Clinical trial NCT02556203
Conditions: Transcatheter Aortic Valve Replacement
Keywords: TAVR TAVI Transfemoral aortic valve implantation
Sponsor: Bayer
Start date: 2015-12-16; Completion date: 2018-11-27
Enrollment: 1653 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To assess whether a rivaroxaban-based anticoagulation strategy, following successful TAVR, compared to an antiplatelet-based strategy, is superior in reducing death or first thromboembolic events (DTE).

To assess the primary bleeding events (PBE) of the rivaroxaban-based strategy compared to an antiplatelet-based strategy, following TAVR.

Detailed description:

Arms: arm 1: Subjects were treated with Rivaroxaban (10mg once-daily) and ASA (75-100mg once-daily) within first 90 days after randomization. After 90 days, ASA was discontinued and rivaroxaban (10mg once-daily) was to be continued alone. In the event of NOAF (New Onset of Atrial Fibrillation), subjects should be switched to rivaroxaban (20/15mg once-daily) and ASA (75-100mg once-daily) within first 90 days. After 90 days, ASA was discontinued and rivaroxaban (20/15mg once-daily) was to be continued alone. arm 2: Subjects were treated with clopidogrel (75mg once-daily) and ASA (75-100mg once-daily) within first 90 days after randomization. After 90 days, clopidogrel was discontinued and ASA (75-100mg once-daily) was to be continued alone. In the event of NOAF, subjects should start treatment of open-label VKA to target INR 2 to 3 (according to guidelines) and ASA (75-100mg once-daily) within first 90 days. After 90 days, ASA was discontinued and VKA was to be continued alone.
Interventions: intervention 1: Rivaroxaban (Xarelto, BAY59-7939) intervention 2: Acetylsalicylic Acid (ASA) intervention 3: Clopidogrel intervention 4: Rivaroxaban (Xarelto, BAY59-7939) intervention 5: Vitamin K antagonist (VKA)
Intervention descriptions: intervention 1: 10mg OD (once-daily) intervention 2: 75-100mg OD intervention 3: 75mg OD intervention 4: In case of NOAF, 20/15 mg OD (once-daily) intervention 5: In case of NOAF, Open-label VKA therapy to target international normalized ratio (INR) 2-3, according to guidelines

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
Global multicenter, open-label, randomized, event-driven, active-
controlled study comparing a rivaroxaban-based antithrombotic 
strategy to an antiplatelet-based strategy after transcatheter aortic 
valve replacement (TAVR) to optimize clinical outcomes. 
NCT Number: 
NCT02556203 
Document Date: 
17-Aug-2016 
 


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Cover page of the integrated protocol
Global multicenter, open-label, randomized, event-driven, active-controlled study 
comparing a rivaroxaban-based antithrombotic strategy to an antiplatelet-based 
strategy after transcatheter aortic valve replacement (TAVR) to optimize clinical 
outcomes.
This protocol version is an integration of the following documents / sections:
Original protocol, Version 1.0, dated 25 JUN 2015
Amendment 1 (described in Section 15.1)
forming integrated protocol Version 2.0, dated 28 SEP 2015
Amendment 3 (described in Section 15.2)
forming integrated protocol Version 3.0, dated 17 AUG 2016
The following local amendment is not part of this integrated global protocol:

Amendment 2 (Norway), dated 16 FEB 2016


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1.
Title page
Global multicenter, open-label, randomized, event-driven, active-controlled study 
comparing a rivAroxaban-based antithrombotic strategy to an antipLatelet-based 
strategy after transcatheter aortIc vaLve rEplacement (TAVR) to Optimize clinical 
outcomes.
Acronym
GALILEO
Test drug:
BAY 59-7939 / JNJ-39039039 / Rivaroxaban
Clinical study phase:
Phase 3
Date:
17 AUG 2016
Registration:
2015-001975-30
Version no.:
3.0
Sponsor’s study no.:
17938
Sponsor:
Non-US territory:  Bayer AG, D-51368 Leverkusen, Germany
US territory:  Bayer HealthCare Pharmaceuticals Inc.
100 Bayer Boulevard, PO Box 915, Whippany, NJ 07981-0915 USA
Sponsor’s medical expert:
Rua Domingos Jorge, 1100 – Building 9301, 2nd floor
04779-900 São Paulo-SP Brazil
Tel: 
Fax: 
The study will be conducted in compliance with the protocol, 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.
PPD
PPD
PPD
PPD


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Signature of the sponsor’s medically responsible person
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Role:  
 
Date:
Signature:
PPD
PPD


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


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2.
Synopsis
This section was modified by Amendments 1 and 3. For details, please see Sections 15.1 and 
15.2.
Title
Global multicenter, open-label, randomized, event-driven, 
active-controlled study comparing a rivAroxaban-based 
antithrombotic strategy to an antipLatelet-based strategy after 
transcatheter aortIc vaLve rEplacement (TAVR) to Optimize 
clinical outcomes.
Short title
Global study comparing a rivAroxaban-based antithrombotic 
strategy to an antipLatelet-based strategy after transcatheter 
aortIc vaLve rEplacement to Optimize clinical outcomes.
Acronym
GALILEO
Clinical study phase
Phase 3
Study objective(s)
To assess whether a rivaroxaban-based anticoagulation strategy, 
following successful TAVR, compared to an antiplatelet-based 
strategy, is superior in reducing death or first thromboembolic 
events (DTE).
To assess the primary bleeding events (PBE) of the rivaroxaban-
based strategy, following TAVR, compared to an antiplatelet-
based strategy.
Test drug(s)
Name of active ingredient

Rivaroxaban (BAY59-7939 / JNJ-39039039)

Acetylsalicylic Acid (ASA)
Dose(s)
Rivaroxaban-based strategy

Rivaroxaban 10 mg once-daily AND Acetylsalicylic 
Acid (ASA) 75-100 mg once-daily

Rivaroxaban 10 mg once-daily
If new-onset atrial fibrillation (NOAF) occurs:

Rivaroxaban 20 or 15 mg once-daily AND ASA 75-
100 mg once-daily

Rivaroxaban 20 or 15 mg once-daily
Route of administration
Oral


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Duration of treatment
The first dose of rivaroxaban (10 mg once-daily) is started at the 
time of randomization, if the subject is not on clopidogrel, or 
within 1-3 days after the last intake of clopidogrel. In case study 
medication is started the next day post-TAVR, study medication 
should not be started earlier than the time the TAVR was done 
on the previous day and the subject should be stabilized and
complications or bleedings should have been excluded carefully.
Rivaroxaban 10 mg once-daily can be taken with or without 
food. ASA 75-100 mg once-daily is to be continued unchanged 
or started immediately after randomization if not already being 
taken. ASA is discontinued after 90 days from randomization. 
Rivaroxaban is continued until the efficacy cut-off date, i.e. 
when the predefined number of efficacy endpoints is reached or 
earlier if the event rate is unexpectedly low. In the event of 
NOAF the dose of rivaroxaban is switched from 10 mg once-
daily to 20 or 15 mg once-daily, depending on renal function. 
Rivaroxaban 20 and 15 mg once-daily should be taken with 
food. Up to 90 days after randomization, ASA 75-100 mg once-
daily is to be continued unchanged. After 90 days from 
randomization, ASA is discontinued and rivaroxaban 20 or 15 
mg once-daily is continued alone until the efficacy cut-off date.
Reference drug(s)
Name of active ingredient

Clopidogrel hydrogen sulfate (clopidogrel)

ASA
Dose(s)
Antiplatelet-based strategy

Clopidogrel hydrogen sulfate (clopidogrel) 75 mg 
once-daily AND ASA 75-100 mg once-daily

ASA 75-100 mg once-daily
If NOAF occurs:

Vitamin K antagonist (VKA) with a target 
international normalized ratio (INR) 2-3 AND ASA 
75-100 mg once-daily

VKA (target INR 2-3)
Route of administration
Oral
Duration of treatment
Clopidogrel 75 mg once-daily and ASA 75-100 mg once-daily 
are to be continued unchanged, or to be started at the time of 
randomization if not already being taken. In subjects that are 


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clopidogrel-naïve at randomization a single loading dose of at 
least 300 mg clopidogrel should be administered followed by 
clopidogrel 75 mg once-daily. Clopidogrel must be discontinued 
at 90 days post-randomization and ASA 75-100 mg once-daily is 
to be continued until the efficacy cut-off date.
In the event of NOAF, the antiplatelet-based strategy will be 
stopped and a VKA with a target INR 2-3 started. ASA 75-100 
mg once-daily is to be continued in combination with VKA until 
90 days after randomization. After 90 days, ASA must be 
discontinued and VKA continued alone until the efficacy cut-off 
date.
Background treatment
The use of gastric protection drugs that do not interact with 
cytochrome P450 (CYP) 2C19 (such as pantoprazole) is strongly 
recommended.
Indication
Post-successful transcatheter aortic valve replacement (TAVR).
Diagnosis and main criteria for 
inclusion /exclusion
Key inclusion criteria:

Successful TAVR of an aortic valve stenosis (either 
native or valve-in-valve)

By iliofemoral or subclavian access

With any approved/marketed device

Written informed consent (IC)
Key exclusion criteria:

Atrial fibrillation (AF), current or previous, with an 
ongoing indication for oral anticoagulant treatment

Any other indication for continued treatment with any 
oral anticoagulant (OAC)

Known bleeding diathesis (such as but not limited to 
active internal bleeding, clinically significant 
bleeding, platelet count ≤ 50,000/mm3 at screening, 
hemoglobin level < 8.5 g/dL, active peptic ulcer or 
known gastrointestinal (GI) bleeding, history of 
intracranial hemorrhage or subdural hematoma)

Any ongoing absolute indication for dual antiplatelet 
therapy (DAPT) at time of screening that is unrelated 
to the TAVR procedure 

Clinically overt stroke within the last 3 months

Planned coronary or vascular intervention or major 
surgery


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
Severe renal impairment (eGFR < 30 mL/min/1.73 
m2) or on dialysis, or post-TAVR unresolved acute 
kidney injury with renal dysfunction stage 2 or higher

Moderate and severe hepatic impairment (Child-Pugh 
Class B or C) or any hepatic disease associated with 
coagulopathy.
Screening, IC and randomization:
Subjects are screened for inclusion after TAVR. Consenting 
subjects must be randomized within 1-7 days after a successful 
TAVR and before hospital discharge.
Study design
Event-driven, randomized, open-label with blinded endpoint 
evaluation, parallel-group, active-controlled, multicenter,
international study
Methodology
The primary comparison will be to test the superiority of a 
rivaroxaban-based strategy to an antiplatelet-based strategy with 
respect to the primary efficacy endpoint. This comparison is 
preceded by a non-inferiority test that must be satisfied.
Estimates of the hazard ratio for bleeding events together with 
their 95% confidence intervals will be calculated for descriptive 
purposes.
Type of control
Control treatment strategy is composed of active treatments and 
is in line with the current standard of care.
Clinical Event Committee
Yes
Data Safety Monitoring Board
Yes
Number of subjects
A total of 1520 subjects will be randomized.
Primary variable(s)
Primary Efficacy Endpoint: death or first adjudicated 
thromboembolic event (DTE) defined as the composite of all-
cause death and adjudicated any stroke, myocardial infarction 
(MI), symptomatic valve thrombosis, pulmonary embolism (PE), 
deep vein thrombosis (DVT), or non-CNS systemic embolism.
Primary Safety Endpoint: primary bleeding event (PBE) defined 
as the composite of adjudicated life-threatening, disabling or 
major bleeding, classified according to the valve academic 
research consortium (VARC) definitions following the bleeding 
academic research consortium (BARC) classification.


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Time point/frame of 
measurement for primary 
variable(s)
Subjects are treated and followed from randomization until the 
study ends, i.e. when the predefined number of primary efficacy 
endpoints is reached or earlier if the event rate is unexpectedly 
low and study closure activities are completed. Therefore, the 
duration of the treatment period for a given subject will depend 
on the time required to collect these events. The expected 
duration of the study is 750 days, but depending upon the rate of 
subject recruitment and endpoint event rates it may be adapted. 
Regular assessments are planned to take place during the study.
Plan for statistical analysis
The primary endpoints (for efficacy and for safety) are analyzed 
as a time-to-event endpoint, in the full analysis set (FAS) of all 
randomized subjects.
The primary efficacy endpoint (DTE) is tested for superiority
using log-rank test. This test is preceded by a non-inferiority
(NI) test with a hazard ratio NI margin at 1.20 using the on-
treatment approach. If non-inferiority is met, a test for 
superiority is performed using the intention-to-treat (ITT)
approach. 


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Table of contents
1.
Title page ............................................................................................................................2
Signature of the sponsor’s medically responsible person......................................................3
Signature of principal investigator..........................................................................................4
2.
Synopsis...............................................................................................................................5
Table of contents .....................................................................................................................10
Table of figures........................................................................................................................14
Table of tables .........................................................................................................................14
List of abbreviations ...............................................................................................................15
3.
Introduction......................................................................................................................17
3.1.
Population demographics in TAVR............................................................................19
3.2.
Rivaroxaban..................................................................................................................19
3.3.
Previous studies with rivaroxaban..............................................................................20
3.4.
Dose rationale................................................................................................................21
4.
Study objectives................................................................................................................23
4.1.
Primary objective(s) .....................................................................................................23
4.2.
Secondary objectives ....................................................................................................23
4.3.
Other objectives............................................................................................................23
5.
Study design......................................................................................................................24
5.1.
Study flow diagram ......................................................................................................24
5.2.
Study plan......................................................................................................................24
5.3.
Study variable(s)...........................................................................................................26
5.3.1.
Primary variable(s) ...................................................................................................26
5.3.2.
Secondary variable(s)................................................................................................27
5.3.3.
Other variable(s) .......................................................................................................27
6.
Study population..............................................................................................................28
6.1.
Inclusion criteria...........................................................................................................28
6.2.
Exclusion criteria..........................................................................................................29
6.3.
Withdrawal of subjects from study.............................................................................30
6.3.1.
Withdrawal................................................................................................................31
6.3.1.1.
Discontinuation of treatment ................................................................................31
6.3.1.1.1.
Temporary discontinuation of assigned therapy.............................................31
6.3.1.1.2.
Permanent discontinuation of assigned therapy..............................................32
6.3.1.2.
Withdrawal of IC...................................................................................................32
6.3.1.3.
Lost-to-follow-up....................................................................................................34
6.3.2.
Replacement...............................................................................................................34
6.4.
Subject identification....................................................................................................34
7.
Treatment(s).....................................................................................................................35
7.1.
Treatments to be administered....................................................................................35
7.1.1.
Rivaroxaban-based strategy (experimental strategy)............................................35


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7.1.1.1.
After NOAF............................................................................................................36
7.1.2.
Antiplatelet-based strategy (control strategy)........................................................36
7.1.2.1.
After NOAF............................................................................................................36
7.2.
Identity of study treatment..........................................................................................37
7.2.1.
Rivaroxaban...............................................................................................................37
7.2.2.
Clopidogrel, ASA and VKA .....................................................................................38
7.3.
Treatment assignment..................................................................................................38
7.4.
Dosage and administration..........................................................................................38
7.5.
Blinding .........................................................................................................................38
7.6.
Drug logistics and accountability................................................................................38
7.7.
Treatment compliance..................................................................................................39
7.7.1.
Rivaroxaban...............................................................................................................39
7.7.2.
Clopidogrel, ASA and VKA .....................................................................................39
8.
Non-study therapy ...........................................................................................................39
8.1.
Prior and concomitant therapy ...................................................................................39
8.2.
Post-study therapy........................................................................................................41
9.
Procedures and variables................................................................................................41
9.1.
Tabular schedule of evaluations..................................................................................41
9.2.
Visit description............................................................................................................45
9.2.1.
Screening period (screening and randomization) ..................................................45
9.2.2.
Planned treatment period.........................................................................................47
9.2.3.
Post-treatment period ...............................................................................................50
9.3.
Population characteristics............................................................................................51
9.3.1.
Demographics ............................................................................................................51
9.3.2.
Medical history..........................................................................................................51
9.4.
Efficacy..........................................................................................................................52
9.5.
Pharmacokinetics / pharmacodynamics.....................................................................52
9.6.
Safety .............................................................................................................................52
9.6.1.
Adverse events ...........................................................................................................52
9.6.1.1.
Definitions...............................................................................................................52
9.6.1.2.
Classifications for adverse event assessment.......................................................53
9.6.1.2.1.
Seriousness ..........................................................................................................54
9.6.1.2.2.
Intensity...............................................................................................................54
9.6.1.2.3.
Causal relationship.............................................................................................54
9.6.1.2.4.
Action taken with study treatment....................................................................55
9.6.1.2.5.
Other specific treatment(s) of adverse events..................................................55
9.6.1.2.6.
Outcome...............................................................................................................56
9.6.1.3.
Assessments and documentation of adverse events ............................................56
9.6.1.4.
Reporting of SAEs/ AEs.........................................................................................56
9.6.1.5.
Expected adverse events........................................................................................58
9.6.1.6.
Adverse events of special safety interest..............................................................59
9.6.2.
Pregnancies ................................................................................................................59
9.6.3.
Further safety ............................................................................................................59
9.6.3.1.
Laboratory evaluations .........................................................................................59
9.6.3.2.
Physical examination .............................................................................................60


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9.6.3.3.
12-lead ECG ...........................................................................................................60
9.6.3.4.
Vital signs................................................................................................................60
9.7.
Other procedures and variables..................................................................................60
9.8.
Appropriateness of procedures / measurements .......................................................60
10. Statistical methods and determination of sample size..................................................60
10.1. General considerations.................................................................................................60
10.2. Analysis sets ..................................................................................................................61
10.2.1. Full analysis set (FAS) ..............................................................................................61
10.2.2. Data scopes.................................................................................................................61
10.3. Variables and planned statistical analyses.................................................................62
10.3.1. Primary variables......................................................................................................62
10.3.2. Secondary variables ..................................................................................................62
10.3.3. Other variables..........................................................................................................62
10.3.4. Subgroup variables ...................................................................................................63
10.3.5. Analysis of the primary efficacy variable ...............................................................63
10.3.5.1. Testing for superiority...........................................................................................64
10.3.5.2. Testing for non-inferiority ....................................................................................65
10.3.5.3. Exploratory analyses of the primary efficacy variable ......................................65
10.3.6. Analysis of secondary and other efficacy variables ...............................................65
10.3.7. Analysis of the safety variables ................................................................................66
10.3.8. Subgroup analysis .....................................................................................................66
10.4. Determination of sample size.......................................................................................67
10.5. Planned interim analyses .............................................................................................68
11. Data handling and quality assurance.............................................................................68
11.1. Data recording ..............................................................................................................68
11.2. Monitoring.....................................................................................................................69
11.3. Data processing.............................................................................................................70
11.4. Missing data ..................................................................................................................70
11.5. Audit and inspection.....................................................................................................70
11.6. Archiving.......................................................................................................................71
12. Premature termination of the study...............................................................................71
13. Ethical and legal aspects..................................................................................................72
13.1. Investigator(s) and other study personnel..................................................................72
13.1.1. Committees ................................................................................................................72
13.1.2. Other study personnel...............................................................................................72
13.2. Funding and financial disclosure ................................................................................73
13.3. Ethical and legal conduct of the study........................................................................73
13.4. Subject information and consent ................................................................................74
13.5. Publication policy and use of data ..............................................................................75
13.6. Compensation for health damage of subjects / insurance ........................................75
13.7. Confidentiality ..............................................................................................................75
14. Reference list ....................................................................................................................76
15. Protocol amendments ......................................................................................................82


