6.1 
Source data and documents ...................................................................................23 
6.2 
Direct access to data ..............................................................................................24 
6.3 
Storage, transformation of data and preparation for analysis ..................................24 
7 
Amendment ...................................................................................................................24 
7.1 
Changes in chapter 1.2.2. Main secondary outcomes ............................................25 
7.2 
Changes in chapter 2.6 Timing of final analysis ......................................................25 
7.3 
Changes in chapter 3.3.2 Per Protocol population (PP) ..........................................25 
7.4 
Changes in chapter 4.2 Recruitment ......................................................................25 
7.5 
Changes in chapter 4.4 Baseline patient characteristics (Definition of table 1) and 
correction of Appendix A ...................................................................................................26 
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7.6 
Changes in chapter 5.1.2 Event definition ..............................................................28 
7.7 
Changes in chapter 5.4 Missing data analysis ........................................................28 
7.8 
Changes in chapter 5.5. Sensitivity Analyses .........................................................29 
7.9 
Changes in chapter 5.7. Subgroup Analyses ..........................................................29 
7.10 
Changes in chapter 5.8. Additional Analyses..........................................................30 
8 
References ....................................................................................................................30 
9 
Appendix .......................................................................................................................31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Version history 
Version 
Date 
Section number 
changed 
Description/Changes made 
1  
15.10.2019  
New version based on the of the former 
SAP prepared by Gregory Chlouverakis 
2-6 
29.10.2020 complete 
Changes in Section 5 S,Sehner, A.Ozga 
 
Censoring 
 
Primary and secondary endpoint 
analyses 
 
Missing data analyses 
 
Sensitivity analyses 
 
Per protocol analyses 
 
7 
04.05.2021 Minor things in 
some sections 
5.4 deleted; 2.5. written in past tense; 
Reference section 
8 
06.09.2021 All 
Cleaning 
9 
17.12.2021 2.6, 3.2, 5.7 
 
More description of timing of final 
analysis 
 
Compliance changed to 
adherence 
 
Adherence as subgroup 
10 
12.05.2022 3.2 
Protocol deviations specified 
Final 
Version 
27.08.2022 All 
Finalization 
Final 
Version with 
Amendment, 
i.e version 2 
17.10.2022 Amendment 
Amendment added after first SAP version 
was signed (before unblinding) 
Final 
Version with 
Amendment, 
i.e version 3 
08.02.2023 Amendment 
Further clarification of analysis (before 
unblinding), i.e. Analysis of: adherence, 
AHRE during the study duration, Baseline 
variables 
Second 
Final 
Version 
21.03.2023 Amendment 
Finalization (typos) 
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Abbreviations 
ACS 
Acute coronary syndrome 
AF 
Atrial fibrillation 
AFNET 
Kompetenznetz Vorhofflimmern e.V. 
AHRE 
Atrial high rate episodes 
ALT             Alanine aminotransferase 
aPTT           Activated partial thromboplastin time 
ASA 
Acetylsalicylic acid 
AST             Alanine aminotransferase 
BMI             Body-mass-index 
CABG 
Coronary artery bypass graft 
CONSORT Consolidated standards of reporting trials 
CRI 
The Clinical Research Institute GmbH 
DAPT 
Dual antiplatelet therapy 
DSMB 
Data safety monitoring board 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EHRA 
European heart rhythm association 
ERC 
Endpoint review committee 
FMI 
Fraction of missing information 
GOT            Glutamic-oxaloacetic transaminase 
GPT             Glutamic pyruvic transaminase 
I/E criteria 
Inclusion/exclusion criteria 
ILR 
Implantable loop recorder 
IMP 
Investigational medicinal product 
INR              International normalized ratio 
IQR 
Inter-quartile range 
IRB 
Institutional Review Board 
ISTH 
International society on thrombosis and haemostasis 
LLT 
Lowest level terms 
MACE(s) 
Major adverse cardiac event(s) 
MedDRA 
Medical dictionary for regulatory activities 
MI 
Myocardial infarction 
MICE 
Multivariate imputation by chained equations 
mITT 
Modified intention-to-treat 
MoCA 
Montreal cognitive assessment 
NOAC(s) 
Non-vitamin K antagonist Oral anticoagulant(s) 
NOAH 
Non-vitamin K Antagonist Oral Anticoagulants in Patients with Atrial High Rate ^ Episodes 
OD 
Once daily 
PCI 
Percutaneous coronary intervention 
PP 
Per protocol 
PROs 
Patient-reported outcomes 
PT 
Preferred term 
SAE(s) 
Severe adverse event(s) 
SAP 
Statistical Analysis Plan 
SC 
Steering committee 
SD 
Standard deviation 
SmPC 
Summary of Product Characteristics 
SOC 
System organ class 
TIA 
Transient ischemic attack 
UKE 
University medical-center Hamburg-Eppendorf 
VKA(s) 
Vitamin K antagonist(s) 
 
