Clinical trial NCT02313909
Conditions: Stroke
Keywords: Rivaroxaban Xarelto Aspirin Acetylsalicylic acid (ASA) Oral Anticoagulant Blood Thinner Stroke Ischemic Stroke Cryptogenic Stroke Embolic stroke of undetermined source ESUS Transient Ischemic Attack Thromboembolism Cerebrovascular Disease
Sponsor: Bayer
Start date: 2014-12-23; Completion date: 2018-02-15
Enrollment: 7213 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study in patients who recently had a brain attack (stroke) and in whom no clear cause of the stroke could be identified. These strokes are likely due to a blood clot and therefore, can be called embolic stroke of undetermined source. The abbreviation is ESUS. The study will compare 2 blood thinners. Patients will be randomly assigned to either Rivaroxaban 15 mg or Aspirin 100 mg and the study is intended to show, if patients given rivaroxaban have fewer blood clots in the brain (stroke) or in other blood vessels.

Detailed description:

Arms: arm 1: Rivaroxaban 15 mg orally once daily arm 2: Aspirin 100 mg orally once daily
Interventions: intervention 1: Rivaroxaban (Xarelto, BAY59-7939) intervention 2: Acetylsalicylic acid (Aspirin, BAY1019036) intervention 3: Rivaroxaban-Placebo intervention 4: Aspirin-Placebo
Intervention descriptions: intervention 1: 15 mg, once daily, orally, tablet intervention 2: 100 mg, once daily, orally, tablet intervention 3: Matching placebo, once daily, orally, tablet intervention 4: Matching placebo, once daily, orally, tablet

Protocol documents:
Prot_001.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
Multicenter, randomized, double-blind, double-dummy, active-
comparator, event-driven, superiority phase III study of secondary 
prevention of stroke and prevention of systemic embolism in 
patients with a recent Embolic Stroke of Undetermined Source 
(ESUS), comparing rivaroxaban 15 mg once daily with aspirin 100 
mg (NAVIGATE ESUS) 
NCT Number: 
NCT02313909 
Document Date: 
05 November 2015 
 


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Cover page of the integrated protocol
Multicenter, randomized, double-blind, double-dummy, active-comparator, event-driven, 
superiority phase III study of secondary prevention of stroke and prevention of systemic 
embolism in patients with a recent Embolic Stroke of Undetermined Source (ESUS), 
comparing rivaroxaban 15 mg once daily with aspirin 100 mg (NAVIGATE ESUS)
For this study, the protocol and subsequent protocol amendments were released as follows:

Original protocol, Version 1.0, dated 16 JUL 2014

Amendment 1 for Japan, dated 10 NOV 2014

Amendment 2 for Ireland dated 16 DEC 2014 

Amendment 3 for South Korea dated 23 JAN 2015

Amendment 4 for Canada dated 31 MAR 2015

Global Amendment 5 (described in Section 13.1), forming integrated protocol 
Version 2.0, dated 05 NOV 2015
This document integrates the original protocol and the global amendment.


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Title page
Multicenter, randomized, double-blind, double-dummy, active-comparator, event-driven, 
superiority phase III study of secondary prevention of stroke and prevention of systemic 
embolism in patients with a recent Embolic Stroke of Undetermined Source (ESUS), 
comparing rivaroxaban 15 mg once daily with aspirin 100 mg (NAVIGATE ESUS)
Secondary prevention of stroke in patients with a recent ESUS
Test drug:
BAY 59-7939/rivaroxaban
Clinical study phase:
III
Date:
05 NOV 2015  
EudraCT no.:
2013-000768-27
Version no.: 2.0    
Study no.:
BAY 59-7939/16573   
Sponsor:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
Sponsor’s medical expert:
Bayer Vital GmbH, 51368 Leverkusen, Germany 
Tel. 
The study will be conducted in compliance with the protocol, International Conference on 
Harmonisation – Good Clinical Practice (ICH-GCP) and any applicable regulatory 
requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether in part 
or in full - to parties not associated with the clinical investigation, or its use for any other purpose, 
without the prior written consent of the sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
Rivaroxaban (BAY-59-7939, JNJ-39039039) is being co-developed under a collaboration and license 
agreement between Bayer HealthCare AG (BHC) and Ortho McNeil Pharmaceuticals, Inc. (OMP) dated 
01 Oct 2005.  As determined by the parties, both BHC and Janssen Pharmaceuticals Inc. (successor in interest 
to OMP) may use affiliated corporate entities to conduct this clinical study.  With regard to Janssen 
Pharmaceuticals Inc., such affiliates may include Janssen Research & Development, LLC (formerly Johnson & 
Johnson Pharmaceutical Research & Development LLC), Janssen Scientific Affairs, LLC, and Janssen-Cilag 
International N.V (Corporation).  The term “sponsor” or “designee” is used to represent these various legal 
entities that have been identified to perform various clinical study services; the actual sponsor or designee is 
identified on the Contact Information page that accompanies this protocol. 
PPD
PPD


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Signature of Bayer’s medically responsible person
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
 
Date:
Signature:
Signature of the principal investigators for the study
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
 
Co-principal investigator
Affiliation:
 
Population Health Research Institute, 
Hamilton, Canada
Date:
Signature:
Name:
Co-principal investigator
Affiliation:
 
Population Health Research Institute, Hamilton, Canada
Date:
Signature:
PPD
PPD
PPD
PPD
PPD
PPD


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Signature of the principal investigator at the study site
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this page containing the signature of the study center’s principal investigator 
are stored in the sponsor’s study file and in the respective center’s investigator site file.


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Synopsis - amended
Title
Multicenter, randomized, double-blind, double-dummy, active-comparator, 
event-driven, superiority phase III study of secondary prevention of stroke and 
prevention of systemic embolism in patients with a recent Embolic Stroke of 
Undetermined Source (ESUS), comparing rivaroxaban 15 mg once daily with 
aspirin 100 mg (NAVIGATE ESUS)
Short title
Secondary prevention of stroke in patients with ESUS
Clinical study phase
III
Study objectives
The primary efficacy objective is:

To evaluate whether rivaroxaban is superior to aspirin in reducing the 
risk of recurrent stroke and systemic embolism in patients with a 
recent ESUS
The secondary efficacy objective is:

To evaluate whether rivaroxaban is superior to aspirin in reducing 
cerebrovascular events, cardiovascular events, and mortality in 
patients with a recent ESUS
The safety objective is to document the incidence of clinically relevant 
bleeding
Study medication
Rivaroxaban 15 mg (immediate-release film-coated tablets), or
Aspirin 100 mg (enteric-coated tablets)
Type of control
Double dummy:  Matching placebo will be provided for rivaroxaban and 
aspirin
Route of administration
Study medication is administered orally once daily and should be taken with 
food
Indication
Secondary prevention of stroke and prevention of systemic embolism in 
patients with a recent ESUS


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Diagnosis and main criteria for 
inclusion
Recent ESUS (between 7 days and 6 months), defined as:

Recent ischemic stroke (including transient ischemic attack with 
positive neuroimaging) visualized by brain imaging that is not 
lacunar, and

Absence of cervical carotid atherosclerotic stenosis > 50% or 
occlusion1, and

No atrial fibrillation after ≥ 24-hour cardiac rhythm monitoring (at 
least 20 hours acceptable)2, and

No intra-cardiac thrombus on either transesophageal or transthoracic  
echocardiography,3 and

No other specific cause of stroke (for example, arteritis, dissection, 
migraine/vasospasm, drug abuse)
Study design
Multicenter, randomized, double-blind, double-dummy, active-comparator, 
event-driven, superiority phase III study
Methodology
Patients who fulfill all inclusion and none of the exclusion criteria after giving 
informed consent will be randomly allocated 1:1 to either rivaroxaban 15 mg 
or aspirin 100 mg orally once daily. Randomization will be stratified by 
country and age <60 and ≥60 years.  4
At randomization, patients will receive study medication and instructions for 
its administration.  Thereafter, patients will return to the clinic at 1, 6, and 12 
months and then every 6 months until the end of study (efficacy cut-off date) is 
announced.  At 3 months, patients will be contacted by telephone. Throughout 
the study and at clinic visits, patients will be assessed for efficacy (stroke, 
systemic embolism, myocardial infarction, cardiovascular death, and all-causes 
mortality) and safety vital signs, bleeding, serious adverse events which are not 
outcome events, pregnancies, non-serious adverse events leading to permanent 
study drug discontinuation, and any non-serious adverse events of particular 
concern to the investigator).  
Suspected clinical study outcomes (efficacy and bleeding) will be assessed by 
an Independent Central Adjudication Committee blinded to treatment 
allocation.  Adjudicated results will be the basis for the final analyses. 
The study is event-driven and thus, all patients will be treated (or followed-up 
in case of permanent discontinuation of study medication) until the required 
approximately 450 confirmed primary efficacy outcomes are expected to have 
occurred.
An Independent Data Monitoring Committee will monitor patient safety during 
the study and give recommendations to the Steering Committee. 
                                                
1 Prior to global Protocol Amendment 5, stenosis was ≥ 50%.
2 The phrase in parentheses was added with global Protocol Amendment 5 to reflect routine practice.
3 “Transesophageal” was added with global Protocol Amendment 5.
4 The following statement was deleted with global Protocol Amendment 5:  “No more than 10% of the total 
patient population will be randomized into the age group <60 years.”  See Section 13.1 for details.


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Number of subjects
The study is event-driven and it is estimated that approximately 7000 patients
(3500 per treatment group) are to be enrolled in order to have 450 patients
experiencing a positively adjudicated primary efficacy outcome event.
The number of patients enrolled in the total study may be adjusted or 
enrollment in the age group 50-59 years may be stopped based on a blinded 
review of the observed overall event rate of confirmed primary efficacy 
outcomes during the study.5
Primary variable
Time from randomization to first occurrence of any of the components of the 
composite outcome (adjudicated); including:

Stroke (ischemic, hemorrhagic, and undefined stroke, transient 
ischemic attack with positive neuroimaging)

Systemic embolism
Plan for statistical analysis
The primary efficacy analyses will be based on the intent-to-treat population.  
Rivaroxaban treatment will be compared with the aspirin control group using a 
stratified log-rank test.  Kaplan-Meier curves for the cumulative incidence risk 
and cumulative incidence functions will be provided to evaluate the timing of 
event occurrence.  Risk reduction will be estimated with the stratified Cox 
proportional hazards model.  
Secondary efficacy outcomes will be analyzed using similar methods as for the 
primary efficacy analysis.  Testing will be performed in hierarchical order. 
There will be 2 formal interim analyses to assess efficacy and stop for 
overwhelming superiority, which will occur when approximately 50% and 
67% of the planned primary efficacy outcomes have accrued. 6
The analysis of the safety outcomes will be similar to those described for the 
primary efficacy outcome.
Anticipated total study duration 
and study duration per patient
Total study duration: ~3 years 
Randomization period: ~2 years
Treatment duration of last patient randomized: ~1 year
Mean treatment duration per patient: ~2 years
The study is event driven and these timelines may vary depending on the 
enrollment rate and event rate in the study. 
                                                
5 Sentence was revised with global Protocol Amendment 5.  See Section 13.1 for details.
6 A second interim analysis was added with global Protocol Amendment 5.  See Section 13.1 for details.


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Table of procedures – amended 7
Screen
Random
Treatment Phase
Washout
V1
V2
V3
V4
V5
V6
V7-V∞EOT a
Safety 
Visit
Timelines
-6 to 0 
wks b
0
1 Mo
3 Mo
6 Mo
12 Mo
every 
6 Mo
End 
of 
Treat
1 Mo 
post EOT
Visit Window (weeks)
±1
±4
±4
±4
±4
±1
Type of Visit  
Visit
Visit
Visit L

Visit
Visit
Visit
Visit

Initiation procedures
Informed consent
●
Eligibility criteria
●
Demographics
●
Medical history and 
stroke risk factors
●
Treatment and 
diagnosis of stroke c
●
Pregnancy test d
●
eGFR e
●
Weight/height f
●
●
□
Medication
ConMeds g
●
●
□
●
1st study drug 
●
Drug dispense 
●
●
●
●
Drug return + 
accountability
●
●
●
●
Efficacy/Safety 
Outcomes h
Safety
Adverse events i
Vital signs j
●
●
●
□
●
Outcomes Research
EQ-5D
●
●
●
●
●
MoCA and SAGE
●
●
●
Modified Rankin 
Score k
●
●
●
Abbreviations:  EOT = end of treatment; Mo = month; V = visit, = telephone contact; eGFR = estimated 
glomerular filtration rate; ConMeds = Concomitant medications; MoCA = Montreal Cognitive Assessment; 
SAGE = Standard Assessment of Global-Activities in the Elderly; EQ-5D = European Quality of Life-5 
Dimensions questionnaire; SAE = serious adverse event; TIA = transient ischemic attack; MI = myocardial 
infarction
a
End of treatment visit is to be performed within the trial close-out window before the end of the study (efficacy 
cut-off date) or once the patient has permanently discontinued study medication and when no further visits at 
the site will be performed
b
Screening visit can be the same as randomization visit, if all required tests for eligibility criteria are available 
at screening visit. Maximum screening period 6 weeks.
c
Acute and chronic therapy of stroke (for example [e.g.], thrombolysis, aspirin [ASA]) and diagnostic tests 
performed to diagnose acute stroke and Embolic Stroke of Undetermined Source (ESUS) as well as National 
Institutes of Health Stroke Score (NIHSS)
                                                
7 Global Protocol Amendment 5 made the following changes to this table:  the Digit Symbol Substitution (DSS) 
test was removed; the window for Visit 1 was extended 2 weeks; footnotes a, b, and k were revised; and footnote 
L was added.  See Section 13.1 for details.
continuous reporting
continuous reporting


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d
Only in women of childbearing potential (local urine or serum pregnancy test)
e
Creatinine to be measured at the local laboratory at screening, unless conducted within 1 month prior to 
screening.  The eGFR may be recorded as reported by the local laboratory or otherwise should be calculated 
using Modification of Diet in Renal Disease (MDRD) formula. A calculator may be found at www.mdrd.com. 
During the study creatinine and eGFR should be measured according to local practice.  
f
Height to be measured only at screening
g
Concomitant medications and the changes need to be documented only at the specified visits for chronic 
cerebro- and cardiovascular treatments. In addition, treatments for SAEs and outcome events must be 
reported.
h
All potential outcome events including recurrent stroke, TIA, systemic embolism, MI, hospitalizations for 
cardiac chest pain, deaths, and bleeding must be reported on an ongoing basis even if the patient is 
permanently discontinued from study treatment. Healthcare resource use will be documented for all 
endpoints. See Section 7.6.1.1
i
Only SAEs not exempted from SAE reporting, pregnancy, non-serious AE leading to permanent 
discontinuation, and  non-serious AEs of particular concern to the investigator need to be reported. See 
Section 7.5.3.2.
j
Blood pressure and heart rate
k
For definition see Section 7.6.1.4. In case of recurrent stroke to be done at 7 days post stroke or at 
discharge from hospital in case this occurs before 7 days and again at 3-6 months post stroke
L     Patients who are at a rehabilitation or other clinic at the time of the 1 month visit (Visit 3), more flexibility will 
be allowed and this visit can be performed as a phone call instead of an onsite visit.
● 
To be performed at specified visits
□ 
To be performed only once per year 


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Table of contents
Title page ....................................................................................................................................2
Signature of Bayer’s medically responsible person....................................................................3
Signature of the principal investigators for the study .................................................................3
Signature of the principal investigator at the study site..............................................................4
Synopsis - amended ....................................................................................................................5
Table of contents.......................................................................................................................10
Table of figures.........................................................................................................................12
List of abbreviations .................................................................................................................13
1.
Introduction........................................................................................................................16
1.1
Background ................................................................................................................16
1.2
Embolic stroke of undetermined source.....................................................................16
1.3
Studies assessing the efficacy of anticoagulation for secondary prevention of 
embolic stroke of undetermined source - amended....................................................17
1.4
Efficacy and safety of rivaroxaban in patients with prior stroke ...............................17
1.5
Current guideline recommendations and dose of aspirin...........................................19
1.6
Study rationale............................................................................................................19
1.7
Dose rationale.............................................................................................................20
1.8
Benefit/risk assessment ..............................................................................................20
2.
Study objectives.................................................................................................................21
3.
Investigators and other study personnel.............................................................................21
3.1
Investigator.................................................................................................................21
3.2
Study personnel..........................................................................................................21
3.3
Study committees .......................................................................................................21
3.3.1
Steering Committee ............................................................................................22
3.3.2
Independent Data Monitoring Committee..........................................................22
3.3.3
Independent Central Adjudication Committee...................................................22
4.
Study design.......................................................................................................................22
4.1
Overview ....................................................................................................................22
4.2
Justification of the design...........................................................................................24
4.3
End of study ...............................................................................................................24
5.
Study population – amended..............................................................................................24
5.1
Eligibility....................................................................................................................24
5.1.1
Inclusion criteria - amended ...............................................................................24
5.1.2
Exclusion criteria - amended ..............................................................................25
5.2
Discontinuation of patients from study treatment - amended ....................................26
5.3
Patient identification ..................................................................................................28
6.
Treatments .........................................................................................................................28
6.1
Treatments to be administered ...................................................................................28
6.2
Identity of study treatment .........................................................................................28
6.3
Treatment assignment - amended...............................................................................28
6.4
Dosage and administration.........................................................................................29
6.5
Blinding......................................................................................................................29
6.5.1
Emergency unblinding by the investigator - amended .......................................29
6.6
Drug logistics and accountability...............................................................................29


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6.7
Treatment compliance - amended ..............................................................................30
6.8
Post-study therapy......................................................................................................30
6.9
Prior and concomitant therapy - amended..................................................................30
6.9.1
Guidance for management of participants who require antiplatelet therapy or 
non-steroidal anti-inflammatory drug during the study......................................30
6.9.2
Guidance for management of participants who have atrial fibrillation identified 
during study - amended ......................................................................................31
6.9.3
Guidance for management of participants who have coronary artery disease 
identified during the study..................................................................................31
6.9.4
Guidance for management of participants who have a recurrent ischemic stroke 
during the study ..................................................................................................31
6.9.5
Guidance for management of participants who have bleeding during the study 32
6.9.6
Guidance for management of participants with overdose ..................................32
7.
Procedures and variables ...................................................................................................32
7.1
Schedule of procedures ..............................................................................................32
7.1.1
Tabulated overview ............................................................................................33
7.1.2
Timing of assessments........................................................................................33
7.2
Population characteristics...........................................................................................35
7.2.1
Demographics.....................................................................................................35
7.2.2
Medical history...................................................................................................35
7.3
Efficacy ......................................................................................................................35
7.3.1
Assessments and procedures at occurrence of efficacy outcome events............35
7.3.2
Definition of efficacy outcome events................................................................36
7.3.3
Efficacy variables ...............................................................................................37
7.4
Pharmacokinetics/pharmacodynamics .......................................................................38
7.5
Safety..........................................................................................................................38
7.5.1
Primary safety variable - amended .....................................................................38
7.5.2
Secondary safety variables .................................................................................38
7.5.3
Adverse events....................................................................................................39
7.6
Other procedures and variables..................................................................................43
7.6.1
Health Economics and Outcomes Research .......................................................43
8.
Statistical methods and determination of sample size .......................................................44
8.1
General considerations ...............................................................................................44
8.2
Analysis sets...............................................................................................................45
8.2.1
Efficacy data set..................................................................................................45
8.2.2
Safety data set.....................................................................................................45
8.2.3
Data scopes .........................................................................................................45
8.3
Variables.....................................................................................................................45
8.3.1
Subgroup variables .............................................................................................45
8.4
Statistical and analytical plans ...................................................................................46
8.4.1
Analysis of the primary efficacy variable...........................................................46
8.4.2
Analysis of secondary efficacy variables ...........................................................47
8.4.3
Analysis of safety variables................................................................................47
8.4.4
Subgroup analysis...............................................................................................47
8.4.5
Handling of missing data....................................................................................48
8.5
Planned interim analyses - amended ..........................................................................49


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8.6
Determination of sample size - amended ...................................................................49
9.
Data handling and quality assurance .................................................................................50
9.1
Data recording - amended ..........................................................................................50
9.2
Monitoring..................................................................................................................50
9.3
Data processing ..........................................................................................................51
9.4
Audit and inspection...................................................................................................51
9.5
Archiving....................................................................................................................51
10. Premature termination of the study....................................................................................52
11. Ethical and legal aspects....................................................................................................52
11.1
Ethical and legal conduct of the study .......................................................................52
11.2
Subject information and consent................................................................................53
11.3
Publication policy.......................................................................................................54
11.4
Compensation for health damage of subjects/insurance ............................................54
11.5
Confidentiality............................................................................................................54
12. Reference list .....................................................................................................................54
13. Protocol amendments.........................................................................................................58
13.1
Amendment 5 .............................................................................................................58
13.1.1
Overview of changes to the study.......................................................................58
13.1.2
Changes to the protocol text ...............................................................................60
14. Appendices.........................................................................................................................68
14.1
Substudies...................................................................................................................68
14.1.1
MRI substudy - amended....................................................................................68
14.1.2
Biomarker substudy............................................................................................70
Table of figures
Figure 4–1:  Study design schematic - amended ..................................................................... 23
Figure 7–1:  Outcome and adverse event collection and reporting schematic ........................ 41


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List of abbreviations
ACS
Acute coronary syndrome
AE
Adverse event
AF
Atrial fibrillation
APCC
Activated prothrombin complex concentrate
ARISTOTLE
Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE)
ASA
Acetylsalicylic acid; aspirin
AVERROES
A Phase III Study of Apixaban in Patients With Atrial Fibrillation (AVERROES)
BHC
Bayer HealthCare
b.i.d.
Twice daily
CABG
Coronary artery bypass graft
CAD
Coronary artery disease
CI
Confidence interval
ConMed
Concomitant medication
CRO
Contract research organization
CT
Computed tomography
cTn
Cardiac troponin
CV
Cardiovascular
CYP3A4
Cytochrome P450 isoenzyme 3A4
DSS
Digit Symbol Substitution test
DVT
Deep vein thrombosis
ECG
Electrocardiogram
eCRF
Electronic case report form
EINSTEIN
Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep 
Vein Thrombosis -The EINSTEIN DVT Study
e.g.
for example
eGFR
Estimated glomerular filtration rate
ENGAGE
Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs Standard
Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (EngageAFTIMI48)
EOT
End-of-treatment
EQ-5D
European Quality of Life-5 Dimensions questionnaire
ESUS
Embolic stroke of undetermined source
EU
European Union
FAS
Full analysis set
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
H
hypothesis
HDPE
High-density polyethylene
HR
Hazard ratio
ICAC
Independent Central Adjudication Committee
ICF
Informed consent form
ICH
International Conference on Harmonisation


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IB
Investigator’s brochure
i.e.
id est (that is) 
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
INR
International ratio
IRB
Institutional Review Board
ISTH
International Society on Thrombosis and Haemostasis
ITT
Intent-to-treat
IxRS
Interactive web/voice response system
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities 
MI
Myocardial infarction
Mo
Month
MoCA
Montreal Cognitive Assessment
MR
Magnetic resonance
MRI
Magnetic resonance imaging
NIHSS
National Institutes of Health Stroke Score
NSAID
Non-steroid anti-inflammatory drug
NV
Corporation (in The Netherlands)
NVAF
Non-valvular atrial fibrillation
NT-proBNP
N-terminal of the prohormone brain natriuretic peptide
o.d.
Once daily
OMP
Ortho McNeil Pharmaceuticals
p
p-value
PCC
prothrombin complex concentrate
PCI
percutaneous coronary intervention
PE
Pulmonary embolism
P-gp
P-glycoprotein
PICCS
Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS)
PID
Patient identification 
PPS
Per protocol set
PT
Prothrombin time
PV
Pharmacovigilance
QA
Quality assurance
ROCKET AF
An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke 
and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular 
Atrial Fibrillation
RRR
Relative risk reduction
S
survival
SAE
Serious adverse event
SAF
Safety data set
SAGE
Standard Assessment of Global-Activities in the Elderly
SAP
Statistical analysis plan


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SC
Steering Committee
SUSAR
Suspected unexpected serious adverse reaction
TIA
Transient ischemic attack
USA
United States of America
TOAST
Trial of Org 10172 in Acute Stroke Treatment
V
Visit
VKA
Vitamin K antagonist
vs.
versus
VTE
Venous thromboembolism
WARSS
Warfarin-Aspirin Recurrent Stroke Study
WHO
World Health Organization
WMH
White matter hyperintensities


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1. Introduction
1.1
Background
Globally, cerebrovascular disease (stroke) is the second leading cause of death (1) and the 
fourth leading cause of disease burden as measured in disability-adjusted life years. (2) The 
World Health Organization (WHO) estimates that worldwide 16 million people suffer a first 
ever stroke annually, with 5 million deaths due to stroke in 2005, and another 5 million left 
permanently disabled. (3)
The incidence of stroke is declining in many developed countries, largely as a result of better 
control of high blood pressure and reduced levels of smoking.  However, the absolute number 
of strokes continues to increase because of the ageing population.  In the absence of 
additional population-wide interventions, the numbers are expected to rise to 18 million 
first-ever strokes and 6.5 million deaths in 2015 and 7.8 million deaths in 2030.  
Approximately two-thirds of patients are left with physical or cognitive disabilities.  Stroke 
costs the United States (US) an estimated $54 billion each year. (4) In the US, 75% of all 
strokes are first or new strokes and 25% are recurrent strokes. (5)
About 87% of all strokes are of ischemic origin. Sub-types of ischemic stroke are defined 
using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. (6)
Approximately 30% of all ischemic strokes are due to arteriosclerosis of the intra- and 
extracranial large arteries; 20 % are lacunar, i.e., due to small artery disease; 20% have a 
cardioembolic source such as atrial fibrillation; and 5% are classified as “unusual” (for 
example [e.g.], dissections, arteritis). For the remaining 25% of strokes, the term 
‘Cryptogenic Stroke’ has been used to describe patients with ischemic stroke in whom there 
is no clear etiology. (7) In cryptogenic stroke the source of embolism or thrombosis cannot 
be readily determined in each and every patient, and in fact, it is not uncommon to identify 
more than one potential cause in the individual patient.
1.2
Embolic stroke of undetermined source
Recently, the concept of “embolic stroke of undetermined source” (ESUS) has developed, 
recognizing that except for lacunar strokes, most cryptogenic strokes are embolic.(7) The 
sources of embolism underlying ESUS include the heart (either within the heart or via 
paradoxical embolism from a venous source), aortic arch, or the large cervical and cerebral 
arteries. 
Investigations to establish a diagnosis of ESUS involves exclusion of lacunar stroke and 
stroke related to severe occlusive atherosclerotic disease of intra- and extracranial large 
arteries.  Lacunar strokes need to be excluded, as the great majority of these are due to in-situ 
thrombosis on microatheroma or non-thrombotic occlusions of small cerebral arteries.  Newly 
detected, previously unrecognized, major-risk cardioembolic sources such as atrial fibrillation 
and left ventricular thrombus that warrant anticoagulation therapy must also be excluded. 
In summary, ESUS is defined as a non-lacunar brain infarct without proximal arterial stenosis 
or major-risk cardioembolic sources that have a clear indication for anticoagulation. 