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15.1. Amendment 1................................................................................................................82
15.1.1. Overview of changes .................................................................................................82
15.1.1.1. Modification 1: IMP/NIMP terms removed from protocol ...............................82
15.1.1.2. Modification 2: Clarification on supply of standard-of-care drugs..................82
15.1.2. Changes to the protocol text.....................................................................................82
15.1.2.1. Synopsis...................................................................................................................82
15.1.2.2. Section 7.1 Treatments to be administered..........................................................83
15.1.2.3. Section 7.2 Identity of study treatment................................................................83
15.1.2.4. Section 7.2.1 Rivaroxaban.....................................................................................83
15.1.2.5. Section 7.2.2 Clopidogrel, ASA and VKA ...........................................................83
15.2. Amendment 3................................................................................................................84
15.2.1. Overview of changes .................................................................................................84
15.2.1.1. Modification 1:  Clarify the timing of the first dose of rivaroxaban.................84
15.2.1.2. Modification 2:  Revision of TAVR inclusion criterion......................................84
15.2.1.3. Modification 3:  Clarification to the DAPT exclusion criteria ..........................84
15.2.1.4. Modification 4:  Timing of assessments ...............................................................85
15.2.1.5. Modification 5:  Update the list of abbreviations................................................85
15.2.1.6. Modification 6:  Allowance of subjects with history of prostate cancer to 
participate...............................................................................................................85
15.2.1.7. Modification 7:  Clarification made to the recording and use of prior 
and concomitant medications................................................................................86
15.2.1.8. Modification 8:  Text added to visit 1 – baseline / randomization.....................86
15.2.1.9. Modification 9:  An end of study visit has been added.......................................86
15.2.1.10. Modification 10:  Laboratory testing at screening .............................................87
15.2.1.11. Modification 11:  Purpose of physical examination added ................................87
15.2.1.12. Modification 12:  Revision of statistical methods................................................87
15.2.1.13. Modification 13:  Exclusion of planned interim analysis ...................................88
15.2.1.14. Modification 14:  Minor editorial/consistency/clarification/ 
administrative changes..........................................................................................89
15.2.1.15. Modification 15:  Text updated to account for local legal requirements..........89
15.2.1.16. Modification 16:  CRO and ARO specification...................................................89
15.2.2. Changes to the protocol text.....................................................................................89
15.2.2.1. Signature of sponsor’s medically responsible person.........................................90
15.2.2.2. Synopsis...................................................................................................................90
15.2.2.3. List of abbreviations ..............................................................................................94
15.2.2.4. Section 4.1  Primary objective(s)..........................................................................94
15.2.2.5. Section 5.1  Study flow diagram ...........................................................................95
15.2.2.6. Section 5.2  Study plan...........................................................................................96
15.2.2.7. Section 5.3.3  Other variable(s).............................................................................97
15.2.2.8. Section 6.1  Inclusion criteria................................................................................98
15.2.2.9. Section 6.2  Exclusion criteria...............................................................................99
15.2.2.10. Section 7.1.1  Rivaroxaban-based strategy (experimental strategy)...............100
15.2.2.11. Section 7.6  Drug logistics and accountability...................................................100
15.2.2.12. Section 8.1  Prior and concomitant therapy......................................................101
15.2.2.13. Section 9.1  Tabular schedule of evaluations.....................................................103
15.2.2.14. Section 9.2.1  Screening period (screening and randomization)......................109


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15.2.2.15. Section 9.2.2  Planned treatment period............................................................111
15.2.2.16. Section 9.2.3  Post-treatment period ..................................................................111
15.2.2.17. Section 9.6.3.1  Laboratory evaluation...............................................................112
15.2.2.18. Section 10.2.2  Data scope....................................................................................112
15.2.2.19. Section 10.3.4  Subgroup variables.....................................................................113
15.2.2.20. Section 10.3.5  Planned statistical analysis ........................................................113
15.2.2.21. Section 10.3.5  Analysis of the primary efficacy variable.................................113
15.2.2.22. Section 10.3.5.1.1  Test for validity of the proportional hazard 
assumption............................................................................................................113
15.2.2.23. Section 10.3.5.1  Testing for superiority ............................................................114
15.2.2.24. Section 10.3.5.2  Testing for non-inferiority......................................................116
15.2.2.25. Section 10.3.5.1.4  Testing for superiority in case of rejection of the 
proportional hazards assumption.......................................................................117
15.2.2.26. Section 10.3.5.3  Exploratory analyses of the primary efficacy variable........118
15.2.2.27. Section 10.3.6  Analysis of secondary and other efficacy variable ..................118
15.2.2.28. Section 10.3.7  Analysis of safety variables........................................................118
15.2.2.29. Section 10.3.8  Subgroup analysis.......................................................................119
15.2.2.30. Section 10.4  Determination of sample size........................................................119
15.2.2.31. Section 10.5  Planned interim analyses ..............................................................120
15.2.2.32. Section 11.1  Data recording ...............................................................................121
15.2.2.33. Section 11.2  Monitoring......................................................................................121
15.2.2.34. Section 12  Premature termination of study......................................................121
15.2.2.35. Section 16.2  Definition of terms.........................................................................122
16. Appendices......................................................................................................................123
16.1. Endpoint definitions...................................................................................................123
16.1.1. Death or first adjudicated thromboembolic event (DTE) ...................................123
16.1.2. Primary bleeding event (PBE) ...............................................................................126
16.2. Definitions of terms ....................................................................................................129
Table of figures
Figure 1: Study flow diagram ...................................................................................................24
Figure 2: Study treatment flow diagram...................................................................................45
Figure 3: Outcome and (S)AE collection and reporting schematic..........................................58
Table of tables
Table 1: Schedule of evaluations..............................................................................................42


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List of abbreviations
This section was modified with Amendment 3. For details, see Section 15.2.
ACS
Acute coronary syndrome
FDA
Food and Drug Administration
ACC
American college of cardiology
FAS
Full analysis set
ADR
Adverse drug reaction
GEE
Generalized estimation equations
AE
Adverse event
GI
Gastrointestinal
AF
Atrial fibrillation
GP
General practitioner
AHA
American heart association
GCS
Global clinical supplies
AKIN
Acute kidney injury
GPV
Global pharmacovigilance
APT
Antiplatelet therapy
GCP
Good clinical practice
ARO
Academic research organization
AS
Aortic stenosis
GMP
Good manufacturing practice
ASA
Acetylsalicylic acid
h
Hour(s)
BARC
Bleeding academic research consortium
HIV
Human immunodeficiency virus
CNS
Central nervous system
HR
Hazard ratio
CVE
Cerebrovascular event
IB
Investigator’s brochure
COPD
Chronic Obstructive Pulmonary Disease
IC
Informed consent
CEC
Clinical Event Committee
ICH
International Council for Harmonization
CSP
Clinical study protocol
i.e.
Id est  (that is)
CSR
Clinical study report
IEC
Independent ethics committee
CTAF
Clinical trial application form
INR
International normalized ratio
CI
Confidence interval
IMP
Investigational medicinal product
CRO
Contract research organization
INN
International non-proprietary name
CABG
Coronary artery bypass grafting
ISTH
International Society on Thrombosis and 
Haemostasis
CAD
Coronary artery disease
ITT
Intention-to-treat
CIOMS
Council for international organizations of 
medical sciences
IRB
Institutional review board
CYP
Cytochrome P
ISRCTN
International standard randomized controlled trial 
number register
d
Day(s)
IxRS
Interactive Web or Voice Response System
DSMB
Data safety monitoring board
LPLV
Last patient last visit
DTE
Death or first adjudicated thromboembolic 
event
LVEF
Left ventricular ejection fraction
DVT
Deep vein thrombosis
ML
maximum partial likelihood method
DAPT
Dual-antiplatelet therapy
MAR
Medical affairs responsible
ECG
Electrocardiogram
MedDRA Medical dictionary for regulatory activities
eCRF
Electronic case report form
min
Minutes
EOT
End-of-treatment
MI
Myocardial infarction
eGFR
Estimated glomerular filtration rate
NB
Nota bene  (note carefully)
e.g.
Exempli gratia (for example)
NI
Non-inferiority
EMA
European medicines agency
NIMP
Non-investigational medicinal product
et al.
Et alii (and others)
NOAF
New-onset atrial fibrillation
etc.
Et cetera  (and so on)
NOAC
Non-vitamin K oral anticoagulants
EU
European union
NSAID
Non-steroidal anti-inflammatory drugs
EudraCT EU data repository for clinical trials
NVAF
Non-valvular atrial fibrillation


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FXa
Factor Xa
od
Once-daily
FDAAA
FDA Amendment Act
OAC
Oral anticoagulant
PVL
Paravalvular leak
SAC
Statistical analysis center
PCI
Percutaneous coronary intervention
SAPT
Single-antiplatelet therapy
PK
Pharmacokinetics
STS
Society of Thoracic Surgeons’
PDF
Portable data format
SPC
Summary of product characteristics
PBE
Primary bleeding event
SAVR
Surgical aortic valve replacement
PT
Pro-thrombin time
SUSAR
Suspected unexpected serious adverse reaction
PPM
Prosthesis-patient mismatch
TOC
Table of contents
PE
Pulmonary embolism
TIMI
Thrombolysis in Myocardial Infarction
QA
Quality assurance
THR
Total hip replacement
RCT
Randomized control trial
TKR
Total knee replacement
RRR
Relative risk reduction
TAVR
Transcatheter aortic valve replacement
SAE
Serious adverse event
TIA
Transient ischemic attack
SDV
Source data verification
VARC
Valve academic research consortium
SOP
Standard operating procedure
VKA
Vitamin K antagonists
SAP
Statistical analysis plan
US(A)
United States (of America)
SID
Subject identification


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3.
Introduction
Calcific aortic valve stenosis is the most common cause of aortic stenosis (AS) among adults
in Europe and in the United States (1). Its pathobiological basis involves chronic valvular 
tissue inflammation, lipoprotein deposition, osteoblast activation, and extracellular 
calcifications (2).With a pooled prevalence of 3.4%, the burden of aortic valve stenosis 
disease among the elderly due to severe aortic stenosis is substantial. Prevalence increases
with age, and severe AS, if left untreated, is fatal in a few years from symptom onset. Since 
no medical treatment has been proven to be effective in severe AS, the treatment of choice 
has been aortic valve replacement, either by surgical aortic valve replacement (SAVR) or
transcatheter aortic valve replacement (TAVR) (1-4). Under the current indications, 
approximately 290,000 elderly patients with severe AS are TAVR candidates in the European 
countries and in the United States; and nearly 27,000 patients become eligible for TAVR 
annually (3). The prevalence of moderate or severe AS was found to be age-dependent rising 
from 0.02% in subjects aged 18–44 years to 2.8% in patients aged ≥75 years (4). And it is 
well recognized that the natural history of mild and moderate AS is also associated with 
excess mortality and major adverse events (AEs) (4).
Among patients at prohibitive surgical risk, TAVR has become the treatment of choice. The
introduction of TAVR has further modified the treatment of high surgical risk patients and 
based on the available data the indication for TAVR has become a valid alternative to SAVR
in patients deemed at intermediate-to-high surgical risk (5-8). The safety and efficacy of 
TAVR compared with medical management and SAVR has been demonstrated in clinical
trials using the two most commonly used TAVR devices, the balloon-expandable Edwards
Sapien / SAPIEN XT valve (Edwards Sapien, CA) and the Medtronic CoreValve Revalving 
System (Medtronic Inc., CA) (6, 7, 9, 10). PARTNER trial cohort B results showed that 
TAVR improved survival in patients who cannot undergo SAVR compared with medical 
management. TAVR was also compared with SAVR both, among high-risk patients in the 
PARTNER trial cohort A, where it was associated with similar rates of survival at 1 year, and 
among intermediate-to-high-risk patients in the CoreValve trial where a significantly higher 
rate of survival was observed at 1 year (5-7). Of note, patients undergoing TAVR remain at 
high-risk of peri- and post-procedural cardiovascular events, mainly strokes, and mortality
(11). In high-risk patients receiving TAVR in the PARTNER trial (i.e. cohort A) all-cause 
mortality was as high as 24% at 1 year, and approximately 34% at 2 years, whereas
cardiovascular mortality was 14% and 21%, respectively. The composite of the rate of all-
cause death or stroke was 27% and 37% in the TAVR group after 1 and 2 years, respectively
(12).
Even though part of the strokes occur during the peri-procedural period, the patients remain 
at risk of stroke throughout the first months after the procedure (13). Stortecky et al (14) have 
provided a depiction of the time-dependent risk of strokes after TAVR where the predictors 
for stroke are considered including new-onset atrial fibrillation (NOAF). NOAF is observed 
in over 30% of patients undergoing TAVR and has been demonstrated as single, independent 
predictor of stroke during the subacute phase after TAVR (14). In the PARTNER trial (cohort
A, high-risk patients cohort), the rates of stroke remained high amounting to 4.6% at 30 days, 
6.0% at 1 year, and 7.7% at 2 years of follow-up (12). Similarly, in the PARTNER trial 


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(cohort B, inoperable patients cohort) the rate of stroke was 6.7% at 30 days, 11.2% at 1 year,
and 13.8% at 2 years of follow-up (15).
Stenotic aortic valves, unlike normal aortic valve leaflets, are characterized by large amounts 
of tissue factor and thrombin, which might contribute to increased inflammation and 
thrombogenicity (16). While the diseased aortic valve is resected in case of SAVR before the 
prosthesis implantation, the pathologic native valve remains in situ in case of TAVR. During 
both the preparation of the balloon aortic valvuloplasty and the implantation of the TAVR 
device the diseased native valve may be subject to fractures and injuries, which may induce 
the exposure and/or embolization of valvular components into the arterial circulation (17, 18).
Recently, van Mieghem et al demonstrated that > 50% of cerebral emboli during TAVR are 
composed of thrombotic material (19). However, also calcific atherosclerotic emboli are 
common during catheter and device manipulation of a stenotic aortic valve (19). Moreover, 
the insertion of a prosthesis without removal of the diseased aortic valve creates an irregular 
zone around the valvular frame that may predispose to thrombus formation. In addition to this
pro-thrombotic environment created by the implanted valve, the occurrence of atrial 
arrhythmias, platelet dysfunction, and associated comorbidities may predispose patients to 
bleeding or ischemic events. In fact, NOAF as mentioned above is frequently observed
following TAVR and has been demonstrated as single, independent predictor of stroke during 
the subacute phase after TAVR (5, 20-22).
Transcatheter heart valve thrombosis is a rare event but may result in increased transvalvular 
gradients requiring anticoagulant therapy. One case of transcatheter heart valve thrombosis 
(0.8%) was reported among the 130 TAVR subjects enrolled in the PARTNER EU trial (23).
Bleeding is a frequent periprocedural complication after TAVR, which has been shown to be 
associated with worse prognosis (21, 24-28). Although acute and sub-acute post-TAVR 
bleeding complications (up to 30 days) are linked to procedural or technical factors (e.g., 
vascular complications (29)), the impact of late bleeding events (after 30 days) in this 
population is still unclear. Data from the randomized cohorts and continued access registries 
in the PARTNER trials (27) suggest that major late bleeding complications occur in 
approximately 6% of patients between 30 days and 1 year, with GI and neurological 
bleedings being most frequent and are associated with an increased rate of death and 
morbidity. Independent predictors for late major bleeding events after TAVR included the 
presence of AF, moderate or severe residual paravalvular leak (PVL), presence of low 
baseline hemoglobin, and increased left ventricular mass.
Currently, dual-antiplatelet therapy (DAPT) with ASA and mainly clopidogrel for 3 to 6 
months (if no indication for anticoagulation is present) is an empirical strategy widely 
accepted and incorporated as guideline recommendation for patients undergoing TAVR (26, 
30-33). However, clopidogrel duration or loading dose is not specifically defined in 
guidelines, and lately the general usefulness of clopidogrel in combination with ASA in 
TAVR patients has been questioned (32, 34, 35) . In two small non-randomized studies 
comparing DAPT to single-antiplatelet therapy (either ASA or clopidogrel), DAPT did not 
reduce the rate of cerebrovascular events but was associated with a higher rate of major and 
life-threatening bleeding complications (34, 36).


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Since it is unclear whether thrombi produced during and after TAVR have a platelet- or 
thrombin-based origin, an antiplatelet-based strategy alone may not be the optimal treatment 
in these patients. Controversy also exists for patients with a history of pre-existing atrial 
fibrillation. There are only individual reports on treatment with triple therapy (37) and no 
evidence regarding warfarin with one antiplatelet or warfarin alone and the American and 
Canadian guidelines discourage the use of triple therapy (31, 35). Therefore triple therapy 
after TAVR should be avoided in patients with a high inherent bleeding risk. The 
combination of one oral anticoagulant with one antiplatelet has resulted in better safety 
results, without excess ischemic events, in comparison to triple therapy in AF patients 
undergoing PCI (36, 38). Thus, to date the optimal strategy and pharmacological treatment to 
reduce the long-term thromboembolic risk after TAVR is unknown. In fact, as the current 
antithrombotic management during and after TAVR is not based on randomized controlled 
clinical trials but only on consensus, there is an unmet need to identify the best 
antithrombotic treatment in patients without AF undergoing TAVR.
Consequently, non-vitamin K oral anticoagulants (NOAC) such as rivaroxaban may 
potentially reduce the TAVR-related thrombogenicity without increasing the bleeding risk.
3.1.
Population demographics in TAVR
Patients undergoing TAVR are mostly octo-/nona-genarians with approximately 50% being 
female. Comorbid conditions are frequent and include congestive heart failure (uniformly),
AF in one third of patients, severe chronic obstructive lung disease in 14% of patients, 
coronary artery disease in 70% of patients, renal impairment in close to 80% of patients,
peripheral vascular disease in 30% of patients, and concomitant mitral regurgitation in 30% 
of patients (39). However, recent evidence points to a change in clinical practice with many 
more patients at intermediate risk undergoing TAVR and with a corresponding decline in 
procedural complications and improved clinical outcomes. Propensity-score matched 
comparisons between TAVR and conventional SAVR in patients at intermediate risk suggest 
similar survival (few years horizon) (40), and currently two prospective randomized trials 
directly compare TAVR with SAVR in intermediate risk patients (41, 42). Owing to the rapid 
progress in transcatheter valve technology with improved procedural success and low rates of 
paravalvular aortic regurgitation, it is anticipated that the indication of TAVR will continue to 
widen.
Important clinical considerations in a TAVR population include age, gender, renal 
impairment, atrial fibrillation, congestive heart failure class, and established coronary or 
vascular atherosclerosis. Clinical decision-making often relies on a subject’s absolute risk of 
a disease event of interest. However, in a frail population, competing risk events may 
preclude the occurrence of the event of interest and defaulting to all-cause (rather than 
specific etiology related) mortality appears well substantiated in this patient population.
3.2.
Rivaroxaban
Rivaroxaban (BAY 59-7939, JNJ-39039039) is a potent and highly selective oral 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 (43). 
Of the administered dose, approximately 2/3 undergoes metabolic degradation, with half then 


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being eliminated renally and the other half eliminated by the faecal route. The final 1/3 of the 
administered dose undergoes direct renal excretion as unchanged active substance in the 
urine, mainly via active renal secretion. The elimination half-life is 5 - 9 hours in young 
individuals, and 11 - 13 hours in the elderly. Plasma concentrations correlate with the 
prothrombin time and the activated partial thromboplastin time (43).
Please refer to the latest available version of the investigator’s brochure (IB) (44) for further 
comprehensive information regarding rivaroxaban.
3.3.
Previous studies with rivaroxaban
Preclinical and clinical studies
-
Rivaroxaban has been tested in a wide range of dose levels and is approved in various 
indications across distinct areas of use: DVT/PE prophylaxis (VTE prevention in 
Orthopedic surgery): 10 mg orally once-daily for prophylaxis of DVT following hip 
or knee replacement surgery (RECORD 1-4) (45-48).
The REgulation of Coagulation in major ORthopedic surgery to prevent DVT and PE 
(RECORD) program was the first phase III program initiated in support of the clinical 
development of the first indication for rivaroxaban, the prevention of venous 
thromboembolic disease in patients undergoing major orthopedic surgery such as total 
hip (THR) or total knee (TKR) replacement. Rivaroxaban 10 mg once-daily was 
significantly more effective than enoxaparin in the prevention of VTE after THR and 
TKR with similar bleeding rates in the RECORD program.
-
Venous thromboembolism (VTE) treatment and prevention of recurrent DVT and PE: 
15 mg orally twice-daily for three weeks followed by 20 mg orally once-daily 
(EINSTEIN DVT, EINSTEIN PE) (49, 50) or 20 mg orally once-daily (EINSTEIN 
Extension) to reduce the risk of recurrence of DVT/PE.
-
Non-valvular AF: 20 or 15 mg once-daily depending on renal function was able to 
reduce the risk of stroke or non-CNS systemic embolism in patients with non-valvular 
AF (ROCKET AF) (51-53).
ROCKET AF (Rivaroxaban Once-daily oral direct Factor Xa inhibition Compared 
with vitamin K antagonist for the prevention of stroke and Embolism Trial in Atrial 
Fibrillation) was the first phase III study with rivaroxaban for the indication of stroke 
prevention in atrial fibrillation. ROCKET AF, a randomized, double-blind, double-
dummy, event-driven study, in which 14,264 subjects with non-valvular atrial 
fibrillation were randomized to receive either once-daily rivaroxaban or warfarin.
Subjects with a history of prior ischemic stroke, transient ischemic attack (TIA), or 
systemic embolism, or 2 or more of the following risk factors: heart failure and/or left 
ventricular ejection fraction (LVEF) ≤35%, hypertension, age ≥75 years, or diabetes 
mellitus were randomized to either rivaroxaban 20 mg once-daily (reduced dose of 15
mg once-daily for subjects with moderate renal impairment at baseline) or dose-
adjusted warfarin (target INR 2-3). Overall, in ROCKET AF, active treatment with 
rivaroxaban was non-inferior to warfarin for the primary composite endpoint of stroke 
or non-CNS systemic embolism, a comparable rate of major and non-major clinically 
relevant bleeding, and a significantly lower rate of intracranial hemorrhage (51).