 
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1 Introduction 
This Statistical Analysis Plan (SAP) is based on the study protocol version 5.1 of October 1, 
2020 and corresponding amendment no.5 and follows the guideline for statistical analysis 
plans (Gamble, et al., 2017). Some points of the statistical methods and of the study design 
are already described in the study protocol. This SAP aims to further specify the procedures 
and statistical methods applied during the final analysis of the study data. 
1.1 Background and rationale 
Atrial fibrillation (AF) is a common cause of stroke, especially ischemic stroke. So far, all 
available data that demonstrate a beneficial effect of oral anticoagulation for stroke prevention 
have been collected in populations with AF documented by conventional electrocardiogram 
(ECG) recordings. It is well established that a large proportion of AF episodes remain 
undiagnosed ("silent AF"), and many of these patients present with a stroke as the first clinical 
sign of AF. Earlier initiation of anticoagulation could prevent such events. Continuous 
monitoring of atrial rhythm by implanted devices could close this diagnostic gap. Pacemakers, 
defibrillators, and cardiac resynchronization devices already provide automated algorithms 
alerting to the occurrence of highly organized atrial tachyarrhythmia episodes, also called 
"subclinical atrial fibrillation" or, more commonly, "atrial high rate episodes" (AHRE). Data from 
large prospectively followed patient cohorts demonstrated that stroke rate is increased in 
patients with AHRE. A sizeable portion of these patients develops clinically detected AF over 
time. In these patients, AHRE can be considered as an early manifestation of paroxysmal AF. 
A few AHRE patients do not develop clinically overt AF, and the absolute stroke rates are lower 
in patients with AHRE when compared to stroke rates in patients with clinically diagnosed AF. 
In light of the bleeding complications associated with oral anticoagulant therapy, there is thus 
uncertainty about the optimal antithrombotic therapy in patients with AHREs. 
The Non-vitamin K antagonist Oral anticoagulants (NOACs) provide similar or slightly better 
stroke prevention, and appear slightly safer compared to vitamin K antagonists (VKAs). In 
addition, no individual therapy adjustment of NOACs has to be performed. Edoxaban, a newly 
introduced NOAC, at a dose regime of 60 mg once daily (OD) has a favorable profile compared 
to dose-adjusted VKA therapy: In the ENGAGE-TIMI 48 trial (Giugliano, et al., 2013), edoxaban 
prevented strokes at least as effectively as VKA therapy but caused less major bleeding events 
than VKA therapy. 
1.2 Objectives 
To demonstrate that oral anticoagulation with the NOAC edoxaban is superior (test for 
difference) to current therapy (antiplatelet therapy or no therapy depending on cardio-vascular 
risk) to prevent stroke, systemic embolism, or cardiovascular death in patients with AHRE but 
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without overt AF and at least two stroke risk factors leading to a modified CHA2DS2VASc score 
of 2 or more. 
1.2.1 Primary outcome 
The primary outcome parameter of NOAH is defined as the time from randomization to the first 
occurrence of a composite of ischemic stroke, systemic embolism or cardiovascular death. 
1.2.2 Main secondary outcomes 
The secondary outcome parameters are defined as 
a) time from randomization to components of the primary outcome (time to first event, i.e. 
for the non-fatal events (ischemic stroke and systemic embolism) only the respective 
first event is used),  
b) time from randomization to all-cause death, 
c) time from randomization to first occurrence of Major Adverse Cardiac Events (MACEs: 
cardiovascular death, myocardial infarction, acute coronary syndrome (ACS); 
percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG)), 
d) time from randomization to first occurrence of ischemic stroke or systemic arterial 
embolism (composite), 
e) time to first occurrence of major bleeding event  
f) number of major bleeding events according to the International Society on Thrombosis 
and Haemostasis (ISTH) definitions, 
g) quality of life changes at 12 and 24 months compared to baseline (assessed by EQ-5D 
including its visual-analogue scale and by the Karnofsky scale (EuroQol Research 
Foundation, 2019), (van Hout & Janssen, 2012), 
h) patient satisfaction changes at 12 and 24 months compared to baseline (assessed by 
modified EHRA score and PACT-Q2 (Prins, et al., 2009a), (Prins, et al., 2009b)) 
i) cognitive function changes (MoCA) at 12 and 24 months compared to baseline 
j) changes of autonomy status only in patients with stroke during study participation, 
assessed at each clinical follow-up visit by modified Rankin scale; a maximum of 2 
subsequent assessments in follow-up per patient with stroke should be performed. 
 
1.2.3 Patient Reported Outcome (PRO) 
Are captured in section 1.2.2 g), h). 
 
1.2.4 Safety outcome parameters 
Are captured in section 1.2.1 and 1.2.2 c), d), e), f).  
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Additionally the combined outcome of time from randomization to death or time from 
randomization to first occurrence of major bleeding (composite endpoint) will be analyzed.  
2 Study Methods 
2.1 Trial design 
Investigator-initiated, prospective, parallel-group, randomized, controlled, double-blind, event-
driven, multi-centre trial. Although it can be argued that the indication tested is within the 
registered label of edoxaban, NOAH will be conducted as a phase IIIb study. 
2.2 Randomization and blinding 
The randomization sequence was generated using STATA12 SE (StataCorp, 2011) with 
blocks of variable sizes of 4 to 8 entries to ensure allocation concealment could not be 
breached, by guessing the sequence at the end of each block. Patients were randomized in a 
1:1 ratio to one of the two parallel groups NOAC or usual care arms, stratified by indication for 
ASA and study site. 
The randomisation was performed with the integrated randomisation service in the web-based 
EDC system MARVIN used as eCRF. According to protocol, requirements and design of the 
eCRF, randomisation could only be performed after informed consent had been obtained and 
all in- and exclusion criteria had been confirmed by study site staff. Multiple randomisations or 
pseudo-randomisations of subjects are prevented by the integrated randomisation service. 
Details can be found in the study protocol, section 6.2.5. 
Patients, all hospital personnel performing direct care and assessments of patients and the 
Endpoint Review Committee (ERC) will be blinded to randomized treatment assignments until 
the database is locked for the primary analysis. The DSMB will be unblinded to treatment 
assignment throughout the study.  
In case of an event which threatens the patient’s health without the knowledge of the study 
drug identity, investigator can unblind the subject’s treatment group in the MARVIN e-CRF. 
The identity of the person having triggered the unblinding as well as date and time of 
unblinding, justification of unblinding and identity of random group are stored in the data base. 
From timepoint of unblinding, the subject is censored for analysis in the mITT (modified 
intention-to-treat; see Section 3.3.1) population. 
2.3 Sample size 
NOAH is an event-driven trial with a planned number of randomised and treated patients of 
n=2,538 and an anticipated number of primary endpoints of n=220. The protocol includes an 
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adjustment of the sample size based on an analysis of events after 1000 observed patient-
years. Details of sample size calculation can be found in the study protocol, section 12.2. 
2.4 Framework 
NOAH intends to demonstrate that oral anticoagulation with the NOAC edoxaban differs to 
current therapy (antiplatelet therapy or no therapy depending on cardio-vascular risk) to 
prevent the occurrence of the primary endpoint defined as the time from randomization to the 
first occurrence of a composite of stroke, systemic embolism or cardiovascular death. For all 
other (secondary) endpoints a test for difference will also be used. 
2.5 Statistical interim analyses and stopping guidance 
The Steering Committee (SC) has assessed pooled event rates after about 1,000 patient-years 
of observation in the mITT (modified intention-to-treat; see Section 3.3.1) study population 
(without knowledge of study group assignment or study treatment). Alternatively the interim 
analysis could have been conducted after about 24 months after enrolment of the first patient 
(this was not the case). Sample size or inclusion criteria (e.g. enrichment for patients at higher 
risk for events should low event rates be observed, or adaptation of sample size based on 
observed event rates, or alternatively reduction of the number of patients needed based on 
observed events) were adapted to reflect the observed event rates. 
The pooled event rate was calculated as the ratio of the sum of all observed primary events 
until the time point of interim analysis and corresponding person-years, defined as the sum of 
all observed follow-up times (in years) for each patient between randomization and the event 
date (patients with primary events), or the date of development of overt AF, date of unblinding, 
or the last documented follow-up information (all other patients). The corresponding 95%-
confidence interval was estimated using the quadratic approximation to the Poisson log 
likelihood for the log-rate parameter. 
The event rate of 4.4%, assumed for the sample size calculations, was not greater than the 
upper 95% limit. Adjustments in the sample size or in the inclusion criteria were discussed in 
the SC based on this result. No changes were decided. 
 