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1.3
Studies assessing the efficacy of anticoagulation for secondary 
prevention of embolic stroke of undetermined source - amended
The only available randomized clinical trial data in patients with cryptogenic stroke stem 
from a subgroup analysis in the Warfarin-Aspirin Recurrent Stroke Study (WARSS; 
1993-2000),(8) where patients were randomly assigned to aspirin (acetylsalicylic acid; ASA)
325 mg once daily (o.d.) or warfarin (target International Ratio [INR] 1.4 to 2.8). This 
subgroup included 576 out of the 2206 patients. Cryptogenic stroke was based on the 
TOAST criteria (6) (2 or more causes identified or a negative evaluation, or an incomplete 
evaluation) (7,9). The primary outcome of ischemic stroke or death occurred in 15.0% 
assigned to warfarin vs. 16.5% assigned to ASA over two years (Hazard Ratio [HR] 0.92, 
95% Confidence Interval [CI] 0.6-1.4). (9)  The INRs achieved were relatively low (median 
achieved INR = 1.9) and were a noteworthy reflection of the relative efficacy of 
anticoagulation vs. antiplatelet agents in patients with cryptogenic stroke.  The rates of major 
hemorrhage were low (2.22 per 100 patient-years in the warfarin group and 1.49 per 100 
patient-years in the ASA group).
For 338 participants with cryptogenic stroke whose computed tomography (CT) showed an 
“embolic topography” the 2 year rate of recurrent ischemic stroke or death was 12% with 
warfarin vs. 18% with ASA (HR=0.66, 95% CI 0.4-1.2). (9)
In summary, despite a low therapeutic warfarin anticoagulation range (median INR = 1.9) and 
limited statistical power, WARSS data from a randomized comparison support the concept 
that anticoagulation may be substantially more efficacious than ASA for patients with 
cryptogenic ischemic stroke with embolic features (i.e., those comparable to ESUS patients).  
In addition, in the PICSS study, 98 participants with a patent foramen ovale, the primary 
outcome (2 year rate of recurrent ischemic stroke or death) was halved in those assigned to 
warfarin (9.5% warfarin vs. 17.9% ASA).8 (10)
Vitamin K antagonists (VKAs) are not routinely used for cryptogenic stroke/ESUS. A 
Cochrane Collaboration meta-analysis of trials for secondary prevention in patients with a 
history of non-cardioembolic stroke of various causes, such as large artery atherosclerosis, 
intracranial artery stenosis, small penetrating artery disease, and strokes of unknown cause 
(i.e., cryptogenic stroke) suggested that higher intensity anticoagulation with VKAs could be 
associated with higher all-cause mortality and major bleeding events. (11)
1.4
Efficacy and safety of rivaroxaban in patients with prior stroke 
Rivaroxaban is an oral, highly selective direct Factor Xa inhibitor. Inhibition of Factor Xa 
interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both 
thrombin formation and development of thrombi. 
Rivaroxaban has been tested in interventional and non-interventional trials involving more 
than 70,000 patients and the cumulative worldwide exposure during 5.5 years of marketing 
(since SEP 2008) is estimated at approximately 2.4 million patient years in approximately 8 
million patients treated overall.  Rivaroxaban is approved in adults for the prevention of 
                                                
8 Data in this sentence were corrected with global Protocol Amendment 5.  See Section 13.1.2 for additional 
details.


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venous thromboembolism (VTE) following elective hip or knee replacement surgery, 
treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of 
recurrent DVT and PE.  It has been approved in the European Union (EU) and other countries 
for the prevention of atherothrombotic events in adult patients after an acute coronary 
syndrome (ACS) with elevated cardiac biomarkers when co-administered with ASA or ASA 
plus clopidogrel or ticlopidine. 
Rivaroxaban is also approved for prevention of stroke and systemic embolism in patients with 
non-valvular atrial fibrillation (NVAF) with one or more risk factors. Approval was based on 
the ROCKET-AF trial, (12) in which rivaroxaban was shown to be non-inferior to warfarin. 
There was also no significant between-group difference in the risk of major bleeding. A 
pre-specified subgroup analysis showed that the efficacy and safety of rivaroxaban compared 
with warfarin among patients with and without a previous transient ischemic attack (TIA) or 
ischemic stroke was consistent. (13)
A major advantage of the novel oral anticoagulants over warfarin that emerged from recent 
phase III randomized clinical trials involving non-valvular atrial fibrillation patients is the 
reduced risk of intracranial hemorrhage. (12,14,15) In the ROCKET-AF trial, intracranial 
hemorrhage was reduced (HR 0.67; p=0.02) by rivaroxaban relative to warfarin. (12)
Prior stroke is a risk factor for intracerebral hemorrhage during warfarin anticoagulation.  In 
ROCKET-AF, there was no significant interaction between prior stroke and relative effect of 
rivaroxaban vs. warfarin on hemorrhagic stroke. (13) While patients with recognized AF will 
be excluded from the proposed trial, the cause of ESUS in many patients is unrecognized 
cardiogenic embolism, including undiagnosed paroxysmal atrial fibrillation, and hence these 
observations may be relevant.
Patients with cryptogenic ischemic stroke are likely to have a higher risk of intracranial 
hemorrhage than patients with vascular disease without prior stroke/TIA. The absolute rate 
of intracranial hemorrhage in patients with cryptogenic ischemic stroke, if given rivaroxaban, 
is likely to be less than that observed in ROCKET-AF participants with prior stroke/TIA 
(0.59%/year). This is due to a lower average age of patients with cryptogenic stroke (a 
powerful independent risk factor for intracranial hemorrhage [16]) compared with the high 
risk ROCKET-AF population.  
The only large-scale comparison of a novel oral anticoagulant (apixaban) with ASA, the 
AVERROES study, involving patients with NVAF who were unsuitable to VKA treatment 
was stopped prematurely by the Independent Data Monitoring Committee (IDMC) for 
overwhelming efficacy. (17) A significant reduction in the primary efficacy outcome (stroke 
and systemic embolism) was reported for all patients (HR 0.45) and in the patients with 
previous stroke or TIA the HR was 0.29. (18) Major bleeding was more frequent in patients 
with a history of stroke or TIA than in patients without (HR 2.88) but the overall risk for 
these events was small and only slightly more reported in the apixaban group (44 vs. 39 
events, HR 1.13). There was also no difference in intracranial bleeding with apixaban vs. 
ASA, albeit based on a relatively small number of events (apixaban = 11, ASA = 13). (17) In 
a recent comprehensive meta-analysis, based on indirect comparison, the risk of subdural 
hematoma (comprising 30% of intracranial hemorrhages) was equal comparing oral factor Xa 
inhibitors with ASA. (19) Consequently, intracranial hemorrhage is unlikely to limit a 


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comparison of rivaroxaban with ASA for secondary prevention of stroke in patients with 
ESUS.
1.5
Current guideline recommendations and dose of aspirin
The 2008 American College of Chest Physicians guideline and 2008 American Heart 
Association guideline specifically recommended antiplatelet therapy for patients with 
cryptogenic ischemic stroke. (20, 21)  The 2008 European Stroke Organization guideline, the 
2014 American Heart Association revised guideline, the 2012 American College of Chest 
Physicians guideline, and the 2008 Canadian Best Practice Recommendations for Stroke Care 
do not comment specifically on cryptogenic stroke, but recommend antiplatelet therapy for 
patients with non-cardioembolic ischemic stroke.(22-25)  These are primarily Grade 
1A/(Class I, Level of Evidence A) recommendations.  Aspirin is the drug most frequently 
used.  A daily dosage range of 50 mg to 325 mg of ASA is recommended in current 
guidelines, although the data for doses < 75 mg are limited.  An ASA dosage of 100 mg daily 
is included in most major guidelines and is acceptable to most clinicians around the world.  
Guidelines recommend initiation of ASA immediately after brain imaging has excluded 
intracerebral hemorrhage, if the patient can swallow, and this is standard of care.  The 
long-term (> 5 years) treatment is recommended. (25)  
1.6
Study rationale
Randomized clinical trials have addressed secondary prevention for all major ischemic stroke 
subtypes except for cryptogenic stroke or ESUS. Among the estimated 300,000 patients with 
acute cryptogenic stroke annually in North America and Europe there has been little progress 
in secondary prevention during the past two decades. There is a substantial unmet medical 
need in this patient population, as despite treatment with antiplatelets, the recurrent stroke rate 
still remains at 3 to 6% annually. (7)
There is persuasive evidence that the dominant underlying pathophysiology of ESUS is 
embolism (cardioembolic, arteriogenic, or paradoxical).  Improvements in imaging 
technology and an increased appreciation of the underlying pathophysiology of ESUS have 
resulted in better understanding and in a practical clinical definition of ESUS (7) so that these 
patients can be reliably identified. 
Based on evidence for superior efficacy of warfarin anticoagulation over ASA for other types 
of embolic stroke, anticoagulation is expected to be superior to ASA in ESUS patients.  The 
direct oral Factor Xa-inhibitor rivaroxaban, when compared with VKAs, has been 
demonstrated to be effective against embolic stroke related to non-valvular AF.  Because of
its predictable anticoagulant activity and low risk of intracranial hemorrhage, it is expected 
that rivaroxaban will reduce stroke recurrence in ESUS compared with ASA, and with an 
acceptable safety (bleeding) profile.  Rivaroxaban has also been shown to be efficacious for 
the treatment of DVT and PE, prevention of recurrent DVT and PE, prevention of VTE 
following total hip and total knee replacement, and also for prevention of atherothrombotic 
events after an ACS with elevated cardiac biomarker. Rivaroxaban has no dietary restrictions 
and only few drug interactions and does not require routine coagulation laboratory 
monitoring.  


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Given these considerations, a large, multicenter, randomized, double-blind, double-dummy, 
active-comparator, event-driven, superiority study comparing rivaroxaban 15 mg o.d. with 
ASA 100 mg o.d. for the secondary prevention of stroke and prevention of systemic 
embolism will be conducted.
1.7
Dose rationale
This will be the first study investigating rivaroxaban for secondary prevention of stroke in 
patients with ESUS.
Data in patients with NVAF in the ROCKET-AF study with rivaroxaban as well as data from 
other new oral anticoagulants (apixaban, dabigatran, edoxaban) and Vitamin K antagonists 
give support for the benefit of rivaroxaban in this indication, as in both patient populations 
strokes are primarily of thromboembolic origin. Apixaban, one of the Factor Xa inhibitors 
showed superiority to ASA (AVERROES study). However, studies comparing anticoagulants 
to antiplatelets have shown higher bleeding rates. 
We assume that in the proposed study rivaroxaban 15 mg will reduce recurrent stroke and 
systemic embolism as compared to ASA 100 mg. 15 mg is expected to show significant 
efficacy combined with an acceptable bleeding profile for the following reasons:

A dose as high as 20 mg as used in embolic stroke prevention in patients with non-
valvular atrial fibrillation (ROCKET AF study) might not be necessary for efficacy
o
Modelling data show an overlap of exposure (rivaroxaban plasma 
concentrations over time) for 15 mg with 20 mg rivaroxaban  
o
15 mg was effective and safe in ROCKET AF in patients with moderate renal 
impairment and J-ROCKET in patients with normal/mild renal impairment

15 mg rivaroxaban will likely lead to less bleeding compared to 20 mg, which is 
important in an ESUS population that is more vulnerable for intracranial hemorrhage 
Because the dose selected for this study is already an adjustment down from the dose used for 
stroke prophylaxis in NVAF, a dose adjustment for patients with moderate-severe renal 
impairment is not considered necessary.  
1.8
Benefit/risk assessment
Worldwide, 16 million people suffer a first ever stroke annually and 25% of all ischemic 
strokes are recurrent strokes.  The ischemic stroke recurrence rate is substantial and remains 
at 3 to 6% per year during ASA treatment, the standard guideline recommended 
antithrombotic therapy for secondary prevention in most patients without major-risk 
cardioembolic causes. 
No specific treatment has been tested for patients with ESUS.  Only recently have insights 
into this disease revealed that most of these strokes are due to embolism.  Data from the 
WARSS study and clinical trials with oral anticoagulants in patients with non-valvular atrial 
fibrillation support that anticoagulation is likely to be the better treatment option for embolic 
stroke compared with antiplatelet therapy.  Based on these findings, it is expected that the 


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NAVIGATE ESUS trial will show that rivaroxaban is superior to ASA for secondary 
prevention of stroke in patients with ESUS. 
Rivaroxaban has been well tolerated in all studies conducted to date.  The main safety finding 
is bleeding, a recognized complication shared by all anticoagulants.  Occurrence of major 
bleeding is relatively low and importantly, intracranial bleeding was substantially lower in 
patients receiving rivaroxaban compared to warfarin in the ROCKET-AF study. 
The 15 mg o.d. dose for rivaroxaban has been selected to balance benefit and risk for ESUS 
patients treated in the study.
Approximately 25% of the worldwide stroke incidence is caused by ESUS.  If the results of 
this trial, which will focus on this population of patients, favor the use of rivaroxaban, 
millions of patients could benefit from this treatment.
2. Study objectives
The primary efficacy objective is:

To evaluate whether rivaroxaban is superior to aspirin in reducing the risk of recurrent 
stroke and systemic embolism in patients with a recent ESUS
The secondary efficacy objective is:

To evaluate whether rivaroxaban is superior to aspirin in reducing the risk of 
cerebrovascular events, cardiovascular events, and mortality in patients with a recent 
ESUS
The safety objective is to document the incidence of clinically relevant bleeding.
3. Investigators and other study personnel
3.1
Investigator
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature sheet before patient
recruitment may start at the respective center.  Likewise, all protocol amendments/integrated 
protocols must be signed and dated by the principal investigator before coming into effect at 
the respective center.
3.2
Study personnel
Study personnel relevant for the centers will be available in each center’s investigator site 
file.
3.3
Study committees
Separate charters will be prepared for all study committees overseeing the study including the 
personnel, responsibilities, procedures, and meeting frequencies.  


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3.3.1
Steering Committee
The Steering Committee (SC) will consist of the 2 co-principal investigators, National 
Leaders from all countries, and sponsor representatives. The SC will be responsible for all 
scientific aspects of the study and will ensure that study execution and management of the 
study are of the highest quality. The SC will convene regularly to discuss and report on 
ongoing supervision of the study.
3.3.2
Independent Data Monitoring Committee
The primary role of the IDMC is to ensure the safety of the patients in the ongoing study. 
The IDMC will comprise a chair, co-chair, and members who have recognized expertise in 
clinical trials, neurologic and/or cardiovascular disease, and biostatistics; and who are not 
members of the SC, or involved as investigators or otherwise in the trial.
3.3.3
Independent Central Adjudication Committee
The Independent Central Adjudication Committee (ICAC) will comprise members with 
clinical and methodological expertise in neurology and cardiology who will be responsible 
for adjudication and classification of outcome events in the study.
4. Study design
4.1
Overview
This is a multicenter, randomized, double-blind, double-dummy, active-comparator, 
event-driven, superiority study in patients with a recent ESUS. 
Following provision of informed consent, patients who meet all of the inclusion criteria and 
none of the exclusion criteria will be randomly allocated by an interactive voice/web response 
system (IxRS) to either rivaroxaban 15 mg o.d. or ASA 100 mg o.d. in a 1:1 ratio. No dose 
adjustment will be made for patients with mild or moderate renal impairment.  
Patients may be randomized and receive the first study medication intake between 7 days and 
6 months after the index stroke event.  In case of minor strokes (National Institutes of Health 
Stroke Score [NIHSS] ≤ 3), study medication may be initiated as early as 3 days after stroke 
onset if all eligibility assessments have been completed. In the presence of hemorrhagic 
transformation on the qualifying brain imaging study or if intravenous thrombolysis therapy 
was given for the index stroke, study medication will not be initiated before 10 days after the 
acute stroke event unless a repeat CT or magnetic resonance imaging (MRI) performed before 
randomization documents the absence of new or extension of hemorrhage.  
Patients will be randomized9 as early as possible after the required diagnostic evaluation is 
complete and eligibility criteria are fulfilled.  The goal is that the majority of patients are 
enrolled within 3 months, and fewer patients between 3 and 6 months.
Randomization will be stratified by country and age <60 and ≥60 years.  Patients < 60 years 
will need to have at least one risk factor such as stroke (includes covert/silent strokes on 
                                                
9 Prior to global Protocol Amendment 5, “randomized” was “enrolled.”


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neuroimaging) or TIA prior to index stroke, diabetes, hypertension, current tobacco smoker or
heart failure. 10
At randomization, patients will receive study medication and instructions for its 
administration.  Thereafter, patients will return to the clinic at 1, 6, and 12 months and then 
every 6 months until the end of study (efficacy cut-off date) is announced.  At 3 months, the 
patient will be contacted by telephone.  Throughout the study and at clinic visits, patients will 
be assessed for efficacy (stroke, systemic embolism, MI, CV death, or all-cause mortality) 
and safety (vital signs, bleeding, serious adverse events [SAEs] which are not outcome 
events, non-serious adverse events [AEs] leading to permanent discontinuation of study 
treatment, and any non-serious AEs of particular concern to the investigator).
The trial will continue until approximately 450 patients are anticipated to have experienced a 
positively adjudicated primary efficacy outcome event.  This is anticipated to occur 
approximately 3 years after the first patient is randomized, but may vary depending on the 
recruitment rate as well as the primary event rate.  A telephone safety visit will be performed 
1 month after the end-of-treatment (EOT) visit. 
Patients permanently discontinuing study treatment will continue to be followed, and 
outcome events and vital status must be assessed in these patients until the end of the study 
via either clinic visits or telephone contacts. 
All efficacy and safety analyses are based on time from randomization to time of first event.  
Suspected clinical study outcomes will be assessed by the ICAC, which will be blinded to 
treatment allocation.  Adjudicated results will be the basis for the final analyses.  The IDMC 
will monitor patient safety during the study and give recommendations to the SC and sponsor. 
A schematic of the study design is provided in Figure 4–1.
Figure 4–1:  Study design schematic - amended
                                                
10 Paragraph revised with global Protocol Amendment 5.  See Section 13.1 for details.


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4.2
Justification of the design
The target patient population comprises patients with a recent ESUS.  These patients have 
substantial risk for recurrent stroke and other thromboembolic events despite antiplatelet 
therapy, the current standard of care.  A double-blind, randomized trial design comparing 
rivaroxaban with ASA is deemed the most appropriate design to allow for an unbiased 
evaluation of rivaroxaban as a treatment option for this patient population in an international 
trial.
4.3
End of study
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit of the last patient for all centers in the respective 
country has occurred.  However, as the primary efficacy outcome of this study is event-driven 
and requires adjudication by an ICAC, the end of the study as a whole will only be reached 
when the final efficacy outcome event has been adjudicated for patients from all participating 
clinical sites (EU and non-EU).
5. Study population – amended 
This Phase III, multi-national, study will be conducted in approximately 30 countries11
worldwide in approximately 7000 patients recruited primarily from hospital-based stroke 
units.  Patients who will be enrolled in this study must meet all of the inclusion criteria and 
none of the exclusion criteria listed in Section 5.1.
5.1
Eligibility
5.1.1
Inclusion criteria - amended
1. Embolic stroke of undetermined source (ESUS) defined as:

Recent ischemic stroke (including TIA with positive neuroimaging) visualized by
brain CT or MRI that is not lacunar (i.e., lacunar infarcts are subcortical infarcts 
≤1.5 cm in the territory of middle cerebral artery or pons; infarcts involving the 
cerebellum or lateral medulla are not considered as lacunar infarcts). Patients with 
multiple simultaneous acute lacunar infarcts on DWI imaging may be included.  In 
case of embolic large artery occlusions clearly documented on angiography who 
undergo successful recanalization, visualization of infarct on neuroimaging is not
mandated 12, and

Absence of cervical carotid atherosclerotic stenosis (or vertebral and basilar artery 
atherosclerotic stenosis in case of posterior circulation stroke), that is > 50%, or 
occlusion in arteries supplying the area of ischemia in CT or magnetic resonance 
(MR) angiography or conventional angiography or ultrasound, and 13
                                                
11 Was 25 to 30 countries prior to global Protocol Amendment 5.
12 Text was revised with global Protocol Amendment 5.  See Section 13.1 for details.
13 Bulleted text was revised with global Protocol Amendment 5.  See Section 13.1 for details.


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
No history of AF, no documented AF on 12-lead electrocardiogram (ECG) or episode 
of AF lasting 6 minutes or longer detected after ≥24-hour cardiac rhythm monitoring
(Holter or telemetry; at least 20 hours acceptable14), and

No intra-cardiac thrombus on either transesophageal or transthoracic 
echocardiography15, and

No other specific cause of stroke identified by routine clinical care (e.g., arteritis, 
dissection, migraine/vasospasm, drug abuse)
2. Time from recent ischemic stroke to randomization and first study medication intake (and 
only if the investigator regards it as safe to initiate therapy with an anticoagulant) between 
7 days and 6 months except:

in case of minor strokes (NIHSS ≤3), study medication may be initiated as early as 
3 days after stroke onset.

in case of intravenous thrombolysis treatment or hemorrhagic transformation seen on 
the qualifying CT or MRI, study medication will not be initiated before 10 days after 
the acute stroke event unless a repeat CT or MRI scan performed before 
randomization documents the absence of new or extension of hemorrhage.
3. All planned diagnostic tests for stroke evaluation must be completed.  Brain imaging and 
24-hour cardiac monitoring must be repeated if new symptoms of stroke/TIA occurred 
after the initial stroke evaluation, as does 24-hour cardiac monitoring if symptoms 
suggestive of AF occur.
4. Age ≥50 years 16
5. For patients with age 50-59 years at least one of the following risk factors: stroke or TIA 
prior to index stroke (includes covert/silent strokes on neuroimaging), diabetes, 
hypertension, current tobacco smoker, or heart failure.17
6. Written informed consent consistent with local regulations governing research in human 
subjects
5.1.2
Exclusion criteria - amended
1. Severely disabling stroke (modified Rankin score ≥4 at screening)
2. If imaging of intracranial arteries is performed by CT or MR angiography or transcranial 
Doppler:  > 50% luminal stenosis or occlusion in arteries supplying the area of ischemia18
3. Patent foramen ovale with plans for closure
4. Known serious infection or inflammatory disease that may be the cause of stroke
                                                
14 Global Protocol Amendment 5 added the allowance of monitoring for at least 20 hours to reflect routine 
practice.
15  Transesophageal was added with global Protocol Amendment 5.
16 Prior to global Protocol Amendment 5, patients were eligible for inclusion if they were ≥18 years of age (or 
>18 years based on country).  See Section 13.1.1 for additional details.
17 This criterion was revised with global Protocol Amendment 5.  See Section 13.1 for details.
18 Prior to global Protocol Amendment 5, luminal stenosis or occlusion was ≥ 50%.  See Section 13.1 for details.