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-
Secondary prevention of acute coronary syndromes (ACS): In ATLAS ACS (54, 55)
Rivaroxaban 2.5 mg twice-daily in combination with ASA ± clopidogrel or 
ticlopidine reduced the risk of recurrence of atherothrombotic events in patients after 
an ACS with elevated cardiac biomarkers.
3.4.
Dose rationale
This will be the first study investigating rivaroxaban for prevention of cardiovascular events 
in subjects who underwent a successful TAVR.
Based on the reasons outlined below, it is anticipated that the 10 mg once-daily dose of 
rivaroxaban, when used in combination with ASA for the first 90 days and thereafter alone 
without antiplatelet therapy, will provide an adequate efficacy and an acceptable safety 
(bleeding) profile compared to standard of care in this population:
i.
In the ROCKET AF study, treatment with rivaroxaban 20 mg once-daily was non-
inferior to warfarin in terms of prevention of stroke or non-CNS systemic embolism in 
the ITT population and was superior in the safety on-treatment population. There was 
no significant between-group difference in the risk of major bleeding. Importantly, 
intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.
ii.
However, the 20 mg once-daily dose, especially when administered in combination 
with ASA, is considered too high in the TAVR population with increased risk of 
bleeding where the optimal balance between benefit and risk is crucial. Warfarin, 
when compared to ASA, is more efficacious in patients with non-valvular atrial 
fibrillation (NVAF) (relative risk reduction [RRR] 39%) (56), but may increase 
bleeding.  Thus, testing a dose lower than 20 mg of rivaroxaban not only may reveal a 
relevant efficacy benefit, but it may also provide an improved safety profile in terms 
of bleeding. This is important as the current standard of care used in TAVR patients is 
DAPT for 3 - 6 months after the TAVR procedure followed by single antiplatelet 
therapy lifelong, which has a lower risk for bleeding. Based upon these 
considerations, there is a strong argument to use a rivaroxaban dose lower than 20/15 
mg for patients without established indication for anticoagulation in this study.
iii.
The 10 mg once-daily dose of rivaroxaban is deemed to demonstrate the best benefit-
risk balance considering the high risk of bleeding and the comparator being DAPT in 
the first 90 days after TAVR followed by single antiplatelet therapy. Rivaroxaban will 
be administered in addition to single antiplatelet therapy with ASA during the first 90 
days post-TAVR and thereafter alone without antiplatelet therapy.
iv.
The 10 mg once-daily rivaroxaban dose is approved and is shown to be efficacious 
and safe in VTE prevention in major orthopedic surgery.
v.
Simulations showed that plasma concentrations of a 10 mg once-daily dose of 
rivaroxaban in elderly patients with renal impairment were within the variability 
range confidence interval of the average patient, suggesting that at this dose all these 
influencing factors should not lead to significant alterations in rivaroxaban (predicted 
Cmax of rivaroxaban for all patients was within the 5th–95th percentile ranges 
calculated for the average patient in the population).
vi.
Efficacy of rivaroxaban in the elderly patients was similar to observations in younger 
patients with smaller differences at lower rivaroxaban concentrations but with a 


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favorable benefit-risk profile in all age groups. The differences in plasma 
concentrations of rivaroxaban in the elderly are mainly due to reduced renal clearance 
but, because the dose selected for this study is already a downward adjustment from 
the dose used for stroke prophylaxis in NVAF, an additional dose adjustment for 
patients with moderate to severe renal impairment is not considered necessary.
Furthermore, for the rivaroxaban dose of 10 mg once-daily, approved for the 
prevention of VTE in major orthopedic surgery patients, no dose adjustment in 
normal to moderate renal impairment is required.
vii.
While the proposed study will enroll subjects without previous AF post-TAVR, a 
considerable proportion of patients will develop NOAF after the TAVR procedure 
and it is currently unknown whether this incidence is underestimated. While subjects 
without previous AF will receive rivaroxaban 10 mg once-daily post-TAVR, the 
20/15 mg once-daily dose tested in the moderate to high risk AF patients in ROCKET 
AF is considered to be necessary once the patient develops NOAF after the TAVR 
procedure. Patients who develop NOAF after randomization will therefore be 
switched to the 20/15 mg once-daily dose of rivaroxaban.
Overall, a 10 mg once-daily dose of rivaroxaban is believed to be the optimal treatment 
regimen to balance benefit-risk in patients after a TAVR implantation currently treated with 
antiplatelets. The 20 mg/ 15 mg once-daily dose of rivaroxaban is anticipated to be needed 
for efficacy only if the patient develops manifest AF after the TAVR implantation.
Rationale of the study
Calcific aortic valve stenosis is characterized by an increased thrombogenic and 
inflammatory profile (2). Long-term oral antithrombotic treatment after TAVR aims to 
prevent complications, notably ischemic stroke and MI as well as thrombo-embolism related 
to deep vein thrombosis, pulmonary embolism, valve thrombosis, or systemic embolism 
while minimizing bleeding risk. The baseline risk for ischemic and thromboembolic 
complications is determined by comorbidities such as concomitant coronary artery disease
(CAD), which is present in 20–70% of patients eligible for TAVR. Furthermore, in-hospital 
AF may occur in about one-third of patients referred for TAVR (20).
Therefore, the actual standard of care after TAVR, i.e. DAPT, is not optimal in targeting the 
underlying pathophysiological mechanisms in severe AS. Rivaroxaban, through the inhibition 
of the pathways underlying the increased thrombogenicity, may effectively prevent 
thrombotic complications after TAVR without exposing this elderly (57) population to an 
increased bleeding risk.
Stroke and TIA are estimated to occur in 5% of patients at 30 days and 10% of patients at 1 
year after TAVR, based on the PARTNER cohorts, on the CoreValve trial, and on a large 
meta-analysis by Athappan et al (5, 7, 11). Approximately half of the strokes at 30 days occur 
within the first 24 hours (13).
The investigation of anticoagulation in the medical management of patients following TAVR 
is further justified by the fact that the incidence of NOAF after TAVR may be 
underestimated. Dumont and his group reported that one-third of patients with no prior 


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history of AF had NOAF after TAVR and this was associated with a higher rate of 
stroke/systemic embolism at 30 days and 1 year (20). Thus, despite the number of 
mechanisms that may be involved in stroke after TAVR, there is a particularly strong 
relationship between post-procedural AF and stroke occurring after 24 hours suggesting that 
cardioembolic origin might significantly contribute to stroke after TAVR. Finally, the 
clustering of thromboembolic risk factors in TAVR populations such as renal impairment
(close to 80%), severe COPD (15%), coronary artery disease (70%), peripheral vascular 
disease (30%), and moderate to severe mitral regurgitation (30%), could indicate that long-
term anticoagulation therapy (beyond 12 months) after TAVR can be of value.
4.
Study objectives
4.1.
Primary objective(s)
This section was modified with Amendment 3. For details, see Section 15.2.
To assess whether a rivaroxaban-based anticoagulation strategy, following successful TAVR, 
compared to an antiplatelet-based strategy, is superior in reducing death or first 
thromboembolic events (DTE). This comparison is preceded by a non-inferiority test that 
must be satisfied.
To assess the primary bleeding events (PBE) of the rivaroxaban-based strategy, following 
TAVR, compared to an antiplatelet-based strategy.  PBE is defined as the composite of life-
threatening, disabling, or major bleeding events and is classified according to the VARC 
definitions following the BARC classification.
4.2.
Secondary objectives
The secondary efficacy objectives are to compare the effects of the rivaroxaban-based 
strategy and antiplatelet-based strategy with respect to the net-clinical-benefit, defined as the 
composite of death or first thromboembolic events and life-threatening, disabling, or major 
bleeding events classified according to the VARC definitions following the BARC 
classification.
Whereas the secondary safety objectives are safety criteria with respect to bleeding 
(thrombolysis in myocardial infarction [TIMI] major or minor bleeds, international society on 
thrombosis and haemostasis [ISTH] major bleeding, and BARC 2, 3, or 5 bleeds).
4.3.
Other objectives
Other secondary efficacy and safety objectives are to compare the effects of a rivaroxaban-
based strategy and an antiplatelet-based strategy with respect to the individual components of 
the composite of ischemic and thromboembolic complications and of the composite of life-
threatening, disabling, or major bleeding, respectively.
The effect of rivaroxaban-based strategy, following successful TAVR, compared to an 
antiplatelet-based strategy, on the mean transaortic valve pressure gradient at 360 days as 
measured by echocardiography will be assessed as an exploratory study endpoint.


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5.
Study design
5.1.
Study flow diagram
The study flow diagram was modified with Amendment 3. For details, see Section 15.2.
The study design is detailed in Figure 1 Study flow diagram.
Figure 1: Study flow diagram
Successful transcatheter aortic valve replacement (TAVR) as defined in Section 6.1.
§ The duration of the planned treatment period will depend on the time needed to reach the efficacy 
cut-off date, i.e. to collect the predefined number of efficacy endpoints or earlier if the event rate is 
unexpectedly low. The expected duration of the treatment is 720 days but may be adjusted depending 
upon the rate of subject recruitment and efficacy event rates.
R, randomization; ASA, acetylsalicylic acid; OD, once-daily.
5.2.
Study plan
This section was modified with Amendment 3. For details, see Section 15.2.
This is an event-driven, randomized, open-label with blinded endpoint evaluation, parallel-
group, active-controlled, multicenter, international study comparing the efficacy and safety of 
a rivaroxaban-based strategy versus a standard antiplatelet-based strategy for the prevention
of ischemic and thromboembolic complications while minimizing the bleeding risk in 
subjects who successfully underwent TAVR.
The study is divided into a screening period, a planned treatment period, and an observational
post-treatment period.


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The screening period begins after TAVR. Subjects who have successfully undergone a 
TAVR procedure of an  aortic valve stenosis (either native or valve-in-valve) by iliofemoral
or subclavian access with any approved/marketed device type available in the participating 
countries are potentially eligible for inclusion in the study. All inclusion and exclusion 
criteria should be reviewed before IC is signed. Subjects with an ongoing/continued 
indication for oral anticoagulation at the time of randomization are excluded from this study.
Once IC has been obtained and eligibility has been confirmed, subjects are randomized (1:1), 
to a rivaroxaban-based strategy or to an antiplatelet-based strategy. The investigator must 
inform each subject before signature of IC of the aspects of premature withdrawal from the 
study including the retention and use of all collected data until the end of study as described 
in Section 6.3 and 13.3.
Randomization must take place within 1-7 days post-TAVR and before hospital discharge. 
Randomization is performed by an Interactive Web or Voice Response System (IxRS) and
stratified by site. Stratification by site is performed to ensure balance across potential local
differences in treatment practices.
The assigned treatment strategy is implemented after randomization (please refer to Section
7.4).
Subjects randomized to rivaroxaban-based strategy: In the rivaroxaban-based strategy, 
rivaroxaban is started at the time of randomization if the subject is not on clopidogrel. If the 
subject is treated with clopidogrel, clopidogrel is stopped immediately after randomization 
and rivaroxaban is started within 1-3 days after the last intake of clopidogrel. In case study 
medication is started the next day post-TAVR, study medication should not be started earlier 
than the time the TAVR was done on the previous day and the subject should be stabilized 
and complications or bleedings should have been excluded carefully. Rivaroxaban 10 mg 
once-daily can be taken with or without food. ASA 75-100 mg once-daily is continued 
unchanged or started immediately after randomization if not already being taken.
Subjects randomized to antiplatelet-based strategy: In the antiplatelet-based strategy
clopidogrel 75 mg once-daily and ASA 75-100 mg once-daily are to be continued unchanged, 
or to be started at the time of randomization if not already being taken. If clopidogrel is 
started at the time of randomization in a clopidogrel-naïve subject, a single loading dose of at 
least 300 mg should be administered followed by clopidogrel 75 mg once-daily.
For both strategies, the selection of the ASA dose (75-100 mg) is left at the discretion of the 
treating physician. In case the ASA dose before randomization was > 100 mg once-daily, the 
dose has to be decreased to 75-100 mg once-daily immediately after randomization.
In each strategy, one antiplatelet therapy agent is dropped after 90 days. This means that in 
the rivaroxaban-based strategy, ASA is discontinued after 90 days and rivaroxaban is to be 
continued. Whereas, in the antiplatelet-based strategy, clopidogrel must be discontinued after 
90 days and ASA is to be continued.
Study treatments are continued until the efficacy cut-off date , i.e. when 440 subjects are 
anticipated to have experienced a positively adjudicated primary efficacy endpoint, when 
subjects will be transitioned from the assigned strategy to an appropriate therapy, as per the 
clinical site standard of care (Section 9.2.3). This is anticipated to occur approximately 720 


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days after the first patient is randomized, but may vary depending on the recruitment rate as 
well as the on the primary efficacy event rate. One on-site visit will be scheduled for each 
patient when the efficacy cut-off date is anticipated.
In the event of NOAF, study treatments are changed as follows:
Subjects randomized to rivaroxaban-based strategy: Subjects randomized to the rivaroxaban-
based strategy should be switched to rivaroxaban 20 mg once-daily (or 15 mg once-daily
dose for moderate renal impairment with eGFR < 50 and ≥30 mL/min/1.73m2).
Subjects randomized to antiplatelet-based strategy: Subjects randomized to the antiplatelet-
based strategy are switched to treatment with VKA with a target INR 2-3.
In case NOAF is diagnosed within the first 90 days after randomization, ASA 75-100 mg 
once-daily will be continued in both treatment arms in addition to oral anticoagulation with 
rivaroxaban 20 mg/ 15 mg once-daily or VKA, respectively. ASA 75-100 mg once-daily will 
be discontinued at 90 days after randomization and anticoagulation continued alone with 
rivaroxaban 20 mg/ 15 mg once-daily or VKA, respectively. NOAF subjects remain in the 
study, the timing of on-site visits and/or phone assessments will be kept unchanged until the 
efficacy cut-off date when an on-site visit and remaining study closure activities take place.
Subject contacts are planned to take place at least at 30, 90, and 180 days after randomization
and from 180 days onward, every 180 days until the efficacy cut-off date is anticipated, and 
the study medication is stopped. Thirty days after the permanent discontinuation of the 
assigned study medication, a telephone assessment will be performed (please refer to Section 
9.1).
All randomized subjects must be followed until the efficacy cut-off date. Study closure 
activities should be completed for all randomized subjects, including those that for any reason
did not take the assigned study medication, or prematurely discontinued study medication, or 
have developed either NOAF or any type of efficacy or safety endpoint. All this information 
must be captured in the eCRF. Every effort should be made to maintain a subject’s follow-up
compliance. As per agreement, contacting the subject’s general practitioner or referring 
cardiologist should be considered in case the subject cannot be reached in order to obtain
information about the subject’s health status (especially regarding endpoints occurrence), and 
should be documented in the electronic case report form (eCRF). Death registry databases or 
other publicly available sources should be consulted by the sites according to availability and 
local applicable laws. If explicitly requested by the subject on-site visits may be replaced by 
telephone contacts.
Study assessments are performed according to the visit scheme provided under Section 9.1. 
The subject treatment flow diagram (Figure 2) is depicted in this same section.
5.3.
Study variable(s)
5.3.1.
Primary variable(s)
The primary efficacy endpoint is death or first adjudicated thromboembolic event (DTE),
defined as the adjudicated composite of:

All-cause death


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
Any stroke

Myocardial infarction (MI)

Symptomatic valve thrombosis

Pulmonary embolism (PE)

Deep vein thrombosis (DVT)

Non-central nervous system (CNS) systemic embolism
The primary safety endpoint is primary bleeding event (PBE), defined according to VARC 
definitions following the BARC classification as the adjudicated composite of:

life-threatening bleed

disabling bleed

major bleed
The endpoint definitions and the definitions of terms are located in Sections 16.1 and 16.2, 
respectively. Acronyms and abbreviations are defined in the List of abbreviations.
5.3.2. Secondary variable(s)
The secondary endpoints include:

The adjudicated composite of cardiovascular death, any stroke, myocardial 
infarction, symptomatic valve thrombosis, pulmonary embolism, deep vein 
thrombosis, or non-CNS systemic embolism

The net-clinical-benefit defined as the adjudicated composite of all-cause death, 
any stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary 
embolism, deep vein thrombosis, non-CNS systemic embolism (efficacy); life-
threatening, disabling and major bleeds (safety).
The secondary safety endpoints are bleeding complications according to:

The composite of TIMI major or minor bleeds

ISTH major bleeding

The composite of BARC 2, 3, or 5 bleeding
5.3.3. Other variable(s)
This section was modified with Amendment 3. For details, see Section 15.2.
The individual components of the primary efficacy and safety endpoint will be assessed as 
other endpoints.
The mean transaortic valve pressure gradient at approximately 360 days after randomization
as measured by routine echocardiogram (TTE or TEE), if available, will be captured in the 
eCRF and it is considered as an exploratory study endpoint.