2.6 Timing of final analysis 
NOAH is an event-driven trial with a planned number of randomised patients of n=2,538 and 
a fixed number of valid events (n=220). The total duration of the trial is an estimate based on 
observed outcome rates in other large trials with similar populations. The total number of 
events in the trial is depending on the time at risk that is the follow-up time of all patients. In 
practice, the event-driven design may result in slight variation of the expected trial duration and 
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of the total number of patients enrolled if observed event rates do not exactly match the 
assumed rates. All patients will be followed until the global end of the trial. Remaining 
medication will be collected at the final visit. As given in the study protocol following estimation 
for the study duration is made: Screening and enrolment of patients is expected to be 
accomplished after 71 months. Based on the sample size estimation, it is expected that the 
required number of adjudicated (verified primary outcome events) will be reached 12 months 
after enrolment of the last patient. Due to the time required to obtain follow-up information and 
to adjudicate events (about 3 months to perform a final study visit in all patients still in the trial 
plus 4 months for receiving adjudication by ERC to confirm that the required number of 
adjudicated endpoints have been reached), a total study duration of 71 + 12 + 3 + 4 = 90 
months is expected. The total study duration of 90 months (about 7.5 years) was adapted 
based on an interim analysis. After that and data management the final analysis can be 
conducted.  
Global end of study (EOS) is defined as the last Final Visit performed in a study patient. This 
date will be approved by the sponsor and announced by the CRI. 
The global end of study will be announced by the CRI after all necessary primary endpoints 
have been reached.  
This procedure can result in more than the anticipated primary events within the final analysis 
(depending on the amount of events that can be adjudicated). 
 
The accrual time and hence the total study time was further adapted in 2022 due to loss of 
Ukrainian participants and the lower than expected event rate. The steering committee decided 
to censor all Ukrainian patients on the last documented contact before the 24th February 2022, 
the day of the outbreak of war in Ukraine, to protect the trial against unexpected changes in 
event rates due to the influence of war on Ukrainian patients.  
 
3 Statistical Principles 
3.1 Confidence intervals and P values 
All applicable statistical tests will be two-sided and will be performed using a 5% significance 
level. All confidence intervals presented will be 95% and two-sided. Analyses of secondary, 
safety and patient reported outcomes will be performed exploratory without adjustment for 
multiplicity. 
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3.2 Adherence and protocol deviations 
Adherence with study drug is defined as following (percentages refer to the period between 
the last documented follow-up visit and the next, ideally 6 months): 
 
Non-adherence: Intake of study drugs < 80% of the number of daily dosages calculated 
for the corresponding time period.  
 
Acceptable adherence: Intake of study drugs 80% to < 90% of the number of daily 
dosages calculated for the corresponding time period. 
 
Good adherence: Intake of study drugs 90% or more of the number of daily dosages 
calculated for the corresponding time period. 
Thereby, the duration of discontinuation is not considered. 
In case of non-adherence the investigator has to instruct the patient about importance of 
regular drug intake. 
Adherence is measured by count of remaining pills in each returned medication box by the site 
staff. The pill count entered into the eCRF system for each blister and medication box is 
confirmed by a second pill count performed by Monitors during Monitoring or Site Close-Out 
visits at end of study. Successful intake of one daily dosage is defined as the intake of one pill 
of product ASA (or placebo) and one pill of product edoxaban (or placebo). Blisters and 
medication boxes that were disposed by the patient as being confirmed completely used by 
the patient, are considered as intake of all contained daily dosages in a best-case scenario. 
 
Permanent discontinuation of study medication is documented in the eCRF. A sensitivity 
analysis comparing the two randomised groups during exposure to study medication will be 
planned. For this analysis, all patients will be censored at the time of permanent discontinuation 
of study medication. 
 
Major protocol violations are any unapproved changes in the research study design and/or 
procedures that are within the investigator’s control and not in accordance with the IRB- or EC-
approved protocol that may affect the participant’s rights, safety or well-being, or the 
completeness, accuracy and reliability of the study data. Patients with major protocol violations 
will be excluded from the per protocol analysis. Some major protocol violations may be 
reported to regulatory authorities within defined time periods as mandated. Study specific 
definitions of major protocol violations will be given by the SC. 
The type and reason of protocol violation will be documented in this study, and the summary 
of protocol violations will be reported in both arms.  
Following protocol deviations were specified by the SC: 
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 
deviation from inclusion criteria is a major protocol deviation, i.e. if the following is not 
fulfilled: 
o Pacemaker, defibrillator or insertable cardiac monitor implanted for any reason 
with feature of detection of AHRE, implanted at least 2 months prior to 
randomisation (not major for ILR (implantable loop recorder)) 
o AHRE detection feature activated for adequate detection of AHRE (not major if 
AHRE episodes were reviewed by site and adequate criteria found) 
o AHRE (≥ 170 bpm atrial rate and ≥ 6 min duration) documented by the 
implanted device via its atrial lead and stored digitally. Any AHRE episode 
recorded is potentially eligible, but AHRE episodes detected in the first 2 months 
after implantation of a new device involving placement or repositioning of atrial 
electrodes are not eligible. AHRE episodes recorded in the first two months 
after a simple “box change” operation, i.e. exchange of a pacemaker or 
defibrillator device without exchange or repositioning of atrial electrodes, are 
eligible. 
o modified CHA2DS2VASc score of 2 or more 
 
deviation from exclusion criteria is a major protocol deviation, i.e. if the following is 
observed: 
o Any disease that limits life expectancy to less than 1 year 
o Participation in another controlled clinical trial, either within the past two months 
or still ongoing. 
o Previous participation in the present trial NOAH - AFNET 6. 
o Drug abuse or clinically manifest alcohol abuse. 
o Any history of overt AF or atrial flutter 
o Indication for oral anticoagulation (e.g. deep venous thrombosis). 
o Contraindication for oral anticoagulation in general 
o Contraindication for edoxaban as stated in the current SmPC. 
o Indication for long-term antiplatelet therapy other than acetylsalicylic acid or a 
need for treatment with any antiplatelet agent in addition to edoxaban, 
especially dual antiplatelet therapy (DAPT). Patients with a transient 
requirement for DAPT (e.g. after receiving a stent) will be eligible when the need 
for DAPT is no longer present. 
o Acute coronary syndrome, coronary revascularisation (PCI or bypass surgery), 
or overt stroke within 30 days prior to randomisation. 
o End stage renal disease (creatinine clearance < 15 ml/min as calculated by the 
Cockcroft-Gault method). 
o All persons exempt from participation in a clinical trial by law. 
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 
Deviation related to study therapy defined as major: 
o Intake of study drugs < 80% of the number of pills calculated for the 
corresponding time period 
o Permanent stop of IMP intake without indication or contraindication for oral 
anticoagulation 
o Measurement of creatinine value at baseline visit older 28 days if it is not 
measured within 6 months of therapy initiation 
 
Deviation related to study procedures defined as major: 
o No complete chain of medication supply if interruption is 20% or more of the 
planned treatment time (aligned with definition of adherence) 
o Simultaneous intake of study medication and other oral anticoagulation 
o Simultaneous intake of study medication and any antiplatelet agent 
 