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5. Patient has or is intended to receive an implantable ECG loop recorder 
6. Indication for chronic anticoagulation based on guideline recommendations or 
investigator´s judgment; e.g., patient with prosthetic mechanical valve, venous 
thromboembolism, hypercoagulable state 
7. Indication for chronic antiplatelet therapy based on investigator´s judgment, in which 
anticoagulation is not a reasonable substitute, or chronic therapy with a conventional non-
steroid anti-inflammatory drug (NSAID) for a non-stroke indication
8. Hypersensitivity or any other contraindication listed in the local labeling for ASA or 
rivaroxaban 
9. Active bleeding, major bleeding within last 6 months, high risk for serious bleeding 
contraindicating anticoagulant or antiplatelet therapy or history of primary intracranial 
hemorrhage19
10. Hepatic disease associated with coagulopathy (prothrombin time prolonged beyond the 
normal range) and clinically relevant bleeding risk including cirrhotic patients with Child 
Pugh B and C
11. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 as assessed at local 
laboratory within 1 month of screening
12. Life expectancy less than 6 months
13. Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 (CYP3A4) 
and P-glycoprotein (P-gp), i.e., human immunodeficiency virus protease inhibitors and 
the following azole-antimycotics agents: ketoconazole, itraconazole, voriconazole, or 
posaconazole, if used systemically
14. Female of childbearing potential who are not surgically sterile, or, if sexually active not 
willing to use adequate contraceptive measures with a failure rate less than 1% per year
(e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, 
double-barrier method, male partner sterilization) before entry and throughout the study,
as well as pregnant or breast feeding women
15. Inability to cooperate with the study procedures 
16. Previous randomization to this study or participation in a study with an investigational 
drug or medical device within 30 days prior to randomization
17. Close affiliation with the investigational site; e.g. a close relative of the investigator, 
dependent person (e.g., employee or student of the investigational site)
5.2
Discontinuation of patients from study treatment - amended
An excessive rate of patient discontinuations from either treatment or “drop-outs” from the 
study may render the trial non-interpretable.  In this study, outcome events and vital status 
data are crucial to the primary analysis and must be collected until the end of the study, even 
if patients are no longer taking study medication.  Therefore, all efforts will be taken to 
                                                
19 Criterion revised with global Protocol Amendment 5.  See Section 13.1 for details.


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motivate patients to comply with all study procedures and to continue to be followed 
until the end of the trial.
Patients may discontinue study medication at their own request and without giving reasons 
(even though providing a reason is encouraged), based on the investigator´s judgment, if the 
patient is pregnant, or at the request of the sponsor (exceptional circumstances). In case a 
patient is diagnosed with atrial fibrillation with an episode of at least 6 minutes during the 
study trial medication must be stopped (see section 6.9.2).20 Study drug will not be 
routinely discontinued in participants reaching a potential outcome event unless there is 
a safety concern or a clear indication for an alternative antithrombotic therapy as 
determined by the local investigator.
In case of a temporary study medication interruption21 for any reason, study medication will 
be restarted as soon as medically justified in the opinion of the investigator.  There is no 
defined maximum limit for temporary treatment interruption.  
For all patients who permanently discontinue study medication, the patients will still be 
part of the study, and outcome events and vital status must be reported until the efficacy 
cut-off date for the study is announced.  All safety data will continue to be collected for 1 
month after the last study medication intake (safety follow-up visit).  The investigator and 
patient must discuss and determine further follow-up options.  Options for follow-up are 
listed below, in descending order of preference:
1. Patient continues the regular study clinic visits at the investigator’s site as outlined in 
the protocol
2. Patient will be contacted by phone at the regular follow-up intervals
3. Patient allows his/her general practitioner or a family relative to be contacted (if 
allowed in respective country) at the regular follow-up interval
4. Patient will be contacted once at the end of the study 
5. Patient withdraws consent.  This will be the last option and means that the patient 
does not agree to any kind of follow-up and specifically refuses any further contact 
with the investigator.  This should happen only in exceptional cases.  If possible by 
local regulations, this decision will be provided in writing.  Vital status will be 
obtained at study end through public information according to local guidelines and as 
allowed by local regulations.
For patients who do not agree to attend regular study visits, the investigator will encourage 
the patient to return to the clinic for at least one final visit in order to perform all assessments 
as outlined for the EOT visit.
If a patient fails to return for a study visit or is lost-to-follow-up, the investigator should 
explore all possible options to contact the patient.  In that respect, the investigator should ask 
the patient at the study start for the contact details of a relative or friend who can be contacted 
in case the patient cannot be reached.  The site must document all attempts to try to contact 
the patient in the medical records/source documents.  If all attempts fail, depending on local 
                                                
20 Global Protocol Amendment 5 added “with an episode of at least 6 minutes” to this sentence.
21 Prior to global Protocol Amendment 5, “interruption” had been “discontinuation.”


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legislation, death registries or other registries may be accessed or private investigation to 
locate a patient may be initiated.
If study medication is temporarily interrupted or permanently discontinued, the investigator 
will document the reason for in the medical records and on the electronic case report form 
(eCRF).22
5.3
Patient identification
Each patient will be allocated a unique patient identification number after informed consent is 
obtained and an additional randomization number will be assigned by IxRS at time of 
randomization. This randomization number will allow subsequent identification of treatment 
allocation.
6. Treatments
6.1
Treatments to be administered
The treatments to be administered are rivaroxaban 15 mg o.d. or ASA 100 mg o.d..
6.2
Identity of study treatment
All study drugs will be labeled according to the requirements of local law and legislation.  
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.
For all study drugs, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk ware of the ingredients.  Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies Quality Assurance (QA) group. 
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor study file.
6.3
Treatment assignment - amended
Patients will be randomly assigned to treatment in a blinded manner to one of 2 study arms:

Rivaroxaban plus placebo ASA

ASA plus placebo rivaroxaban
Allocation to treatment will be done centrally by IxRS. Allocation will be performed in a 
1:1 ratio to each study treatment and will be stratified by country and by age (<60 or ≥60 
year).
Specific procedures for treatment assignment through the IxRS are described in the IxRS 
manual.23
                                                
22 Global Protocol Amendment 5 deleted the following sentence from this section: “Patients who permanently 
discontinue the study for any reason will not be reactivated”  because this section covers discontinuation of 
study treatment, not study, and this point is covered by exclusion criterion 16.


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6.4
Dosage and administration
Patients will be provided with a high-density polyethylene (HDPE) -bottle containing 
immediate-release film-coated tablets of rivaroxaban 15 mg or matching placebo and an 
HDPE bottle containing enteric-coated tablets of ASA 100 mg or matching placebo. 
One tablet from each bottle should be taken once daily with food. If a dose is missed the 
patient should take study medication immediately and continue on the following day with the 
once daily intake. The dose should not be doubled within the same day to make up for a 
missed dose.
6.5
Blinding
The study is double-blinded using matching placebo medication as described in Section 6.4.
6.5.1
Emergency unblinding by the investigator - amended
Unnecessary unblinding should be avoided and should only be undertaken by the investigator 
or the treating physician when it is essential for the patient´s safety. In such a situation, the 
investigator will be able to unblind the patient via the country toll-free help line. 24
Investigators will be provided with the details on the emergency unblinding procedure at 
study start.
For unblinding in case of a Suspected Unexpected Serious Adverse Reaction (SUSAR) see 
Section 7.5.3.2.
6.6
Drug logistics and accountability
Study medication will be provided by Bayer and labeled according to local law and 
regulation. A complete record of batch numbers, expiry dates and labels will be maintained 
in the study file.
All study medication needs to be stored at the investigational site according to the labeled 
storage advice and in accordance with Good Clinical Practice (GCP) and GMP requirements. 
Study medication should not be stored above 30°C. The study drug is to be kept in a secure 
area (e.g., locked cabinet) without access to unauthorized personnel. Site personnel will 
confirm receipt of study medication via IxRS and will use study medication only for this 
study and in accordance with this protocol. Receipt, distribution, return and destruction (if 
any) of the study medication must be properly documented according to local regulation and 
specified procedures.
Written instructions on medication destruction for unused medication returned to the sites by 
the patient as well as undispensed medication will be made available to affected parties as 
applicable.
                                                                                                                                                       
23 The following sentence was deleted from this section with global Protocol Amendment 5:  “No more than 
10% of the total patient number will be randomized into the age group <60 years.”  See Section 13.1 for details.
24 This paragraph was revised with global Protocol Amendment 5.  See Section 13.1 for details.


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6.7
Treatment compliance - amended
Compliance will be evaluated by interview and by counting the tablets returned by the patient 
to the site versus the tablets expected to be taken by the patient.
First dose, last dose, and any dose interruptions of study medication due to AEs, study 
outcome events,25 or of >7 days for any other reason will be reported in the eCRF.
6.8
Post-study therapy
After discontinuation of study medication (either at study end or in case of permanent 
premature discontinuation), initiation of standard of care therapy is the responsibility and at 
the discretion of the investigator.
6.9
Prior and concomitant therapy - amended
Acute and chronic therapies given for the qualifying stroke will be recorded in the eCRF.  
During the study, chronic concomitant therapy will be recorded at the visits (cerebro- and 
cardiovascular therapies) or at the time of occurrence of any efficacy outcome, bleeding, or 
SAE.
For patients at risk of ulcerative gastrointestinal disease or bleeding or who develop 
symptoms of these complications during the study, an appropriate gastro-protective 
prophylactic treatment may be recommended by the investigator but will not be supplied by 
the study.
26No specific concomitant medications are prohibited other than strong inhibitors of both 
CYP3A4 and Pgp inhibitors.  This includes human immunodeficiency virus protease 
inhibitors and the following azole antimycotics agents:  ketoconazole, itraconazole, 
voriconazole, or posaconazole, if used systemically.  However, fluconazole is allowed.
In addition, concomitant use with antiplatelets and anticoagulants is outlined in the sections 
below.
6.9.1
Guidance for management of participants who require antiplatelet 
therapy or non-steroidal anti-inflammatory drug during the study
Patients who enter the study receiving antiplatelet therapy (e.g., ASA) will have non-study 
antiplatelet therapy discontinued when study medication is started.
The concomitant use of NSAID and non-study antiplatelet therapy during the study is 
strongly discouraged since it increases the risk for bleeding.  However, if a NSAID drug is 
indicated, the lowest possible dosage must be selected.  Should analgesics be needed, use of 
paracetamol/acetaminophen is recommended.
                                                
25 Global Protocol Amendment 5 added “study outcome events” to this sentence.
26 The last 2 paragraphs in this section were added with global Protocol Amendment 5.


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6.9.2
Guidance for management of participants who have atrial fibrillation 
identified during study - amended
If a patient is diagnosed with AF during the study that requires oral anticoagulation according 
to the investigator´s judgment, the patient will stop double-blind study medication.  Per 
protocol, study medication must be permanently discontinued if AF is seen in a 12-lead ECG 
or if an AF episode of ≥6 minutes is identified during cardiac monitoring.27  The patient will 
be offered open-label rivaroxaban according to the local label (if acceptable by local 
regulations) or alternatively, the investigator may prescribe other standard of care e.g., VKA.  
If the patient is switched to a VKA, adequate anticoagulation during the initiation phase needs 
to be ensured according to the Xarelto® Summary of Product Characteristics, due to the 
length of time required to achieve therapeutic anticoagulation with VKAs.
Patients receiving open-label rivaroxaban will continue with the regular study visits.  For 
patients treated differently, the instructions for permanent discontinuation of study medication 
as outlined in Section 5.2 should be followed. 
6.9.3
Guidance for management of participants who have coronary artery 
disease identified during the study
Patients diagnosed with coronary artery disease (CAD) during the study and in whom 
treatment with dual antiplatelet therapy is warranted (e.g., after percutaneous coronary 
intervention [PCI]) will interrupt study medication for the duration of dual antiplatelet 
therapy, as the combination of dual antiplatelet therapy and rivaroxaban 15 mg may lead to an 
increased bleeding risk.  Study medication will be restarted once dual antiplatelet therapy is 
stopped.
For patients in whom treatment with ASA is recommended (e.g., stable CAD) the investigator 
can consider continuing study medication with non-study ASA only if the dose of ASA is 
<100 mg daily.  Use of higher doses of ASA will require interruption of study medication.
6.9.4
Guidance for management of participants who have a recurrent 
ischemic stroke during the study
For patients who have a recurrent ischemic stroke during the study, a complete diagnostic 
work-up including brain imaging, at least 24-hour cardiac rhythm monitoring, and 
echocardiography is encouraged.  All available clinically-obtained diagnostic results will be 
recorded on eCRFs for the purposes of event adjudication and secondary analyses.
No high-quality data are available regarding the use of intravenous thrombolysis for acute 
stroke in patients receiving rivaroxaban; therefore, the use of thrombolytic agents will follow 
local practice. 
Based on the half-life of rivaroxaban of 11-13 hours in elderly patients, it may be anticipated 
that little or no drug is present in circulation, if the last dose of study medication was given at 
least 48 hours before.  The anti-Factor Xa chromogenic assay, when used with validated 
calibrators and controls and where available, may be used to confirm that little or no residual 
                                                
27 This sentence was modified with global Protocol Amendment 5.  See Section 13.1 for details.


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anticoagulant effect is present.  In addition, a normal prothrombin time (PT) value (measured 
using a rivaroxaban-sensitive reagent) suggests there is no clinically relevant anticoagulant 
effect of rivaroxaban.
As there is no contraindication for use of intravenous thrombolysis in patients with acute 
ischemic stroke who are receiving ASA, the treatment assignment can be emergently 
unblinded to facilitate decisions regarding intravenous thrombolysis.
Mechanical clot removal may be performed in any case.
6.9.5
Guidance for management of participants who have bleeding during 
the study
If a patient has serious bleeding during study treatment, the following routine measures could 
be considered:

Delay the next study medication administration or discontinue study medication, if 
indicated

Consider usual supportive treatment for bleeding, including local control of bleeding 
(if possible), fluid replacement, and blood transfusion
If bleeding cannot be controlled, consider administration of one of the following 
procoagulants (according to the dosages advised in the package insert):

Prothrombin complex concentrate (PCC)

Activated prothrombin complex concentrate (APCC)

Recombinant Factor VIIa 
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of 
rivaroxaban. Due to the high plasma protein binding, rivaroxaban is not expected to be 
dialysable.
6.9.6
Guidance for management of participants with overdose
Due to limited absorption, a ceiling effect with no further increase in average plasma 
exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.
A specific antidote is not available.  The use of activated charcoal to reduce absorption may 
be considered.
7. Procedures and variables
7.1
Schedule of procedures
As this is an event-driven study, patients will have different numbers of study visits.  Patients 
will visit the clinic at screening, randomization, 1, 6, and 12 months and then every 6 months 
until the end of the study.  At 3 months after randomization, the patient will be contacted by 
telephone.  Patients will come to the clinic for an EOT visit followed by a telephone contact 
(Safety Visit) 1 month later.


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7.1.1
Tabulated overview
A tabulated overview of the procedures conducted in this study is provided in the Table of 
procedures, provided at the end of the Synopsis.
7.1.2
Timing of assessments
7.1.2.1
Visit 1 (screening) - amended
Visit 1 will be used to assess the eligibility of the patient.  After obtaining signed informed 
consent, the investigator will review the diagnostic tests required to diagnose ESUS.  All 
diagnostic assessments for ESUS should be completed before the screening visit.  If 
prolonged cardiac rhythm monitoring and/or echocardiography are not performed at time of 
screening, this can be done during the screening period.  All acute therapies for stroke (e.g., 
thrombolysis) and diagnostic tests performed to diagnose acute stroke and ESUS will be 
recorded in the eCRF. 28  
Demographic data (age, gender, race/ethnicity), weight (kg), height (cm), and medical history 
including reporting of stroke risk factors will be recorded at this visit.  Laboratory 
assessments will include creatinine and eGFR (if not conducted at local laboratory within 1 
month before screening, use value for eGFR as reported on laboratory report, otherwise 
calculate eGFR using MDRD formula, for which a calculator can be found for example on 
the internet www.mdrd.com) and pregnancy testing (only in women of childbearing 
potential).  The modified Rankin score will be assessed as part of the exclusion criteria and 
NIHSS as part of the inclusion criteria.
The screening period will be 6 weeks maximum.29
7.1.2.2
Visit 2 (randomization visit) - amended
Once all inclusion/exclusion criteria are fulfilled the patient will be randomized by accessing 
the IxRS system.  The study medication will be assigned, and the patient will receive the 
study medication and instructions for its administration. The first dose of study medication 
can be given at this visit or at the time the patient will usually take study medication (same 
day or next day).
During this visit, study procedures will include the recording of ConMeds (Section 6.9) and 
vital signs (blood pressure [millimeters of mercury; mmHg] and heart rate [beats per minute; 
bpm].  Outcomes research questionnaires (Section 7.6.1) will be completed by the patient: 30

European Quality of Life-5 Dimensions (EQ-5D) Questionnaire 

Montreal Cognitive Assessment (MoCA) 

Standard Assessment of Global-Activities in the Elderly (SAGE) questionnaire 
                                                
28 This paragraph was revised with global Protocol Amendment 5.  See Section 13.1 for details.
29 This sentence was added with global Protocol Amendment 5.
30 The DSS test was removed with global Protocol Amendment 5 because implementation is not feasible due to 
a missing license. 


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Procedures for Visits 1 and 2 may be combined and performed at the same visit, if all 
eligibility criteria can be assessed at Visit 1 and no additional assessments are required before 
randomization (e.g., eGFR).
7.1.2.3
Regular study visits (visits 3 and onward) - amended
Patients will return to the study clinic at 1 month, 6 months, and then every 6 months.  
Patients who are at a rehabilitation or other clinic at the time of the 1 month visit (Visit 3), 
more flexibility will be allowed and this visit can be performed as a phone call instead of an 
onsite visit. 31 At 3 months, the patient will receive a telephone call to obtain safety and 
outcome data and reinforce adherence to study medication and to avoiding non-study ASA.
The patient will be instructed to report any hospitalization or other significant illness to the 
investigator on an ongoing basis in order to allow a timely reporting of study outcomes and 
SAEs.  In addition, at all visits, the patient will be specifically asked about potential study 
outcomes and AEs.  If a suspected study outcome is reported, the respective eCRF will be 
completed and an adjudication package expeditiously compiled and submitted.
Vital signs will be collected at 6 months, 1 year, and then yearly thereafter.
Concomitant medications and weight will be collected once per year.  If an SAE or study 
outcome event is reported, the use of any additional ConMeds should be recorded at that 
time.32
The outcomes research questionnaires (MoCA and SAGE)33 will be completed by the patient 
at the 1 year visit only.  The EQ-5D will be completed every 6 months.
If a recurrent stroke is reported, the modified Rankin Score is to be assessed at 7 days post 
stroke or at hospital discharge, if this occurs before 7 days, and again at 3-6 months post 
stroke.34  The modified Rankin score is also to be recorded at 1 year after stroke.
Study medication will be dispensed and returned every 6 months and study drug 
accountability and compliance will be recorded at these visits.
7.1.2.4
End of treatment (EOT) visit - amended
Within the trial close-out window prior to the end of the study (efficacy cut-off date), all 
patients must return to the clinic within 6 weeks in order to make a final assessment.  In 
addition, for patients that permanently discontinued study medication and when further 
follow-up will no longer be done by site visits and rather by phone or third party contact, the 
patient will be encouraged to come for the EOT visit as soon as possible after discontinuation 
of study medication. For these patients a final vital status and outcome events will be 
collected during the trial close-out window.  At this EOT visit, study procedures will include 
the collection of efficacy and safety outcome data, (S)AEs, vital signs, ConMeds, EQ-5D, 
                                                
31 Sentence was added with global Protocol Amendment 5 to allow flexibility for patients after a stroke.
32 Global Protocol Amendment 5 added “or study outcome event” to this sentence for clarification.
33 The DSS test was removed with global Protocol Amendment 5 because implementation is not feasible due to 
a missing license.
34 The 3-month time point was expanded to 3-6 months with global Protocol Amendment 5 to allow flexibility 
and avoid additional visits.


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MoCA, and SAGE questionnaires, and modified Rankin score.  In addition, the study staff 
will collect the patient’s empty and unused study medication bottles to allow final drug 
accountability and compliance checks. 35
Study medication will be stopped at this visit, and it will be left to the discretion of the 
investigator to initiate any antiplatelet or anticoagulation therapy during the transition of care 
to the patient’s personal physicians.
7.1.2.5
Safety visit
Patients will be contacted by telephone 1 month after the last study medication intake to 
allow the collection of safety data.
7.2
Population characteristics
7.2.1
Demographics
Demographics include age, gender, race/ethnicity
7.2.2
Medical history
Medical history findings (i.e., previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected: 

Not pertaining to the study indication 

Start before signing of the informed consent form (ICF)

Considered relevant to the study
Medical history parameters to be collected at screening will include:

Disease history associated with cerebro- and cardiovascular diseases and risk factors 
(stroke, transient ischemic attack, MI, angina pectoris, heart failure, peripheral artery 
disease, diabetes, hypertension, tobacco use) 

Surgical history (cerebro- and cardiovascular revascularizations) 

Other relevant diseases (renal dysfunction, liver disease, cancer, bleeding requiring 
transfusion)
7.3
Efficacy
7.3.1
Assessments and procedures at occurrence of efficacy outcome events
The analysis of efficacy outcome events will be based on events as adjudicated by the ICAC.
Occurrence of outcomes must be reported within 3 days of the site’s notification of the event.
Patients are requested to inform the site as soon as possible if they are hospitalized (regardless 
of reason) in order to ensure timely identification of potential CV events.
                                                
35 This paragraph was amended with global Protocol Amendment 5.  See Section 13.1 for details.


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The following events will be reported on Outcome/CV Event reporting forms and will 
undergo adjudication by the ICAC: 

All deaths

Stroke (ischemic, hemorrhagic or undetermined) and TIA

Systemic embolism

MI and hospitalization for cardiac chest pain
These events are exempted from SAE reporting with the exception of non-CV deaths.
In addition to investigator identified CV events, safety data will be reviewed regularly for 
potential CV events.  In particular, Medical Dictionary for Regulatory Activities (MedDRA) 
preferred terms assigned to investigator reported AEs will be screened for potential outcome 
events and investigators may then be asked to further investigate whether or not a CV event 
occurred and potentially initiate the outcomes reporting process.
7.3.2
Definition of efficacy outcome events
The following efficacy outcome events will be assessed and are defined in the following 
subsections of this protocol:  

stroke (Section 7.3.2.1) 

systemic embolism (Section 7.3.2.2) 

MI (Section 7.3.2.3) 

CV death (Section 7.3.2.4) 

all-cause mortality (Section 7.3.2.5) 
Additional standard definitions for these efficacy outcomes will be provided in a separate 
ICAC manual.
7.3.2.1
Stroke
Stroke is an acute episode of neurological dysfunction caused by focal or global brain 
vascular injury and includes ischemic stroke, hemorrhagic stroke, and undetermined stroke.  
This includes fatal and non-fatal strokes.  In case signs and symptoms resolve <24 hours, 
stroke requires neuroimaging evidence of acute brain ischemia (i.e. TIA with positive 
neuroimaging).
7.3.2.2
Systemic embolism
Systemic embolism is defined as abrupt vascular insufficiency associated with clinical or 
radiological evidence of arterial occlusion in the absence of other likely mechanisms.
7.3.2.3
Myocardial infarction
The term acute MI is used when there is evidence of myocardial necrosis in a clinical setting 
consistent with acute myocardial ischemia. The diagnosis of MI requires the combination of:


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
Evidence of myocardial necrosis (either changes in cardiac biomarkers or 
post-mortem pathological findings); and

Supporting information derived from the clinical presentation, electrocardiographic 
changes, or the results of myocardial or coronary artery imaging
The MI Universal Definition from 2012 (28) describes 5 types of myocardial infarction:

Type 1 Spontaneous myocardial infarction

Type 2 MI secondary to an ischemic imbalance

Type 3 MI resulting in death when biomarker values are unavailable

Type 4a MI related to percutaneous coronary intervention (PCI) 

Type 4b MI related to stent thrombosis

Type 5 MI related to coronary artery bypass grafting (CABG)
7.3.2.4
Cardiovascular death
Cardiovascular death includes death due to stroke, myocardial infarction, heart failure or 
cardiogenic shock, sudden death or any other death due to other cardiovascular causes. In 
addition, death due to hemorrhage will be included.
7.3.2.5
All-cause mortality
All-cause mortality includes all deaths.
7.3.3
Efficacy variables
7.3.3.1
Primary efficacy variable
The primary efficacy variable is the time from randomization to first occurrence of any of the 
components of the composite outcome (adjudicated), including:

Stroke (ischemic, hemorrhagic, and undefined stroke, TIA with positive 
neuroimaging)

Systemic embolism
7.3.3.2
Secondary efficacy variables
The secondary efficacy variables of this study are the time from randomization to first 
occurrence of:

Cardiovascular death (including death due to hemorrhage), recurrent stroke, systemic 
embolism, and MI

All-cause mortality

Individual components of the primary and secondary efficacy outcomes (stroke, CV 
death, and MI) as well as ischemic stroke, and disabling stroke (modified Rankin
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7.4
Pharmacokinetics/pharmacodynamics
Not applicable.
7.5
Safety
The safety outcomes are bleeding events using the International Society on Thrombosis and 
Haemostasis (ISTH) major bleeding definition (29), and other definitions derived from these 
as listed in Section 7.5.1 and Section 7.5.2.  Bleeding events will be reported on the bleeding 
reporting forms and exempted from SAE reporting.  Potential major bleeding will undergo 
adjudication. 
Information on bleeding will be collected in a way to also allow additional analysis using 
different bleeding definitions, e.g., Thrombolysis In Myocardial Infarction (TIMI) major 
bleeding and Global Use of Strategies to Open Occluded Arteries (GUSTO) 
severe/life-threatening bleeding.  The analysis will be defined in the statistical analysis plan 
(SAP).
7.5.1
Primary safety variable - amended
The primary safety variable is the time from randomization to time of first occurrence of a 
major bleeding defined as a bleeding event that meets at least one of the following criteria:

Fatal bleeding, and/or

Symptomatic36 bleeding in a critical area or organ (intracranial, intraocular, 
intraspinal, pericardial, retroperitoneal, intraarticular, or intramuscular with
compartment syndrome), and/or 

Clinically overt bleeding associated with a recent decrease in the hemoglobin level of 
≥2 g/dL37 (20 g/L; 1.24 mmol/L) compared to the most recent hemoglobin value 
available before the event, and/or 

Clinically overt bleeding leading to transfusion of 2 or more units of packed red blood 
cells or whole blood
7.5.2
Secondary safety variables
The secondary safety variables are the time from randomization to time of first occurrence of:

Life-threatening bleeding, defined as a subset of major bleeding that meet at least one 
of the following criteria: 
o
Fatal bleeding
o
Symptomatic intracranial bleeding
o
Reduction in hemoglobin of at least 5 g/dl (50 g/l; 3.10 mmol/L)
o
Transfusion of at least 4 units of packed red cells or whole blood
                                                
36 “Symptomatic” was added with global Protocol Amendment 5 in order to be consistent with the ISTH 
definition.
37 Typographical error corrected with global Protocol Amendment 5 (more than 2 g/dL corrected to ≥ 2 g/dL).