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End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject has 
been reached in all centers in all participating countries.
The primary completion event for this study occurs when the 440th subject experiences a 
positively adjudicated primary efficacy endpoint or earlier if the event rate is unexpectedly 
low. The efficacy cut-off date is defined as the date of the primary completion event.
For practical purposes, the anticipated efficacy cut-off date is set based on a projection of the 
date of the primary completion event before 400 subjects have experienced a positively 
adjudicated primary efficacy endpoint. When the anticipated efficacy cut-off date is set, on-
site visit will be scheduled for all subjects within 6 weeks. 
The primary completion date for this study according to the FDA Amendment Act is 
specified in a separate document (not part of this study protocol).
6.
Study population
This section was modified with Amendment 3. For details, see Section 15.2.
6.1.
Inclusion criteria
Potential subjects must satisfy the following criteria to be enrolled in the study:

Man or woman of 18 years of age or older

Have a successful TAVR of an aortic valve stenosis (either native of valve-in-
valve)

Via iliofemoral or subclavian access

With any approved/marketed TAVR device

Provide written IC
Successful TAVR (29) is defined:
1. Correct positioning of a single prosthetic heart valve into the proper anatomical location.
2. Intended performance of the prosthetic heart valve - presence of all 3 conditions post-
TAVR:
a.
mean aortic valve gradient < 20 mmHg
b. peak transvalvular velocity (aortic valve maximum velocity) < 3.0 m/s
c.
no severe or moderate aortic valve regurgitation
3. Absence of periprocedural complications, such as:
a.
Any type of periprocedural stroke
b. VARC graded life-threatening bleeding
c.
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d. Major vascular complication requiring intervention (including access-site vascular 
complications, any new ipsilateral peripheral ischemia, distal embolization from a 
vascular source, aortic dissection, aortic rupture, ventricular perforation, cardiac 
tamponade, and annulus rupture)
e.
Unresolved acute valve thrombosis
f.
Any requirement of a repeat procedure
6.2.
Exclusion criteria
Subjects are NOT eligible to participate in this trial if they meet ANY of the following 
exclusion criteria:
General
1. Any atrial fibrillation (AF), at the time of randomization or previous, with an ongoing 
indication for oral anticoagulant treatment
2. Any other indication for continued treatment with any oral anticoagulant (OAC)
Bleeding risks or systemic conditions
3. Known bleeding diathesis, such as but not limited to:
a.
active internal bleeding, clinically significant bleeding, bleeding at a non-
compressible site, or bleeding diathesis,
b. platelet count ≤ 50,000/mm3 at screening
c.
hemoglobin level < 8.5 g/dL
d. history of intracranial hemorrhage or subdural hematoma
e.
major surgery, biopsy of a parenchymal organ, or serious trauma within 30 days 
before randomization
f.
active peptic ulcer or known upper GI bleeding within the last 3 months
Concomitant and study medication
4. Any ongoing absolute indication for dual-antiplatelet therapy (DAPT) at time of 
screening that is unrelated to the TAVR procedure 
5. Known hypersensitivity or contraindication to acetylsalicylic acid, clopidogrel or
rivaroxaban or hypersensitivity to contrast media that could not be solved neither by 
switching to an alternate contrast media nor with pre-treatment with appropriate 
medication
6. Routine use of oral non-steroidal anti-inflammatory drugs (NSAID)
7. Concomitant therapy with systemic drugs that are strong inhibitors of both CYP 3A4 and 
P-gp (azole antimycotics such as ketoconazole and itraconazole or HIV protease 
inhibitors such as ritonavir)
8. Concomitant therapy with drugs that are strong CYP 3A4 inducers (e.g. carbamazepine, 
phenytoin, rifampin, St. John’s wort)


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9. Concomitant therapy with omeprazole or esomeprazole that cannot be switched to an 
alternate medication.
Concomitant conditions
10. Planned coronary or vascular intervention or major surgery
11. Clinically overt stroke within the last 3 months
12. Severe renal impairment (eGFR < 30 mL/min/1.73 m2) or on dialysis, or post-TAVR 
unresolved acute kidney injury with renal dysfunction stage 2 or higher
13. Moderate and severe hepatic impairment (Child-Pugh Class B or C) or any hepatic 
disease associated with coagulopathy
14. Active infective endocarditis
15. Active malignancy (diagnosed within 5 years) except for adequately treated non-
melanoma skin cancer or other non-invasive or in situ neoplasm (e.g., cervical cancer in 
situ that has been successfully treated or non-active prostate cancer)
Other exclusion criteria
16. Dementia or forgetfulness hindering compliance with medication intake or other study 
procedures
17. Legally incompetent to provide IC
18. Previous (30 days before enrolment) or concomitant participation in another clinical study 
with investigational medicinal product(s).
19. Previous assignment to treatment during this study
20. 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) or sponsor
21. Female of childbearing potential
a.
Who are not surgically sterile, or who are sexually active and not willing to use 
adequate contraceptive measures with a failure rate less than 1% per year (e.g. oral 
contraceptives, contraceptive injections, intrauterine device, double-barrier method, 
male partner sterilization) before entry and throughout the study, or
b. For whom a negative pregnancy test is unavailable before study entry, or
c.
Who are pregnant or breast feeding before study entry.
6.3.
Withdrawal of subjects from study
All subjects will be encouraged to remain under observation for the full duration of the study. 
However, at any time during the study and without giving reasons, a subject may decline to 
participate further. The subject will not suffer any disadvantage as a result.
It is important though, to note that discontinuation of the assigned study treatment strategies 
is not equivalent to withdrawal of IC.


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Moreover, withdrawal of IC does not mean withdraw of permission to collect further 
information. In whether this refers to permanent discontinuation or interruption of the 
assigned therapy (the most common expected scenario), unwillingness to attend on-site 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. general practitioner) is to 
be assessed by the investigator. See Section 6.3.1.2 for detailed information on withdrawal of 
IC.
The reason for withdrawal (e.g. lost-to-follow-up, withdrawal of consent, protocol violation, 
AE, efficacy outcome reached, or subject unable/unwilling to comply with study medication, 
etc.) must be recorded in the eCRF and in the subject's medical records.
In all cases, every effort must be made to continue to follow the subject and survival status 
information must be determined for all randomized subjects by the end of the study.
6.3.1.
Withdrawal
A subject who withdraws IC before randomization or who develops a violation of the 
selection criteria before randomization is defined as a screening failure. No follow-up of 
screening failures will be performed.
6.3.1.1.
Discontinuation of treatment
Neither erroneous randomization of subject in the presence of exclusion criteria or non-
fulfilment of inclusion criteria nor a post-randomization change in health status that results in 
the subject meeting one or more of the exclusion criteria should not automatically lead to the 
interruption or permanent discontinuation of the assigned therapies, unless continuing the 
medications places the subject at undue risk as determined by the investigator. Such 
situations though very rare, may occur and should be handled on a case-by-case basis.
6.3.1.1.1.
Temporary discontinuation of assigned therapy
Study assigned therapies may be temporarily discontinued however these interruptions should 
be kept to a minimum. Subjects should resume the assigned therapy as soon as the treating 
physician considers it safe to do so. During and after a temporary discontinuation, subjects 
will continue to undergo on-site visits and phone assessments and the timing of such visits 
should if possible remain the same. If the subject cannot return for an on-site visit, a 
telephone assessment will be performed.
The reason for temporary discontinuation of the assigned therapy must be recorded in the 
eCRF and in the subject's medical records. Please refer to Section 8.1 for other potential 
reasons for interruption of the assigned therapies.
If an invasive procedure or surgical intervention is required, rivaroxaban 10/15/20 mg once-
daily should be stopped at least 24 hours before the intervention, if possible, and based on the 
clinical judgment of the physician. If the procedure cannot be delayed the increased risk of 
bleeding should be assessed against the urgency of the intervention. Rivaroxaban should be 
restarted after the invasive procedure or surgical intervention as soon as possible provided the 
clinical situation allows and adequate hemostasis has been established and the treating 
physician considers it safe to do so.


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The management of subjects assigned to the antiplatelet-based strategy in need of an invasive 
procedure or clinical intervention is at the discretion of the treating physician. It is advised 
that the summary of product characteristics as well as the appropriate local and national 
guideline recommendations are followed.
For clinically significant bleeding events, the assigned study medication may be temporarily 
stopped to allow its management. The decision to restart or permanently withdraw study 
medication after resolution of a bleeding event is at the discretion of the investigator.
6.3.1.1.2.
Permanent discontinuation of assigned therapy
Any subject who discontinues prematurely the assigned study medication after he/she has 
been randomized with no intention to restart is defined as having a permanent 
discontinuation.  Study assessments must be continued according to the visit scheme 
provided under Section 9.1 and the subject treatment flow diagram.
The reason for a permanent discontinuation must be recorded in the eCRF and in the subject's 
medical records. Study medication assigned to the discontinued subject must not be assigned 
to another subject.
The assigned therapy must be subject of a permanent discontinuation for any of the following 
reasons:

If any AE occurs which is not acceptable in the opinion of the investigator and/or 
participating subject

Continuous treatment is required with an excluded medication for the remaining 
duration of the study

Calculated CrCl declines below 30 mL/min on 2 consecutive occasions (control 
within 24 hours) or subject requires dialysis

Non-compliance with the study medication regimen in the judgment of the 
investigator

Pregnancy (as confirmed by serum or urine pregnancy test)

Development of hepatic disease associated with coagulopathy leading to a 
clinically relevant bleeding risk in the judgment of the treating physician
It is noted however, that permanent discontinuation of the assigned therapy is discouraged 
wherever possible. If a subject early permanently discontinues the assigned therapy, clinical 
follow-up should be continued until the efficacy cut-off date.
In case of permanent discontinuation of the assigned therapy in a subject randomized to the 
rivaroxaban-based strategy, ASA 75-100 mg once-daily for the remaining duration of the 
study is recommended if the treating physician considers it safe and the clinical situation 
allows doing so.
6.3.1.2.
Withdrawal of IC
A subject may withdraw the IC and still allow further release of information. In this situation, 
the subject’s consent to the collection of further data should be documented in the site’s 


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source documents.
Clinical follow-up should be considered unless the subject explicitly refuses any type of 
collection of information.
The following possibilities may be observed if a subject withdraws consent:
1. Collection of further information allowed
2. Collection of vital status only allowed
3. Collection of further information not allowed
1. Withdrawal of consent and collection of further information allowed:
Follow-up data will be collected for these subjects and it is imperative to obtain complete 
data including information on efficacy and safety endpoints, whether or not they receive the 
assigned therapy.
For patients who do not agree to attend regular study visits, the scheduled visits can be 
performed by phone and the investigator will encourage the patient to return to the clinic for 
at least one final on-site visit once the anticipated efficacy cut-off date is set in order to 
perform all assessments as outlined.
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 if he/ she is willing to provide for 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 legislation, death registries or other registries may be accessed or 
private investigation to locate a patient may be initiated.
For subjects who withdraw IC with collection of further information allowed, the investigator 
should continue to conduct clinical follow-up contacts according to the schedule of 
evaluations (see details Section 9.1 and Figure 2) until the efficacy cut-off date. The 
information to be obtained at each subject contact remains as described under the standard 
Visit description (Section 9.2). At a minimum, the following information should be obtained 
and documented in the eCRF for subjects who withdrawal consent with collection of further 
information allowed:

Vital status

Efficacy and safety endpoints

NOAF assessment

SAEs
2. Withdrawal of consent and collection of vital status only allowed:
For subjects who withdraw consent for release of information, vital status only should be 
obtained. The measures taken for follow-up must be documented in the source data.


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Vital status should be obtained when the anticipated efficacy cut-off date is set.
3. Withdrawal of consent and collection of further information not allowed:
In cases where subjects indicate they do not want to be contacted to collect vital status, the 
withdrawal of consent must be made separately as described under Section 13.3.
In this instance, all collected data so far remain in the study database.
6.3.1.3.
Lost-to-follow-up
In case a subject is identified as potential lost-to-follow-up, every possible effort must be 
made by study site personnel to contact the subject and obtain complete data while 
determining the reason for withdrawal from the study.
At a minimum, the following information should be obtained and documented in the eCRF 
for subjects’ lost-to-follow-up:

Vital status

SAEs

Efficacy and safety endpoints
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.
6.3.2.
Replacement
A study subject that has been withdrawn from the study will not be replaced.
6.4.
Subject identification
The subject identification (SID) is a 9 digit number consisting of:
Digits 1 to 2 =  Country code
Digits 3 to 5
=  Center number within the country
Digits 6 to 9
=  Current subject number within the center
The SID numbers must be used in sequence and no number should be skipped, substituted, or 
re-used.
Registration of the screening will be performed via a central web-based system. The IxRS 
will be filled by each investigational site, and the system will allocate to the subject a unique 
ID number.


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7.
Treatment(s)
7.1.
Treatments to be administered
This section was modified by Amendment 1. For details, see Section 15.1.2.2.
Study treatment assignment will be open-label. Study treatments consist of rivaroxaban and 
in addition of the standard of care treatments clopidogrel, ASA, and VKA, which are 
systematically prescribed to TAVR subjects in accordance to the relevant guidelines and 
routine clinical practice (8, 30, 33).
Eligible study subjects will be randomized in a ratio of 1:1 to one of the 2 following 
treatment arms:
7.1.1. Rivaroxaban-based strategy (experimental strategy)
This section was modified with Amendment 3. For details, see Section 15.2.
Drugs:

Rivaroxaban 10 mg once-daily

Acetylsalicylic Acid (ASA) 75-100 mg once-daily

First 90 days:
o
Rivaroxaban 10 mg once-daily AND ASA 75-100 mg once-daily
The first dose of rivaroxaban is given at the time of randomization if 
the subject is not on clopidogrel or within 1-3 days after the last intake 
of clopidogrel. In case study medication is started the next day post-
TAVR, study medication should not be started earlier than the time the 
TAVR was done on the previous day and the subject should be 
stabilized and complications or bleedings should have been excluded 
carefully.  ASA 75-100 mg once-daily is continued unchanged or 
started immediately after randomization if not already being taken.
The selection of the ASA dose (75-100 mg) is left at the discretion of 
the treating physician. In case the ASA dose before randomization was 
> 100 mg once-daily, the dose has to be decreased to 75-100 mg once-
daily immediately after randomization.

After the first 90 days:
o
Rivaroxaban 10 mg once-daily alone.
o
ASA 75-100 mg once-daily is discontinued.


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7.1.1.1. After NOAF

First 90 days:
o
Rivaroxaban 20 mg once-daily OR 15 mg once-daily for subjects with 
moderate renal impairment (i.e. eGFR < 50 and ≥30 mL/min/1.73m2, 
estimated by the MDRD formula)
o
ASA is continued unchanged, as 75-100 mg once-daily.

After the first 90 days:
o
Rivaroxaban 20 mg once-daily OR 15 mg once-daily for subjects with 
moderate renal impairment (i.e. eGFR <50 and ≥30 mL/min/1.73 m2).
Rivaroxaban is continued alone.
o
ASA 75-100 mg once-daily is discontinued.
7.1.2.
Antiplatelet-based strategy (control strategy)
Drugs:

Clopidogrel hydrogen sulfate (i.e. Clopidogrel) 75 mg once-daily

ASA 75-100 mg once-daily

First 90 days:
o
DAPT: clopidogrel 75 mg once-daily AND ASA 75-100 mg once-
daily
In subjects that are clopidogrel-naïve at randomization a single loading 
dose of at least 300 mg clopidogrel should be administered followed by 
clopidogrel 75 mg once-daily.
The choice of P2Y12 inhibitor should follow the current TAVR 
guidelines and recommendations (32, 33, 35).
The selection of the ASA dose (75-100 mg) is left at the discretion of 
the treating physician. In case the ASA dose before randomization was 
> 100 mg once-daily, the dose has to be decreased to 75-100 mg once-
daily immediately after randomization.

After the first 90 days:
o
ASA 75-100 mg once-daily alone.
o
Clopidogrel 75 mg once-daily is discontinued.
7.1.2.1. After NOAF

First 90 days:
o
Open-label VKA therapy to target INR 2-3, according to guidelines.


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o
Clopidogrel 75 mg once-daily is discontinued.
o
ASA 75-100 mg once-daily is continued unchanged.

After the first 90 days:
o
Open-label VKA therapy alone to target INR 2-3.
o
Clopidogrel 75 mg once-daily must remain discontinued.
o
ASA 75-100 mg once-daily is discontinued.
Initiation of VKA therapy will be performed according to the summary of product 
characteristics (SPC) or relevant product label for the respective VKA. INR values will be 
measured according to local standard of practice. The investigator should assess if a 
parenteral anticoagulant drug (such as low molecular weight heparin) for bridging purposes is 
needed in addition to VKA therapy as per standard of care until the target INR of at least 2.0 
is achieved.
In case NOAF is diagnosed and the patient refuses to switch to the full oral anticoagulation as 
described above (whether rivaroxaban 20/15 mg once-daily in the rivaroxaban-based strategy 
or VKA in the antiplatelet-based strategy), the patient may remain on the study treatment 
assigned before NOAF for the remaining duration of the study if the treating physician 
considers it safe and the clinical situation allows doing so (58, 59).
In case atrial flutter is diagnosed after randomization with an ongoing indication for full oral 
anticoagulant treatment, the choice of the full anticoagulation should follow the treatment 
recommendation for NOAF as per the assigned treatment strategy and described above.
7.2.
Identity of study treatment
This section was modified by Amendment 1. For details, see Section 15.1.2.3.
Rivaroxaban 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.
A system of numbering in accordance with all requirements of good manufacturing practice 
(GMP) will be used, ensuring that each dose of rivaroxaban can be traced back to the 
respective bulk batch 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 rivaroxaban as well as the labels will 
be maintained in the sponsor’s study file.
7.2.1. Rivaroxaban
This section was modified by Amendment 1. For details, see Section 15.1.2.4.
Xarelto® (rivaroxaban, BAY59-7939) will be provided by Bayer as film coated immediate 
release tablets containing 10 mg, 15 mg or 20 mg of rivaroxaban in high-density polyethylene 
(HDPE) bottles. Tablets are for oral use. Rivaroxaban is part of the rivaroxaban-based 
treatment strategy.