3.3 Analysis populations 
3.3.1 Modified Intention to treat Population (mITT) 
The modified intention to treat population (mITT) consists of all randomised patients with a 
qualifying AHRE and intake of at least one dose of study drug. The mITT doesn't include 
patients that were randomized but a) have AF onset before 1st dose of IMP, or b) die before 
1st dose of IMP, c) withdrew their consent before 1st dose of IMP or d) are lost to follow up 
before 1st dose of the IMP.  
3.3.2 Per Protocol population (PP) 
The Per Protocol population consists of mITT populations patients who have no major protocol 
deviation. Definition of major protocol deviation are given is Section 3.2. 
3.3.3 Safety Population 
Safety data will be collected on all enrolled patients (i.e. all patients that signed informed 
consent) in this study. 
4 Trial Population 
4.1 Eligibility 
The number of ineligible patients randomised, i.e. those randomised by not fulfilling the 
inclusion and exclusion criteria, will be reported, with reasons for ineligibility. 
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4.2 Recruitment 
A CONSORT (Schulz, Altman, & Moher, 2010) flow diagram will be used to summarise the 
number of patients (per treatment group where appropriate) who were: 
 
enrolled (patients documented in MARVIN, numbers will be provided by CRI to IMBE 
for construction of CONSORT flow chart) 
o fulfilling I/E-Criteria at screening 
o not fulfilling I/E-Criteria at screening* 
o post-hoc violation of I/E-Criteria* 
 
randomised 
 
not randomised* 
 
received the randomised treatment 
 
did not receive the randomised treatment* 
 
lost to follow-up*  
 
randomised and included in the primary analysis 
 
randomised and excluded from the primary analysis* 
*reasons will be provided 
 
4.3 Withdrawal / follow-up 
Information on the number and level of withdrawals/drop outs, number included in the analysis 
and the number died will be presented in CONSORT diagram format with numbers and 
reasons for withdrawal and/or exclusion from analysis given at each visit. Levels of withdrawal 
are defined as: 
 
Modification of consent (MOC):  
Patients who wish to withdraw from the study are asked to maintain consent for minimal 
effort follow-up, allowing to use their clinical data achieved at the clinically indicated 
visits. All available data will be used until the end of study (no drop out of patient). 
 
Withdrawal of consent (WOC):  
 If patients withdraw consent to any further study participation, data will be used until 
time of withdrawal and censored afterwards. 
 
Complete withdrawal:  
Patient request deletion of all his/her data. 
 
Early withdrawal: Withdrawal of patient’s consent (WOC) within the first month after 
study inclusion. Patients with early withdrawal will be included in primary analysis. 
Furthermore, a sensitivity analysis will be conducted without these patients.  
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4.4 Baseline patient characteristics (Definition of table 1) 
Patients will be described with respect to age, gender, and clinical features, both overall and 
separately for the two randomised groups. A shell table is included in the appendix. 
Categorical data will be summarised by numbers and percentages. Continuous data will be 
summarised by mean, SD, median, 1st and 3rd quartile, and minimum and maximum. 
Histograms and boxplots will be used to check the distribution and possible outliers for 
continuous variables. Number of available observations and number of missing observations 
will be presented for the treatment groups separately. Tests of statistical significance will not 
be undertaken for baseline characteristics; rather the clinical importance of any imbalance will 
be noted (Senn, 1994). 
5 Analysis 
5.1 Censoring and event definition 
5.1.1 Trial specific censoring 
Patients who develop overt AF during the trial period will be censored at that point in time but 
followed according to protocol until the global end of the trial.  
From time point of unblinding, the subject is censored for analysis in the mITT population. 
Patients without an event at the end of follow-up will have their efficacy measure censored at 
the end of follow-up. 
If a patient is lost to follow-up, the last time point of contact is used as censoring time point in 
case of no event, else the event time point is used for analysis. 
If a patient withdraws his/her consent but accepts that data till this time point of withdrawal can 
be used, the time point of last contact is used as censoring time point in case of no event, else 
the event time point is used for analysis. 
 
5.1.2 Event definition 
No matter what, i.e. although events might occur in quick succession, the first event that was 
observed is used within analysis.  Primary outcomes that occur within one day of unblinding 
will be counted as primary outcomes. 
5.2 Primary endpoint analysis 
The primary outcome analysis will be performed in the mITT population using the adjudicated 
endpoint data of the ERC. The primary endpoint is the time from randomisation to the first 
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occurrence of ischemic stroke, systemic embolism or cardiovascular death. Deaths of 
unknown cause will be classified as cardiovascular death (Hicks, et al., 2018) in all analyses. 
All patients who will not reach the primary endpoint by the global end of the study will be 
censored at that time point.  
Because all-cause death acts as a competing event for the primary endpoint the following 
methods will be applied: 
 
Primary analysis: Cause-specific Cox-proportional hazards model with frailty for 
centers and the fixed effects random group and ASA, i.e. an adjusted estimated (cause-
specific) hazard ratio (hazard ratio of edoxaban vs usual care) with two-sided 95% 
confidence interval, and corresponding p-value will be provided. 
 
Graphical display of results: cumulative incidence curves (Aalen-Johansen estimates)  
The proportional hazards assumption will be checked graphically (e.g. Schoenfeld residuals, 
-log-log-survival). 
 
5.3 Secondary endpoints analysis 
5.3.1 Time-to-event endpoints 
The following secondary endpoints will be analysed in the same way as the primary endpoint:  
a) time to components of primary outcome, 
c) time to first occurrence of major adverse cardiac events, 
d) time to first occurrence of stroke or arterial embolism,  
e) time to first major bleeding events.  
 
b) Time to all-cause death will be analysed using an adjusted Cox-proportional hazards 
model (hazard ratio of edoxaban vs usual care) with the fixed effects random group 
and ASA and a frailty term for study side.  
 
All results will be reported within tables with estimated hazard ratios, corresponding confidence 
intervals, and p-values and visualized by cumulative incidence curves (Aalen-Johansen 
estimates in case of the competing event all-cause death; for all-cause death Kaplan-Meier 
type estimates). 
  
5.3.2 Continuous endpoints 
The following continuous secondary endpoints: 
g) change in quality of life (EQ-5D and Karnofsky score),  
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h) patient satisfaction (PACT-Q2, EHRA), 
i) cognitive function (MoCA), 
at 12 and 24 months will be analysed using the difference to baseline as outcome in 
the following model: 
 baseline and randomization strata (ASA) adjusted linear mixed effects regression, 
 with a time (12 and 24 months) by treatment interaction if interaction p-value <0.05; 
else only both main effects 
 the dependency structure of the time points will be modelled by including the study 
side as random effect (independent identically distributed) and patient nested within 
study side, with an unstructured variance covariance matrix of the residuals matrix 
(time points). 
Normal distributed residuals will be checked graphically via histogram of residuals.  
 