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o
Associated with hypotension requiring the use of intravenous inotropic agents 
o
Necessitated surgical intervention

Clinically relevant non-major bleeding, defined as non-major overt bleeding but
o
Requires medical attention (e.g., hospitalization, medical treatment for 
bleeding), and/or
o
Is associated with a study drug interruption of more than 14 days.

Intracranial hemorrhage
7.5.3
Adverse events
7.5.3.1
Definitions
An adverse event (AE) is any untoward medical occurrence including an exacerbation of a 
pre-existing condition or abnormal laboratory finding in a patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. 
An AE is considered serious (SAE) if it fulfills one or more of the following criteria: 

Results in death

Is life-threatening

Requires or prolongs hospitalization

Is a congenital anomaly or birth defect 

Is a persistent or significant disability/incapacity

Is another important medical event
Important medical event: Any adverse event may be considered serious because it may 
jeopardize the patient and may require intervention to prevent another serious condition. 
Important medical events either refer to or might be indicative of a serious disease state. 
Such reports warrant special attention because of their possible association with serious 
disease state and may lead to more decisive action than reports on other terms.
Hospitalizations, which were planned before inclusion in the study (e.g., elective or scheduled 
surgery or other interventions arranged prior to the start of the study), will not be regarded as 
SAEs. This pertains also to hospitalizations which are ambulant (<12 hours) or are part of the 
normal treatment or monitoring of the studied disease or another disease present before 
inclusion in the study and which are not due to a worsening of the disease.
When AEs are captured on the Adverse Event Report Form of the eCRF its seriousness, 
duration, relationship to study drug, action taken, and outcome must be addressed. 
7.5.3.2
Adverse event reporting - amended
The safety observation period extends from the time the signed informed consent is 
obtained through the completion of the final study visit, 1 month post the EOT visit.  In case 


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of permanent discontinuation of study medication, AEs other than outcome events must be 
reported up to 1 month after the last dose of study medication intake (Safety Visit). 
All SAEs, all non-serious AEs leading to permanent discontinuation of study-drug treatment, 
and any non-serious AEs of particular concern to the investigator will be captured in the 
eCRF.  Other non-serious AEs will not be collected due to the large available safety database 
for rivaroxaban.  
The following detailed rules apply to AE and SAE handling: 

SAEs which are primary or secondary efficacy outcomes or appear indicative of an 
outcome event, e.g., TIA, MI or cardiac chest pain requiring hospitalization will be 
captured on an Outcome/CV Event page of the eCRF.  

All fatal events which are not considered cardiovascular deaths will be captured as 
outcomes (Death eCRF) but will also be reported to the sponsor’s Pharmacovigilance 
(PV) Department in an expedited manner. 

All bleeding events including fatal bleeding will be captured in the eCRF (Bleeding 
page).  Serious adverse events which are bleeding terms will not be reported to the 
sponsor’s PV Department in an expedited manner.  Symptomatic intracerebral
/intraparenchymal hemorrhages as well as symptomatic subarachnoid hemorrhages 
will be captured as bleeding and as stroke.  All subdural/epidural hematoma and 
asymptomatic intracranial bleeding are only reported as bleeding.38

All other events (including complications of efficacy or safety outcome events) that 
fulfill the seriousness criteria will be reported as SAEs in an expedited manner.

All pregnancies in female study patients or in female partners of a male study patient 
will be reported as Pregnancy reports in an expedited manner.  

Non-serious AEs that have led to permanent study-drug discontinuation will be 
recorded on the AE page of the eCRF. 

Non-serious AEs which the investigator considers of particular concern will be 
recorded on the AE page of the eCRF.  These may include events that are unexpected 
and/or reveal a pattern that is suggestive of a possible causal association or other 
non-serious events significant enough as to prompt the investigator to bring them to 
the attention of the sponsor.

Out of the AEs reported to sponsor’s PV Department, reportable events (i.e., 
SUSARs) will be unblinded and reported to the competent authorities and 
Independent Ethics Committees/Institutional Review Boards (IECs/IRBs) according 
to legal requirements.

In order to maintain the integrity of the study, SUSARs that derive from outcome 
events including complications of outcome events (e.g., those arising from lack of 
expected drug effect or from hemorrhagic events, whether or not fatal) will be 
exempted from unblinding during the course of the trial and from expedited reporting 
                                                
38 The last 2 sentences in this bullet were added with global Protocol Amendment 5 to provide additional 
guidance for documentation in the eCRF.


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as SUSARs.  However, cases including non CV deaths will be eligible for unblinding 
and SUSAR reporting.
If reported, SAEs occurring after the protocol-defined observation period will be processed 
by the sponsor according to all applicable regulations.
A schematic of the outcome and event collection and reporting process is provided in Figure 
7–1.  
Figure 7–1:  Outcome and adverse event collection and reporting schematic
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs described above as requiring expedited reporting to sponsor’s PV Department.  The 
report recipients are detailed in the instructions for SAE reporting included in the Investigator 
File.
The investigator is responsible for continuing to follow all SAE reports (whether or not 
related to study drug) until resolution or until the event is considered chronic and/or stable by 
the investigator and/or other physician who has the responsibility for the patient’s medical 
care.  Follow-up SAE reports will be reported according to the same timelines as initial 
reports, as soon as new significant information becomes available.


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7.5.3.3
Causal relationship of adverse events to study drug
The assessment of the causal relationship between an AE and the use of study drug is a 
clinical decision made by the investigator, who is a qualified physician, based on all available 
information at the time of the completion of the eCRF.  The assessment is based on the 
question whether or not there was a "reasonable possibility" that the study drug caused the 
event.  Possible answers are “yes” or “no”.
An assessment of no would include the existence of a clear alternative explanation. Other 
reason for an assessment of no may be lack of plausibility, e.g., the patient is struck by an 
automobile when there is no indication that the drug caused disorientation that may have 
caused the event; cancer developing a few days after the first drug administration. 
An assessment of yes indicates that there is a reasonable suspicion that the AE is associated 
with the use of the study drug. Factors in assessing the relationship of the AE to study drug 
include the temporal sequence from drug administration (the event should occur after the drug 
is given) and the length of time from drug exposure to event should be evaluated in the 
clinical context of the event. Furthermore, recovery on drug discontinuation (de-challenge), 
and recurrence on drug re-introduction (re-challenge, if available), underlying, concomitant, 
or intercurrent diseases should be evaluated in the context of the natural history and course of 
the disease being treated. In addition, concomitant medication or treatment, the 
pharmacology and pharmacokinetics of study drug should be considered.
7.5.3.4
Intensity of an adverse event, action taken, and outcome - amended
The intensity of an AE is assessed as mild (usually transient in nature and generally not 
interfering with normal activities), moderate (sufficiently discomforting to interfere with 
normal activities), and severe (prevents normal activities).
Any action on study treatment to resolve the AE is to be documented as:  study drug 
withdrawn, interrupted, dose not changed, not applicable, or unknown.39  Other specific 
treatment of AEs will be documented as:  none, remedial drug therapy or other.  The outcome 
of the AE is to be documented as: recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, not recovered/not resolved, fatal or unknown. 
7.5.3.5
Pregnancy reports
For a study patient, the outcome of the pregnancy should be followed up carefully, and any 
abnormal outcome of the mother or the child should be reported. For the pregnancy of a 
partner of a male study patient, all efforts should be made to obtain similar information on 
course and outcome, subject to the partner’s consent. For all pregnancy reports, the forms 
provided are to be used. The investigator should submit them within the same timelines as an 
SAE, i.e., within 24 hours of his/her awareness.
                                                
39 The options “dose reduced” and “dose increased” were removed with global Protocol Amendment 5 as they 
do not pertain to this study.


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7.5.3.6
Expected adverse events
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document which for this study is the most current version of the investigator’s 
brochure (IB)/company core data sheet.  If new relevant safety information is identified, it 
will be integrated into an update of the IB and distributed.  
Unexpected adverse events
An unexpected AE is any AE whose specificity or severity is not consistent with the IB or 
company core data sheet.  Also, reports which add significant information on specificity or 
severity of an already documented AE constitute unexpected AEs.  For example, an event 
more specific or more severe than described in the investigator brochure would be considered 
“unexpected”.  
In compliance with applicable regulations, in the event of a SUSAR, the patient’s treatment 
code will usually be unblinded before reporting to the competent authorities, IECs/IRBs. For 
reporting to investigators the treatment blind, if possible, will be kept. For handling different 
events classified as SUSARs see Section 7.5.3.2.
7.6
Other procedures and variables
7.6.1
Health Economics and Outcomes Research
Patients will be asked to complete a quality of life questionnaire, and 3 cognitive and 
functional assessment questionnaires during the study conduct.
7.6.1.1
Healthcare Resource Use
Health care resource utilization data related to all efficacy and safety outcomes events will be 
collected for all patients during the study. These will include: hospitalizations (total days 
length of stay, intensive care unit/cardiac care unit days, ward type); emergency room visits;
unscheduled outpatient physician consultations; or visits related to bleeding, surgeries, other 
selected procedures (inpatient and outpatient); and post-stroke care (status of care, home 
health or rehabilitation center or long term care). Days off-work will also be documented. 
Only occurrence of these events (with identifying information such as types of procedures) 
will be collected. Country-specific cost data will be linked at a later stage.
7.6.1.2
European Quality of Life-5 Dimensions
A quality of life assessment tool, the European Quality of Life-5 Dimensions Questionnaire 
(EQ-5D) will be administered at Day 0 (randomization), every 6 months, and at the EOT 
visits. This is a standardized instrument for use as a measure of health outcomes. The 
assessment is applicable to a wide range of health conditions and treatments and it provides a 
simple descriptive profile and a single index value for health status. The EQ-5D is primarily 
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7.6.1.3
Montreal Cognitive Assessment and Standard Assessment of Global-
Activities in the Elderly - amended
40The MoCA will be included in the study to assess cognition and the SAGE questionnaire 
will be used to assess functional outcome.  These tests and questionnaires will be
administered at Day 0 (randomization), 1 year, and at the EOT visits.  The patients will be 
asked to independently complete the MoCA test to the best of their ability. Otherwise, the 
reason for not completing must be documented. The SAGE questionnaire may be completed 
with the help of the study staff.
7.6.1.4
Modified Rankin Score - amended
In addition to the regular assessments at screening, 1 year, and EOT, the Modified Rankin 
Score will be assessed by the investigator at 7 days or at discharge, if this occurs before 
7 days, and again at 3-6 months41 after a recurrent stroke. The scale spans 0-6, perfect health 
without symptoms to death.
0 - No symptoms.
1 - No significant disability.  Able to carry out all usual activities, despite some 
symptoms.
2 - Slight disability.  Able to look after own affairs without assistance, but unable to carry 
out all previous activities.
3 - Moderate disability.  Requires some help, but able to walk unassisted.
4 - Moderately severe disability.  Unable to attend to own bodily needs without 
assistance, and unable to walk unassisted.
5 - Severe disability.  Requires constant nursing care and attention, bedridden, 
incontinent.
6 - Dead.
8. Statistical methods and determination of sample size
8.1
General considerations
A general description of the statistical methods is outlined below. An SAP will be provided 
in a separate document and will contain a more technical and detailed description of the 
principal features of the planned analyses, e.g., censoring schemes for time-to-event 
variables.
The core SAP will be finalized prior to study enrollment.  Amendments and/or appendices to 
the core SAP will provide more details on the coding guidelines, data-handling, and output 
tables and figures. These SAP associated documents are targeted for completion 6 months 
                                                
40 The DSS test was deleted with global Protocol Amendment 5 because implementation is not feasible due to 
missing license.
41 The 3-month time point was expanded to 3-6 months with global Protocol Amendment 5 to allow flexibility 
and avoid additional visits.


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before planned study end to take into account emerging data external to the trial that could 
influence study interpretation. All SAP associated documents will be finalized without 
knowledge of any emerging results from the trial.
Analyses will be performed using SAS software (SAS Institute Inc., Cary, NC, USA).
8.2
Analysis sets
8.2.1
Efficacy data set
The efficacy analysis will be based on the ITT population, which comprises all randomized 
patients.  In the International Conference on Harmonisation (ICH) E9 guideline this is also 
termed the full analysis set, FAS.  Patients will be categorized to the group to which they 
were assigned by the IxRS.
8.2.2
Safety data set
The safety analysis will be based upon the safety data set (SAF) which will comprise all 
treated patients, i.e., randomized patients who received at least one dose of study drug.  For 
the purpose of safety analyses, patients will be categorized to the group to which they were 
assigned by the IxRS unless the incorrect treatment was received throughout the study.  
8.2.3
Data scopes
The following data scopes will be defined for efficacy and safety analyses.
Data scope according to intention-to-treat principle
The ITT data scope includes all outcome events observed from randomization until the 
efficacy cut-off date. The follow-up period for each patient will be as long and complete as 
possible. This will be the primary data scope for the efficacy analyses.
Data scope according to treatment
The on-treatment data scope will include all outcome events observed from randomization 
until 2 days following permanent discontinuation of the study drug.
8.3
Variables
The efficacy variables are defined in Sections 7.3.3.1 and 7.3.3.2.
The safety variables are defined in Sections 7.5.1 and 7.5.2.
8.3.1
Subgroup variables
The following subgroup analyses based on baseline demographics are planned:

Age:  <60; 60-75; >75 age 

Sex:  male; female

Race:  White; Black; Asian; other

Region:  North America; South America; Western Europe; Eastern Europe; Asia


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
BMI: < 25; ≥ 25 to < 30; ≥ 30kg/m2

Weight:  <70; 70-90; >90 kg

eGFR:  <50; 50-80; >80 mL/min

Stroke or TIA prior to index event:  yes or no

Time from index stroke to randomization:  ≤30 days; 30 days to 3 months; > 3months

Presence of patent foramen ovale:  present or absent / not known

Cardiac rhythm monitoring:  <48; ≥ 48 hours

Hypertension:  yes or no 

Diabetes:  yes or no
Even though rivaroxaban has not been tested in patients with ESUS, based on earlier studies 
with rivaroxaban a consistent (relative) treatment effect across all of the planned subgroups is 
expected.  However, higher efficacy event rates are expected for the following subgroups:  
older age, females, renal impairment, stroke or TIA prior to index event, hypertension, and 
diabetes.
8.4
Statistical and analytical plans
Summaries by treatment group using appropriate descriptive statistics will be provided for all 
study variables including demographic and baseline characteristics. Mean, median, standard 
deviation, minimum, and maximum will be used to summarize continuous variables. Counts 
and percentages will be used to summarize categorical variables.
8.4.1
Analysis of the primary efficacy variable
In order to evaluate whether rivaroxaban is superior to ASA in prolonging the time to a
primary efficacy outcome event in patients with ESUS, the following null hypothesis (H) will 
be tested at the significance level of 0.025:
H0, PE: SR(t) = SA(t) for all time points t ≥ 0, (i.e. “there is no difference between the 
rivaroxaban treatment group and the ASA control group regarding the primary 
efficacy outcome for all time points”)
The one-sided alternative hypothesis will be:
H1, PE: SR(t) > SA(t) for at least one time point t ≥ 0, and SR(t) ≥ SA(t) for all time 
points t ≥ 0, (i.e. “there is a difference between the two groups in favor of rivaroxaban 
regarding the primary efficacy outcome for at least one time point“)
where SR denotes the survival function of the rivaroxaban and SA denotes the survival 
function of the ASA group.
The following decision rule to test the null hypothesis will be applied:
According to the size of this study, it is justified to assume under H0, PE a sufficiently
close approximation of the one-sided stratified (according to age) log-rank test to the 
normal distribution. If the z-value from the one-sided log-rank test (for the difference 


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SR(t) - SA(t) with stratification42) is larger than the critical quantile from the normal 
distribution (z0.975 =1.96), the null hypothesis will be rejected in favor of the 
alternative hypothesis.
Kaplan-Meier estimates of cumulative risk and cumulative hazard functions will be provided 
to evaluate the timing of event occurrence in the different treatment groups and the 
consistency of the respective treatment effects for all time points.
Hazard ratio, relative risk reduction, and corresponding two-sided 95% confidence intervals 
will be estimated based on an age-group stratified Cox proportional hazards models. The 
plausibility of proportional hazards assumption will be assessed by visually comparing the 
plot of the log of cumulative hazard between treatments and by additionally adding a 
treatment by logarithm-transformed time interaction into the Cox model. Censoring will be 
assumed independent of the treatment group assignment. 
Further details will be specified in SAP.
8.4.2
Analysis of secondary efficacy variables 
The secondary efficacy outcomes will be ordered and tested in a sequential manner as listed 
in Section 7.3.3.2
If the superiority of rivaroxaban for the primary outcome is declared, the following 
alternative hypotheses, superiority of rivaroxaban compared with ASA for the secondary 
efficacy outcomes will be tested in the sequential order.  That is, the subsequent ordered 
secondary outcome will be tested only if superiority can be shown for the previous outcomes.  
If an individual test during any step is not statistically significant, further testing may 
continue but significance will not be claimed.  This hierarchical testing procedure will control 
the global Type 1 error level.
The analysis methods will be similar to those described for the primary efficacy outcome.
8.4.3
Analysis of safety variables
The analysis methods will be similar to those described for the primary efficacy outcome.
8.4.4
Subgroup analysis
Subgroup analyses for the primary efficacy and safety outcomes will be performed based on 
the same analysis sets and data scopes as in the main analyses of the study outcomes.  The 
subgroup analyses will be presented descriptively without formal hypotheses testing.
Homogeneity of treatment effect in subgroups, both in magnitude and direction, will be 
assessed by adding a covariate for the subgroup variable and the corresponding 
treatment-subgroup interaction to the respective Cox proportional hazards model used in the 
main analysis.  Additionally the hazard ratio for the treatment effect will be estimated 
separately within each level of a subgroup variable using the same Cox proportional hazards.  
As the number of subgroup analyses may be large, the probability of observing at least one 
                                                
42 Typographical error was corrected with global Protocol Amendment 5 (“without stratification” was corrected 
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spurious interaction is high despite the lack of a biological or pharmacological basis for 
expecting an interaction.  Thus, any interactions with a p-value below the 5% type I error 
level in the analysis of primary outcomes will be interpreted as “flags” to prompt further 
investigation.  This further investigation includes the likelihood ratio test proposed by Gail 
and Simon to test for qualitative interaction. 
8.4.5
Handling of missing data
All efforts will be made to collect complete data for all patients randomized in this study.
Patients will be followed to the study end and all required data will be collected, regardless of 
their compliance with study medications or visits.
When an event date is not known, the site investigator will be asked to provide a best estimate 
as to when the event occurred. Even though the exact date of an event is unknown, the 
investigator often does know some information that would indicate the approximate date, 
such as the first week of a month, in the fall of a year, or the middle of a particular year, or at 
least the date when the patient was last seen or contacted. This information can be 
meaningfully incorporated into the estimated date recorded, as this is likely to be closer to the 
true date than any produced by an uninformed computer program. This estimated date should 
be the middle date within the period that the event is known to have occurred. If the event is 
known to have occurred in the first week of a month, then the date in the middle of that week 
should be recorded as the estimate. If it occurred in the fall of a year, then the middle date in 
the fall is the appropriate estimate. If no information is known then the date in the middle of 
the plausible time period should be given, based on the last contact with the patient prior to 
the event and the date of contact when information about the event was known.


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8.5
Planned interim analyses - amended
43The IDMC will monitor the study for greater than expected efficacy and for safety.  There 
will be 2 formal interim analyses to assess efficacy, which will occur when approximately 
50% and 67% of the planned primary efficacy events have accrued.  The IDMC may 
recommend early study termination at these interim analyses, if there is overwhelming 
superiority of rivaroxaban (Z>4) for efficacy. Also, secondary efficacy and safety will be 
considered.  The study will be stopped early if the totality of data suggests an overwhelming 
benefit of rivaroxaban over ASA.
The IDMC has the flexibility to initiate further interim analyses after the first formal efficacy 
analysis at 50%, if deemed appropriate. Given the conservative nature of the monitoring 
guidelines used in the trial, no adjustment of the significance level for the final analysis is 
required.
The execution of the interim analyses and decision rules will be specified in the IDMC 
charter.  
8.6
Determination of sample size - amended
The study is event-driven and it is estimated that 7000 patients (3500 per treatment group) 
need to be randomized in order to have approximately 450 patients experiencing a confirmed 
primary efficacy outcome event.  This number of events will allow the demonstration of 
superiority of rivaroxaban compared to ASA with regard to the primary outcome with a 
power of 90% and a one-sided level of significance α=0.025 under the following 
assumptions:

An average yearly event rate of the composite primary efficacy outcome of 3.8% in 
the ASA group (4.0% for patients with age ≥60 years, 2.0% for 10% of patients with 
age <60 years)

A 30% RRR for stroke and systemic embolism in the rivaroxaban group compared to 
ASA 

Approximately 10% of patients will permanently discontinue study medication in the 
first year and 7% in following years

Approximately 5% of patients with a diagnosis of AF will switch to standard 
treatment during study conduct

Approximately 3% patient deaths per year and 1% of patients lost to follow-up per 
year
Under these assumptions the expected RRR to be observed in this study would be 26% for the 
primary efficacy outcome. 
                                                
43 Global Protocol Amendment 5 added an interim analysis and changed the criteria and approach for assessing 
overwhelming superiority of rivaroxaban.  Details of the interim analyses will no longer be specified in the SAP, 
but in the IDMC charter only.  The second paragraph was also added.