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7.2.2. Clopidogrel, ASA and VKA
This section was modified by Amendment 1. For details, see Section 15.1.2.5.
Clopidogrel, ASA and VKA will be supplied from local investigative centers’ resources and 
will be used according to the product labeling for the approved formulations. If required by 
local regulations, Bayer will purchase these drugs from local commercial sources, and label 
and distribute to the investigational site.
7.3.
Treatment assignment
Randomization will be performed via a central IxRS with stratification by investigational site.
The randomization scheme will be securely stored at the statistical department of the database
management center.
Each investigational site will enter the IxRS and fill in relevant subject details needed to 
randomize the subject. Based on this information, the system will assign a unique treatment
number for that subject. Subjects will be randomly assigned in a 1:1 ratio to receive a 
rivaroxaban-based strategy or an antiplatelet-based strategy. This is an open-label trial and 
once subject is assigned to a treatment arm, no treatment cross-over is permitted.
7.4.
Dosage and administration
The selection of the treatment doses as described in Section 7.1 above have been justified 
under Section 3.4.
Study medication should be taken at approximately the same time each day throughout the 
study (approximately 24 hours apart).
During the study, study drug will be dispensed at appropriate intervals, as depicted in the 
Tabular schedule of evaluations (Section 9.1), to ensure subjects have adequate quantities of 
study drug between study visits. Subjects should be advised to finish taking all the pills in 
one bottle before starting the next one.
The planned duration of the treatment period for a given subject will vary depending on the 
rate of subject recruitment and actual event rates.
7.5.
Blinding
This trial is an open-label trial and therefore both investigators and study subjects are aware 
of the treatment arm assigned.
7.6.
Drug logistics and accountability
This section was modified by Amendment 3. For details, see Section 15.2.
Rivaroxaban will be stored at the investigational site in accordance with GCP and GMP 
requirements and according to the instructions given by the clinical supplies department of 
the sponsor (or its affiliate/CRO/academic research organization [ARO]), and will be 
inaccessible to unauthorized personnel. Special storage conditions and a complete record of 
batch numbers and expiry dates can be found in the sponsor’s study file; the site-relevant 
elements of this information will be available in the investigator site file.  On the day of 


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receipt, the responsible site personnel will confirm receipt of rivaroxaban via IxRS.  The 
study personnel will use rivaroxaban only within the framework of this clinical study and in 
accordance with this protocol. Receipt, distribution, return, and destruction (if any) of 
rivaroxaban must be properly documented according to the sponsor’s agreed and specified 
procedures. Re-supply of rivaroxaban is automatically initiated through the IxRS module in 
the eCRF.
The drug accountability process is described in further detail separately in the Monitoring 
Manual. Written instructions on medication destruction will be made available to the affected 
parties as applicable.
7.7.
Treatment compliance
7.7.1. Rivaroxaban
Study personnel will maintain a log of all rivaroxaban dispensed. Drug supplies for each 
subject will be inventoried and reconciled throughout the study. Any discrepancies between 
actual and expected amount of returned study medication must be discussed with the subject 
at the time of the visit, and any explanation must be documented in the source records and 
captured in the eCRF.
Subjects will return empty study drug containers and unused study drug at those visits when a 
new supply of rivaroxaban is to be received.
During the treatment period, the subject will be provided with sufficient medication to cover 
the period until the next on-site visit.
If a dose is missed the subject should take rivaroxaban immediately and continue on the 
following day with the once-daily intake as recommended. The dose should not be doubled 
within the same day to make up for a missed dose.
Subjects should report any missed doses at each on-site visit or telephone assessment. These 
data will be collected in the eCRF. It is understood that subjects may occasionally miss a 
dose or that a subject may be placed on temporary discontinuation (see Section 6.3.1.1.1) but 
this should be avoided or at least kept to a minimum.
7.7.2. Clopidogrel, ASA and VKA
Prescribed units of clopidogrel, ASA, and VKA will be recorded in the eCRF. Subjects will 
be queried on general drug adherence. It is understood that subjects may occasionally miss a 
dose or that a subject may be placed on temporary discontinuation (see Section 6.3.1.1.1).
8.
Non-study therapy
8.1.
Prior and concomitant therapy
This section was modified with Amendment 3. For details, see Section 15.2.
All ongoing medications at screening and used during the study (prescription and over-the-
counter), including adjunct therapy or medical devices, will be recorded in the appropriate 


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section of the eCRF throughout the study.  Use of ASA and clopidogrel or any other P2Y12 
inhibitor prior and during TAVR procedure should also be recorded.
It is advised that the appropriate local and national guideline recommendations are followed 
for any concomitant medications.
The concomitant medication should be evaluated when considering AE causal relationship 
(Section 9.6.1.2).
Use of medications listed below is allowed with the following restrictions:

ASA doses >100 mg once-daily after randomization may be used on a temporary 
basis, but should be avoided for chronic use during the study if possible. If 
analgesics are required use of paracetamol/acetaminophen are recommended. 

Non-steroidal anti-inflammatory drugs (NSAIDs) may be used on a temporary 
basis, but should be avoided for chronic use during the study if possible. If 
analgesics are required use of paracetamol/acetaminophen are recommended.

Medicines that reduce gastric acid (e.g., H-2 antagonists or proton pump inhibitors 
[PPIs]) may reduce the incidence of GI bleeding in subjects’ post-TAVR who are 
treated with antithrombotics and unless contraindicated their use is recommended. 
The choice of gastric protection drugs (such as pantoprazole) is at the discretion of 
the treating physician. PPIs that interact with cytochrome P450 2C19 (such as 
omeprazole or esomeprazole) are disallowed in the antiplatelet-based strategy, 
during concomitant use of clopidogrel.
Concomitant use (with study treatment strategies) of the following therapies is disallowed
during the study:

Single or dual antiplatelet therapy other than assigned study strategy

VKA other than the assigned study strategy and low molecular weight or 
unfractionated heparin if used for reasons other than short-term bridging of VKA 
therapy until the target INR is established

Factor IIa inhibitors and factor Xa inhibitors other than the study medication

In the rivaroxaban-based strategy concomitant use of 
o
P2Y12 inhibitors in combination with rivaroxaban
o
During concomitant use of rivaroxaban systemic treatment with drugs that 
are strong inhibitors of both CYP 3A4 and P-gp (azole antimycotics such 
as ketoconazole and itraconazole or HIV protease inhibitors such as 
ritonavir). The azole antimycotic fluconazole, a moderate CYP 3A4 
inhibitor, has however less effect on rivaroxaban exposure and can be co-
administered. 
o
During concomitant use of rivaroxaban systemic treatment with drugs that 
are strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampin, St. 
John’s wort)


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
In the antiplatelet-based strategy concomitant use of
o
P2Y12 inhibitor for > 3 months (> 90 days) after randomization
o
Omeprazole or esomeprazole that cannot be switched to an alternative 
medication during concomitant use of clopidogrel 
The prohibited therapies may be administered on a temporary basis provided the study drug is 
(temporarily) discontinued first but should be avoided whenever possible. Study drug may be 
restarted after the prohibited therapy has been discontinued and after completion of a suitable 
washout period at the investigator’s discretion (see Section 6.3.1.1.1). The sponsor (or its 
affiliate/CRO) must be notified in advance (or as soon as possible thereafter) of any instances 
in which prohibited therapies are co-administered.
8.2.
Post-study therapy
After the anticipated efficacy cut-off date is set and an on-site visit is completed, there will be 
an observation period to follow subjects in the transition from study treatment strategies to an 
appropriate therapy, as per the clinical site standard of care. This post-study therapy should 
also be recorded in the eCRF.
9. Procedures and variables
9.1.
Tabular schedule of evaluations
This section was modified with Amendment 3. For details, see Section 15.2.


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Table 1: Schedule of evaluations
Visit number
1
2
3
4
5
6, 7, (n)
Period
Screening
Planned treatment
Post-
treatment
Visit
Screening
Baseline / 
Randomizationb
On-site 
visit
On-site 
visit
Phone 
call
On-site 
visit
On-site 
visit
On-site 
visit
Phone 
call
Day
1-7 days a
post-TAVR
0
30
90
180 c
360 c
540,720c, z
every 180d 
EOT d
EOT+30d e
Window (day[s])
± 7d
± 15d
± 15d
± 30d
± 30d
d
± 7d
Study Assessments
Informed consent a
X
Demographics f
X
Medical history
X
Prior medication
X
TAVR assessment
X
In /exclusion criteria
X
X
Concomitant medication
X
X
X
X
X
X
X
X
Physical exam p
X
X
X
X
X
X
Vital signs g
X
X
X
X
X
X
Echocardiogram (TTE 
or TEE) h
X
X
12-lead ECG
X
X
X
X
X
X
Study Medication
Prescribing/dispensing
assigned strategy
X i
X
X
X
X
Treatment strategy 
adjustment j
X
Transition to other 
therapy
X


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Visit number
1
2
3
4
5
6, 7, (n)
Period
Screening
Planned treatment
Post-
treatment
Visit
Screening
Baseline / 
Randomizationb
On-site 
visit
On-site 
visit
Phone 
call
On-site 
visit
On-site 
visit
On-site 
visit
Phone 
call
Day
1-7 days a
post-TAVR
0
30
90
180 c
360 c
540,720c, z
every 180d 
EOT d
EOT+30d e
Window (day[s])
± 7d
± 15d
± 15d
± 30d
± 30d
d
± 7d
Laboratory Assessments (local labs)
Hematology k
X
Liver tests L
X
Renal function m
X
Ongoing study assessments
Efficacy endpoints
X
X
X
X
X
X
X
X
Safety endpoints
X
X
X
X
X
X
X
X
NOAF assessment and 
adjustment of treatment n
X
X
X
X
X
X
X
X
(Serious) AEs o
X
X
X
X
X
X
X
X
X
Vital status
a Consenting subjects must be randomized within 1-7 days post-TAVR and before hospital discharge.
b Once randomized, a subject has entered the study and all randomized subjects will be followed until the efficacy cut-off date when the predefined number of 
efficacy endpoints is anticipated or earlier if the event rate is unexpectedly low, even if they did not take assigned study medication or prematurely 
discontinued study medication. In case of early permanent discontinuation of study medication, all relevant information must be captured in the eCRF as 
soon as possible after stopping the assigned study medication. The timing of on-site visits and of telephone contacts must be kept unchanged.
c The study is event-driven and the number of visits will depend on when the anticipated efficacy cut-off date is set. Subject contacts are planned to take place at 
30, 90, and 180 days after randomization and from 180 days onward every 180 days until the anticipated efficacy cut-off date is set.
d All randomized subjects must continue clinical follow-up until the anticipated efficacy cut-off date is set, i.e. when the sponsor informs each investigational site to 
schedule an on-site visit within 6 weeks. If study assigned medication was taken as planned, this assessment coincides with the EOT visit.
e A telephone assessment is planned 30 days (±7 days) after a permanent discontinuation of the assigned study medication for all randomized subjects.


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f Demographics: year of birth, sex and race/ ethnicity, if allowed per local regulations.
g Vital signs: blood pressure, heart rate, weight, and height. Note that height only needs to be determined at screening.
h The mean transaortic valve pressure gradient post-TAVR should be determined, if available, from either routine transthoracic echocardiogram (TTE) or 
transesophageal echocardiogram (TEE) recordings and captured in eCRF before discharge and at 360 days after randomization according to local standard 
of care for TAVR. An echocardiogram at 360 ± 30 days after randomization is preferred. However, if unavailable last available between 180-360 days after 
randomization can be considered.
i The first study drug administration.
j Adjust treatment strategy as described in section 7.1 (in the rivaroxaban-based strategy, ASA is discontinued and in the antiplatelet-based strategy, clopidogrel 
is discontinued).
k Hematology tests include hemoglobin, platelet count and white cell count.
L Liver tests include transaminases (AST/ALT), total bilirubin and its components (conjugated and/or unconjugated fractions) in case of elevated total bilirubin, 
and alkaline phosphatase, if available as current standard of care.  Liver test results collected before TAVR procedure can be used as long as performed as 
part of the standard of care for the index-TAVR procedure.
m Renal function will be estimated by creatinine clearance (CrCl). The creatinine clearance will be estimated by the MDRD formula using serum creatinine levels.
n In case of NOAF after randomization subjects in: (a) the rivaroxaban-based treatment strategy will be switched to rivaroxaban 15 or 20 mg once-daily, based on 
kidney function. eGFR will be used as reported in lab printouts or calculated from serum creatinine levels using the MDRD formula. Subjects with moderate 
renal impairment and eGFR < 50 and ≥ 30 mL/min/1.73m2 will received an adjusted dose of rivaroxaban of 15 mg once-daily. Both of these doses must be 
taken with food. (b) Subjects in the antiplatelet-based treatment strategy will switch to vitamin K antagonist after INR assessment (INR target 2-3). These 
subjects must return for an unscheduled visit as described under section 13.3.
o For details, see Section 9.6.1.4 and 9.6.1.6. Only SAEs, AE of special interest (even if classified as non-serious), or AEs that lead to permanent discontinuation 
of the assigned study medication are to be reported. The investigator must report immediately (within 24 hours of the investigator’s awareness) all (S)AEs as 
described in Figure 3.
p  Physical examination aims to investigate any occurrence of a safety or efficacy outcome.
AEs, adverse events; EOT, end-of-treatment; d, days; ECG, electrocardiogram.


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Figure 2: Study treatment flow diagram.
9.2.
Visit description
The study will be conducted in 3 phases: a screening period (including screening and 
baseline/randomization), a planned treatment period (consisting of on-site visits and 
telephone assessment), and a post-treatment observational period. If not stated otherwise, the 
measures listed in the following section will be performed by or under the supervision of the 
investigator.
9.2.1. Screening period (screening and randomization)
This section was modified with Amendment 3. For details, see Section 15.2.
Before any study specific screening examinations take place, potentially eligible subjects will 
be given a full explanation as to what the study would involve, both verbally and in writing in 
the form of a written subject information sheet (refer to Section 13.3 for details). Study 
specific screening examinations will only be performed after having received the subject's 
written IC. Please note that if screening procedures are performed as part of routine medical 
practice (e.g. laboratory parameters) these are not required to be repeated as long as they 
meet the protocol requirements described below.
Hematology tests and renal function results from standard of care can be used as long as 
collected after the index-TAVR procedure and before randomization. Liver test results 
collected before TAVR procedure can be used as long as performed as part of the standard of 
care for the index-TAVR procedure. Before the IC form is obtained the inclusion and 
exclusion criteria are reviewed to assess the subjects’ eligibility. 
If the subject meets all of the inclusion and none of the exclusion criteria, and IC has been 
obtained, he/she is eligible to be randomly assigned (1:1) to receive either a rivaroxaban-
based strategy or an antiplatelet-based strategy and, therefore, should be randomized.


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Randomization by IxRS, must take place within 1-7 days post-TAVR, and before hospital 
discharge. The allocated treatment strategy is implemented after randomization.
If allowed by the subject or for local legal requirements, his/her general practitioner (GP) will 
be informed of the subject’s participation in the trial by means of a letter from the 
investigator. Information will be included on the treatment strategies as well as on specific 
clinical assessments that must come to the attention of the investigational study center before 
subject’s treatment is modified (such as, if NOAF is detected).
Screening (1-7 days post-TAVR)
The following procedures will be performed 1-7 days after the index-TAVR and prior to 
randomization:
Obtainment of written IC
NB: No screening procedures may be performed unless written IC has been obtained.

Eligibility check (in- and exclusion criteria)

Register the screening in IxRS (the IxRS system will allocate the subject a unique 
ID number (refer to Section 6.4 for details)

Demographic data check

Medical history

Prior medication

TAVR assessment

Laboratory assessments (see Section 9.6.3.1)

Routine echocardiogram (TTE or TEE) post-TAVR and before hospital discharge 
if available per local standard of care for TAVR.
Visit 1 – Baseline / Randomization
Reconfirmation of eligibility (in- and exclusion criteria)
NB: No subject may be randomized unless adherence to all selection criteria as given in section 6
is established.

Concomitant medication check

Physical examination

Vital signs

12-lead electrocardiogram (ECG) or any other method documenting heart rhythm 
(e.g. ECG strip) able to exclude atrial fibrillation

Randomization via IxRS (see Section 7.3)
The following procedures will be performed 1-7 days after the index-TAVR, after 
randomization and before discharge:


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
First administration of assigned treatment strategy, including instructions on the 
use of study’s treatment strategies

Continuous assessment of (S)AEs

Assess if any efficacy and/or safety endpoints occurred

Assess if NOAF occurred
9.2.2. Planned treatment period
This section was modified with Amendment 3. For details, see Section 15.2.
The duration of the planned treatment period for a given subject will depend on the time 
needed to reach the efficacy cut-off date, i.e. to collect the predefined number of primary 
adjudicated efficacy endpoints in the total study population or earlier if the event rate is 
unexpectedly low. The expected duration of the treatment period is 720 days but may be 
longer or even shorter depending upon the rate of subject recruitment and efficacy event 
rates. Visits are scheduled at 30, 90, 180 days after randomization, and every 180 days
thereafter until the anticipated efficacy cut-off date is set (see Section 9.1 Tabular schedule of 
evaluations Table 1) at which time a final on-site visit will be scheduled. Once notified, the 
study center must contact each randomized subject and schedule this visit within 6 weeks. 
Subjects must continue to take their study medication until they return for this on-site visit.
Subjects, who have a permanent discontinuation of study medication, will be also followed 
between randomization and the visit scheduled after the anticipated efficacy cut-off date is 
set, unless the subject has withdrawn his/her IC without allowing collection of further 
information. For more details, please refer to Section 6.3.1.2 and 13.3.
Visit 2 - On-site visit: 30 days (± 7 days)
The following procedures will be performed during this on-site visit:

Concomitant medication check

Physical examination

Vital signs check

12-lead electrocardiogram (ECG)

Continuous assessment of (S)AEs

Assess if any efficacy and/or safety endpoints occurred

Assess if NOAF occurred

Prescription of assigned therapy and rivaroxaban dispensation, as needed
Visit 3 - On-site visit: 90 days (± 15 days)
The following procedures will be performed during this on-site visit:

Concomitant medication check

Physical examination


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
Vital signs check

12-lead electrocardiogram (ECG)

Continuous assessment of (S)AEs

Assess if any efficacy and/or safety endpoints occurred

Assess if NOAF occurred

Adjust treatment strategy as described in Section 7.1 (rivaroxaban-based strategy, 
ASA is discontinued; antiplatelet-based strategy, clopidogrel is discontinued)

Prescription of assigned therapy and rivaroxaban dispensation, as needed
Visit 4 - Telephone assessment: 180 days (± 15 days)
The following procedures will be performed during this telephone contact:

Concomitant medication check

Continuous assessment of (S)AEs

Assess if any efficacy and/or safety endpoints occurred

Assess if NOAF has been diagnosed
Visit 5 - On-site visit: 360 days (± 30 days)
The following procedures will be performed during this on-site visit:

Concomitant medication check

Physical examination

Vital signs check

12-lead electrocardiogram (ECG)

Continuous assessment of (S)AEs

Assess if any efficacy and/or safety endpoints occurred

Assess if NOAF occurred

Prescription of assigned therapy and rivaroxaban dispensation, as needed

Routine echocardiogram (TTE or TEE) approximately at 360 days after 
randomization if available per local standard of care for TAVR.
NB: An echocardiogram at 360 ± 30 days after randomization is preferred. However, if unavailable 
last available echocardiogram between 180-360 days after randomization can be considered.
Visit 6 – On-site visit: 540 days (± 30 days)
The following procedures will be performed during this on-site visit:

Concomitant medication check


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
Physical examination

Vital signs check

12-lead electrocardiogram (ECG)

Continuous assessment of (S)AEs

Assess if any efficacy and/or safety endpoints occurred

Assess if NOAF occurred
Visit 7 through Visit n - On-site visit: 720 days and every 180 days (± 30 days)
The following procedures will be performed during this on-site visit:

Concomitant medication check

Physical examination

Vital signs check

12-lead electrocardiogram (ECG)

Continuous assessment of (S)AEs

Assess if any efficacy and/or safety endpoints occurred

Assess if NOAF occurred
Unscheduled on-site visit - NOAF-related
In the event of NOAF after randomization, the assigned therapy should be modified as 
defined per protocol (Section 7.1) and the following procedures should be performed during 
the unscheduled on-site visit:

Concomitant medication check

Physical examination

Vital signs check

12-lead electrocardiogram (ECG)

Continuous assessment of (S)AEs

Assess if any efficacy and/or safety endpoints occurred

For subjects in the rivaroxaban-based strategy:
o Assess creatinine clearance
o Dispense dose of rivaroxaban according to 7.1.1.1

For subjects in the antiplatelet-based strategy:
o Subjects will be transitioned to an open-label vitamin K antagonist (VKA) 
strategy according to 7.1.2.1 and to the appropriate local guidelines


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o Assess INR to adjust dose to target INR 2-3. It is recommended to 
monitor INRs at least every 4 weeks but the frequency of INR monitoring 
is left to the discretion of the treating physician.
On-site visit: EOT 
This visit takes place as soon as possible after the last intake of the assigned study 
medication.
All subjects must complete this visit to the exception of those with full withdrawal of IC (see 
Section 6.3.1.2).
The following procedures will be performed during this on-site visit:

Concomitant medication check

Physical examination

Vital signs check

12-lead electrocardiogram (ECG)

Continuous assessment of (S)AEs

Assess if any efficacy and/or safety endpoints occurred

Assess if NOAF occurred

Subject transition from assigned study therapy to an appropriate therapy as per the
clinical site standard of care.
When the anticipated efficacy cut-off date is set, the sponsor informs each investigational site 
and all subjects must return to the clinic within 6 weeks in order to have a final assessment. 
This assessment will coincide with the EOT visit for the subjects under treatment.
Subjects with an early permanent discontinuation of the assigned therapy will be also 
followed between randomization and the visit scheduled after the anticipated efficacy cut-off 
date is set, unless the subject opposes by withdrawing the IC and not allowing collection of 
further information. For this, he/she needs to sign a corresponding declaration of objection; 
alternatively, the subject’s oral objection may be documented in the subject’s source data. For 
more details, please refer to Section 13.3.
9.2.3. Post-treatment period
This section was modified with Amendment 3. For details, see Section 15.2.
After the last dose intake of the study assigned medication, there will be an observation 
period to follow subjects after transition from study treatment strategies to an appropriate 
therapy, as per the clinical site standard of care. All subjects will have a telephone assessment 
after 30 days (±7 days) including the subjects who had an early permanent discontinuation of 
the study treatment strategies. For recommendations on the appropriate therapy in case of 
early permanent discontinuation of the study treatment strategies, please see Section 
6.3.1.1.2.