Adjusted mean values and adjusted effect estimators (mean differences) with corresponding 
confidence intervals and p-values will be given. 
 
f) Number of major bleeding events according to ISTH: randomization strata adjusted 
mixed negative binomial regression with the individual observational time as offset.  
 
5.3.3 Change in autonomy status. 
Changes in autonomy status will be quantified by comparing modified Rankin scales over 
time after a stroke using a shift analysis (Ganesh, Luengo-Fernandez, Wharton, & Rothwell, 
2018). For this, a cumulative ordinal regression is used with random group and ASA as fixed 
effects and center as random effect. The joint adjusted odds ratio (OR) with two-sided 95% 
confidence interval, and corresponding p-value will be provided. 
 
5.4 Missing data analysis 
For the primary outcome the worst case scenario will be used for missing values, i.e. deaths  
of unknown cause will be classified as CVD (Hicks, et al., 2018) in all analyses. 
No other imputation will be conducted for primary endpoint analysis. 
 
Missing values for continuous secondary outcomes will be imputed using chained equations 
(MICE) with of at least 20 imputations (M) if the assumption of M=100*FMI (Largest Fraction 
of Missing Information) is fulfilled (White & Royston, 2009). The imputation model includes 
simultaneously all above described variables at all measured time points and the following 
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clinical relevant predictors at all measured time points: age, sex, body mass index, NYHA 
class, documentation of overt atrial fibrillation, left ventricular ejection fraction, eligibility for 
aspirin therapy, estimated creatinine clearance.  
If possible we will use a parametric approach depending on the measurement level of the 
variable, otherwise predictive mean matching with the ten nearest neighbors will be used. 
Imputation will be performed stratified by treatment. 
If possible sum-scores will be imputed on item level. If, due to complexity of the model, the 
imputation on item level is not possible the sum-score will be used.  
This imputation model will be used if estimateable, else a further reduction of the complexity 
of the model will be performed. The results of the imputed data will be primarily reported.  
For outcome g) death can be imputed (with 0), but for others outcomes which are no time to 
event endpoints this is not possible and hence information on these patients remains missing.  
 
5.5 Sensitivity analyses 
For sensitivity analyses for the primary endpoint will be estimated: 
 
using the per-protocol population, 
 
using the mITT population with censoring of patients at the time of discontinuation of 
IMP (“on treatment analysis”) 
 
without censoring for overt AF or for unblinding,  
 
using the Fine-and-Gray model with random group and ASA as fixed effects but without 
a frailty for study site, 
 
without patients who withdrew their consent (early or late and early only, i.e. <1 month), 
For further sensitivity analyses for secondary continuous outcomes complete case analysis 
will be conducted, i.e. analysis without imputed data. 
 
5.6 Per protocol analyses 
The primary endpoint will be evaluated in the PP population as a sensitivity analysis in the 
same manner as described in Section 5.2.  
 
5.7 Subgroup analyses 
Explorative subgroup analyses with respect to the primary outcome that allow identifying 
determinants of treatment success will be performed by the appropriate interaction tests for 
each subgroup separately. Each test will be performed at a significance level of alpha=5% and 
within the mITT population.  
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Predefined subgroups are: 
 
Sex 
 
Age groups split by median as well as ≥75 years 
 
Maximal duration of AHRE episodes (≥24 hours vs other) 
 
Maximal AHRE duration split by median  
 
Stratified by CHA2DS2VASc score / factors  
o congestive heart failure history 
o hypertension history 
o diabetes history 
o Stroke/TIA/thromboembolism history 
o Vascular disease history (prior MI, peripheral artery disease, or aortic plaque) 
 
high comorbidity burden (CHA2DS2VASc score ≥5 and CHA2DS2VASc score > 
median) 
 
Adherence:  
o Non-adherence: Intake of study drugs < 80% of the number of daily dosages 
calculated for the corresponding time period.  
o Acceptable adherence: Intake of study drugs 80% to < 90% of the number of 
daily dosages calculated for the corresponding time period. 
o Good adherence: Intake of study drugs 90% or more of the number of daily 
dosages calculated for the corresponding time period. 
 
Patients without any AHRE during the study duration 
 
5.8 Additional analyses 
A more detailed extended analysis of the primary outcome will be performed in the mITT 
population after global end of the study by statistical model building based on cause-specific 
Cox proportional hazard models with fixed effects for random group and ASA and a frailty for 
study site and the inclusion of several covariates. In particular variables that differ clinically 
relevant between the random groups at baseline will be determined with respect to the primary 
outcome. In addition to clinical predictors available in the locked data base, further analyses 
will determine potential genetic and biomolecule-based predictors of outcomes. 
5.9 Safety analyses (SAE) 
Safety analyses will be performed based on the data of the safety population following the ITT 
principle. The primary safety outcome in this study is a composite of cardiovascular death, 
ischemic stroke, and systemic embolism, which will be analysed using time-to-event 
methodology, as described for the primary outcome analysis. Time to first occurrence of Major 
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Adverse Cardiac Events, time to first occurrence of stroke or systemic arterial embolism, and 
time to first occurrence of major bleeding event are also considered as safety outcomes and 
already captured in secondary endpoint analysis. Additionally the composite of time to death 
or time to first occurrence of major bleeding event will be analysed in the same cause-specific 
time-to-event manner. 
SAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, Version 
19.1) dictionary in its actual version at the start of the study by Lowest Level Terms (LLT). 
Treatment related SAEs will be summarized under each treatment group, by system organ 
class (SOC) and preferred term (PT). SAEs will be summarized by severity and relation to 
study treatment received. 
5.10 Harms 
The investigational medicinal product (edoxaban) has a known safety profile and is approved 
for use in patients with atrial fibrillation. Knowing that the administration of edoxaban in AHRE 
patients without overt non-valvular AF is not in-line with the approved label, adverse events 
are expected to occur in similar clinical manifestations and at a comparable rate as the known 
adverse events of the approved therapies applied in the trial (i.e. “low risk trial”). The safety 
profile includes major bleeding events. As stated in Section 5.9 we will therefore compare the 
secondary outcome time to first occurrence of major bleeding and a combined outcome of time 
to death or time to first major bleeding between the random groups. 
 