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The number of patients enrolled in the total study may be adjusted or enrollment in the age 
group 50-59 years may be stopped based on a blinded review of the observed overall event 
rate of confirmed primary efficacy outcomes during the study.44
9. Data handling and quality assurance
9.1
Data recording - amended
It is the expectation of the sponsor that all data entered into the eCRF has source 
documentation available at the site.  The site must implement processes to ensure this 
happens.  A source document checklist will be used at the site to identify the source data for 
all data points collected and the monitor will work with the site to complete this.
Data recorded from “only screened patients (screening failures)”
Data of 'only screened patients' will be recorded as source data, as far as the reason for not 
randomizing the patient into the study is identifiable.  At minimum, data to be recorded in the
eCRF are demographic information (patient number, date of birth/age, sex, race and 
ethnicity), the reason for screening failure and date of last visit. 45  These data will be 
transferred to the respective database.
For screening failures with an SAE, the following additional data should be collected in the
eCRF, in addition to demographic information, primary reason for discontinuation and date of 
last visit:

All information about the SAE

All information related to the SAE such as: 
o
concomitant medications
o
medical history
o
other information needed for SAE complementary page
9.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s (contract research 
organization’s) procedures, monitors will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and sponsor’s requirements. When reviewing data collection procedures, 
the discussion will also include identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete

Safety and rights of patients are being protected
                                                
44 Sentence revised with global Protocol Amendment 5.  See Section 13.1 for details.
45 The first 2 sentences of this paragraph were revised for clarification with global Protocol Amendment 5.  See 
Section 13.1 for details.


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
Study is conducted in accordance with the currently approved protocol (including 
study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
9.3
Data processing
The data collection tool for this study will be a validated electronic system called iDataFax.  
Patient data necessary for analysis and reporting will be transmitted into a validated database 
or data system (e.g., TOSCA; SAS).  Clinical data management will be performed in 
accordance with agreed standards and data cleaning procedures.  This is applicable for data 
recorded on eCRF as well as for data from other sources (e.g., IxRS, adjudication 
committees).
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used.
9.4
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or 
a designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible.  The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all 
relevant documents and allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any issues.  Audits and inspections may occur at any 
time during or after completion of the study.
9.5
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change (e.g., 
relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.


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The contract with the investigator/institution will contain all regulations relevant for the study 
center.
10.Premature termination of the study
The sponsor has the right to close this study or centers at any time, which may be due but not 
limited to the following reason: 

If risk-benefit ratio becomes unacceptable owing to, for example,
o
Safety findings from this study (e.g., SAEs)
o
Results of the review by the IDMC
o
Results of parallel clinical studies
The investigator has the right to close his/her center at any time. In this case it may be 
explored whether patients can still be further followed-up for outcome events and vital status 
or whether patients could be switched to another investigational site.
Closures should occur only after consultation between involved parties and all affected
institutions must be informed as applicable according to local law.
Details for individual patient's discontinuation of study medication and withdrawal of consent 
can be found in Section 5.2.
11.Ethical and legal aspects
11.1
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
GCP guidelines and under the guiding principles detailed in the Declaration of Helsinki.  The 
study will also be carried out in keeping with applicable local law(s) and regulation(s).
Documented approval from appropriate IECs/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the Sponsor.  The responsible unit (e.g., 
IEC/IRB, head of the study center/medical institution) must supply to the Sponsor, upon 
request, a list of the IEC/IRB members involved in the vote and a statement to confirm that 
the IEC/IRB is organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.  
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial patients without prior IEC/IRB/sponsor approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 


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proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 10.
11.2
Subject information and consent
All relevant information on the study will be summarized in integrated patient information 
sheets and ICFs, provided by the sponsor.  Sample patient information sheets and ICFs are 
provided as a document separate to this protocol.
Based on the patient information sheet for the respective study phase, the investigator or 
designee will explain all relevant aspects of the study to each patient/legal representative or 
proxy consenter (if the patient is under legal protection), prior to his/her entry into the study 
(i.e., before any examinations and procedures associated with the selection for the study are 
performed or any study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IEC/IRB has been obtained.
Each patient/legal representative or proxy consenter will have ample time and opportunity to 
ask questions and will be informed about the right to withdraw from the study at any time 
without any disadvantage and without having to provide reasons for this decision.
Only if the patient/legal representative or proxy consenter voluntarily agrees to sign the ICF 
and has done so, may he/she enter the study.  Additionally, the investigator and other 
information provider (if any) will personally sign and date the form.  The patient/legal 
representative or proxy consenter will receive a copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or patient´s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
If the patient is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of the sponsor and the 
investigator).  This is to be documented by a signature from the informing physician as well 
as by a signature from the witness.
For adults under legal protection, consent shall be given by the legal guardian(s).  The 
consent of an adult under legal protection shall also be requested where such a person is able 
to express his/her own will.  His/her refusal or the withdrawal of his/her consent may not be 
disregarded.
The ICF and any other written information provided to patients/legal representatives or proxy 
consenters will be revised whenever important new information becomes available that may 
be relevant to the patient’s consent, or there is an amendment to the protocol that necessitates 
a change to the content of the patient information and/or the written ICF.  The investigator 
will inform the patient/legal representative or proxy consenter of changes in a timely manner 
and will ask the patient to confirm his/her participation in the study by signing the revised 


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ICF.  Any revised written ICF and written information must receive the IEC/IRB`s 
approval/favorable opinion in advance of use.
11.3
Publication policy
The study results will be reported irrespective of the outcome of the study.  The SC will 
decide on the authorship of all papers.  The main study results will be written by a writing 
group lead by members of the SC on behalf of the whole study group, and may include 
additional individuals who have made substantial and sustained contributions.
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.  
11.4
Compensation for health damage of subjects/insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
11.5
Confidentiality
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Patient names will not be supplied to the sponsor.  Only the patient number will be recorded 
in the eCRF, and if the patient name appears on any other document (e.g., pathologist report
or documents sent for adjudication of outcome events), it must be obliterated before a copy of 
the document is supplied to the sponsor.  Study findings stored on a computer will be stored 
in accordance with local data protection laws.  As part of the informed consent process, the 
patients will be informed in writing that representatives of the sponsor, IEC/IRB, or 
regulatory authorities may inspect their medical records to verify the information collected, 
and that all personal information made available for inspection will be handled in strictest 
confidence and in accordance with local data protection laws.
If the results of the study are published, the patient’s identity will remain confidential.
The investigator will maintain a list to enable patients to be identified.
12.Reference list 
1.
WHO Fact Sheets: The top 10 causes of death Fact sheet N°310, July2013
http://who.int/mediacentre/factsheets/fs310/en/
2.
Strong K, Mathers C, Bonita R. Preventing stroke: saving lives around the world. 
Lancet Neurol 2007; 6:182-7.
3.
WHO The Atlas of Heart Disease and Stroke. 
http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_
stroke.pdf?ua=1


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4.
Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, et al. 
Forecasting the future of cardiovascular disease in the United States: a policy 
statement from the American Heart Association. Circulation. 2011;123:933-44. Epub 
2011 Jan 24.
5.
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart 
disease and stroke statistics—2014 update: A report from the American Heart 
Association. Circulation. 2014;129:e28–29
6.
Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE III. 
Classification of subtype of acute ischemic stroke: definitions for use in a multicenter 
clinical trial. Stroke. 1993;24:35–41.
7.
Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, et al. 
Embolic strokes of undetermined source: the case for a new clinical construct. The 
Lancet Neurology 2014 Apr;13(4):429-38.
8.
Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, et al. A comparison 
of warfarin and aspirin for the prevention of recurrent ischemic stroke. NEJM 
2001;345:1444-51.
9.
Sacco RL, Prabhakaran S, Thompson JLP, Murphy A, Sciacca RR, Levin B, et al. 
Comparison of warfarin vs. ASA for the prevention of recurrent stroke or death: 
Subgroup analyses from the Warfarin-ASA Recurrent Stroke Study. Cerebrovas Dis 
2006; 22: 4-12.
10.
Homma S, Sacco RL, DiTullio MR, Sciacca RR, Mohr JP, PFO in Cryptogenic Stroke 
Study (PICSS) Investigators. Effect of medical treatment of stroke patients with 
patent foramen ovale. Circ 2002; 105:2625-31.
11.
De Schryver EL, Algra A, Kappelle LJ, van Gijn J, Koudstaal PJ. Vitamin K 
antagonists versus antiplatelet therapy after transient ischaemic attack or minor 
ischaemic stroke of presumed arterial origin. Cochrane Database Syst Rev. 2012 Sep 
12;9:CD001342.
12.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban 
versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883–91.
13.
Hankey GJ, Patel MR, Stevens SR, Becker RC, Breithardt G, Carolei A, et al. 
Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous 
stroke and transient ischemic attack: a subgroup analysis of ROCKET-AF. Lancet 
Neurol 2012; 11:315-22.
14.
Hart RG, Diener H-C, Yang S, Connolly SJ, Wallentin L, Reilly PA, et al. Intracranial 
hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or 
dabigatran: the RE-LY trial. Stroke 2012; 43: 1511-17
15.
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. 
Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 
2011;365:981-92.


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16.
Hankey GJ, Stevens S, Piccini JP, Lokhnygina Y, Mahaffey KW, Halperin JL, et al. 
Predictors of Intracranial Hemorrhage Among Anticoagulated Patients with Atrial 
Fibrillation: Insights from the Rivaroxaban Once-daily oral Direct Factor Xa 
Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and 
Embolism Trial in Atrial Fibrillation (ROCKET-AF). Stroke 2012; 43 A152
17.
Connolly S, Eikelboom J, Joyner C, Diener C, Hart R, Golitsyn S, et al. Apixaban in 
Patients with Atrial Fibrillation. N Engl J Med 2011; 364: 806-17.
18.
Diener HC, Eikelboom J, Connolly SJ, Joyner CD, Hart RG, Lip GY, et al. Apixaban 
versus ASA in patients with atrial fibrillation and previous stroke or transient 
ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised 
trial. Lancet Neurol 2012; 11: 225–31.
19.
Connolly BJ, Pearce LA, Hart RG. Vitamin K Antagonists and Risk of Subdural 
Hematoma. Meta-Analysis of Randomized Clinical Trials. Stroke 2014; 45:1672-78
20.
Adams RJ, Albers G, Alberts MJ, Benavente O, Furie K, Goldstein LB, et al. Update 
to the AHA/ASA recommendations for the prevention of stroke in patients with stroke 
and transient ischemic attack. Stroke 2008;39: 1647-52.
21.
Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and 
thrombolytic therapy for ischemic stroke (8th edition). Chest 2008; 133: 630s-669S.
22.
Canadian Best Practice Recommendations for stroke care (update 2008). Canadian 
Med Assoc J 2008; 179 (12 Suppl): S1-S25).
23.
European Stroke Organization (ESO) Executive Committee and ESO Writing 
Committee. Guidelines for the management of ischemic stroke and transient ischemic 
attack 2008. Cerebrovas Dis 2008; 25: 457-505. 
24.
Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et 
al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic 
attack. A guideline for healthcare professionals from the American Heart 
Association/American Stroke Association. Stroke. 2014; 45(7):2160-236.
25.
Lansberg MG, O'Donnell MJ, Khatri P, Lang ES, Nguyen-Huynh MN, Schwartz NE, 
et al.  Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic 
Therapy and Prevention of Thrombosis, 9th ed: American College of Chest 
Physicians Evidence-Based Clinical Practice Guidelines.  Chest. 2012 Feb;141(2 
Suppl):e601S-36S. doi: 10.1378/chest.11-2302
26.
Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent 
stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 
146(12): 857-67
27.
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al.
Edoxaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 
2013;369:2093-104.


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28.
Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al.
Expert Consensus Document: Third Universal Definition of Myocardial Infarction 
JACC 2012; 60 (16): 1581-96
29.
Schulman S, Kearon C. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 
2005;3:692-694
30.
Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. 
Vascular contributions to cognitive impairment and dementia: a statement for 
healthcare professionals from the American Heart Association/American Stroke 
Association. Stroke:  A Journal of Cerebral Circulation 2011; 42(9):2672-713.
31.
Vermeer SE, Longstreth WT, Jr., Koudstaal PJ. Silent brain infarcts:  a systematic 
review. Lancet Neurology 2007; 6(7):611-9.
32.
Dufouil C, Chalmers J, Coskun O, Besancon V, Bousser MG, Guillon P, et al. Effects 
of blood pressure lowering on cerebral white matter hyperintensities in patients with 
stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) 
Magnetic Resonance Imaging Substudy. Circulation. 2005; 112(11):1644-50.
33.
Weber R, Weimar C, Wanke I, Moller-Hartmann C, Gizewski ER, Blatchford J, et al. 
Risk of recurrent stroke in patients with silent brain infarction in the Prevention 
Regimen for Effectively Avoiding Second Strokes (PRoFESS) imaging substudy. 
Stroke:  A Journal of Cerebral Circulation. 2012; 43(2):350-5.
34.
Cavalieri M, Schmidt R, Chen C, Mok V, de Freitas GR, Song S, et al. B vitamins and 
magnetic resonance imaging-detected ischemic brain lesions in patients with recent 
transient ischemic attack or stroke:  the VITAmins TO Prevent Stroke (VITATOPS) 
MRI-substudy. Stroke:  A Journal of Cerebral Circulation. 2012; 43(12):3266-70.


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13.Protocol amendments
13.1
Amendment 5
13.1.1
Overview of changes to the study
The following modifications are introduced in Protocol Version 2.0:
1.
The following eligibility criteria were revised (the synopsis, Figure 4-1, Sections 4.1, 
5.1.1, 5.1.2, and 6.3 were updated):
o
More details have been provided in the definition of a lacunar stroke in order to 
avoid protocol deviations.
o
Due to the approximation of the reporting of cervical carotid atherosclerotic 
stenosis, subjects will be included if there is no stenosis > 50% rather than 
≥50% to prevent eligible patients from being excluded.  Likewise, they will be 
excluded if there is an intracranial stenosis > 50%.
o
For patients with intracranial arterial occlusions in the territory of the qualifying 
stroke, it was clarified that a patient is eligible if the investigator believes the 
occlusion is due to embolism, and not atherosclerotic based on absence of 
intracranial atherosclerosis elsewhere.  
o
For the 24-hour cardiac rhythm monitoring assessment to exclude the presence 
of AF, an allowance was added to accept a 20-hour recording to reflect routine 
practice.  
o
For the determination of intra-cardiac thrombus, the allowance of 
transesophageal echocardiography was added as well as transthoracic 
echocardiography.
The recruitment of patients was changed from 18 years of age or older to 50 years of 
age or older because this will only allow inclusion of patients with a high risk for a 
recurrent stroke.
Additional clarifications were made to the to the inclusion criterion regarding the 
patients enrolled with certain risk factors:  
o
Clarification that covert/silent strokes on neuroimaging and current tobacco 
smoker count as risk factors.
o
Clarification that each risk factor counts separately (ie, “stroke or TIA prior to 
index stroke, diabetes, hypertension, and heart failure” changed to “stroke or 
TIA prior to index stroke [includes covert/silent strokes on neuroimaging], 
diabetes, hypertension, current tobacco smoker, or heart failure”)
o
The rate of recurrent stroke is not known for ESUS patients between ages 50 and 
59 who also have additional risk factors and cannot be reliably estimated from 
available data.  Therefore, the age restriction has changed from < 60 years of age 
with a cap at 10% of the total study population to ≥ 50 years and requirement for 
an additional risk factor for patients between 50-59 years. Also, clinicians want 


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to know whether to anticoagulate the substantial fraction of ESUS patients who 
are under 60 years of age.  NAVIGATE ESUS as originally designed (ie, the 
10% recruitment cap) would not provide sufficient data to address this question 
meaningfully.
Clarification was made to the bleeding exclusion criterion 9.
2.
The number of patients enrolled in the total study may be adjusted or enrollment in the 
age group 50-59 years may be stopped based on a blinded review of the observed 
overall event rate of confirmed primary efficacy outcomes during the study.  The 
synopsis (Number of subjects) and Section 8.6 were revised.
3.
To allow flexibility, changed that all diagnostic assessments for ESUS must be 
completed before the screening visit to should be completed before the screening visit.  
If prolonged cardiac rhythm monitoring and/or echocardiography are not performed 
by the time of screening, these assessments can be done during the screening period.  
The screening period was extended from 4 weeks to 6 weeks (maximum) to allow for 
this.   The Table of procedures and Section 7.1.2.1 were revised.
4.
The DSS testing requirement was removed.  Due to a missing license, the 
implementation of this test is not feasible.  The Table of procedures and Sections
7.1.2.2, 7.1.2.3, 7.1.2.4, 7.6.1.3, and 14.1.1 were updated.
5.
Clarifications were made to avoid misunderstanding regarding the required 
assessments at EOT.  The Table of procedures and 7.1.2.4 were revised.
6.
In order to allow more flexibility for patients who are at a rehabilitation clinic after a 
stroke at the time of Visit 3, a phone call may replace the onsite visit.  The Table of 
procedures and Section 7.1.2.3 (it was also clarified that if a study outcome event is 
reported ConMeds should be reported) were revised.
7.
Corrections were made to data from the PICSS study in Section 1.3.
8.
The number of participating countries was updated in Section 5.
9.
In Section 5.2, it was clarified that in case a patient is diagnosed with atrial fibrillation 
with an episode of ≥  6 minutes during the study, trial medication must be stopped and 
that a temporary study medication is a “interruption” and not a “discontinuation.”   
Also, a sentence that stated that patients who permanently discontinue the study will 
not be reactivated was deleted because this point is covered by exclusion criterion 16
and the statement does not belong in this section.
10.
Unblinding will be by a country toll-free help line only (no web-based unblindings).  
The possibility for treating physicians to unblind was added.  Section 6.5.1 was 
updated.
11.
Information about collecting drug interruption details relating to study outcome events 
was added to Section 6.7.
12.
Additional information was provided in Section 6.9 regarding prohibited concomitant 
medications.


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13.
Clarification was added for diagnosing AF during the study.  In addition to cardiac 
monitoring, a 12-lead ECG is permissible in lieu of a Holter or other prolonged 
monitoring method.  Section 6.9.2 was revised.
14.
The definition of major bleeding was revised for consistency with the ISTH definition.  
Section 7.5.1 was revised.
15.
Additional guidance has been provided in Section 7.5.3.2 for the documentation of 
intracranial hemorrhage. 
16.
Dose increases and reductions are not applicable in this study, therefore these options
were deleted from the list of choices for “study treatment action” due to AEs in 
Section 7.5.3.4.
17.
The Modified Rankin Score assessment is required 3 months after a recurrent stroke.  
A range was added (3 to 6 months) to allow flexibility and avoid an additional site 
visit.  The Table of procedures and Sections 7.1.2.3 and 7.6.1.4 were revised.
18.
A second interim analysis has been added and the criteria and approach for assessing 
overwhelming superiority of rivaroxaban has changed as requested by the IDMC.  An
option to initiate further interim analyses after the first formal efficacy analysis at 50% 
was added.  Details of the interim analyses will no longer be specified in the SAP, but 
in the IDMC charter only. The synopsis and Section 8.5 was revised.  
19.
Wording was clarified in Section 9.1 in order to avoid misunderstanding between 
“premature discontinuation” and “screening failure” and that source data should be 
documented.
20.
The following revisions were made to the MRI substudy in Section 14.1.1:

The primary endpoint was changed to allow a more sensitive analysis for the entire 
study population.  The secondary endpoint was updated accordingly.

For the baseline MRI, text pertaining to the timing was clarified.  A provision was 
added for a repeat scan  in the event the initial scan was not technically acceptable.  

Further specification was made as to the timing of the follow-up MRI
21.
Some typographically errors were corrected and minor editorial and formatting 
changes were made in Sections 5.1.1, 6.9.2, 7.5.1, 8.4.1, 12, and 14.  
13.1.2
Changes to the protocol text
All sections of the protocol affected by the amendment are shown below.  Deleted text is 
crossed out and added text is underlined.  Corrections of typographical errors or editorial 
corrections are not highlighted.
Synopsis, Diagnosis and main criteria for inclusion
•
Absence of cervical carotid atherosclerotic stenosis greater than or equal to46 50% or 
occlusion, and
                                                
46 Symbols are used in the text (ie, ≥ and >)


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•
No atrial fibrillation after ≥ 24-hour cardiac rhythm monitoring (at least 20 hours 
acceptable), and
•
No intra-cardiac thrombus on either transesophageal or transthoracic 
echocardiography, and
Synopsis, Methodology
Patients who fulfill all inclusion and none of the exclusion criteria after giving informed 
consent will be randomly allocated 1:1 to either rivaroxaban 15 mg or aspirin 100 mg orally 
once daily.  Randomization will be stratified by country and age <60 and ≥60 years.  No more 
than 10% of the total patient population will be randomized into the age group <60 years.
Synopsis, Number of subjects
The number of patients enrolled in the total study may be adjusted or enrollment in the age 
group 50-59 years may be stopped based on a blinded review of the observed overall event 
rate of confirmed primary efficacy outcomes during the study.
Synopsis, Plan for statistical analysis
There will be 1 2 formal interim analysis analyses to assess efficacy and stop for 
overwhelming superiority, which will occur when approximately 50% and 67% of the 
planned primary efficacy outcomes have accrued.


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Table of procedures 
Screen
Random
Treatment Phase
Washout
V1
V2 
V3
V4
V5
V6
V7-V∞EOT a
Safety 
Visit
Timelines
-4 6 to 
0 
wks b
0
1 Mo
3 
Mo
6 Mo
12 Mo
every 
6 Mo
End 
of 
Treat
1 Mo 
post EOT
Visit Window (weeks)
±1
±4
±4
±4
±4
±1
Type of Visit  
Visit
Visit
Visit L

Visit
Visit
Visit
Visit

……..
EQ-5D
●
●
●
●
●
MoCA, DSS, and 
SAGE
●
●
●
Abbreviations:  EOT = end of treatment; Mo = month; V = visit, = telephone contact; eGFR = estimated 
glomerular filtration rate; ConMeds = Concomitant medications; MoCA = Montreal Cognitive Assessment; 
DSS = Digit Symbol Substitution test; SAGE = Standard Assessment of Global-Activities in the Elderly; EQ-
5D = European Quality of Life-5 Dimensions questionnaire; SAE = serious adverse event; TIA = transient 
ischemic attack; MI = myocardial infarction
a 
End of treatment visit is to be performed within the trial close-out window before the end of the study (efficacy 
cut-off date) or once the patient has permanently discontinued study medication and when no further visits at 
the site will be performed
b 
Screening visit can be the same as randomization visit, if all required tests for eligibility criteria are available 
at screening visit.  Maximum screening period 4 6 weeks.
……
k
For definition see Section 7.6.1.4.  In case of recurrent stroke to be done at 7 days post stroke or at 
discharge from hospital in case this occurs before 7 days and again at 3-6 months post stroke
L     Patients who are at a rehabilitation or other clinic at the time of the 1 month visit (Visit 3), more flexibility will 
be allowed and this visit can be performed as a phone call instead of an onsite visit.
…… 
Section 1.3  Studies assessing the efficacy of anticoagulation for secondary prevention of 
embolic stroke of undetermined source, last sentence of 3rd paragraph
In addition, in the PICSS study, 260 98 participants with a patent foramen ovale, the primary 
outcome (2 year rate of recurrent ischemic stroke or death) was halved in those assigned to 
warfarin (9.5% warfarin vs. 17.9% ASA). 
Section 4.1 Overview, 4th and 5th paragraphs
Patients will be enrolled randomized as early as possible after the required diagnostic 
evaluation is complete and eligibility criteria are fulfilled.  The goal is that the majority of 
patients are enrolled within 3 months, and fewer patients between 3 and 6 months.
Randomization will be stratified by country and age <60 and ≥60 years.  No more than 10% 
of the total patient population will be randomized into the age group <60 years, as patients 
with <60 years have a lower risk for recurrent stroke. Patients < 60 years will need to have at 
least one risk factor such as stroke (includes covert/silent strokes on neuroimaging) or TIA 
prior to index stroke, diabetes, hypertension, current tobacco smoker or and heart failure.