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Telephone assessment: permanent discontinuation of assigned strategy + 30d (±7 days)
The following procedures will be performed during this telephone contact:

Medication check

Continuous assessment of (S)AEs

Assess if any efficacy and/or safety endpoints occurred

Assess if NOAF has been diagnosed
End of study visit
This visit takes place within 6 weeks of the announcement of the anticipated efficacy cut-off 
date.  
This visit will be performed for subjects who early permanent discontinue the study 
medication and had the expectation to keep the regular scheduled visits as planned by the 
time of study drug discontinuation. This visit will also be performed for subjects who 
withdraw consent and allow collection of further information.
The following procedures, if applicable, will be performed during this visit:

Assess if any efficacy and/or safety endpoints occurred

Vital status

Assessment of (S)AEs
9.3.
Population characteristics
9.3.1. Demographics
For demographic assessment the following parameters will be recorded:

Year of birth

Sex

Race / ethnicity, if allowed per local regulations
9.3.2.
Medical history
Medical history findings (i.e. previous diagnoses, diseases, or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Not pertaining to the study indication

Start before signature of the IC

Considered relevant for the subject’s study eligibility
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1.


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9.4.
Efficacy
The primary efficacy endpoint is death or first adjudicated thromboembolic event (DTE) as 
described under Section 5.3.1. Pertinent information of all clinical events relating to the 
primary efficacy endpoint or any of its components will be collected between randomization 
and the visit scheduled after the anticipated efficacy cut-off date is set, and up to 30 days
beyond this visit, irrespective of actual treatment of the subject.
Potential efficacy endpoints are adjudicated by the CEC according to the definitions of the 
CEC charter (see Section 16.1.1).
9.5.
Pharmacokinetics / pharmacodynamics
Not applicable.
9.6.
Safety
The primary safety endpoint is primary bleeding event (PBE) as described under Section 
5.3.1 Primary variable(s). Pertinent information of all bleeding episodes requiring medical 
attention will be collected between randomization and the visit scheduled after the anticipated
efficacy cut-off date is set, and up to 30 days beyond this visit, irrespective of actual 
treatment of the subject.
Potential safety endpoints are adjudicated by the CEC according to the definitions of the CEC 
charter (see Section 16.1.2).
Three bleeding event scales (i.e. BARC, TIMI, and ISTH) are used to classify bleeding 
events occurring from randomization until the efficacy cut-off date.
9.6.1.
Adverse events
9.6.1.1.
Definitions
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written IC for participation in the study.  
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
“Any scheduled surgery that is arranged during the study as a result of a new/deteriorated 
condition should be reported as (S)AE”, e.g. a new chest pain (SAE) requiring a PCI/CABG 
(treatment of the SAE).
If laboratory findings reveal abnormal values, if clinically significant, they should be 
documented and reported as an AE. This is up to the physician’s discretion, and should be 
documented in the source documentation.
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal physical examination findings, symptoms, diseases, laboratory, or ECG
findings.


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
Conditions that started before signing of IC and for which no symptoms or 
treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints)

Conditions that started before signing of IC and for which symptoms or treatment 
are present after signing of informed consent, at unchanged intensity, are recorded 
as medical history (e.g. allergic pollinosis)

Conditions that started or deteriorated after signing of IC will be documented as 
adverse events.  This includes intercurrent illnesses
Definition of serious adverse event (SAE)
A SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a.
Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the subject was 
at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
c.
Requires in-patient hospitalization or prolongation of existing hospitalization
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:
The admission results in a hospital stay of less than 24 hours
The admission is not associated with an AE 
(e.g. social hospitalization for purposes of respite care)
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly / birth defect
f.
Is another serious or important medical event as judged by the investigator
9.6.1.2.
Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.


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9.6.1.2.1.
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2.
Intensity
The intensity of an AE is classified according to the following categories:

Mild – usually transient in nature and generally not interfering with normal activities

Moderate – sufficiently discomforting to interfere with normal activities

Severe – prevents normal activities
9.6.1.2.3.
Causal relationship
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the eCRF.
Causality should be assessed separately for each study treatment as detailed in the eCRF. If 
the investigator feels that the event cannot be firmly attributed to one of the study treatments 
(e.g. owing to a suspected underlying interaction), the same assessment will be documented 
for each study treatment.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”
An assessment of “no” would include:
1. The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.
OR
2. Non-plausibility, e.g. the subject 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 the AE is reasonably associated with the use of the 
study treatment strategy. Important factors to be considered in assessing the relationship of 
the AE to study treatment include:

The temporal sequence from drug administration:  The event should occur after the 
drug is given.  The length of time from drug exposure to event should be evaluated in 
the clinical context of the event.

Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge):  Subject’s response after de-challenge or re-challenge should be 
considered in view of the usual clinical course of the event in question.


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
Underlying, concomitant, intercurrent diseases:
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have.

Concomitant medication or treatment:
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them might have caused the event in question.

Known response pattern for this class of drug: clinical/preclinical

Exposure to physical and/or mental stresses: The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event

The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) 
of the study treatment, coupled with the individual subject’s pharmacodynamics 
should be considered.

The assessment is not possible
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”
9.6.1.2.4.
Action taken with study treatment
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.
The study treatment action should be recorded separately for each study treatment as detailed 
in the eCRF.

Drug withdrawn

Drug interrupted

Dose reduced

Dose not changed

Dose increased

Not applicable

Unknown
9.6.1.2.5.
Other specific treatment(s) of adverse events

None

Remedial drug therapy


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
Other
9.6.1.2.6.
Outcome
The outcome of the AE is to be documented as follows:

Recovered/resolved

Recovering/resolving

Recovered/resolved with sequelae

Not recovered/not resolved

Fatal

Unknown
9.6.1.3.
Assessments and documentation of adverse events
The investigator has to record on the respective eCRF pages adverse events as described 
under Section 9.6.1.1 occurring in the period between the signing of the IC and the end of the 
follow-up phase; after the end of the clinical follow-up phase there is no requirement to 
actively collect AEs including deaths.  The type of information that should be assessed and 
recorded by the investigator for each AE is listed in Section 9.6.1.2.
“Death” should not be recorded as an AE on the AE page.  Instead, “death” is the outcome of 
underlying AE(s).
For all serious adverse events (SAEs) the sponsor has to carry out a separate assessment for 
expectedness, seriousness, and causal relationship to study drug.
9.6.1.4.
Reporting of SAEs/ AEs
The definition of serious adverse events (SAEs) is given in Section 9.6.1.1.
The following detailed rules apply to AE and SAE handling and are provided in Figure 3
below:

Primary or secondary efficacy endpoints, including all-cause death, have to be 
recorded on Efficacy Endpoint pages of the eCRF. Only non-cardiovascular (non-
CV) death has to be reported as SAE within 24 hours of the investigator’s 
awareness. All other primary and secondary efficacy endpoints are exempted from 
expedited reporting.

All primary and secondary safety endpoints (i.e. bleedings) have to be recorded in 
the eCRF. Only pericardial bleedings and pulmonary alveolar bleedings/
pulmonary bleedings, which are defined as AEs of special interest (see also Section
9.6.1.6), have to be reported within 24 hours of the investigator’s awareness even if 
classified as non-serious. All other primary and secondary safety endpoints are
exempted from expedited reporting.

All other events (including complications of efficacy or safety endpoints events) 
that fulfill the seriousness criteria have to be recorded on the AE page of the eCRF 
and reported within 24 hours of the investigator’s awareness.


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
All pregnancies in female study subjects or in female partner of a male study 
subject as well as endpoints of the pregnancies have to be reported within 24 hours 
of the investigator’s awareness. For pregnancy reports, the Pregnancy Monitoring 
Forms are to be used.

Non-serious AEs that lead to permanent study drug discontinuation have to be 
recorded on the AE page of the eCRF but do not require further reporting. Non-
serious AEs which DO NOT lead to discontinuation of study medication DO NOT 
NEED to be recorded and reported.  However, non-serious AEs that the 
investigator considers of particular concern may be recorded on the AE page of the 
eCRF to bring them to the attention of the sponsor.
Of the AEs reported, reportable events (i.e. SUSARs) have to be reported to the 
competent authorities and to the Independent IECs/IRBs according to legal 
requirements.
If reported, SAEs occurring after the protocol-defined observation period will be processed 
by the sponsor according to all applicable regulations.
The investigator must report immediately (within 24 hours of the investigator’s awareness) 
all SAEs described above as requiring expedited reporting. The report recipients are detailed 
in the instructions for SAE reporting included in the Investigator File.
The investigator is responsible for continuous monitoring of 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 subject’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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Figure 3: Outcome and (S)AE collection and reporting schematic
9.6.1.5.
Expected adverse events
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB) / summary of product characteristics.
The following events are expected to occur with TAVR and therefore should not be reported
as AEs, unless they occur outside of the stated timeframe:

Back pain related to laying on the procedure table within 3 days after TAVR

Incisional pain (pain at access site) within 3 days after TAVR

Sleep problems or insomnia within 7 days after TAVR

Mild to moderate bruising or ecchymosis within 7 days after TAVR.


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9.6.1.6.
Adverse events of special safety interest
The following events are considered as AEs of special interest:

Pericardial bleedings

Pulmonary alveolar bleedings/pulmonary bleedings
These AEs (even if classified as non-serious) have to be reported within 24 hours of the 
investigator’s awareness by recording them on the AE page of the eCRF.
9.6.2.
Pregnancies
The reporting of pregnancies is described in Section 9.6.1.4.
9.6.3.
Further safety
9.6.3.1.
Laboratory evaluations
This section was modified with Amendment 3. For details, see Section 15.2.
The following local routine laboratory measurements need to be evaluated before 
randomization:

Hematology tests
o
Hemoglobin
o
Platelet count
o
White cell count

Liver tests
o
Transaminases (AST/ALT)
o
Total bilirubin and components (conjugated and/or unconjugated 
fractions in case of elevated total bilirubin)
o
Alkaline phosphatase, if available as current standard of care

Renal function
o
Creatinine clearance (CrCl).
Serum creatinine levels in order to derive the estimated creatinine 
clearance (mL/min/1.73m2) using the MDRD formula. If serum 
creatinine levels are not available the estimated creatinine clearance 
(mL/min/1.73m2) as reported in lab printout should be selected.
Laboratory tests results done as part of standard of care can be used. Hematology tests and 
renal function results from standard of care can be used as long as collected after the index-
TAVR procedure and before randomization. Liver test results collected before TAVR 
procedure can be used as long as performed as part of the standard of care for the index-
TAVR procedure.
For all the laboratory evaluations described above, if multiple values are available, the 
measurement closest to the visit date should be selected.


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9.6.3.2.
Physical examination
A targeted physical examination of the cardiovascular and neurological systems will be 
performed and relevant information will be recorded in the eCRF.
Abnormal physical examination findings are recorded either as medical history or as adverse 
events (see Section 9.6.1.1).
9.6.3.3.
12-lead ECG
Standard 12-lead ECGs will be performed locally as depicted in the schedule of evaluations 
(Section 9.1) and pertinent information will be recorded in the eCRF. Copies of all recorded 
ECGs are stored in the patient hospital files.
9.6.3.4.
Vital signs
For vital signs the following parameters will be recorded:

Heart rate

Blood pressure

Weight

Height (only at screening)
9.7.
Other procedures and variables
Echocardiography
Findings from routine echocardiograms (either TTE or TEE) will be collected post-TAVR 
and at approximately 360 days after randomization (360 ± 90 days or last available between 
180-360 days) if available according to the local standard of care for TAVR. Selected 
hemodynamic parameters will be recorded in the eCRF. Copies of recorded echocardiograms 
are stored in the patient hospital files.
If an investigational study center is routinely collecting 3D TEE in their post-TAVR subjects, 
these recordings may be used as the scheduled echocardiograms described above, as long as 
the sponsor/designated CRO is informed and has approved it accordingly.
9.8.
Appropriateness of procedures / measurements
The measurements and procedures chosen for this study are widely used, and generally 
recognized as reliable and accurate.
10.
Statistical methods and determination of sample size
10.1.
General considerations
A general description of the statistical methods to be used to analyze the efficacy and safety 
of the study drug is outlined below. A more detailed statistical analysis plan (SAP) will be 
provided in a separate document. Statistical analysis will be performed using SAS; the 
version used will be specified in the SAP. The SAP will accommodate protocol amendments 
or unexpected issues in study execution or data that affect planned analyses, and will provide 


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more details on the analytic approaches, coding guidelines, censoring of time-to-event 
variables, and output tables and figures.
If not stated otherwise, all efficacy and the safety analyses will be based on findings as 
confirmed by the Clinical Event Committee (CEC). Definitions of terms and endpoints are 
located in Sections 16.1 and 16.2.
10.2.
Analysis sets
10.2.1.
Full analysis set (FAS)
Both the efficacy analysis and the safety analysis are based on the population of all 
randomized subjects. In accordance with the International Conference on Harmonization 
(ICH) E9 guidelines, the population of all randomized subjects is termed the Full Analysis 
Set (FAS).
Subjects are categorized according to the group to which they were assigned by the 
randomization process.
10.2.2.
Data scopes
This section was modified with Amendment 3. For details, see Section 15.2.
The following data scopes are defined for efficacy and safety analyses.
Data scope according to intention-to-treat principle (ITT analysis)
The ITT data scope includes all outcome events observed from randomization until the 
efficacy cut-off date (i.e. the day of the primary completion event).  The follow-up period for 
each subject will be as long and complete as possible between randomization up to the visit 
scheduled after the anticipated efficacy cut-off date is set.
Data scope according to treatment (OT analysis)
The on-treatment data scope includes all outcome events observed from randomization until 
two days following permanent discontinuation of the randomized treatment strategy. Subjects 
are off the rivaroxaban-based treatment strategy when rivaroxaban has been permanently 
discontinued. Subjects are off the antiplatelet-based treatment strategy when both clopidogrel 
and ASA have been permanently discontinued within the first 3 months or when ASA alone 
has been permanently discontinued after 3 months, except in case of NOAF and receiving 
VKA.
Data scope until NOAF (pre-NOAF analysis)
The pre-NOAF data scope includes all outcome events observed from randomization until the 
NOAF requiring (a switch to) treatment with high dose rivaroxaban or vitamin K antagonists.
Data scope after NOAF (post-NOAF analysis)
The post-NOAF data scope includes all outcome events observed between the treatment 
switch precipitated by NOAF until the efficacy cut-off date.


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10.3.
Variables and planned statistical analyses
10.3.1.
Primary variables
Efficacy variables
The primary efficacy endpoint is the adjudicated composite of all-cause death, any stroke, 
myocardial infarction (MI), symptomatic valve thrombosis, pulmonary embolism (PE), deep 
vein thrombosis (DVT), or non-CNS systemic embolism.
Safety variables
The primary safety endpoint is defined as the adjudicated composite of life-threatening, 
disabling or major bleeds classified according to the VARC definitions following the BARC 
classification. This endpoint is referred to as the primary bleeding event (PBE).
10.3.2.
Secondary variables
The secondary endpoints are:

the adjudicated composite of cardiovascular death, any stroke, myocardial 
infarction, symptomatic valve thrombosis, pulmonary embolism, deep vein 
thrombosis, or non-CNS systemic embolism

The net-clinical-benefit defined as the adjudicated composite of all-cause death, 
any stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary 
embolism, deep vein thrombosis, non-CNS systemic embolism (efficacy), life-
threatening, disabling, and major bleeds (safety).
The secondary safety endpoints are bleeding complications according to:

The composite of TIMI major or minor bleeds

ISTH major bleeding

The composite of BARC 2, 3 or 5 bleeds
10.3.3.
Other variables
Other variables include:

the separate components of the adjudicated primary efficacy and safety endpoint 
being,

All-cause death

Any stroke

Myocardial infarction

Symptomatic valve thrombosis

Pulmonary embolism

Deep vein thrombosis

Non-CNS systemic embolism


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
Life-threatening or disabling bleeds (BARC type 3b, 3c or 5)

Major bleeds (BARC type 3a)

mean transaortic valve pressure gradient at approximately 360 days after 
randomization measured by echocardiogram (TTE or TEE)
10.3.4.
Subgroup variables
This section was modified with Amendment 3. For details, see Section 15.2.
The following subgroup variables based on baseline demographics are planned according to 
the subgroup analysis (see 10.3.8):

Sex (male, female)

Age (< Median, ≥Median)

Weight

BMI

Valve type (balloon-expandable, self-expandable)

Valve-in-valve procedure

Surgical Risk Scores, such as Society of Thoracic Surgeons’ (STS) risk score 
and/or EuroSCORE

Renal function

Hypertension (yes, no)

Diabetes mellitus (yes, no)

History of a prior stroke (ischemic or unknown type) or non-CNS systemic 
embolism (yes, no)

Prior MI (yes, no)

Previous revascularization (CABG or PCI)

CHADS2 and CHA2DS2-VASc scores (< Median, ≥ Median)

HAS-BLED (< Median, ≥Median)

Frailty index
10.3.5.
Analysis of the primary efficacy variable
This section was modified with Amendment 3. For details, see Section 15.2.
The analysis of the primary efficacy variable is performed on the Full Analysis Set (FAS).
For superiority analysis the follow-up is censored at the last date of known outcome status or 
at the efficacy cut-off date, whichever comes first. Non-inferiority analysis is carried out 
under the OT data scope, i.e. follow-up is censored at two days after permanent 
discontinuation of the randomized treatment strategy. Censoring is assumed independent of 
the treatment group assignment.


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10.3.5.1.
Testing for superiority
This section was modified with Amendment 3. For details, see Section 15.2.
In order to evaluate whether the rivaroxaban-based strategy is superior to the antiplatelet-
based strategy in prolonging the time to primary efficacy outcome event in patients with post-
TAVR patients, the following null hypothesis (H0) is tested at the significance level of 2.5%:
H0: SRIV(t) = SAPT(t) for all time points t ≥ 0, (i.e. “there is no difference between the 
rivaroxaban-based treatment group and the antiplatelet-based control group regarding the 
primary efficacy outcome for all time points”)
The one-sided alternative hypothesis is:
H1: SRIV(t) > SAPT(t) for at least one time point t ≥ 0, and SRIV(t) ≥ SAPT(t) for all time 
points t ≥ 0, (i.e. “there is a difference between the two groups in favor of the rivaroxaban-
based treatment group regarding the primary efficacy outcome for at least one time point“)
where SRIV denotes the event-free survival function of the rivaroxaban-based treatment group
and SAPT denotes the event-free survival function of the antiplatelet-based treatment group.
The following decision rule to test the null hypothesis is applied:
According to the size of this study, it is justified to assume under H0 a sufficiently close 
approximation of the one-sided log-rank test to the normal distribution. If the z-value from 
the one-sided log-rank test (for the difference SRIV(t) - SAPT(t)) is larger than the critical 
quantile from the normal distribution (z0.975 =1.96), the null hypothesis is rejected in favor 
of the alternative hypothesis.
Kaplan-Meier estimates of cumulative risk and cumulative hazard functions are 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 and corresponding two-sided 95% confidence intervals are estimated based on a 
Cox proportional hazards models. The parameter estimate β (=ln(HR)), its standard error, p-
value, and 95% Confidence Limits are calculated according to the maximum partial 
likelihood method, with Breslow’s approximation for ties (phreg). 
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. If there is strong 
evidence of non-proportionality, the estimation of time-dependent hazard ratios will be 
considered.
All of the above analyses are carried out under the ITT data scope (i.e. all events are counted 
irrespective of the actual treatment at the time of the event).
Further details will be specified in SAP.