5.11 Statistical software 
 
STATA 17 or newer 
 
R 3.4.1 or newer 
 
SPSS 22.0 or newer 
 
SAS 9.4 or newer 
6 Database Sources 
6.1 Source data and documents 
Source data are defined as all information in original records and certified copies of original 
records of clinical findings, observations or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data are contained in source documents. 
Source documents are defined as original documents, data and records (e.g. hospital records, 
clinical and office charts, electronic patient records, laboratory notes, memoranda, patient 
diaries or evaluation check lists, pharmacy dispensing records, recorded data from automated 
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instruments, copies or transcriptions, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, patient files, records kept at pharmacy, at the laboratories and at 
medico technical departments) involved in this clinical study. 
In case of data that are result of patient reporting and will not be documented in clinical routine, 
the e-CRF is the source document, if the patients answer is documented there without prior 
documentation on paper. 
6.2 Direct access to data 
Direct access is defined as the permission to examine, analyze, verify and reproduce any 
records and reports that are important to evaluation of a clinical study. Any party with direct 
access should take all reasonable precautions within the constraints of the applicable 
regulatory requirements to maintain the confidentiality of patient identities and sponsor 
proprietary information. 
6.3 Storage, transformation of data and preparation for analysis 
All study data, administrative data and relevant metadata are collected, stored and secured 
against deletion or unnoticed manipulation according to current regulatory requirements for 
electronic data capture in clinical trials. The data of the e-CRF database are extracted and 
transformed to structured data sets for analysis in a validated process. All structured data are 
prepared for statistical analysis with the statistical software package R using validated 
functions and scripts.  
 
7 Amendment 
On 2 September 2022, the NOAH-AFNET6 sponsor, the Atrial Fibrillation NETwork (AFNET), 
decided to terminate the NOAH-AFNET6 study prematurely. This decision follows a 
unanimous recommendation by the Data and Safety Monitoring Board (DSMB) on 26 August 
2022 to terminate the study and a unanimous vote by the study's Steering Committee on 2 
September 2022 to follow this recommendation. 
As reasons for its recommendation to terminate NOAH-AFNET6 the DSMB cited an observed 
trend towards futility of efficacy combined with safety concerns. 
Furthermore, on the basis of a unanimous vote of the Steering Committee, the decision was 
taken by the sponsor to orderly terminate the trial, i.e., the final patient visit should be 
performed for each patient still in follow-up as soon as possible, and all patients still taking 
Investigational medicinal product (IMP) should conduct a regular final visit at the study site at 
which the IMP intake ends. 
 
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Due to the premature study termination some changes have to be made to the first version of 
the signed SAP. These are described in this chapter.  
 
7.1 Changes in chapter 1.2.2. Main secondary outcomes 
g)  EQ-5D-5L: The index analysis based on the values of United Kingdom will be 
primarily reported. The index analysis based on the German values or values of the 
Netherlands as well as the analysis of the visual-analogue scale will be reported as 
additional analysis.  
For outcome  
j) changes of autonomy status only in patients with stroke during study participation, 
assessed at each clinical follow-up visit by modified Rankin scale; a maximum of 2 
subsequent assessments in follow-up per patient with stroke should be performed 
the following is added/changed: 
A maximum of two assessments for patients with stroke during study participation is 
foreseen by Rankin Score. This information is only captured in patients with a stroke. First 
and last assessment will be evaluated in the analysis. 
Also, the EQ-5D has been renamed EQ-5D-5L in all subsequent chapters. 
7.2 Changes in chapter 2.6 Timing of final analysis 
Added information on Ukraine: 
All collected data until the 23rd of February 2022 (war started in the early hours on 24th of 
February) will be evaluated. All outcome events occurring on or prior to 23 February will be 
counted in the primary analysis. Patients are lost to follow up if there is no final visit done or 
any contact to the patient. SC will finally decide how to handle special cases. 
 
The SC decided on December 19, 2022 to end the study on December 31, 2022. The date is 
equal to end of observation. 
 
7.3 Changes in chapter 3.3.2 Per Protocol population (PP) 
If possible patients with major protocol deviation are censored at the time of a major protocol 
deviation for the per protocol population. The censoring time of the major protocol deviation 
will be used if it occurs before a primary event or other censoring was observed.  
 
7.4 Changes in chapter 4.2 Recruitment 
The following is added:  
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Lost to follow up: This will be explained if possible, e.g. withdrawn consent, including “no known 
reason” where this is the case. This information will be captured in the CONSORT diagram. 
 
7.5 Changes in chapter 4.4 Baseline patient characteristics (Definition of table 1) 
and correction of Appendix A 
Added information on characteristics of interest, i.e. the following patients’ characteristics will 
be given in this table (also correction of Appendix A): 
- 
Age (years) 
- 
Sex (female, male) 
- 
Weight (kg) 
- 
BMI (body-mass-index) 
- 
AHRE (≥ 170 bpm atrial rate and ≥ 6 min duration) (yes, no) 
- 
CHA2DS2VASc score 
- 
Older than 75 years (yes, no) 
- 
Symptomatic Heart failure (yes, no) 
- 
Hypertension (yes, no) 
- 
Diabetes mellitus (yes, no) 
- 
Stroke or TIA (yes, no) 
- 
Vascular disease (yes, no) 
- 
Indication for ASA (yes, no) 
- 
Unstable angina pectoris (yes, no) 
- 
Acute myocardial infarction (yes, no) 
- 
Prevention of re-infarction (yes, no) 
- 
After arterial vascular or general surgical interventions (e.g. after CABG or after PTCA) 
(yes, no) 
- 
For prevention of transitory ischaemic attacks (TIA) and strokes (yes, no) 
- 
Patient currently has a contraindication for ASA (yes, no) 
- 
Hypertension (yes, no) 
- 
NYHA (No heart failure, I, II, III, IV) 
- 
Cardiomyopathy (No, Hypertrophic cardiomyopathy, Dilatative cardiomyopathy, 
Arrhythmogenic right ventricular cardiomyopathy, Other cardiomyopathy) 
- 
Valvular heart disease (yes, no) 
- 
Confirmed Coronary Artery Disease (yes, no) 
- 
Confirmed carotid stenosis (>50% lumen reduction) (None, left side, right side, both 
sides) 
- 
Arterial hypertension (yes, no) 
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- 
Diabetes mellitus (No, oral antidiabetics, insulin therapy, oral antidiabetics and insulin 
therapy) 
- 
Hypercholesterinaemia (yes, no) 
- 
Peripheral arterial vascular disease (yes, no) 
- 
Overall heart rhythm (Sinus rhythm prevails, Atrial fibrillation prevails, Pacing prevails, 
Pacing and AF, Other) 
- 
Heart rate 
- 
QRS interval 
- 
PR interval 
- 
QT duration 
- 
QT duration calculated 
- 
Amiodarone (yes, no) 
- 
Dronedarone (yes, no) 
- 
Flecainide (yes, no) 
- 
Ibutilide (yes, no) 
- 
Propafenone (yes, no) 
- 
Digoxin or Digitoxin (yes, no) 
- 
Antiarrhythmic drugs (yes, no) 
- 
Antianginal drugs (yes, no) 
- 
Potassium channel inhibitor (yes, no) 
- 
Sodium channel inhibitor (yes, no) 
- 
Diuretics (yes, no) 
- 
Loop diuretics (yes, no) 
- 
Mineralocorticoid receptor antagonist (yes, no) 
- 
Beta blockers (yes, no) 
- 
Calcium channel antagonists (yes, no) 
- 
Rate controlling calcium channel antagonist (yes, no) 
- 
ACE inhibitors or angiotensin II receptor blocker (yes, no) 
- 
Renin inhibitor (yes, no) 
- 
Imidazole and triazole derivatives (yes, no) 
- 
Non-Steroidal Anti-Inflammatory Drugs (yes, no) 
- 
Intravenous anticoagulant (yes, no) 
- 
NOAC (yes, no) 
- 
Platelet inhibitors (yes, no) 
- 
Vitamin K antagonists (yes, no) 
- 
Insulin (yes, no) 
- 
Oral antidiabetics (yes, no) 
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- 
SGLT2 inhibitors (yes, no) 
- 
Statins (yes, no) 
- 
Serum creatinine value (mg/dl) 
- 
Creatinine clearance 
- 
Haemoglobin (g/l) 
- 
Hematocrit 
- 
Red blood cells 
- 
Leucocytes 
- 
Thrombocytes 
- 
INR (international normalized ratio) 
- 
aPTT (activated partial thromboplastin time) 
- 
ALT (alanine aminotransferase) (GPT; glutamic pyruvic transaminase) (U/l)  
- 
AST (aspartate aminotransferase) (GOT; glutamic-oxaloacetic transaminase) (U/l) 
- 
Total bilirubin (µmol/l) 
- 
Cholesterol (mmol/l) 
- 
Karnofsky score 
- 
Atrial fibrillation symptom score (EHRA) (EHRA I, EHRA IIa, EHRA IIb, EHRA III, EHRA 
IV, unknown) 
- 
Cognitive function at baseline (MoCA) 
- 
≤ 12 years formal education (yes, no) 
- 
MoCA (<26) (Cognitive impairment: yes, no) 
- 
EQ-5D-5L: Mobility 
- 
EQ-5D-5L: Self-Care 
- 
EQ-5D-5L: Usual Activities 
- 
EQ-5D-5L: Pain/Discomfort: 
- 
EQ-5D-5L: Anxiety/Depression: 
- 
EQ-5D: State of health rate on a scale of 1 (very poor) to 100 (very good) 
- 
EQ-5D total score 
7.6 Changes in chapter 5.1.2 Event definition 
The following is added: All potential outcome events will be adjudicated by the endpoint review 
committee. That definition defines the nature of each event. 
 