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Figure 4-1
Section 5 Study population
This Phase III, multi-national, study will be conducted in 25 to 30 approximately 30 countries
worldwide in approximately 7000 patients recruited primarily from hospital-based stroke 
units.  
Section 5.1.1 Inclusion criteria
1.
Embolic stroke of undetermined source (ESUS) defined as:
•
Recent ischemic stroke (including TIA with positive neuroimaging) visualized by 
brain CT or MRI that is not lacunar (i.e., lacunar infarcts are subcortical infarcts
≤1.5 cm in the territory of middle cerebral artery or pons; infarcts involving the 
cerebellum or lateral medulla are not considered as lacunar infarcts). Patients with 
multiple simultaneous acute lacunar infarcts on DWI imaging may be included.  In 
case of embolic large artery occlusions clearly documented on angiography who 
undergo successful recanalization, visualization of infarct on neuroimaging is not
mandated, and 
•
Absence of cervical carotid atherosclerotic stenosis (or vertebral and basilar artery 
atherosclerotic stenosis in case of posterior circulation stroke), that is greater than or 
equal to47 50%, or occlusion in arteries supplying the area of ischemia in CT or 
magnetic resonance (MR) angiography or conventional angiography or ultrasound, 
and
•
No history of AF, no documented AF on 12-lead electrocardiogram (ECG) or episode 
of AF lasting 6 minutes or longer detected after ≥ 24-hour cardiac rhythm monitoring 
(Holter or telemetry; at least 20 hours acceptable), and
•
No intra-cardiac thrombus on either transesophageal or transthoracic 
echocardiography, and
…
                                                
47 Symbols are used in the text (ie, ≥ and >)


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4.
Age ≥18 50 years (or respective country specific legal lower age limit if this is >18 
years)
5.
For patients with age < 60 50-59 years at least one of the following risk factors:  
stroke or TIA prior to index stroke (includes covert/silent strokes on neuroimaging), 
diabetes, hypertension, current tobacco smoker and or heart failure.
Section 5.1.2 Exclusion criteria
2.
If imaging of intracranial arteries is performed by CT or MR angiography or 
transcranial Doppler:  greater than or equal to48  50% luminal stenosis or occlusion in 
arteries supplying the area of ischemia
9.
Active bleeding, major bleeding within last 6 months, history of primary intracranial 
hemorrhage or high risk for serious bleeding contraindicating anticoagulant or 
antiplatelet therapy or history of primary intracranial hemorrhage
Section 5.2 Discontinuation of patients from study treatment, 2nd , 3rd , and 8th
paragraphs
Patients may discontinue study medication at their own request and without giving reasons 
(even though providing a reason is encouraged), based on the investigator´s judgment, if the 
patient is pregnant, or at the request of the sponsor (exceptional circumstances). In case a 
patient is diagnosed with atrial fibrillation with an episode of at least 6 minutes during the 
study trial medication must be stopped (see section 6.9.2)….
In case of a temporary study medication discontinuation interruption for any reason, study 
medication will be restarted as soon as medically justified in the opinion of the investigator.  
There is no defined maximum limit for temporary treatment interruption.  
….
Patients who permanently discontinue the study for any reason will not be reactivated.
Section 6.3 Treatment assignment, sentence deleted
No more than 10% of the total patient number will be randomized into the age group < 60 
years.
Section 6.5.1 Emergency unblinding by the investigator 
Unnecessary unblinding should be avoided and should only be undertaken by the investigator 
or the treating physician when it is essential for the patient´s safety.  In such a situation, the 
investigator will be able to unblind the patient via the IxRS system country toll-free help line.
Section 6.7 Treatment compliance
First dose, last dose, and any dose interruptions of study medication due to AEs, study 
outcome events, or of >7 days for any other reason will be reported in the eCRF.
Section 6.9 Prior and concomitant therapy
                                                
48 Symbols are used in the text (ie, ≥ and >)


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No specific concomitant medications are prohibited other than strong inhibitors of both 
CYP3A4 and Pgp inhibitors.  This includes human immunodeficiency virus protease 
inhibitors and the following azole antimycotics agents:  ketoconazole, itraconazole, 
voriconazole, or posaconazole, if used systemically.  However, fluconazole is allowed.
In addition, concomitant use with antiplatelets and anticoagulants is outlined in the sections 
below.
Section 6.9.2 Guidance for management of participants who have atrial fibrillation 
identified during the study
If a patient is diagnosed with AF during the study that requires oral anticoagulation according 
to the investigator´s judgment, the patient will stop double blind study medication.  Per 
protocol, study medication must be permanently discontinued if AF is seen in a 12-lead ECG 
or if an AF episode of greater than or equal49 to 6 minutes is identified during cardiac 
monitoring.  
Section 7.1.2.1 Visit 1 (screening)
Visit 1 will be used to assess the eligibility of the patient.  After obtaining signed informed 
consent, the investigator will review the diagnostic tests required to diagnose ESUS.  All 
diagnostic assessments for ESUS must should be completed before the screening visit.  If 
prolonged cardiac rhythm monitoring and/or echocardiography are not performed at time of 
screening, this can be done during the screening period.
The screening period will be 6 weeks maximum.
Section 7.1.2.2 Visit 2 (randomization visit)
Outcomes research questionnaires (Section 7.6.1) will be completed by the patient:  
•
European Quality of Life-5 Dimensions (EQ-5D) Questionnaire 
•
Montreal Cognitive Assessment (MoCA) 
•
Digit Symbol Substitution (DSS) test 
•
Standard Assessment of Global-Activities in the Elderly (SAGE) questionnaire
Section 7.1.2.3  Regular study visits (visits 3 and onward), 1st , 4th, 5th and 6th paragraphs 
Patients will return to the study clinic at 1 month, 6 months, and then every 6 months.  
Patients who are at a rehabilitation or other clinic at the time of the 1 month visit (Visit 3), 
more flexibility will be allowed and this visit can be performed as a phone call instead of an 
onsite visit.  At 3 months, the patient will receive a telephone call to obtain safety and 
outcome data and reinforce adherence to study medication and to avoiding non-study ASA.
…
Concomitant medications and weight will be collected once per year.  If an SAE  or study 
outcome event is reported, the use of any additional ConMeds should be recorded at that time
                                                
49 Symbols are used in the text (ie, > and ≥).


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The outcomes research questionnaires (MoCA, DSS, and SAGE) will be completed by the 
patient at the 1 year visit only.  The EQ-5D will be completed every 6 months.
If a recurrent stroke is reported, the modified Rankin Score is to be assessed at 7 days post 
stroke or at hospital discharge, if this occurs before 7 days, and again at 3-6 months post 
stroke.  The modified Rankin score is also to be recorded at 1 year after stroke.
Section 7.1.2.4 End of treatment (EOT) visit 
When the sponsor announces Within the trial close-out window prior to the end of the study 
(efficacy cut-off date), all patients must return to the clinic within 6 weeks in order to make a 
final assessment.  In addition, for patients that permanently discontinued study medication 
and when further follow-up will no longer be done by site visits and rather by phone or third 
party contact, the patient will be encouraged to come for the EOT visit as soon as possible 
after discontinuation of study medication. For these patients a final vital status and outcome 
events will be collected during the trial close-out window.  At this EOT visit, study 
procedures will include the collection of efficacy and safety outcome data, (S)AEs, vital 
signs, ConMeds, EQ-5D, MoCA, DSS and SAGE questionnaires, and modified Rankin score.  
In addition, the study staff will collect the patient’s empty and unused study medication 
bottles to allow final drug accountability and compliance checks.
Section 7.5.1 Primary safety variable

Symptomatic bleeding in a critical area or organ (intracranial, intraocular, intraspinal, 
pericardial, retroperitoneal, intraarticular, or intramuscular with compartment 
syndrome), and/or 
Section 7.5.3.2 Adverse event reporting, 3rd bullet

All bleeding events including fatal bleeding will be captured in the eCRF (Bleeding 
page).  Serious adverse events which are bleeding terms will not be reported to the 
sponsor’s PV Department in an expedited manner.  Symptomatic 
intracerebral/intraparenchymal hemorrhages as well as symptomatic subarachnoid 
hemorrhages will be captured as bleeding and as stroke.  All subdural/epidural 
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Section 7.5.3.4  Intensity of an adverse event, action taken, and outcome
Any action on study treatment to resolve the AE is to be documented as:  study drug 
withdrawn, interrupted, dose reduced, dose not changed, dose increased, not applicable, or 
unknown.
Section 7.6.1.3 Montreal Cognitive Assessment, Digit Symbol Substitution test, and 
Standard Assessment of Global-Activities in the Elderly
The MoCA and DSS will be included in the study to assess cognition and the SAGE 
questionnaire will be used to assess functional outcome.  These tests and questionnaires will 
be administered at Day 0 (randomization), 1 year, and at the EOT visits.  The patients will be 
asked to independently complete the MoCA and DSS tests to the best of their ability.  
Otherwise, the reason for not completing must be documented.  The SAGE questionnaire may 
be completed with the help of the study staff.
Section 7.6.1.4  Modified Rankin Score
In addition to the regular assessments at screening, 1 year, and EOT, the Modified Rankin 
Score will be assessed by the investigator at 7 days or at discharge, if this occurs before 7 
days, and again at 3-6 months  after a recurrent stroke.
Section 8.5 Planned interim analyses
The IDMC will monitor the study for greater than expected efficacy and for safety.  There 
will be 1 2 formal interim analysis analyses to assess efficacy, which will occur when 
approximately 50% and 67% of the planned primary efficacy events have accrued.  The study 
may be stopped early, IDMC may recommend early study termination at these interim 
analyses if there is overwhelming superiority of rivaroxaban (p<0.0001 Z>4) for efficacy 
(e.g., following the conservative Haybittle-Peto approach). Also, secondary efficacy and 
safety will be considered.  The study will be stopped early if the totality of data suggests an 
overwhelming benefit of rivaroxaban over ASA.
The IDMC has the flexibility to initiate further interim analyses after the first formal efficacy 
analysis at 50 %, if deemed appropriate. Given the conservative nature of the monitoring 
guidelines used in the trial, no adjustment of the significance level for the final analysis is 
required.
The execution of the interim analyses and decision rules will be specified in the IDMC 
charter and the SAP for the interim analysis.  
Section 8.6 Determination of sample size, 3rd paragraph
The number of patients enrolled in the total study may be adjusted or enrollment in the age 
group 50-59 years may be stopped based on a blinded review of the observed overall event 
rate of confirmed primary efficacy outcomes during the study
Section 9.1 Data recording, 2nd paragraph
Data of 'only screened patients' will be recorded at least as source data, as far as the reason for 
the premature discontinuation (reason for not randomizing the patient into the study) is 
identifiable.  At minimum, data to be recorded in the eCRF are demographic information 
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discontinuation screening failure and date of last visit. These data will be transferred to the 
respective database.
Section 14.1.1 MRI substudy, 2nd, 3rd, and 7th paragraphs
The primary objective of this substudy is to determine the effect of rivaroxaban compared 
with aspirin on MRI-defined covert and clinical infarcts  (i.e. all incident infarcts) in 
individuals with a recent ESUS.   ...
Secondary objectives will be to determine the effect of rivaroxaban compared to aspirin for 
reducing covert and clinical infarcts (i.e. all incident infarcts), the progression of volume of 
white matter hyperintensities (WMH), functional decline (SAGE), and cognitive decline 
(DSS, MoCA) in the patients with recent ESUS enrolled in this substudy.
…
Two MRIs will be required:

Baseline:  within 7 days of randomization if the patient is randomized within 30 days 
of the index event or from 7 days before to 30 days after randomization, if the patient 
is randomized >30 days after the index event.  The MRI for the index event may 
qualify as the baseline MRI, if the imaging was performed within 7 days of before
randomization.  In the event of a technically unsatisfactory scan as determined by the 
core laboratory, the site will have 30 days from notification by the coordinating center 
to repeat the scan.

Follow-up:  within 30 days of EOT visit in individuals who have not experienced a 
symptomatic stroke prior to EOT or within 30 days of a symptomatic stroke.
14.Appendices
14.1
Substudies
Two substudies are planned at selected sites. Participation in the substudies is not a 
requirement.  The substudies do not necessarily need to be conducted at the same sites and in 
the same patients.
Conduct of these substudies is contingent on review and approval by the appropriate Health 
Authorities and the site’s IRB or EC. Patients must sign separate ICFs for participation in 
these substudies.
14.1.1
MRI substudy - amended
Covert ischemic strokes are defined as strokes not identified clinically at the time of their 
occurrence but resulting in radiologic evidence of brain infarction.  Covert strokes are 
frequent with a prevalence of 20% at the age of 65 years and are 5 times as common as 
symptomatic strokes.(30,31)  Covert strokes may be manifested as subtle cognitive decline, 
loss of independence, gait impairment, and falls.  The post stroke population is characterized 
as having a high incidence of these covert infarctions (4% to 24% from 3 cohort studies) and 
subsequent cognitive and functional impairment.(32-34)


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The primary objective of this substudy is to determine the effect of rivaroxaban compared 
with aspirin on MRI-defined covert and clinical infarcts (i.e. all incident infarcts) in 
individuals with a recent ESUS.50  The primary analysis will be performed on an ITT 
population (i.e. all patients with baseline and follow-up MRIs, including those with early 
study drug discontinuation), based on the assessment by an MRI Core facility.  An additional 
analysis will be performed on patients with baseline and follow-up MRIs who take study drug 
until the efficacy cutoff date.
Secondary objectives will be to determine the effect of rivaroxaban compared to aspirin for 
reducing covert infarcts, the progression of volume of white matter hyperintensities (WMH), 
functional decline (SAGE), and cognitive decline (MoCA) in the patients with recent ESUS 
enrolled in this substudy.51
Exploratory objectives will be to determine the imaging profile which predicts clinical 
recurrence as well as the radiologic pattern of recurrent lesions, and to evaluate the predictors 
of covert infarcts at baseline in the ESUS population.
Approximately 1000 patients will be enrolled in this substudy that is designed to detect a 35% 
reduction in covert strokes by rivaroxaban with 80% power and a two-sided alpha of 0.05,
assuming an annual covert stroke rate of 10% in patients receiving aspirin, a mean follow-up 
of 24 months, and a drop-out rate of 15%.
The substudy will be conducted at sites with access to 1.5 or 3Tesla MRI.  Patients with no 
contraindication to MRI as assessed using local institutional protocols, e.g., claustrophobia, 
metal-containing devices or foreign bodies, will be enrolled.  
Two MRIs will be required 52:

Baseline: within 7 days of randomization if the patient is randomized within 30 days 
of the index event or from 7 days before to 30 days after randomization, if the patient 
is randomized >30 days after the index event.  The MRI for the index event may 
qualify as the baseline MRI, if the imaging was performed within 7 days before
randomization.  In the event of a technically unsatisfactory scan as determined by the 
core laboratory, the site will have 30 days from notification by the coordinating center 
to repeat the scan.

Follow-up: within 30 days of EOT visit in individuals who have not experienced a 
symptomatic stroke prior to EOT or within 30 days of a symptomatic stroke.
If a recurrent stroke occurs, all information on MRI or CT performed as routine diagnostic 
will be collected.
Detailed information regarding image acquisition and processing will be found in an MRI 
Imaging Manual.
                                                
50 The primary endpoint was revised with global Protocol Amendment 5 to allow a more sensitive analysis for 
the entire study population.  See Section 13.1.2 for details.
51 The secondary endpoint was revised with global Protocol Amendment 5 accorded to the revised primary 
endpoint.  The reference to DSS was also removed.
52 Additional guidance and clarifications were made to this paragraph with global Protocol Amendment 5.  See 
Section 13.1 for details.


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A pooling of data from this MRI substudy with substudy data from the ongoing COMPASS 
study is planned. The later COMPASS MIND MRI substudy will be conducted in 1500 
patients with coronary and peripheral artery disease, who receive either aspirin 100 mg o.d., 5 
mg rivaroxaban b.i.d., or 2.5 mg rivaroxaban b.i.d. plus aspirin 100 gm o.d.. The 2 substudies 
will share the set-up, outcome definitions (MRI and cognitive), and MRI Core Facility. 
14.1.2
Biomarker substudy
Biomarker samples (plasma, RNA, and DNA) will be collected in this exploratory substudy 
to promote, facilitate, and improve individualized healthcare by better 
understanding/predicting ESUS, recurrent stroke, and associated diseases as well as treatment 
response.  Specifically, the intention is to establish ESUS as a distinct clinical entity in which 
propensity to coagulation is critical, both as a marker of ESUS and as a risk factor for 
recurrent stroke.
A total of 18 mL of blood in up to 3000 patients will be collected at the time of randomization 
for analysis, including, but not limited to: blood biomarker and blood gene expression, as 
well as genetic determinants.  
Biomarkers established in other CV diseases may also play a role in ESUS and recurrent 
stroke.  For example, available data on the N-terminal of the prohormone brain natriuretic 
peptide (NT-proBNP) indicate a link to covert atrial fibrillation.  Therefore, potential blood 
biomarkers that may be measured are: NT-proBNP, hsTroponin, and D-dimer.  In addition,
other biomarkers of coagulation, pro-thrombotic markers, inflammation markers, and markers 
linked to stroke or other CV diseases may be analyzed.  
Blood gene expression profiles and genetic determinants will be analyzed in a hypothesis free 
approach with the goal to identify new genes or genetic determinants that are linked to ESUS, 
recurrent stroke, and other CV diseases.
All genetic information will be doubly de-identified and kept on secure, password protected, 
computer servers.
Detailed information regarding sampling, processing and storage of blood samples will be 
found in a Biomarker Manual.

SAP_000.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
Multicenter, randomized, double-blind, double-dummy, active-
comparator, event-driven, superiority phase III study of secondary 
prevention of stroke and prevention of systemic embolism in 
patients with a recent Embolic Stroke of Undetermined Source 
(ESUS), comparing rivaroxaban 15 mg once daily with aspirin 100 
mg (NAVIGATE ESUS) 
NCT Number: 
NCT02313909 
Document Date: 
20 December 2017 
 


          Statistical Analysis Plan
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Multicenter, randomized, double-blind, double-dummy, active-
comparator, event-driven, superiority phase III study of secondary 
prevention of stroke and prevention of systemic embolism in patients with 
a recent Embolic Stroke of Undetermined Source (ESUS), comparing 
rivaroxaban 15 mg once daily with aspirin 100 mg (NAVIGATE ESUS)
Secondary prevention of stroke in patients with a recent ESUS
Bayer study drug
BAY 59-7939/rivaroxaban
Clinical study 
phase:
III
Date:
20 December 2017
Study No.:
16573
Version:
3.0
Authors:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


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Table of Contents
Table of Tables..........................................................................................................................3
Abbreviations ............................................................................................................................4
1.
Introduction - amended .................................................................................................6
2.
Study Objectives .............................................................................................................7
3.
Study Design....................................................................................................................7
4.
General Statistical Considerations................................................................................9
4.1
General Principles ............................................................................................................9
4.2
Handling of Non-compliance to Study Treatment or Follow up......................................9
4.3
Handling of Missing Data ..............................................................................................10
4.4
Interim Analyses and Data Monitoring ..........................................................................11
4.5
Data Rules ......................................................................................................................12
4.5.1
Analysis Dates - amended...........................................................................................12
4.5.2
Data Scopes - amended ...............................................................................................13
4.5.3
Censoring rules for time-to-event variables - amended ..............................................13
4.5.4
Determination of baseline values................................................................................14
4.5.5
Handling of repeated measurements - amended .........................................................14
4.6
Determination of sample size.........................................................................................14
5.
Analysis Sets..................................................................................................................15
5.1
Assignment of analysis sets............................................................................................15
5.1.1
Intention-to-treat analysis set (ITT) ............................................................................15
5.1.2
Safety analysis set (SAF) ............................................................................................15
6.
Statistical Methodology................................................................................................15
6.1
Population characteristics...............................................................................................15
6.1.1
Disposition ..................................................................................................................15
6.1.2
Demographics .............................................................................................................16
6.1.3
Medical history............................................................................................................17
6.1.4
Protocol Deviations.....................................................................................................17
6.1.5
Prior and Concomitant Medications............................................................................17
6.1.6
Extent of Exposure and Compliance - amended.........................................................18
6.2
Efficacy...........................................................................................................................18
6.2.1
Primary efficacy variable ............................................................................................18
6.2.2
Secondary efficacy variables.......................................................................................19
6.2.3
Subgroup variables......................................................................................................19
6.2.4
Analysis of the primary efficacy variable ...................................................................20
6.2.5
Analysis of secondary efficacy variables....................................................................22
6.2.6
Subgroup analysis .......................................................................................................23
6.2.7
Sensitivity analyses - amended ...................................................................................24


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6.3
Pharmacokinetics / pharmacodynamics .........................................................................24
6.4
Safety..............................................................................................................................24
6.4.1
Adverse events - amended ..........................................................................................24
6.4.2
Primary safety variable ...............................................................................................25
6.4.3
Secondary safety variables..........................................................................................25
6.4.4
Other safety variables..................................................................................................26
6.4.5
Analysis of safety variables ........................................................................................26
6.5
Other procedures and variables ......................................................................................26
6.6
Net clinical Benefit.........................................................................................................28
7.
Document history and changes in the planned statistical analysis ..........................28
7.1
Overview Changes to SAP – Amendment 1 ..................................................................29
7.2
Overview Changes to SAP – Amendment 2 ..................................................................30
8.
References .....................................................................................................................31
Appendix A: Patient follow-up ..............................................................................................32
Appendix B: Region definition - amended............................................................................33
Table of Tables
Table 1.  Classification of countries to regions.........................................................................33


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Abbreviations
AE
Adverse event
AF
Atrial fibrillation
APCC
Activated prothrombin complex concentrate
ARISTOTLE
Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation 
(ARISTOTLE)
ASA
Acetylsalicylic acid; aspirin
AVERROES
A Phase III Study of Apixaban in Patients With Atrial Fibrillation (AVERROES)
BHC
Bayer HealthCare
b.i.d.
Twice daily
CABG
Coronary artery bypass graft
CAD
Coronary artery disease
CI
Confidence interval
ConMed
Concomitant medication
CRO
Contract research organization
CSR
Clinical Study Report
CT
Computed tomography
cTn
Cardiac troponin
CV
Cardiovascular
CYP3A4
Cytochrome P450 isoenzyme 3A4
DSS
Digit Symbol Substitution test
DVT
Deep vein thrombosis
ECG
Electrocardiogram
eCRF
Electronic case report form
e.g.
for example
eGFR
Estimated glomerular filtration rate
ENGAGE
Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs 
Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation
(EngageAFTIMI48)
EOT
End-of-treatment
EQ-5D
European Quality of Life-5 Dimensions questionnaire
ESUS
Embolic stroke of undetermined source
EU
European Union
FAS
Full analysis set
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
H
Hypothesis
HDPE
High-density polyethylene
HEOR
Health Economics, Outcomes & Reimbursement
HR
Hazard ratio
ICAC
Independent Central Adjudication Committee
ICF
Informed consent form
ICH
International Conference on Harmonisation
IB
Investigator’s brochure
i.e.
id est (that is)
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
INR
International ratio
IRB
Institutional Review Board
ISAC
Independent Statistical Analysis Centre
ISTH
International Society on Thrombosis and Haemostasis
ITT
Intent-to-treat


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IxRS
Interactive web/voice response system
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
Mo
Month
MoCA
Montreal Cognitive Assessment
MR
Magnetic resonance
MRI
Magnetic resonance imaging
NIHSS
National Institutes of Health Stroke Score
NSAID
Non-steroid anti-inflammatory drug
NV
Corporation (in The Netherlands)
NVAF
Non-valvular atrial fibrillation
NT-proBNP
N-terminal of the prohormone brain natriuretic peptide
o.d.
Once daily
OMP
Ortho McNeil Pharmaceuticals
p
p-value
PCC
Prothrombin complex concentrate
PCI
Percutaneous coronary intervention
PE
Pulmonary embolism
P-gp
P-glycoprotein
PICCS
Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS)
PID
Patient identification
PPS
Per protocol set
PT
Prothrombin time
PV
Pharmacovigilance
QA
Quality assurance
RRR
Relative risk reduction
S
Survival
SAE
Serious adverse event
SAF
Safety set
SAGE
Standard Assessment of Global-Activities in the Elderly
SAP
Statistical analysis plan
SMQ
Standardised MedDRA Query
SC
Steering Committee
SUSAR
Suspected unexpected serious adverse reaction
TEE
Transesophageal echocardiogram
TIA
Transient ischemic attack
TTE
Transthoracic echocardiogram
USA
United States of America
V
Visit
VKA
Vitamin K antagonist
vs.
versus
VTE
Venous thromboembolism
WARSS
Warfarin-Aspirin Recurrent Stroke Study
WHO
World Health Organization
WMH
White matter hyperintensities


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1.
Introduction - amended
Globally, cerebrovascular disease (stroke) is the second leading cause of death and the fourth 
leading cause of disease burden as measured in disability-adjusted life years. The World 
Health Organization (WHO) estimates that worldwide 16 million people suffer a first ever 
stroke annually, with 5 million deaths due to stroke in 2005, and another 5 million left 
permanently disabled.
Recently, the concept of “embolic stroke of undetermined source” (ESUS) has developed, 
recognizing that except for lacunar strokes, most cryptogenic strokes are embolic. The 
sources of embolism underlying ESUS include the heart (either within the heart or via 
paradoxical embolism from a venous source), aortic arch, or the large cervical and cerebral 
arteries.
Randomized clinical trials have addressed secondary prevention for all major ischemic stroke 
subtypes except for cryptogenic stroke or ESUS. Among the estimated 300,000 patients with 
acute cryptogenic stroke annually in North America and Europe there has been little progress 
in secondary prevention during the past two decades. There is a substantial unmet medical 
need in this patient population, as despite treatment with antiplatelets, the recurrent stroke 
rate still remains at 3 to 6% annually.
There is persuasive evidence that the dominant underlying pathophysiology of ESUS is 
embolism (cardioembolic, arteriogenic, or paradoxical). Improvements in imaging 
technology and an increased appreciation of the underlying pathophysiology of ESUS have 
resulted in better understanding and in a practical clinical definition of ESUS so that these 
patients can be reliably identified.
Based on evidence for superior efficacy of warfarin anticoagulation over ASA for other types 
of embolic stroke, anticoagulation is expected to be superior to ASA in ESUS patients. The 
direct oral Factor Xa-inhibitor rivaroxaban, when compared with VKAs, has been 
demonstrated to be effective against embolic stroke related to non-valvular AF. Because of its 
predictable anticoagulant activity and low risk of intracranial hemorrhage, it is expected that 
rivaroxaban will reduce stroke recurrence in ESUS compared with ASA, and with an 
acceptable safety (bleeding) profile. Rivaroxaban has also been shown to be efficacious for 
the treatment of DVT and PE, prevention of recurrent DVT and PE, prevention of VTE 
following total hip and total knee replacement, and also for prevention of atherothrombotic 
events after an acute coronary syndrome with elevated cardiac biomarker. Rivaroxaban has 
no dietary restrictions and only few drug interactions and does not require routine coagulation 
laboratory monitoring.
Given these considerations, a large, multicenter, randomized, double-blind, double-dummy, 
active-comparator, event-driven, superiority study comparing rivaroxaban 15 mg o.d. with 
ASA 100 mg o.d. for the secondary prevention of stroke and prevention of systemic 
embolism will be conducted.