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10.3.5.2.
Testing for non-inferiority
This section was modified with Amendment 3. For details, see Section 15.2.
Using a log rank test adapted to non-inferiority testing the following (inferiority) null 
hypothesis (H0) is tested at a one-sided significance level of 2.5%:
H0: HR(t) ≥ 1.2 for all time points t ≥ 0, (i.e. “the hazard for the primary efficacy 
endpoint in the rivaroxaban-based treatment group is more than 20% larger than that 
in the antiplatelet-based control group regarding”)
The one-sided alternative hypothesis (H1) is:
H1: HR(t) < 1.2 for all time points t ≥ 0, (i.e. “the hazard in the rivaroxaban-based 
treatment group for the primary efficacy endpoint is such that the HR is below 1.20”)
The following decision rule to test the null hypothesis of inferiority is applied:
If the upper boundary of 95% confidence interval (CI) for HR falls below 1.20, the 
null-hypothesis of inferiority (H0) is rejected and non-inferiority of the rivaroxaban-
based strategy (relative to the antiplatelet-based strategy) with regard to the primary 
efficacy endpoint can be claimed.
Hazard ratio and corresponding two-sided 95% confidence intervals are estimated based on a 
Cox proportional hazards model. 
In order to preserve the type I error rate for efficacy testing, the two tests for the primary 
efficacy endpoint are technically placed in a hierarchical order, (1) testing for non-inferiority 
as described in this section followed by (2) testing for superiority as described in the previous 
section.
10.3.5.3.
Exploratory analyses of the primary efficacy variable
In the primary analyses, switches to full dose anticoagulation are treated as integral part of 
the treatment strategy. Pre-NOAF analyses, with censoring at the time of the switch to 
anticoagulation therapy, are carried out as exploratory analyses. Post-NOAF analyses, with 
starting at the time of the treatment switch precipitated by NOAF are carried out as 
exploratory analyses.
10.3.6.
Analysis of secondary and other efficacy variables
The secondary efficacy and net-benefit variables are tested sequentially in a hierarchical 
order as listed in Section 10.3.2.
If the superiority of rivaroxaban-based strategy for the primary efficacy outcome is declared, 
the following alternative hypotheses, superiority of rivaroxaban-based strategy compared 
with antiplatelet-based strategy for the secondary efficacy endpoints is tested in the sequential 
order.  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 controls the 
global Type 1 error level.
The analysis methods are similar to those described for the primary efficacy variable. The 
analyses are carried out under the ITT data scope. In these analyses, testing for superiority is 
not preceded by testing for non-inferiority.


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10.3.7.
Analysis of the safety variables
This section was modified with Amendment 3. For details, see Section 15.2.
The analysis of the primary safety variable is performed on the Full Analysis Set (FAS) under 
the ITT data scope — that is, events are analyzed irrespective of their time of occurrence 
relative to termination of assigned study treatment strategy. Follow-up is censored at the last 
date of known outcome status or at the efficacy cut-off date, whichever comes first.
Kaplan-Meier estimates of cumulative risk and cumulative hazard functions for the primary 
safety variable are 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.
If the proportional hazards assumption holds for the primary safety variable, hazard ratio and 
corresponding two-sided 95% confidence intervals are estimated based on a Cox proportional 
hazards models.
On treatment analyses, pre-NOAF and post-NOAF analyses of the primary safety variable are 
performed as exploratory analyses.
All of the above analyses of the primary safety variable are descriptive, without formal 
statistical tests being performed.
The analyses of secondary safety variables are similar to those for secondary efficacy 
variables, without any sequential order.
10.3.8.
Subgroup analysis
Subgroup analyses for the primary efficacy and safety variables are based on the same 
analysis sets and data scopes as in the main analyses of the study outcome variables.  The 
subgroup analyses are presented descriptively without formal hypotheses testing.
Homogeneity of treatment effect in subgroups, both in magnitude and direction, is 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 is 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 variables 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.


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10.4.
Determination of sample size
This section was modified with Amendment 3. For details, see Section 15.2.
The sample size determination for the study was driven by requirements for testing 
superiority of the rivaroxaban-based strategy over the antiplatelet-based strategy as described 
above.
The expected 540 days event rate of the primary efficacy endpoint is 33.0% (5-7, 10). The 
target Relative Risk at 540 days is 0.80, i.e. a reduction of the 540 days event rate from 
33.0% under antiplatelet-based regimen to 26.4% under the rivaroxaban-based regimen. 
Under the assumption of an exponential distribution, the hazard ratio equals 0.7654.
Under the above assumptions, with 360 days accrual period, and an 540 days median follow-
up (minimum 360 days and maximum 720 days), randomization of 2 x 740 analyzable 
subjects is expected to yield 440 primary events (196 in the rivaroxaban-based treatment
group and 244 in the antiplatelet-based control group). This provides 80% power at a 5% 
significance level, without interim analyses for efficacy.
The power calculation was based on a test using the Cox proportional hazards model and was 
performed with PASS version 12.0.6, with the module for two survival curves using Cox’s 
proportional hazards model.
A sample size of sample size of 2 x 760 subjects allows for an attrition rate of 2.63%. The 
study is event driven and the number of randomized subjects is estimated to be required to 
collect 440 primary efficacy events. The study is planned to run until this number of events 
has been reached or to stop earlier if the event rate is unexpectedly low.
With this sample size, the study has > 90% power to show non-inferiority with a non-
inferiority margin of 1.20 if the underlying hazard ratio ≤ 0.90 at a one-sided significance 
level of 2.5%. The non-inferiority margin of 1.20 was selected based on clinical 
appropriateness.
The final sample size will depend on multiple factors including the rate of accrual of the 
primary endpoint events. The Steering Committee of the trial will monitor the aggregate 
(blinded) event rate and may increase the sample size or duration of follow-up to achieve the 
planned target number of events in consultation with the sponsor.
Non-inferiority margin
The non-inferiority margin of 1.20 for the HR for the efficacy comparison as described in 
Section 10.3.5.2 was selected based on both clinical appropriateness and relevant studies in 
the area of TAVR.
The event rates for mortality and ischemic events after TAVR are high. In high-risk subjects
receiving TAVR in the PARTNER trial the composite of the rate of all-cause death or stroke 
was at 27% and 37% in the TAVR group after 1 and 2 years, respectively (14). The standard 
of care antithrombotic treatment after TAVR is dual antiplatelet therapy followed by single 
antiplatelet therapy with ASA although evidence from randomized control trials (RCTs) is 
lacking. Moreover, no prospective randomized studies to date have compared an active to no 
antithrombotic treatment in subjects after TAVR.


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Earlier studies comparing TAVR with SAVR used a non-inferiority margin of 1.23 for RR of 
one year all-cause mortality (5, 10, 61).
In addition, NOAF is observed in up to 30% of subjects undergoing TAVR and has been 
demonstrated as single, independent predictor of stroke during the subacute phase after 
TAVR (13). Rivaroxaban has been approved for stroke prevention in non-valvular AF based 
on the positive results from the ROCKET AF trial (52), investigating rivaroxaban compared 
to VKA. In ROCKET AF a NI margin of 1.46 was applied but for a much lower event rate
(2.2% per 100 patient years) than the one expected post-TAVR.
Taking into consideration both the historical NI margins used in TAVR trials together with 
the expected high event rates and the considerable proportion of subjects with NOAF after 
randomization, a non-inferiority margin of 1.20 was chosen for this study.
10.5.
Planned interim analyses
This section was modified with Amendment 3. For details, see Section 15.2.
No formal interim analysis is planned.
11.
Data handling and quality assurance
11.1.
Data recording
This section was modified with Amendment 3. For details, see Section 15.2.
The data collection tool for this study is a validated electronic data capture system called 
MARVIN (XClinical).
Data required according to this protocol are recorded by investigational site personnel via 
data entry into the internet based eCRF system, which Cardialysis (CRO) licenses from 
XClinical. MARVIN is validated by XClinical and Cardialysis for use in its clinical studies. 
MARVIN allows for the application of software logic to set-up data entry screens and data 
checks to ensure the completeness and accuracy of the data entered by the site personnel. 
Cardialysis extensively applies the logic to ensure data are complete and reflect the clinical 
data requirements of the study. Data queries resulting from the application of the software 
logic are resolved by the site personnel. The data are stored at a secure host facility 
maintained by XClinical and will be downloaded by Cardialysis each night. All access to the 
MARVIN system is through a password-protected security system that is part of the 
MARVIN software.
All internal Cardialysis, internal Mount Sinai (ARO), Bayer, and external investigator site 
personnel seeking access must go through a MARVIN training process before they are 
granted access to MARVIN for use in Bayer's clinical studies. Training records are 
maintained.
All personnel with access to the MARVIN system are supported by a Service Desk. The 
Service Desk is staffed with trained personnel to answer questions and ensure access is 
maintained such that data entry can proceed in a timely manner.


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The MARVIN System contains a system-generated audit trail that captures any changes made 
to a data field, including who made the change, why the change was made, the date, and time 
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the MARVIN eCRF screens are supported by source documents maintained 
for all subjects enrolled in this study.
Source documentation
It is the expectation of the sponsor that key data entered into the eCRF has source 
documentation available at the site. 
Study-specific data not needed for the subject’s routine medical care (e.g. scores or 
questionnaires) may be entered directly into the eCRF, without availability of corresponding 
source documentation.
The site must implement processes to ensure availability of all required source 
documentation. A source document checklist (not part of this protocol) will be used at the site 
to identify the source data for key data points collected and the monitor will work with the 
site to complete this.
Data recorded from screening failures
Data of 'only screened subjects' will be recorded at least as source data, as far as the reason 
for the screening failure is identifiable.  At minimum, the following data should be recorded 
in the eCRF:

Demographic information (SID number; year of birth / age; sex; if applicable race / 
ethnicity)

Date of IC

Reason for failure of screening

Date of last visit
If a subject is deemed a screening failure, all SAEs experienced during the screening period 
are documented and reported as described in Section 9.6.1.4 and 9.6.1.6.
11.2.
Monitoring
This section was modified with Amendment 3. For details, see Section 15.2.
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s/ARO’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
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes)


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
Safety and rights of subjects are being protected

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.
11.3.
Data processing
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures.  This is applicable for data recorded on eCRF as well as for data from other 
sources (e.g. IxRS, laboratory, ECG, adjudication committees).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
11.4.
Missing data
Every effort will be undertaken to enhance completeness of data.
In time-to-event analysis subjects who have intentionally terminated follow-up will be 
censored at the time of the efficacy cut-off date. If loss-to-follow-up occurs, follow-up will be 
censored at the last date of known clinical outcome status.
Unless otherwise specified in the statistical analysis plan, no statistical techniques will be 
used to impute missing data for continuous or categorical variables. The number of subjects 
included in each analysis will be reported so that the reader can assess the potential impact of 
missing data.
11.5.
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.


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11.6.
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.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
This section was modified with Amendment 3. For details, see Section 15.2.
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due but not limited to 
the following reasons:

If benefit-risk ratio becomes unacceptable owing to, for example,

Safety findings from this study (e.g. SAEs)
The DSMB will have the responsibility for recommending early termination of 
the study to the Steering Committee and the sponsor, which will have ultimate 
authority/responsibility for making the decision. The criteria that the DSMB 
will follow to determine whether/when to recommend termination of the study 
will be detailed in DSMB charter (separate document).

Results of parallel clinical studies

Results of parallel animal studies
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).

If the study conduct (e.g. recruitment rate; data quality; protocol compliance) does 
not suggest a proper completion of the trial within a reasonable time frame.
The investigator has the right to close his/her center at any time.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties.  Final 
decision on the closure must be in writing.

All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.


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
All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor. The investigator will retain all other documents until 
notification is given by the sponsor for destruction.

In the event of a partial study closure, ongoing subjects, including those in any 
post-study follow-up, must be taken care of in an ethical manner.
Details for individual subject's withdrawal from the study can be found in Section 6.3 .
13.
Ethical and legal aspects
13.1.
Investigator(s) and other study personnel
13.1.1.
Committees
A Steering Committee will have overall responsibility for the conduct and reporting of the 
study as defined under the Steering Committee Charter. This committee will meet as needed.
An independent Data Safety Monitoring Board (DSMB) will be commissioned for this study. 
This committee will monitor the progress of the study and ensure that the safety of subjects is 
not compromised. Any recommendations from the DSMB will be made available to the 
Steering Committee.
An independent Clinical Endpoint Committee (CEC) blinded to treatment allocation will 
apply the protocol definitions and adjudicate and classify the defined efficacy and safety 
endpoints. These adjudicated endpoints will form the basis for the final study analyses.
Separate charters will be prepared for all study committees overseeing the study including the 
personnel, responsibilities, procedures, and meeting frequencies.
The protocol allows performance of “local” ancillary studies aimed at investigating 
underlying mechanisms of action. Ancillary studies will be fully documented in separate 
protocol annexes and must be approved by the Steering Committee and its local IRB/IEC.
13.1.2.
Other study personnel
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; 
an abbreviated version with personnel relevant for the centers will be available in each 
center’s investigator site file.
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 page and must 
receive all required external approvals (e.g. health authority, ethics committee, sponsor) 
before subject recruitment may start at the respective center. Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.


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The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
13.2.
Funding and financial disclosure
Funding
This study will be funded by its sponsor.
Financial disclosure
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements.  All relevant documentation will be filed in the 
trial master file.
13.3.
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 
Good Clinical Practice (GCP) guidelines and 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 IEC(s)/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 (or its affiliate/CRO).  The 
responsible unit (e.g. IEC/IRB, head of the study center/medical institution) must provide to 
the sponsor (or its affiliate/CRO), upon request, a list of the EC/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 of 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 may 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 subjects 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 
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 12.


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13.4.
Subject information and consent
All relevant information on the study will be summarized in an integrated subject information 
sheet and IC form provided by the sponsor or the study center. The sample of subject 
information sheet and IC form is provided as a document separate to this protocol.
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to the potential eligible subject, 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 IRB/IEC has been obtained.
Each subject will be informed about the following aspects of premature withdrawal:

Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.

The subject’s consent covers post-treatment period examinations as specified in the 
visit description described in Section 9.1 and 9.2.2 to be conducted after 
withdrawal of consent.

The subject’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the statistical analysis plan.

Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen 
such as blood, urine or tissues); these data would also be retained and statistically 
analyzed in accordance with the statistical analysis plan.  The subject has the right 
to object to the generation and processing of this post-withdrawal data.  For this, 
he/she needs to sign a corresponding declaration of objection; alternatively, the 
subject’s oral objection may be documented in the subject’s source data.
Each subject will have ample time and opportunity to ask questions.
Only if the subject voluntarily agrees to sign the IC form and has done so, may he/she enter 
the study.  Additionally, the investigator (or designee) will personally sign and date the form.  
The subject will receive a copy of the signed and dated form.
The signed IC 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 IC is obtained on the date that baseline study procedures are performed, the 
study record or subject´s clinical record must clearly show that IC was obtained prior to these 
procedures.
If allowed by subject, his/her General Practitioner (GP) will be informed of the subject’s 
participation in the trial by means of a letter from the investigator (included in the subject 
information sheet package). Information will be included on the treatment strategies as well 
as on specific clinical assessments that must come to the attention of the study center before 
subject’s treatment is modified (such as, NOAF is detected).The IC form and any other 
written information provided to subjects will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an amendment to 


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the protocol that requires a change to the content of the subject information and / or the 
written IC form.  The investigator will inform the subject of changes in a timely manner and 
will ask the subject to confirm his/her participation in the study by signing the revised IC 
form. Any revised written IC form and written information must receive the IEC/ IRB`s 
approval / favorable opinion in advance of use.
13.5.
Publication policy and use of data
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations. The sponsor is interested in the publication of the 
results of every study it performs.
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study. However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission. To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.
13.6.
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.
13.7.
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the sponsor. Only the subject number will be recorded 
in the eCRF, and if the subject name appears on any other document (e.g. pathologist report), 
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 IC process, the subjects 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 subject’s identity will remain confidential.
The investigator will maintain a list to enable subjects to be identified.


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special contribution of the European Heart Rhythm Association. Eur Heart J. 
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15.
Protocol amendments
15.1.
Amendment 1
Amendment 1 is dated 28 SEP 2015.
15.1.1.
Overview of changes
15.1.1.1.
Modification 1: IMP/NIMP terms removed from protocol
Reference to investigational and non-investigational medicinal products (IMP and NIMP) 
was removed because of different local requirements in the participating countries. 
Sections affected by this modification:

Synopsis

Section 7.1 Treatments to be administered

Section 7.2 Identity of study treatment

Section 7.2.1 Rivaroxaban

Section 7.2.2 Clopidogrel, ASA and VKA
15.1.1.2.
Modification 2: Clarification on supply of standard-of-care drugs
A sentence was added clarifying the supply and labeling of clopidogrel, ASA and VKA.
Section affected by this modification: Section 7.2.2 Clopidogrel, ASA and VKA.
15.1.2.
Changes to the protocol text
15.1.2.1.
Synopsis
This section was changed as a result of Modification 1.
Deleted text:
Dose(s)
[...] In this strategy, rivaroxaban is considered the 
investigational medicinal product (IMP) and ASA is considered 
as a non-investigational medicinal product (NIMP).
Deleted text:
Dose(s)
[...] In this strategy clopidogrel, ASA and VKA are considered 
as a NIMP.