7.7 Changes in chapter 5.4 Missing data analysis 
No imputation for missing values for secondary endpoints will be conducted. Due to the 
premature termination of the trial, not all patients will be followed up until 12 months. Currently 
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60-65% of the patients have undergone or are scheduled to undergo a 12 months visit 
(n=1.680) and for less than 50% after 24 months (n=1.100). This means information is missing 
for the outcomes of interest. The expected number of missing values (ca 1/3) is too large to 
perform reliable imputation. Clinically relevant changes in quality of life can be expected to be 
detectable in ca 1600 patients as well. 
Hence, data analysis will be done for those patients where regular 12 and/or 24 months visits 
and assessments have been done. Patients without 12 and 24 months follow up data 
(roundabout 30%) will not be included in the statistical analysis of the following secondary 
outcomes: 
- 
change in quality of life (EQ-5D-5L and Karnofsky score),  
- 
patient satisfaction (PACT-Q2, EHRA), 
- 
cognitive function (MoCA), 
- 
changes of autonomy status. 
 
7.8 Changes in chapter 5.5. Sensitivity Analyses 
The point  
 
using the mITT population with censoring of patients at the time of discontinuation of 
IMP (“on treatment analysis”) 
changes to 
• 
using the mITT population with censoring of patients at the time of permanent 
discontinuation of IMP (kind of censoring) 
(which is not exactly an “on treatment analysis” but a specific kind of censoring) 
 
7.9 Changes in chapter 5.7. Subgroup Analyses 
The cut-off for CHA2DS2VASc score is changed to ≥5. 
Furthermore, the section is divided into two parts: 
- 
Baseline subgroups, i.e. subgroups specified before randomization and which do not 
change over time 
- 
Subgroups that occur over time, i.e. are not defined by data collected at baseline but 
by data collected after randomization during the course of the study  
The subgroups that are defined by data collected during the course of the study are “Patients 
without any AHRE during the study duration” and “Adherence”. All other subgroups are 
baseline subgroups. 
The baseline subgroups are analyzed as described in Chapter 5.7. 
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For the subgroup “Patients without any AHRE during the study duration” a causal mediation 
analysis will be conducted. Thereby, the variables described in chapter 7.10. will be considered 
in the model as potential confounders. 
“Adherence” as a post randomization event will be analysed as time-dependent covariate and 
interactor for the treatment effect with censoring at study drug discontinuation. 
 
7.10 Changes in chapter 5.8. Additional Analyses 
Potential genetic and biomolecule-based predictors of outcomes will not be part of the current 
SAP analyses but part of secondary subsequent analyses. A dedicated biomolecule SAP will 
be written when they are quantified. 
For the multiple cause-specific Cox proportional hazard models with fixed effects for random 
group and ASA and a frailty for study site and the inclusion of several covariates, the additional 
covariates were chosen by the SC and include: 
- 
age 
- 
sex 
- 
congestive heart failure history 
- 
hypertension history 
- 
diabetes history 
- 
stroke/TIA/thromboembolism history 
- 
vascular disease history (prior MI, peripheral artery disease, or aortic plaque) 
- 
aspirin intake at baseline 
- 
Non-Steroidal Anti-Inflammatory Drugs 
 
8 References 
EuroQol Research Foundation. (2019). EQ-5D-5L User Guide. 
Gamble, C., Krishan, A., Stocken, D., Lewis, S., Juszczak, E., Dore, C., . . . Loder, E. (2017, 
December 19). Guidelines for the Content of Statistical Analysis Plans in Clinical 
Trials. JAMA, 318, pp. 318(23): 2337-2343. 
Ganesh, A., Luengo-Fernandez, R., Wharton, R., & Rothwell, P. M. (2018, November 20). 
Ordinal vs dichotomous analyses of modified Rankin Scale, 5-year outcome, and cost 
of stroke. Neurology, pp. 91(21):e1951-e1960. 
Giugliano, R., Ruff, C. T., Braunwald, E., Murphy, S. A., Wiviott, S. D., Halperin, J. L., . . . 
Antman, E. M. (2013, November 28). Edoxaban versus warfarin in patients with atrial 
fibrillation. N Engl J Med, pp. 369(22): 2093-104. 
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Baseline Characteristics and Demographics 
(mITT Population) 
 
 
Characteristics 
Edoxaban (N = xxx) 
SOC 
(N = xxx) 
All subjects (N = xxx) 
Age (yrs.) 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 