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The IDMC recommended on October 2, 2017 that the NAVIGATE ESUS trial be stopped: “In 
the absence of offsetting benefit, and little chance of showing benefit if the study were completed, 
there is a clear risk of excess bleeding.” There was an increase in ISTH-defined major 
hemorrhage in the rivaroxaban arm that was not unexpected. However there was no offsetting 
benefit in reduction of stroke. Futility analysis showed <1% likelihood of demonstrating a 
substantial benefit for stroke prevention if the trial were continued to the planned termination in 
2018. The Executive Operations Committee carefully reviewed the results and accepted the DMC 
recommendation to close the trial. All investigators and responsible Health Authorities were 
informed about the stop of the study on October 5, 2017.
This core SAP is based on the Clinical Study Protocol BAY 59-7939/16573 amendment 
version 2.0 from 5 November 2015 and contains definitions of analysis sets, key derived 
variables and statistical methods for analysis of efficacy and safety for the ESUS study. It 
provides a technical and detailed elaboration of the principal features of the planned analyses, 
e.g., censoring schemes for time-to-event variables. Amendments and/or appendices to this 
core SAP may be used to provide more details on the coding guidelines, data-handling, and 
output tables and figures.
Titles, mock-ups and programming instructions for all statistical output (tables, figures, and 
listings [TLF]) are provided in a separate TLF specifications document.
2.
Study Objectives
The primary efficacy objective is:

To evaluate whether rivaroxaban is superior to aspirin in reducing the risk of recurrent 
stroke and systemic embolism in patients with a recent ESUS
The secondary efficacy objective is:

To evaluate whether rivaroxaban is superior to aspirin in reducing the risk of 
cerebrovascular events, cardiovascular events, and mortality in patients with a recent 
ESUS
The safety objective is to document the incidence of clinically relevant bleeding.
3.
Study Design
This is a multicenter, randomized, double-blind, double-dummy, active-comparator, event-
driven, superiority study in patients with a recent ESUS.
Following provision of informed consent, patients who meet all of the inclusion criteria and 
none of the exclusion criteria will be randomly allocated by an interactive voice/web 
response system (IxRS) to either rivaroxaban 15 mg o.d. or ASA 100 mg o.d. in a 1:1 ratio. 
No dose adjustment will be made for patients with mild or moderate renal impairment.
Patients may be randomized and receive the first study medication intake between 7 days and 
6 months after the qualifying stroke event. In case of minor strokes (National Institutes of 


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Health Stroke Score [NIHSS] ≤ 3), study medication may be initiated as early as 3 days after 
stroke onset if all eligibility assessments have been completed. In the presence of 
hemorrhagic transformation on the qualifying brain imaging study or if intravenous 
thrombolysis therapy was given for the qualifying stroke, study medication will not be 
initiated before 10 days after the acute stroke event unless a repeat CT or magnetic resonance 
imaging (MRI) performed before randomization documents the absence of new or extension 
of hemorrhage.
Patients will be enrolled as early as possible after the required diagnostic evaluation is 
complete and eligibility criteria are fulfilled. The goal is that the majority of patients are 
enrolled within 3 months, and fewer patients between 3 and 6 months. 
Randomization will be stratified by country and age <60 and ≥60 years. Patients < 60 years 
will need to have at least one risk factor such as stroke or TIA (includes covert/silent strokes 
on neuroimaging) prior to qualifying stroke, diabetes, hypertension, current tobacco smoker 
or heart failure.
At randomization, patients will receive study medication and instructions for its 
administration. Thereafter, patients will return to the clinic at 1, 6, and 12 months and then 
every 6 months until the end of study (efficacy cut-off date) is announced. At 3 months, the 
patient will be contacted by telephone. Throughout the study and at clinic visits, patients will 
be assessed for efficacy (stroke, systemic embolism, MI, CV death, or all-cause mortality) 
and safety (vital signs, bleeding, serious adverse events [SAEs] which are not outcome 
events, non-serious adverse events [AE]s leading to permanent discontinuation of study 
treatment, and any non-serious AEs of particular concern to the investigator).
The trial will continue until approximately 450 patients are anticipated to have experienced a 
positively adjudicated primary efficacy outcome event. This is anticipated to occur 
approximately 3 years after the first patient is randomized, but may vary depending on the 
recruitment rate as well as the primary event rate. A telephone safety visit will be performed 
1 month after the end-of-treatment (EOT) visit.
Patients permanently discontinuing study treatment will continue to be followed, and 
outcome events and vital status must be assessed in these patients until the end of the study 
via either clinic visits or telephone contacts.
All efficacy and safety analyses are based on time from randomization to time of first event. 
Suspected clinical study outcomes will be assessed by the ICAC, which will be blinded to 
treatment allocation. Adjudicated results will be the basis for the final analyses. The IDMC 
will monitor patient safety during the study and give recommendations to the SC and 
sponsor.


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A schematic of the study design is provided in the following figure:
The target patient population comprises patients with a recent ESUS. These patients have 
substantial risk for recurrent stroke and other thromboembolic events despite antiplatelet 
therapy, the current standard of care. A double-blind, randomized trial design comparing 
rivaroxaban with ASA is deemed the most appropriate design to allow for an unbiased 
evaluation of rivaroxaban as a treatment option for this patient population in an international 
trial.
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit of the last patient for all centers in the respective 
country has occurred. However, as the primary efficacy outcome of this study is event-driven 
and requires adjudication by an ICAC, the end of the study as a whole will only be reached 
when the final efficacy outcome event has been adjudicated for patients from all participating 
clinical sites (EU and non-EU).
4.
General Statistical Considerations
4.1
General Principles
All variables will be analyzed by descriptive statistical methods. The number of data 
available and missing data, mean, standard deviation, minimum, quartiles, median, and 
maximum will be calculated for metric data, as appropriate. Frequency tables will be 
generated for categorical data. The statistical evaluation will be performed by using the 
software package SAS release 9.2 or higher (SAS Institute Inc., Cary, NC, USA).
4.2
Handling of Non-compliance to Study Treatment or Follow up
An excessive rate of patient discontinuations from either treatment or study follow up may 
render the trial non-interpretable. In this study, outcome events and vital status data will be 
collected until the end of the study, even if patients are no longer taking study medication. 
This means that clinical data from all randomized patients will be collected at trial close-out 
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A subject who signed an informed consent form, and, for any reason (e.g., failure to satisfy 
the in- and exclusion criteria) terminates the study without being randomized is regarded as a 
“screening failure”.
A randomized subject who permanently discontinue study treatment before their End of 
treatment Visit for any reason is defined as having had a permanent discontinuation of study 
medication (including subjects who were randomized but never started taking any study 
medication). The reason for permanent discontinuation of study medication will be collected.
For subjects who permanently discontinue study medication, different options of follow-up 
will be discussed to collect outcome events and vital status. This can include regular study 
visits, regular phone calls with the patient or otherwise with the general practicioner or family 
relative, or a contact at the end of the study. Patients who do not agree to attend regular study 
visits the investigator will encourage to come to at least one final visit to perform assessments 
to the greatest extent possible as outlined for the End of treatment Visit.
However, all randomized subjects will be encouraged to remain on study treatment and under 
observation for the full duration of the study.  Discontinuation of study treatment is not the 
equivalent to withdrawal of informed consent.  In cases where subjects indicate they do not 
want to “continue”, investigators must determine whether this refers to discontinuation of 
study treatment, unwillingness to attend follow-up visits, unwillingness to have telephone 
contact, unwillingness to have any contact with study personnel, or unwillingness to allow 
contact with a third party (e.g., family member, doctor).  Every effort will be made to 
continue to follow the subject and survival status information must be determined for all 
subjects at the end of the study.  The expectation is that only very few subjects will have 
incomplete follow-up (in any form) within this trial.
A subject will be declared to have incomplete follow-up or to be lost to follow-up (i.e., to be 
completely non-compliant to follow-up) if, despite of all possible efforts, all investigators, 
dedicated site staff, and/or PHRI Project Office (as applicable and as local regulations allow) 
are not able to contact the subject or a third party (e.g., family member, doctor).  Every 
possible effort will be made to contact the subject or a third party and to determine the 
endpoint and survival status and reason for discontinuation as local law permits.  If it is 
documented in the database that the subject is alive at the end of the study, the subject will 
not be classified as lost to follow-up, but as alive.
4.3
Handling of Missing Data
All missing or partial data will be presented in the subject data listing as they are recorded on 
the CRF including best estimate dates of site investigators (see below) collected in the 
clinical database. 
Missing or incomplete event dates
When an event date is not known, the site investigator will be asked to provide a best 
estimate as to when the event occurred.  Even though the exact date of an event is unknown, 


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the investigator often does know some information that would indicate the approximate date, 
such as the first week of a month, in the fall of a year, or the middle of a particular year, or at 
least the date when the subject was last seen or contacted.  This information can be 
meaningfully incorporated into the estimated date recorded, as this is likely to be closer to the 
true date than any produced by an uninformed computer program.  This estimated date should 
be the middle date within the period that the event is known to have occurred.  If the event is 
known to have occurred in the first week of a month, then the date in the middle of that week 
should be recorded as the estimate.  If it occurred in the fall of a year, then the middle date in 
the fall is the appropriate estimate.  If no information is known then the date in the middle of 
the plausible time period should be given, based on the last contact with the subject prior to 
the event (start date of plausible time period) and the date of contact when information about 
the event was known (end date of plausible time period).  This method for date estimation has 
been used in many studies and is recommended by Dubois.
If the date/time information is not sufficient to determine whether an event occurred prior or 
after randomization, the event is considered as an outcome, to be conservative.  The event 
start date will be imputed no earlier than randomization date.
4.4
Interim Analyses and Data Monitoring
The IDMC will monitor the study for efficacy and for safety by reviewing unblinded event 
rates. 
There will be 2 formal interim analyses to assess efficacy, which will occur when 
approximately 50% and 67% of the planned primary efficacy events have accrued. The 
IDMC may recommend early study termination at these interim analyses, if there is 
overwhelming superiority of rivaroxaban for efficacy (Z>4, i.e. a reduction of 4 standard 
deviations in the analysis of the primary efficacy outcome at interim analysis). Also, 
secondary efficacy and safety will be considered. The study will be stopped early if the 
totality of data suggests an overwhelming benefit of rivaroxaban over ASA.
The IDMC has the flexibility to initiate further interim analyses after the first formal efficacy 
analysis at 50%, if deemed appropriate. Given the conservative nature of the monitoring 
guidelines used in this trial, no adjustment of the significance level for the final analysis is 
required.
The execution of the interim analyses and decision rules will be specified in the IDMC 
charter.
All (unblinded) statistical analyses for the IDMC and the interim analysis will be performed 
by the ISAC (Independent Statistical Analysis Centre).
The steering committee will review overall blinded event rates to ensure that they meet 
protocol projections.  If overall event rates are lower than expected, consideration will be 
given to altering the trial design, such as increasing the sample size or extending the study 
duration without knowledge of any treatment effect.


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4.5
Data Rules
4.5.1
Analysis Dates - amended
For the study the following date and time window are of relevance for the analysis:

Efficacy cut-off date:
The efficacy cut-off date is the 5th of October 2017, the date the early stopping of the 
trial was officially announced. 

Trial close-out window: 
The Trial close-out window is the time period when all subjects are to return to the 
clinic for an End of treatment Visit.
For each subject, the following individual dates are of relevance for analysis:

Randomization date: 
The date of randomization to antithrombotic study treatment of the subject. 

End of treatment (EOT) Visit date:
This is the date of the EOT Visit for the individual subject. 
After the announcement of the end of the study, all subjects are to return to the clinic 
for their EOT Visit within the pre-specified window (Trial close-out window). 
If subjects do not have an EOT visit, the date will be missing.  

Date of the last contact prior or equal to efficacy cut-off:
This date is defined as the date of the last trial contact or the efficacy cut-off date, 
whatever comes first.

Date of the last trial contact:
The date of the last documented contact with the subject or a third party (including 
data on subject survival status).
For subjects who die after randomization the date of the last contact is set to the death 
date.

Date of first double-blind dose of antithrombotic study treatment: 
The date of the first dose of rivaroxaban / aspirin study medication.  

Date of last double-blind dose of antithrombotic study treatment: 
The date of the last dose of rivaroxaban / aspirin study medication.  
For a subject with permanent discontinuation of any study medication, the 
corresponding last dose date(s) will be obtained from the CRF “Study Medication 
Discontinuation/Restart Report”. If study medication was continued until the EOT
visit, the date of the last dose of the corresponding study medication will be as 
reported on the EOT visit CRF.
If missing or incomplete, the date of last double-blind dose of antithrombotic study 


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treatment is set to the latest logically possible date of antithrombotic study medication 
administration on or before the earliest of the subject’s following dates, the date of 
last trial contact, the date of death, or the efficacy cut-off date, and no earlier than the 
randomization date.  
4.5.2
Data Scopes - amended
This section describes the coverage of the event data scopes used for the statistical analyses. 
Analysis sets are described in section 5.
Data scope according to intention-to-treat principle (ITT)
The ITT data scope includes all outcome events observed from randomization until the 
efficacy cut-off date. This will be the primary data scope for the analyses.
Analyses according to the intention-to-treat (ITT) principle will be based on the intention-to-
treat analysis set (see section 5.1.1) and will include all outcome events that occur from the 
date of randomization and up until the efficacy cut-off date (inclusive). Subjects will be kept 
in the study group to which they were randomized and the follow-up period for each subject 
will be as long and complete as possible.  This ITT data scope will be applied to the primary 
analysis of the primary and secondary efficacy variables and safety variables.
Data scope according to treatment (on-treatment)
The on-treatment data scope will include all outcome events observed from randomization 
until 2 days following permanent discontinuation of the study drug.
Analyses according to the on-treatment data scope will be based on the safety analysis set 
(see section 5.1.2). 
This on-treatment data scope will be applied to the supportive analysis of the primary and 
secondary efficacy variables and safety variables.
4.5.3
Censoring rules for time-to-event variables - amended
For any time-to-event variable in this study, the following censoring rules will be applied: 
Censoring rules for analyses according to the intention-to-treat principle
For analyses according to the intention-to-treat principle, randomized subjects without 
documentation of an event will be censored at the efficacy cut-off date or the date of the last 
trial contact, whatever comes first.
This censoring rule will be applied to all analyses according to the intention-to-treat principle. 
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of the study but no information on other outcomes, the last follow-up / trial contact where 
survival status information was obtained will still be used to determine the censoring date for 
the subject and if there were no known events up to then the subject will be considered as 
event-free. 
Censoring rules for on-treatment analyses
For on-treatment analyses, all randomized subjects with at least one dose of study medication 
and without documentation of an event within the on-treatment data scope will be censored at 
the date of last double-blind dose of antithrombotic study treatment + 2 days or the date of 
the last trail contact, whatever comes first.  
Note that if a subject stops treatment at the EOT visit and experiences an event up to 2 days 
thereafter, the event will be counted in this analysis but not in the primary analysis.
4.5.4
Determination of baseline values
Baseline is defined as the last non missing value until and including the day of randomization 
visit.
4.5.5
Handling of repeated measurements - amended
In case of multiple measurements per post baseline visits, the 1st non-missing value per visit 
will be taken for analysis.
In case of multiple assessments at different (unscheduled) post baseline visits for TEE, TTE, 
or questionnaires, the 1st non-missing assessment will be taken for analysis, others will be 
listed.
4.6
Determination of sample size
The study is event-driven and it is estimated that 7000 patients (3500 per treatment group) 
need to be randomized in order to have approximately 450 patients experiencing a confirmed 
primary efficacy outcome event using the ITT data scope. This number of events will allow 
the demonstration of superiority of rivaroxaban compared to ASA with regard to the primary 
outcome with a power of 90% and a one-sided level of significance α=0.025 under the 
following assumptions:

An average yearly event rate of the composite primary efficacy outcome of 3.8% in 
the ASA group (4.0% for patients with age ≥60 years, 2.0% for 10% of patients with 
age <60 years)

Effect size: A 30% RRR for stroke and systemic embolism in the rivaroxaban group 
compared to ASA

Length of the recruitment period is 2 years and the total study duration is 3 years


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
Approximately 10% of patients will permanently discontinue study medication in the 
first year and 7% in following years

Approximately 5% of patients with a diagnosis of AF will switch to standard 
treatment during study conduct

Approximately 3% patient deaths per year and 1% of patients lost to follow-up per 
year
Under these assumptions the expected RRR to be observed in this study would be 26% for 
the primary efficacy outcome.
The number of patients enrolled may be adjusted and the study duration may be adapted 
based on a blinded review of the observed overall event rate of confirmed primary efficacy 
outcomes during the study.
Sample size estimation was based on a Statistical Analysis Software (SAS) macro provided 
by Shih.  
5.
Analysis Sets
5.1
Assignment of analysis sets
All subjects who have been randomized in the ESUS study are valid for assignment to 
analysis sets.
5.1.1
Intention-to-treat analysis set (ITT)
The intention-to-treat analysis set, also termed full analysis set in the International 
Conference on Harmonization (ICH) E9 guideline, will include all randomized subjects. 
5.1.2
Safety analysis set (SAF)
The safety analysis set will include all randomized subjects who received at least one dose of 
study medication. 
6.
Statistical Methodology
6.1
Population characteristics
6.1.1
Disposition
The following will be tabulated overall and/or by treatment group:

Study sample sizes (subjects enrolled, randomized, and valid for Safety analysis set)
by region and country


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
Study sample sizes by country and site

Subject disposition

Number of subjects and primary reasons for screening failures (only overall)

Number of subjects and primary reasons for permanent discontinuation of study 
medication (by treatment group and overall for SAF)

Number of subjects and primary reasons for discontinuation of study follow-up (by 
treatment group and overall for ITT and SAF)

Number of subjects withdrew consent as well as Lost to Follow-up
Kaplan-Meier plots will be used to show:

Time from randomization to last study medication,

Time from randomization to last contact prior or equal to efficacy cut-off,

Time from randomization to last trial contact
by treatment group and overall for ITT and SAF.
6.1.2
Demographics
Demographic variables and baseline characteristics will be summarized by treatment group 
and overall in the ITT and SAF.  Summary statistics will be presented for metric variables.  
Frequency tables will be presented for categorical variables. 
Demography includes age, gender, race, ethnicity, region, body height, body weight, body 
mass index (BMI) and smoking history. Age, body weight and BMI will each be given as 
continuous variable and categorized with the following categories:

Age: <60; 60-75; >75 years (for publication: <75; ≥75 years)
additionally <60; >=60 years

BMI: < 25; ≥ 25 to < 30; ≥30kg/m2 (for publication: < 30; ≥ 30kg/m2)

Weight: <70; 70-90; >90 kg (for publication: <50; 50-100; >100 kg)
The following additional baseline characteristics will be analyzed:

Sex: male; female

Race: White; Black; Asian; American Indian or Alaska Native; Native Hawaiian or 
Other Pacific Islander; Not reported; Mixed

Region: North America; South America; Western Europe; Eastern Europe; Asia (see 
Appendix B for definition)

eGFR: <50; 50-80; >80 mL/min/1.73m²


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
Stroke or TIA prior to qualifying event: yes or no

Time from qualifying stroke to randomization: ≤30 days; 30 days to 3 months; > 
3months

Presence of patent foramen ovale: present or absent / not known

Cardiac rhythm monitoring: <48; ≥ 48 hours

Hypertension: yes or no

Diabetes: yes or no

Heart failure: yes or no

Tobacco use: never, former, current
6.1.3
Medical history
Medical history data will be evaluated by frequency tables, showing the number of subjects 
with medical history findings (i.e., listed conditions of previous diagnoses, diseases, or 
surgeries based on the CRF) that started before signing of the informed consent and that are 
considered relevant to the study.
6.1.4
Protocol Deviations
A summary of major protocol deviations will be given by frequency tables showing the 
number of subjects with major protocol deviations overall, by type of deviation. Analysis will 
be based on ITT.
Types of major protocol deviations include:

Significant inclusion criteria not fulfilled

Significant exclusion criteria fulfilled

Failure to obtain informed consent before initiation of study procedures

Prohibited medication use

Failure to report SAE

Failure to report outcome event

Other safety
6.1.5
Prior and Concomitant Medications
Frequency tables by type of medication will be provided for prior medications prior to stroke 
(for antiplatelets and anticoagulants) and prior to randomization (for all) and separately for 
concomitant medication continued after randomization , for visits every 12 months, at EOT 
and post-baseline, i.e. counting every medication that was taken at least once on or after 
randomization. Analyses will be by treatment group and overall based on ITT.