EudraCT number: 2015-003997-33  
 
Page 32 of 37 
 
SAP 4  
 
Confidential 
NOAH // Institute of Medical Biometry and Epidemiology, Medical Center Hamburg-Eppendorf, 
Hamburg 2023 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
Sex 
 
 
 
    Female 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
    Male 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Weight (kg) 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
BMI 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
AHRE (≥ 170 bpm atrial rate 
and ≥ 6 min duration) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
CHA2DS2VASc 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
Older than 75 years 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Sympt. Heart failure 
xxx/xxx (xx.x%)  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Hypertension 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Diabetes mellitus 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Stroke or trans. isch. 
attack 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Vascular disease 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Indication for ASA 
xxx/xxx (xx.x%)  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Unstable angina pectoris 
xxx/xxx (xx.x%)  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Acute myocardial 
infarction 
xxx/xxx (xx.x%)  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Prevention of re-infarction xxx/xxx (xx.x%)  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
After arterial vascular or 
general          surgical 
interventions (e.g. after 
CABG or after PTCA) 
xxx/xxx (xx.x%)  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
   For prevention of 
transitory ischaemic attacks 
(TIA) and strokes 
xxx/xxx (xx.x%)  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Coronary artery disease 
 
 
 
Other indication 
 
 
 
   Patient currently has a 
contraindication for ASA 
xxx/xxx (xx.x%)  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Hypertension 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
NYHA 
 
 
 
    I 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
    II 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
    III 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
    IV 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
206 / 212


EudraCT number: 2015-003997-33  
 
Page 33 of 37 
 
SAP 4  
 
Confidential 
NOAH // Institute of Medical Biometry and Epidemiology, Medical Center Hamburg-Eppendorf, 
Hamburg 2023 
Cardiomyopathy 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
No  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Hypertrophic 
cardiomyopathy ∇  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Dilatative cardiomyopathy 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Arrhythmogenic right 
ventricular 
cardiomyopathy 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Other cardiomyopathy  
 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Valvular heart disease 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Confirmed Coronary Artery 
Disease 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Confirmed carotid stenosis 
(>50% lumen reduction) 
 
 
 
None 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
left side  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
right side 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
both sides 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Arterial hypertension 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Diabetes mellitus 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
No  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
oral antidiabetics  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
insulin therapy  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
oral antidiabetics and 
insulin therapy 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Hypercholesterinaemia 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Peripheral arterial vascular 
disease 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Overall heart rhythm 
 
 
 
Sinus rhythm 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Atrial fibrillation 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Pacing 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Pacing and AF  
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Other 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Heart rate 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
QRS interval 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
PR interval 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
QT duration 
 
 
 
207 / 212


EudraCT number: 2015-003997-33  
 
Page 34 of 37 
 
SAP 4  
 
Confidential 
NOAH // Institute of Medical Biometry and Epidemiology, Medical Center Hamburg-Eppendorf, 
Hamburg 2023 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
QTc (calculated) 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
Serum creatinine value 
(mg/dl) 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
Estimated creatinine 
clearance 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
Haemoglobin (converted to 
"g/l") 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
Hematocrit 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
Red blood cells 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
Leucocytes 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
Thrombocytes 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
INR 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
208 / 212


EudraCT number: 2015-003997-33  
 
Page 35 of 37 
 
SAP 4  
 
Confidential 
NOAH // Institute of Medical Biometry and Epidemiology, Medical Center Hamburg-Eppendorf, 
Hamburg 2023 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
aPTT 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
ALT (GPT) (converted to 
"U/l") 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
AST (GOT) (converted to 
"U/l") 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
Total bilirubin (converted 
to "µmol/l") 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
Cholesterol (converted to 
"mmol/l") 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
Amiodarone 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Dronedarone 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Flecainide 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Ibutilide 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Propafenone 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Digoxin or Digitoxin 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Antiarrhythmic drugs 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Antianginal drugs 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Potassium channel inhibitor 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Sodium channel inhibitor 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Diuretics 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Loop diuretics 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Mineralocorticoid receptor 
antagonist 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Beta blockers 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Calcium channel 
antagonists 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Rate controlling calcium 
channel antagonist 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
209 / 212


EudraCT number: 2015-003997-33  
 
Page 36 of 37 
 
SAP 4  
 
Confidential 
NOAH // Institute of Medical Biometry and Epidemiology, Medical Center Hamburg-Eppendorf, 
Hamburg 2023 
ACE inhibitors or 
angiotensin II receptor 
blocker 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Renin inhibitor 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Imidazole and triazole 
derivatives 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Non-Steroidal Anti-
Inflammatory Drugs 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Intravenous anticoagulant 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
NOAC 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Platelet inhibitors 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Vitamin K antagonists 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Insulin 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Oral antidiabetics 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
SGLT2 inhibitors 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Statins 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Atrial fibrillation symptom 
score (EHRA) 
   EHRA I 
   EHRA IIa 
   EHRA IIb 
   EHRA III 
   EHRA IV 
   unknown 
 
 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
 
 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
 
 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
xxx/xxx (xx.x%) 
Cognitive function at 
baseline (MoCA) 
 
 
 
    N 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
    Median (25th, 75th) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
    Min, Max 
   ≤ 12 years formal 
education  
xx, xx 
xxx (xx.x%) 
xx, xx 
xxx (xx.x%) 
xx, xx 
xxx (xx.x%) 
    Cognitive impairment 
(<26)  
 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
EQ-5D-5L responses at 
baseline 
 
 
 
EQ-5D-5L: Mobility 
    N 
    Mean (SD) 
    Median (25th, 75th) 
    Min, Max 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
EQ-5D-5L: Self-Care 
    N 
    Mean (SD) 
    Median (25th, 75th) 
    Min, Max 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
EQ-5D-5L: Usual Activities 
    N 
    Mean (SD) 
    Median (25th, 75th) 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
210 / 212


EudraCT number: 2015-003997-33  
 
Page 37 of 37 
 
SAP 4  
 
Confidential 
NOAH // Institute of Medical Biometry and Epidemiology, Medical Center Hamburg-Eppendorf, 
Hamburg 2023 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
EQ-5D-5L: Pain/Discomfort 
    N 
    Mean (SD) 
    Median (25th, 75th) 
    Min, Max 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
EQ-5D-5L: 
Anxiety/Depression 
    N 
    Mean (SD) 
    Median (25th, 75th) 
    Min, Max 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
EQ-5D: State of health rate 
on a scale of 1 (very poor) 
to 100 (very good) 
    N 
    Mean (SD) 
    Median (25th, 75th) 
    Min, Max 
 
 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
 
 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
 
 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
EQ-5D total score 
    N 
    Mean (SD) 
    Median (25th, 75th) 
    Min, Max 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
 
xxx (xx.x%) 
xx.x (xx.x) 
xx.x (xx.x, xx.x) 
xx, xx 
 
 
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