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Prior and concomitant medications from the “Concomitant Medications report CRF 350” will 
be analyzed according to the given categories. Other concomitant medication will be coded 
by Anatomical Therapeutic Chemical (ATC) classification system according to the World 
Health Organization Drug Dictionary (WHO-DD) using the version as outlined in the Trial 
Summary (TS) domain and listed in section 16 of CSR. 
Separately the number of patients receiving ASA at any time-point after randomization and 
before last dose of study drug will be displayed distinguishing ASA doses of <=100 mg and 
>100mg.
6.1.6
Extent of Exposure and Compliance - amended
All analyses related to intake of study medication will be by treatment group and overall
based on SAF.
The treatment duration will be calculated (date of last study medication- date of first study 
medication+1 day) and analysed descriptively. Additionally the number of subjects by 
treatment duration category will be given. Categories will include all subjects with at least 3 
months, 6 months, 9 months, 12 months, 18 month, 24 month treatment duration.
The time on study medication will be calculated (treatment duration excluding days off study 
medication) and analysed descriptively.
The number of tablets taken will be calculated (tablets dispensed-tablets returned) and 
analysed descriptively, as well as corresponding extent of exposure (number of tablets 
taken*dose).
Compliance will be tabulated as entered in the CRF and summarized for the whole study. The 
number of subjects with at least 80% compliance will be presented.
6.2
Efficacy
6.2.1
Primary efficacy variable
The primary efficacy variable is the time from randomization to first occurrence of any of the 
components of the composite outcome (adjudicated), including:

Stroke (ischemic, hemorrhagic, and undefined stroke, TIA with positive 
neuroimaging)

Systemic embolism


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6.2.2
Secondary efficacy variables
The secondary efficacy variables of this study are the time from randomization to first 
occurrence of:

Cardiovascular death (CV death; including death due to hemorrhage and death with 
undetermined/unknown cause), recurrent stroke, systemic embolism, and MI

All-cause mortality

Individual components of the primary and secondary efficacy outcomes (stroke, CV 
death, and MI) as well as ischemic stroke, and disabling stroke (modified Rankin 
score 4 and 5)
These are listed in the order of sequential testing.
6.2.3
Subgroup variables
The following subgroup analyses based on baseline demographics are planned for the 
comparison of the primary efficacy and safety outcomes:

Age: <60; 60-75; >75 age (for publication: <75; ≥75 years)
additionally <60; >=60 years

Sex: male; female

Race: White; Black; Asian; other

Region: North America; South America; Western Europe; Eastern Europe; Asia

BMI: < 25; ≥ 25 to < 30; ≥ 30kg/m2 (for publication: < 30; ≥ 30kg/m2)

Weight: <70; 70-90; >90 kg (for publication: <50; 50-100; >100 kg)

eGFR: <50; 50-80; >80 mL/min

Stroke or TIA prior to qualifying stroke: yes or no

Time from qualifying stroke to randomization: ≤30 days; 30 days to 3 months; > 
3months

Presence of patent foramen ovale: present or absent / not known

Cardiac rhythm monitoring: <48; ≥ 48 hours
(≥ 48 hours is fulfilled if in-hospital telemetry was performed and “≥48 hrs” is ticked, 
or ECG Holter was performed and duration is ≥ 48 hours, or other type of prolonged 
monitoring was performed or different types of monitoring have been used and total 
duration is ≥ 48 hours; ranges will be summed up using mid of the range)

Hypertension: yes or no

Diabetes: yes or no
Higher absolute efficacy event rates are expected for the following subgroups: older age, 
females, renal impairment, stroke or TIA prior to qualifying event, hypertension, and 
diabetes. Even though rivaroxaban has not been tested in patients with ESUS, based on 
earlier studies with rivaroxaban a consistent (relative) treatment effect across all of the 
planned subgroups is expected.


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A limited number of additional subgroup analyses may be proposed by the Steering 
Committee.
The randomization was stratified by the dichotomic age group variable for age below 60 
years (No/Yes) and by country.
6.2.4
Analysis of the primary efficacy variable
The primary analysis will include events as adjudicated by the ICAC and will be based on the 
ITT analysis set using the ITT data scope. 
In order to evaluate whether rivaroxaban is superior to ASA in prolonging the time to a 
primary efficacy (PE) outcome event in patients with ESUS, the following null hypothesis 
(H0) will be tested at the significance level of 0.025:
H0, PE: SR(t) = SA(t) for all time points t ≥ 0, (i.e. “there is no difference between the 
rivaroxaban treatment group and the ASA control group regarding the primary 
efficacy outcome for all time points”)
The one-sided alternative hypothesis will be:
H1, PE: SR(t) > SA(t) for at least one time point t ≥ 0, and SR(t) ≥ SA(t) for all time 
points t ≥ 0, (i.e. “there is a difference between the two groups in favor of rivaroxaban 
regarding the primary efficacy outcome for at least one time point“)
where SR denotes the survival function of the rivaroxaban and SA denotes the survival 
function of the ASA group.
The following decision rule to test the null hypothesis will be applied:
According to the size of this study, it is justified to assume under H0, PE a sufficiently 
close approximation of the one-sided stratified (according to dichotomic age group) 
log-rank test to the normal distribution. If the z-value from the one-sided log-rank test 
(for the difference SR(t) - SA(t) with stratification) is larger than the critical quantile 
from the normal distribution (z0.975 =1.96), the null hypothesis will be rejected in 
favor of the alternative hypothesis.
Kaplan-Meier estimates of cumulative risk and Nelson-Aalen estimates of the cumulative 
hazard functions will be provided to evaluate the timing of event occurrence in the different 
treatment groups and the consistency of the respective treatment effects for all time points.
To derive the log-rank Z test statistic and the variance V of the log-rank statistics, SAS 
program code corresponding to the following will be used: 


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PROC LIFETEST DATA = <dataset> ALPHA=0.05 METHOD=KM NELSON;
  STRATA stratumn / GROUP=trtgrpn TEST=(LOGRANK);
  TIME ttevalue * ttecnsr(0);
RUN;
/*
where
dataset  = name of sub-dataset including all ITT subjects randomized 
trtgrpn  = variable coding randomized treatment group
ttevalue = time to first occurrence of primary efficacy outcome event
ttecnsr  = censoring index (0 = right-censored, 1 = event)
stratumn = variable for stratification factor (age group with two levels)
*/
Hazard ratio and corresponding two-sided 95% confidence intervals will be estimated based 
on an age-group stratified Cox proportional hazards models. The plausibility of proportional 
hazards assumption will be assessed by visually comparing the plot of the log of cumulative 
hazard between treatments and by additionally adding a treatment by logarithm-transformed 
time interaction into the Cox model. Censoring will be assumed independent of the treatment 
group assignment.
For the analysis of the primary outcome in this study, the hazard function h(t) is the chance 
that an individual experiences an event of the primary efficacy outcome in the next instant in 
time, given that the individual has not had such an event up to time t. For example, for the 
comparison of rivaroxaban with ASA (control), the corresponding stratified Cox proportional 
hazards model can be described by the following equation:
hk(t,xi) = h0k(t) exp(β xi),
where 
hk(.)
hazard function for primary efficacy outcome for stratum k, k = 1,2 
(k represents age group stratification factor), as a function of time and subject’s 
covariates
h0k(.)
unspecified underlying baseline hazard function for primary efficacy outcome per 
stratum k; hazard of an individual with xi = 0
t
time (in days) relative to the randomization date
xi
treatment group of subject i
β
unknown parameter (to be estimated); hazard ratio = exp(β)
SAS program code corresponding to the following will be used:


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PROC PHREG DATA = <dataset>;
  MODEL ttevalue * ttecnsr(0) = trtgrpn / RL TIES=EFRON ALPHA=0.05;
  STRATA stratumn;
RUN;
/*
where
dataset  = name of sub-dataset including all ITT subjects 
trtgrpn  = variable coding randomized treatment group
ttevalue = time to first occurrence of primary efficacy outcome event
ttecnsr  = censoring index (0 = right-censored, 1 = event)
stratumn = variable for stratification factor (age group with two levels)
*/
Additional procedure options controlling the output may be added to the program codes.
Subjects without a primary efficacy outcome event will constitute a right-censored 
observation (see section 4.5.3 for censoring rules). Primarily, for the time-to-event analysis 
the censoring mechanism will be assumed to be non-informative. Additional sensitivity 
analyses will be performed in order to evaluate the robustness of the statistical results under 
different assumptions (see section 6.2.7).
6.2.5
Analysis of secondary efficacy variables
A single primary efficacy outcome will maintain strict control of the type I error rate. If the 
primary efficacy outcome is statistically significant, the secondary efficacy outcomes will be 
tested in a sequential manner according to the order as listed in section 6.2.2.
If the superiority of rivaroxaban for the primary outcome is declared, the following 
alternative hypotheses, superiority of rivaroxaban compared with ASA for the secondary 
efficacy outcomes will be tested in the sequential order. That is, the subsequent ordered 
secondary outcome will be tested only if superiority can be shown for the previous outcomes.
If an individual test during any step is not statistically significant, further testing may 
continue but significance will not be claimed. This hierarchical testing procedure will control 
the global Type 1 error level.
The primary analysis of the secondary variables will include events as adjudicated by the 
ICAC and will be based on the ITT analysis set using the ITT data scope. 
The first secondary efficacy variable (SE1) of this study is the time from randomization to 
first occurrence of cardiovascular death (including death due to hemorrhage), recurrent 
stroke, systemic embolism, or MI. The following null hypothesis will be tested at the 
significance level of 0.025:


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H0, SE1: SR1(t) = SA1(t) for all time points t ≥ 0,
The one-sided alternative hypothesis will be:
H1, SE1: SR1(t) > SA1(t) for at least one time point t ≥ 0, and SR1(t) ≥ SA1(t) for all time 
points t ≥ 0, 
where SR1 denotes the survival function of the rivaroxaban and SA1 denotes the survival 
function of the ASA group.
The second secondary efficacy variable (SE2) of this study is the time from randomization to 
first occurrence of death from any cause. The following null hypothesis will be tested at the 
significance level of 0.025:
H0, SE2: SR2(t) = SA2(t) for all time points t ≥ 0,
The one-sided alternative hypothesis will be:
H1, SE2: SR2(t) > SA2(t) for at least one time point t ≥ 0, and SR2(t) ≥ SA2(t) for all time 
points t ≥ 0, 
where SR2 denotes the survival function of the rivaroxaban and SA2 denotes the survival 
function of the ASA group.
The analysis methods will be those described for the primary efficacy outcome.
The same analysis will be performed for the individual components of the primary and 
secondary efficacy outcomes (stroke, CV death, and MI) as well as ischemic stroke, and 
disabling stroke (modified Rankin score 4 and 5).
6.2.6
Subgroup analysis
Subgroup analyses for the efficacy and safety outcomes will be performed based on the same 
analysis sets and data scopes as in the main analyses of the study outcomes. The subgroup 
analyses will be presented descriptively without formal hypotheses testing. Additionally 
forest plots will be generated.
Homogeneity of treatment effect in subgroups, both in magnitude and direction, will be 
assessed by adding a covariate for the subgroup variable and the corresponding treatment-
subgroup interaction to the respective (age-group stratified) Cox proportional hazards model 
used in the main analysis. Additionally the hazard ratio for the treatment effect will be 
estimated separately within each level of a subgroup variable using the same Cox 
proportional hazards.
As the number of subgroup analyses may be large, the probability of observing at least one 
spurious interaction is high despite the lack of a biological or pharmacological basis for 
expecting an interaction. Thus, any interactions with a p-value below the 5% type I error 
level in the analysis of primary outcomes will be interpreted as “flags” to prompt further 


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investigation into the consistency of the pattern within secondary and related outcomes. This 
further investigation includes the likelihood ratio test proposed by Gail to test for qualitative 
interaction.
6.2.7
Sensitivity analyses - amended
To support the primary study results and to assess to robustness of the primary analysis 
several sensitivity analyses will be performed (Little).
The analysis of the primary and secondary efficacy variables as described in section 6.2.4 and 
6.2.5 will be repeated based on the safety analysis set using the on-treatment data scope.
The analysis of the primary and secondary efficacy variables as described in section 6.2.4 and 
6.2.5 will be repeated counting outcome events as reported by the investigators.
The analysis of the primary and secondary efficacy variables as described in section 6.2.4 and 
6.2.5 will be repeated using the Cox proportional hazard model without stratification.
The analysis of the primary and secondary efficacy variables as described in section 6.2.4 and 
6.2.5 will be repeated counting adjudicated outcome events up to the last trial contact date, 
i.e. including also events after the efficacy cut-off date.
Despite all efforts it will be hard to completely avoid loss to follow-up within this study
(White). 
6.3
Pharmacokinetics / pharmacodynamics
Not applicable
6.4
Safety
6.4.1
Adverse events - amended
Adverse events (AEs) will be coded by MedDRA.  The version number of MedDRA used for 
the analyses will be stored in the clinical database/system set-up. A listing will be provided 
linking the original investigator terms and the coded terms.
Analyses of reported adverse events will be performed based on the safety analysis set.  
In case of uncertainty (e.g., missing or incomplete dates), adverse events will be classified as 
“treatment emergent” following the worst case approach. 
An overall summary of SAEs and treatment-emergent (TE) AEs will be generated by 
treatment group and overall.


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Incidences of subjects with TEAEs, drug-related and/or serious TEAEs, TEAEs causing 
discontinuation of study drug, and TEAEs of particular concern will be summarized by 
treatment group and overall grouped by MedDRA Primary System Organ Class (SOC) and 
Preferred Term (PT).  In addition, the incidence of pre-treatment AEs and AEs during the 
follow-up will be tabulated.
Serious adverse events (SAEs), AEs leading to discontinuation and AEs of particular concern
will be listed.  The date, relative day (to study medication) and phase of the study (pre-
treatment, during treatment, post-treatment) will be included.
Further summaries of SAEs by intensity and outcome will be provided, consistent with Bayer 
Global Medical Standards.
Adverse events matching the SMQ Haemorrhage terms (excl laboratory terms) will be 
excluded from the AE analysis to avoid double counting of events. This is affecting data from 
Japan where bleeding events are additionally reported as AEs. In general bleeding events are 
reported separately and analyzed as described in the following sections. 
6.4.2
Primary safety variable
The primary safety variable is the time from randomization to time of first occurrence of a
major bleeding (ISTH) defined as a bleeding event that meets at least one of the following 
criteria:

Fatal bleeding, and/or

Symptomatic bleeding in a critical area or organ (intracranial, intraocular, intraspinal, 
pericardial, retroperitoneal, intraarticular, or intramuscular with compartment 
syndrome), and/or

Clinically overt bleeding associated with a recent decrease in the hemoglobin level of
≥2 g/dL (20 g/L; 1.24 mmol/L) compared to the most recent hemoglobin value 
available before the event, and/or

Clinically overt bleeding leading to transfusion of 2 or more units of packed red blood
cells or whole blood
6.4.3
Secondary safety variables
The secondary safety variables are the time from randomization to time of first occurrence of:

Life-threatening bleeding, defined as a subset of major bleeding that meet at least one
of the following criteria:

Fatal bleeding

Symptomatic intracranial bleeding

Reduction in hemoglobin of at least 5 g/dl (50 g/l; 3.10 mmol/L)

Transfusion of at least 4 units of packed red cells or whole blood

Associated with hypotension requiring the use of intravenous inotropic 
agents


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
Necessitated surgical intervention

Clinically relevant non-major bleeding, defined as non-major overt bleeding but

Requires medical attention (e.g., hospitalization, medical treatment for
bleeding), and/or

Is associated with a study drug interruption of more than 14 days.

Intracranial hemorrhage
6.4.4
Other safety variables
All bleeding events will be analyzed. In addition to the analysis according to ISTH as 
described above, bleeding events will be analyzed according to GUSTO, TIMI and BARC 
definitions.
Vital signs and weight will be analyzed descriptively. 
Any pregnancy occurring in a study subject during the subject’s participation in this study 
will be listed in the patient data listing.
6.4.5
Analysis of safety variables
The primary analysis of the safety variables will be based on the ITT analysis set using the 
ITT data scope. Additionally the safety variables will be analyzed based on the safety 
analysis set using the on-treatment data scope. 
The primary and secondary safety variables will be tested parallel without control of the type 
I error level.
In order to evaluate whether rivaroxaban is different to ASA with respect to the time to a 
bleeding event in patients with ESUS, the following null hypothesis will be tested at the two-
sided significance level of 0.05:
H0, B: SRB(t) = SAB(t) for all time points t ≥ 0, 
The two-sided alternative hypothesis will be:
H1, B: SRB(t) ≠SAB(t) for at least one time point t ≥ 0,
where SRB denotes the survival function of the rivaroxaban and SAB denotes the survival 
function of the ASA group.
The analysis methods will be those described for the primary efficacy outcome.
The safety variables will be analyzed by subgroup as describe for the efficacy variables.
6.5
Other procedures and variables
The analysis of other variables will be by treatment group and overall and based on ITT.


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Other variables are:

Healthcare Resource Use
o
hospitalizations (total days length of stay, intensive care unit/cardiac care unit 
days, ward type); emergency room visits; unscheduled outpatient physician 
consultations; or visits related to bleeding, surgeries, other selected procedures 
(inpatient and outpatient); and post-stroke care (status of care, home health or 
rehabilitation center or long term care). Days off-work.

European Quality of Life-5 Dimensions (EQ-5D)
o
EQ-5D is a standardized measure of health status developed by the EuroQol 
Group in order to provide a simple, generic measure of health for clinical and 
economic appraisal. Assessments will be done using both a descriptive system 
and the subject’s self-rated health on a visual analogue scale where the
endpoints are labeled ‘Best imaginable health state’ and ‘Worst imaginable 
health state’.
The following variables are of interest:

EQ-5D single dimensions

EQ-5D Visual Analogue Scale (VAS) values

EQ-5D index score
o
EQ-5D will be analyzed separate from section 14 of CSR.

Montreal Cognitive Assessment (MoCA) 
o
The Montreal Cognitive Assessment (MoCA) test assesses several cognitive 
domains: attention and concentration, executive functions, memory, language, 
visuoconstructional skills, conceptual thinking, calculations, and orientation. 
For each task correctly completed, one point is assigned.  All subscores are 
summed up and adjusted for individuals with ≤ 12 years education to derive a 
total score ranging between 0 (for a totally cognitive impaired subject) and a 
maximum of 30 points (cognitively healthy participant).

Standard Assessment of Global-Activities in the Elderly (SAGE)
o
The SAGE questionnaire comprises 15 items, each describing an activity for 
which the respondent has to indicate how much difficulty the subject has 
encountered in performing this activity in the past month. Regarding scoring 
for an item, 0 points are assigned if the participants endorse the “None/never 
performed” response, 1 point to the “Mild” response, 2 points to the 
“Moderate” response, and 3 points to the “Severe” response.  One additional 
point will be assigned when in response to question 11, 12, and 15 the 


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respondent declares the need for help from another person or a tool to walk, 
jump the stairs or to bath. The total score will range from 0, describing a very 
independent participant over a broad spectrum of activities, to 48, describing a 
very dependent subject.

Modified Rankin Score
o
The modified Rankin Score runs from 0-6, running from perfect health 
without symptoms to death.
o
The score will be analyzed by frequency tables and bar charts comparing 
baseline to EOT. Wilcoxon rank-sum test will be used to give exploratory p-
values comparing treatment groups.
6.6
Net clinical Benefit
The benefit-risk of rivaroxaban vs aspirin will be evaluated based on the excess number of events 
between treatments for events intended to be prevented (benefits) and events that may be caused 
(risks). Excess number of events is defined as the difference in event rate times a hypothetical 
population size (eg, 10,000 patients). To have a comprehensive benefit-risk evaluation, several 
comparisons will be considered.
The first measure of net clinical benefit in this study is the primary efficacy outcome. 
Although named efficacy outcome it includes not only thrombotic events, but also 
hemorrhagic events (hemorrhagic stroke).
The second measure of net clinical benefit is all-cause mortality.
The third measure of net clinical benefit is the composite of stroke, MI, CV death, fatal 
bleeding or bleeding into a critical organ.
As an overall valid measure of net clinical benefit is hard to be defined, a variety of measures 
will be presented side by side to allow weighting positive effects and harms. For the efficacy 
these will include the thrombotic events of the primary and secondary efficacy endpoints. For 
the safety side these will include the hemorrhagic events of the efficacy endpoint, ISTH 
major bleeding, life-threatening bleeding, and intracranial hemorrhage.
Other measures may be added as they may help to assess the net clinical benefit.
7.
Document history and changes in the planned statistical analysis

Draft SAP dated 30 Sep 2014

Second SAP draft for team review dated 10 Nov 2014

Proposed final SAP for team review dated 14 Jan 2015

Approval of the SAP dated 2 Mar 2015

Amendment 1 of the SAP dated 19 May 2017


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
Amendment 2 of the SAP dated 20 Dec 2017
7.1
Overview Changes to SAP – Amendment 1
Editorial, administrative, and typographical corrections were made that do not affect the 
overall integrated SAP.  These changes are not described in this section.
The following changes are introduced in SAP Version 2.0.
Modification 1: Additional interim analysis at 50% of events
Rationale: Changes reflect those in global Clinical Study Protocol amendment 2.0 to be in 
line with the plan for interim analyses of the IDMC Charter as requested by the IDMC.
Section affected: 4.4 Interim Analyses and Data Monitoring
Modification 2: Subgroup definition for age added and for region and cardiac rhythm 
monitoring clarified
Rationale: Additional age group (<60; >=60 years) is reflecting the strata used for 
randomization. Region definition was added. The derivation of the length of cardiac rhythm 
monitoring was clarified.
Section affected: 

6.1.2
Demographics

6.2.3
Subgroup variables

Appendix B: Region definition
Modification 3: Details added/corrected for descriptive statistics
Rationale: “Index stroke” was changed to “qualifying stroke” to reflect the terminology of the 
CRF. Wording “last contact prior to efficacy cut-off” was clarified to “last contact prior or 
equal to efficacy cut-off”. The analysis of medical history and concomitant medication was 
adapted to the CRF design (pre-defined terms). The definition of the efficacy variable
component CV death was clarified to include death with undetermined/unknown cause. The 
SAS code provided for carrying out the stratified log-rank test has been updated to reflect the 
FDA preferred implementation, with the difference being how tied event times are handled.
Term corrected from ”AE” to “SAE” in adverse event section. Analysis method for modified 
Rankin score added. And the DSS was deleted following the protocol amendment.
Section affected: 

4.5.4
Determination of baseline values (new)

4.5.5
Handling of repeated measurements (new)

6.1.3
Medical history

6.1.5
Prior and Concomitant Medications


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
6.2.2
Secondary efficacy variables 

6.2.4
Analysis of the primary efficacy variable 

6.4.1
Adverse events

6.5
Other procedures and variables
Modification 4: Added third measure of net clinical benefit  
Rationale: The rational is the specification of a measure for net clinical benefit that captures 
the major adverse events (stroke, MI, CV death) and important safety outcomes (fatal 
bleeding or bleeding into a critical organ). These are all likely modified by the study 
treatment. 
Section affected: 

6.6
Net clinical Benefit
7.2
Overview Changes to SAP – Amendment 2
Modification 5: Exclusion of bleeding events from AE reporting
Rationale: In Japan bleeding events are additionally reported as AEs. To avoid double 
counting, bleeding events will be excluded from the AE analysis using the SMQ 
Haemorrhage terms (excl laboratory terms). Bleeding events will be analyzed separately.
Section affected: 

6.4.1
Adverse events - amended
Modification 6: Setting the efficacy cut-off date to October 5th 2017
Rational: On October 5th 2017 the early stopping of the study was announced after the 
recommendation by the IDMC. The definitions of the efficacy cut-off date, the trial close-out 
window and the date of last contact prior or equal to the efficacy cut-off date have been 
adapted. This adaption was made in the description of the ITT data scope and the ITT 
censoring rules accordingly. Within the sensitivity analyses section for the primary efficacy 
outcome the obsolete tipping point analysis has been deleted and an analysis including 
efficacy outcome events up to the date of the last trial contact has been added.
Sections affected:

1.
Introduction

4.5.1
Analysis Dates

4.5.2
Data Scopes


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
4.5.3
Censoring rules for time-to-event variables

6.2.7
Sensitivity analyses
Modification 7: Detailed description added for the calculation of treatment compliance.
Section affected:

6.1.6
Extent of Exposure and Compliance
8.
References
Dubois MF, Hébert R. Imputation of missing dates of death or institutionalization for time-to-
event analyses in the Canadian Study of Health and Aging. Int Psychogeriatr. 2001;13 
Supp 1:91-7. 
Shih, J. Sample size calculation for complex clinical trials with survival. Controlled Clinical 
Trials 1995, 16:395-407
Gail M., Simon R. Testing for qualitative interactions between treatment effects and patient 
subsets. Biometrics 1985, 41:361-372.
Li Z., Chuang-Stein C., Hoseyni C. The probability of observing negative subgroup results 
when the treatment effect is positive and homogeneous across all subgroups. Drug 
Information Journal 2007, 41:47-56.
White, IR. Strategy for intention to treat analysis in randomised trials with missing outcome 
data. BMJ 2011;342:d40 
Little RJ, D'Agostino R, Cohen ML, et al. The prevention and treatment of missing data in 
clinical trials. N Engl J Med 2012; 367:1355-1360.


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Appendix A: Patient follow-up


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Appendix B: Region definition - amended
For subgroup analyses according to region, countries will be assigned to regions as shown in Table 1. below. If additional countries 
participate in the trial, their assignment to a region will be described in an amendment to the SAP before unblinding.
Table 1.  Classification of countries to regions
Region 
Countries
North America 
Canada, USA
South America
Argentina, Brazil, Chile, Mexico
Western Europe (plus Australia, 
Israel, and South Afrika)
Australia, Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Israel, Italy, Portugal, 
South Africa, Spain, Sweden, Switzerland, United Kingdom
Eastern Europe 
Czech Republic, Hungary, Poland, Russian federation, Turkey
Asia Pacific
China, Japan, South Korea