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15.1.2.2.
Section 7.1 Treatments to be administered
This section was changed as a result of Modification 1.
Old text:
Study treatment assignment will be open-label. Study treatments consist of the IMP 
(rivaroxaban) and in addition of the NIMPs (clopidogrel, ASA, VKA) which are 
systematically prescribed to TAVR subjects in accordance to the relevant guidelines (8, 30, 
33).
New text:
Study treatment assignment will be open-label. Study treatments consist of rivaroxaban and 
in addition of the standard of care treatments clopidogrel, ASA, and VKA, which are 
systematically prescribed to TAVR subjects in accordance to the relevant guidelines and 
routine clinical practice (8, 30, 33).
15.1.2.3.
Section 7.2 Identity of study treatment
This section was changed as a result of Modification 1.
Old text:
Rivaroxaban is the investigational medicinal product (IMP) and as such will be labeled 
according to the requirements of local law and legislation.
New text:
Rivaroxaban will be labeled according to the requirements of local law and legislation.
15.1.2.4.
Section 7.2.1 Rivaroxaban
This section was changed as a result of Modification 1.
Old text:
Tablets are for oral use. Rivaroxaban is part of the rivaroxaban-based treatment strategy and 
also the study’s investigational medicinal product (IMP).
New text:
Tablets are for oral use. Rivaroxaban is part of the rivaroxaban-based treatment strategy.
15.1.2.5.
Section 7.2.2 Clopidogrel, ASA and VKA
This section was changed as a result of Modifications 1 and 2.
Old text:
Clopidogrel, ASA, and VKA are NIMPs and as such will be supplied from local investigative 
centers’ resources and will be used according to the product labeling for the approved 
formulations. 
New text:
Clopidogrel, ASA and VKA will be supplied from local investigative centers’ resources and 
will be used according to the product labeling for the approved formulations. If required by 


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local regulations, Bayer will purchase these drugs from local commercial sources, and label 
and distribute to the investigational site.
15.2.
Amendment 3
15.2.1.
Overview of changes
15.2.1.1.
Modification 1: Clarify the timing of the first dose of rivaroxaban
Clarification was made when to start rivaroxaban for the subjects who are not on clopidogrel
(ie, at the time of randomization).  The timing of the start of rivaroxaban for the subjects who 
are on clopidogrel was changed from 24-72 hours to 1 to 3 days because of logistical 
concerns regarding the counting of hours.  Timing in relation to TAVR was added in case the 
start of the study medication is on the next day after TAVR.
Sections affected by this modification:

Synopsis

Section 5.2  Study plan

Section 7.1.1  Rivaroxaban-based strategy (experimental strategy)
15.2.1.2.
Modification 2: Revision of TAVR inclusion criterion
Subjects eligible for inclusion are those with successful TAVR of a native aortic valve 
stenosis with any approved/marketed device. This has been revised to also include valve-in-
valve replacements. The word native is deleted to allow inclusion of subjects with previous 
TAVR device implanted or subjects with a surgical aortic valve replacement with a non-
metallic valve device. Non native aortic stenosis subjects that undergo a novel successful 
TAVR procedure and may also benefit to receive a rivaroxaban based strategy.
Clarifications were also made to the definition of a successful TAVR.  The peak transvalvular 
velocity requirement was reworded to be consistent with the eCRF.  Text was added to clarify 
that successful TAVR includes the absence of any type of periprocedural stroke as 
hemorrhagic stroke and ischemic stroke are both clearly addressed in specific exclusion 
criteria.
Sections affected by this modification: 

Synopsis

Section 5.2 Study plan

Section 6.1 Inclusion criteria
15.2.1.3.
Modification 3:  Clarification to the DAPT exclusion criteria
The exclusion criterion was revised because it was not clear to the sites that patients with 
indication of DAPT cannot be randomized because DAPT cannot be kept in rivaroxaban-
based strategy.  The new text clarifies that if the patient has a recommendation of ongoing 
use of DAPT at the time of screening, the patient is not eligible for GALILEO, because the 


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patient has a 50% chance to be randomized to rivaroxaban-based strategy, which does not 
allow the concomitant use of DAPT.
Sections affected by this modification: 

Synopsis

Section 6.2 Exclusion criteria
15.2.1.4.
Modification 4:  Timing of assessments
The timing of randomization has been changed from 2-7 days after a successful TAVR to 1-7 
days after the procedure.  Recent data published regarding TAVR being an option for 
intermediate risk patients leads to a broader indication of TAVR and patients with lower risk 
are discharged from the hospital earlier.  This change reflects current clinical practice.  
“Calendar” was removed when specifying days.
Text was modified for consistency to specify that the screening is 1-7 days post-TAVR rather 
than 1-7 days prior to randomization.
In addition, “Study Day 0” (ie, baseline/randomization) has been deleted because it was 
confusing to the sites.
Clarification was added to specify the timing of visits is from randomization.
Other minor clarifications were made.
Sections affected by this modification: 

Synopsis

Section 5.1  Study flow diagram

Section 5.2  Study plan

Section 9.1 Tabular schedule of evaluations

Section 9.2.1 Screening period (screening and randomization)

Section 9.2.2 Planned treatment period
15.2.1.5.
Modification 5:  Update the list of abbreviations
Effective in 2015, the International Conference on Harmonization is now known as the 
International Council for Harmonization.
Section affected by this modification: 

List of abbreviations
15.2.1.6.
Modification 6:  Allowance of subjects with history of prostate cancer 
to participate 
The criterion excluding subjects from the study with active malignancies has been revised to 
allow subjects with non-active prostate cancer to participate in the study.  Due to the elderly 
population expected in this study, it is anticipated that some subjects will have a history of 
prostate cancer.


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Section affected by this modification: 

Section 6.2  Exclusion criteria
15.2.1.7.
Modification 7:  Clarification made to the recording and use of prior 
and concomitant medications
Clarification was made which medications should be recorded in the eCRF, including
medications used prior and during TAVR.  Also, for some of the disallowed therapies, 
specification was added as to which study treatment strategy they apply to.
Section affected by this modification: 

Section 8.1  Prior and concomitant therapy
15.2.1.8.
Modification 8: Text added to visit 1 – baseline / randomization
For the 12-lead ECG required at Visit 1, the underlined text was added: “12-lead 
electrocardiogram (ECG) or any other method documenting heart rhythm (e.g. ECG strip) 
able to exclude atrial fibrillation” to guarantee that atrial fibrillation is excluded by the time 
of randomization, in case the 12-lead ECG was not performed close to randomization.
Section affected by this modification: 

Section 9.2.1 Screening period (screening and randomization)
15.2.1.9.
Modification 9:  An end of study visit has been added
An end of study visit has been added, which will be done once the 440 outcomes are reached.
This visit will be performed for subjects who early permanently discontinue the study 
medication and had the expectation to keep the regular scheduled visits as planned by the 
time of study drug discontinuation. This visit will also be performed for subjects who 
withdraw consent and allow collection of further information.
GALILEO is an event-driven study and the statistical analysis is based in the intention-to-
treat (ITT) principle. ITT analysis includes every subject who is randomized according to 
randomized treatment assignment. A better application of the ITT approach is possible if 
complete outcome data are available for all randomized subjects. That is why it is so 
important to guarantee that all randomized patients, regardless of the study drug intake, are 
assessed by the end of study at least regarding safety/efficacy outcomes and SAEs/AE of 
special interest, especially those subjects that early permanent discontinue the study drug. 
Therefore, the addition of an end of study visit has the purpose to minimize missing data 
regarding safety and efficacy events and guarantee that high quality data are delivered as the 
analysis set will be based in the ITT approach.
Sections affected by this modification: 

Section 9.1  Tabular schedule of evaluations

Section 9.2.3  Post-treatment period


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15.2.1.10. Modification 10:  Laboratory testing at screening
Specification was added that the testing of total bilirubin and its components will be 
performed in the case of elevated total bilirubin, because the evaluation of conjugated and/or
unconjugated fractions when total bilirubin is within normal range is not clinically 
significant. Laboratory test results evaluated during screening can derive from the standard 
of care. 
A provision was added to allow the use of liver test results collected before TAVR procedure 
as long as performed as part of the standard of care for the index-TAVR procedure. This 
change aims to clarify the time window of the collection of the test as standard of care before 
and after TAVR procedure. 
Specification was added that laboratory tests that are performed as part of routine medical 
practice are acceptable as long as they are done after the TAVR procedure and before 
randomization.  A sentence was deleted specifying that all clinical laboratory results 
performed during screening are used to confirm eligibility for randomization, as some of the 
liver function tests are not directly used to confirm eligibility.  Clarification as to the time of 
the measurements was made.
Sections affected by this modification: 

Section 9.1  Tabular schedule of evaluations

Section 9.2.1  Screening period (screening and randomization)

Section 9.6.3.1  Laboratory evaluations
15.2.1.11. Modification 11:  Purpose of physical examination added
Wording was added to clarify that the purpose of the physical examinations is to investigate 
any occurrence of a safety or efficacy outcome.
Section affected by this modification: 

Section 9.1  Tabular schedule of evaluations
15.2.1.12. Modification 12:  Revision of statistical methods
To the stopping criterion (reaching 440 efficacy events) “or earlier if the event rate is 
unexpectedly low” was added.
Rationale: To enable regular ending of the study in case the rate of efficacy outcomes is much 
lower than expected and the time to reach 440 events would be estimated markedly later than 
beginning of 2018. For a reasonable time point to stop the study the observed overall event 
rate and the overall time at risk (of all patients) will be considered. The treatment effect will 
be assumed to be as in the planning assumption (see determination of sample size). It was 
also considered that the prolongation of the FU time may lead to a dilution of the treatment 
effect, especially in case of study drug discontinuation and treatment switch.
Statistical method was changed to test for superiority of the primary efficacy endpoint using 
log-rank test. 


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Rationale: updated text has been implemented to comply with this Bayer standard, which is 
to be used for one-sided superiority tests in time-to-event analyses.
The text “with the Cox proportional hazard model” was deleted. Reason: Cox proportional 
hazard model described in the synopsis can lead to misleading interpretation of how the 
primary endpoints will be evaluated regarding the changes in the statistical session in this 
protocol amendment.
The text “the primary safety endpoint (PBE) is tested for non-inferiority with a hazard ratio 
NI margin at 1.50 using the ITT approach” was deleted.  Rationale: In response of the FDA 
advise letter, it was committed to remove the non-inferiority margin for the primary safety 
endpoint, as it was agreed that rate of acceptable bleeding is dependent on the magnitude of 
treatment benefit (if any) and the treatment benefit will not be known until the study is 
concluded and analyzed.
The text “therefore, the sample size may be increased if planning assumptions are modified 
based on blinded data review.” was deleted. Rationale: as there will be no formal interim 
analysis, the deleted text is obsolete.
Data scope after NOAF (post-NOAF analysis): The text “i.e. EOT visit performed” was 
deleted.
Rationale: The deletion of this sentence was required because it may not be applicable for 
subjects that early permanently discontinued study drug and will require an end of study visit 
(added in this protocol amendment).
Power analysis for safety was deleted. Rationale: As per FDA letter of advice, there are no 
useful data for establishing an NI margin for primary safety endpoint.
Sections affected by this modification: 

Synopsis 

Section 4.1 Primary objective(s)

Section 5.1  Study flow diagram

Section 5.3.3  Other variable(s)

Section 9.1  Tabular schedule of evaluations

Section 9.2.2  Planned treatment period

Section 10 Statistical methods and determination of sample size
15.2.1.13. Modification 13:  Exclusion of planned interim analysis
The interim analysis has been removed. An interim analysis after day 270 of the last patient 
does not seem feasible/meaningful any more with the new recruitment plan. The study may 
even end earlier. 
An interim analysis after 300 events may be only 3-4 month before the regular study end and 
not much can be gained by stopping early.


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The interim analysis would not affect recruitment. And an early termination of the study 
seems only desirable in case of a negative risk-benefit assessment. In that case the DSMB can 
intervene at any time.
Sections affected by this modification: 

Section 10.5  Planned interim analyses

Section 12  Premature termination of the study
15.2.1.14. Modification 14:  Minor editorial/consistency/clarification/ 
administrative changes
Sections affected by this modification: 

Signature of the sponsor’s medically responsible person

Section 7.6  Drug logistics and accountability

Section 9.1  Tabular schedule of evaluations

Section 9.2.1  Screening period (screening and randomization)

Section 16.2  Definition of terms
15.2.1.15. Modification 15:  Text updated to account for local legal requirements
Subjects’ general practitioners will be notified of their participation in the trial if required by 
local legal requirements.
Section affected by this modification: 

Section 9.2.1  Screening period (screening and randomization)
15.2.1.16. Modification 16:  CRO and ARO specification
Specification has been added to clarify that Cardialysis is the CRO for the study and Mount 
Sinai is the ARO for the study.
Sections affected by this modification: 

List of abbreviations

Section 7.6  Drug logistics and accountability

Section 11.1  Data recording

Section 11.2  Monitoring
15.2.2.
Changes to the protocol text
In this section, all sections affected by the amendment are shown in sequence following the 
previous protocol version.  Administrative, and minor editorial and formatting changes are 
not shown.  Deletions to the protocol text are crossed out; additions are underlined.


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15.2.2.1.
Signature of sponsor’s medically responsible person
This section was changed as a result of Modification 14.
Old text: 
Name:
 
Role:  
  
New text:
Name:
Role:  
  
15.2.2.2.
Synopsis
This section was changed as a result of Modifications 1, 2, 3, 4, and 12.
Old text:
Study objective(s)
To assess whether a rivaroxaban-based anticoagulation strategy, 
following successful TAVR, compared to an antiplatelet-based 
strategy, is superior in reducing death or first thromboembolic 
events (DTE).
To assess whether a rivaroxaban-based strategy, following 
TAVR, compared to an antiplatelet-based strategy, is non-
inferior towards primary bleeding events (PBE).
New text:
Study objective(s)
To assess whether a rivaroxaban-based anticoagulation strategy, 
following successful TAVR, compared to an antiplatelet-based 
strategy, is superior in reducing death or first thromboembolic 
events (DTE).
To assess the primary bleeding events (PBE) of the rivaroxaban-
based strategy, following TAVR, compared to an antiplatelet-
based strategy.
PPD
PPD
PPD
PPD


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Old text:
Duration of treatment
The first dose of rivaroxaban (10 mg once-daily) is given either 
immediately after randomization or within 24-72 hours after the 
last intake of clopidogrel.   Rivaroxaban 10 mg once-daily can 
be taken with or without food. ASA 75-100 mg once-daily is to 
be continued unchanged or started immediately after 
randomization if not already being taken. ASA is discontinued 
after 90 days from randomization. Rivaroxaban is continued 
until the efficacy cut-off date, i.e. when the predefined number 
of efficacy endpoints is reached. In the event of NOAF the dose 
of rivaroxaban is switched from 10 mg once-daily to 20 or 15 
mg once-daily, depending on renal function. Rivaroxaban 20 and 
15 mg once-daily should be taken with food. Up to 90 days after 
randomization, ASA 75-100 mg once-daily is to be continued 
unchanged. After 90 days from randomization, ASA is 
discontinued and rivaroxaban 20 or 15 mg once-daily is 
continued alone until the efficacy cut-off date.
New text:
Duration of treatment
The first dose of rivaroxaban (10 mg once-daily) is started at the 
time of randomization if the subject is not on clopidogrel or 
within 1-3 days after the last intake of clopidogrel.  In case 
study medication is started the next day post-TAVR, study 
medication should not be started earlier than the time the TAVR 
was done on the previous day and the subject should be 
stabilized and complication or bleedings should have been 
excluded carefully.   Rivaroxaban 10 mg once-daily can be taken 
with or without food. ASA 75-100 mg once-daily is to be 
continued unchanged or started immediately after randomization 
if not already being taken. ASA is discontinued after 90 days 
from randomization. Rivaroxaban is continued until the efficacy 
cut-off date, i.e. when the predefined number of efficacy 
endpoints is reached or earlier if the event rate is unexpectedly 
low. In the event of NOAF the dose of rivaroxaban is switched 
from 10 mg once-daily to 20 or 15 mg once-daily, depending on 
renal function. Rivaroxaban 20 and 15 mg once-daily should be 
taken with food. Up to 90 days after randomization, ASA 75-100 
mg once-daily is to be continued unchanged. After 90 days from 
randomization, ASA is discontinued and rivaroxaban 20 or 15 
mg once-daily is continued alone until the efficacy cut-off date.
Old text:
Diagnosis and main criteria for 
inclusion /exclusion
Key inclusion criteria:

Successful TAVR of a native aortic valve stenosis


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….
Key exclusion criteria:
….

Any indication for dual-antiplatelet therapy (DAPT) 
for more than 3 months after randomization (such as 
coronary, carotid or peripheral stent implantation)
….
Screening, IC and randomization:
Subjects are screened for inclusion after TAVR. Consenting 
subjects must be randomized within 2-7 days after a successful 
TAVR and before hospital discharge.
New text:
Diagnosis and main criteria for 
inclusion /exclusion
Key inclusion criteria:

Successful TAVR of an aortic valve stenosis (either 
native or valve-in-valve)
….
Key exclusion criteria:
….

Any ongoing absolute indication for dual antiplatelet 
therapy (DAPT) at time of screening that is unrelated to 
the TAVR procedure
….
Screening, IC and randomization:
Subjects are screened for inclusion after TAVR. Consenting 
subjects must be randomized within 1-7 days after a successful 
TAVR and before hospital discharge.
Old text:
Methodology
The primary comparison will be to test the superiority of a 
rivaroxaban-based strategy to an antiplatelet-based strategy with 
respect to the primary efficacy endpoint. This comparison is 
preceded by a non-inferiority test that must be satisfied.
Further, non-inferiority of a rivaroxaban-based strategy to an 
antiplatelet-based strategy towards the primary safety endpoint 
will be tested.


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New text:
Methodology
The primary comparison will be to test the superiority of a 
rivaroxaban-based strategy to an antiplatelet-based strategy with 
respect to the primary efficacy endpoint. This comparison is 
preceded by a non-inferiority test that must be satisfied.
Estimates of the hazard ratio for bleeding events together with 
their 95% confidence intervals will be calculated for descriptive 
purposes.
Added text:
Time point/frame of 
measurement for primary 
variable(s)
Subjects are treated and followed from randomization until the 
study ends, i.e. when the predefined number of primary efficacy 
endpoints is reached or earlier if the event rate is unexpectedly 
low and study closure activities are completed. Therefore, the 
duration of the treatment period for a given subject will depend 
on the time required to collect these events. The expected 
duration of the study is 750 days, but depending upon the rate of 
subject recruitment and endpoint event rates it may be adapted. 
Regular assessments are planned to take place during the study.


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Old text:
Plan for statistical analysis
The primary endpoints (for efficacy and for safety) are analyzed 
as a time-to-event endpoint with the Cox proportional hazard 
model, in the full analysis set (FAS) of all randomized subjects.
The primary efficacy endpoint (DTE) is tested for superiority. 
This test is preceded by a non-inferiority (NI) test with a hazard 
ratio NI margin at 1.20 using the on-treatment approach. If non-
inferiority is met, a test for superiority is performed using the 
intention-to-treat (ITT) approach. The primary safety endpoint 
(PBE) is tested for non-inferiority with a hazard ratio NI margin 
at 1.50 using the ITT approach.
New text:
Plan for statistical analysis
The primary endpoints (for efficacy and for safety) are analyzed 
as a time-to-event endpoint, in the full analysis set (FAS) of all 
randomized subjects.
The primary efficacy endpoint (DTE) is tested for superiority
using log-rank test. This test is preceded by a non-inferiority 
(NI) test with a hazard ratio NI margin at 1.20 using the on-
treatment approach. If non-inferiority is met, a test for 
superiority is performed using the intention-to-treat (ITT) 
approach. 
15.2.2.3.
List of abbreviations
This section was changed as a result of Modifications 5 and 16.
Old text:
ICH
International conference on harmonization
New text:
ARO
Academic research organization
ICH
International Council for Harmonization
15.2.2.4.
Section 4.1 Primary objective(s)
This section was changed as a result of Modification 12.
Old text:
….
To assess whether a rivaroxaban-based strategy, following TAVR, compared to an 
antiplatelet-based strategy, is non-inferior towards primary bleeding events (PBE). PBE is 


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defined as the composite of life-threatening, disabling, or major bleeding events and is 
classified according to the VARC definitions following the BARC classification.
New text:
….
To assess the primary bleeding events (PBE) of the rivaroxaban-based strategy, following 
TAVR, compared to an antiplatelet-based strategy.  PBE is defined as the composite of life-
threatening, disabling, or major bleeding events and is classified according to the VARC 
definitions following the BARC classification.
15.2.2.5.
Section 5.1 Study flow diagram
This section was changed as a result of Modifications 4 and 12.
Old text:
Successful transcatheter aortic valve replacement (TAVR) as defined in Section 6.1.
§ The duration of the planned treatment period will depend on the time needed to reach the efficacy 
cut-off date, i.e. to collect the predefined number of efficacy endpoints. The expected duration of the 
treatment is 720 days but may be adjusted depending upon the rate of subject recruitment and 
efficacy event rates.
R, randomization; ASA, acetylsalicylic acid; OD, once-daily.


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New text:
Successful transcatheter aortic valve replacement (TAVR) as defined in Section 6.1.
§ The duration of the planned treatment period will depend on the time needed to reach the efficacy 
cut-off date, i.e. to collect the predefined number of efficacy endpoints or earlier if the event rate is 
unexpectedly low. The expected duration of the treatment is 720 days but may be adjusted depending 
upon the rate of subject recruitment and efficacy event rates.
R, randomization; ASA, acetylsalicylic acid; OD, once-daily.
15.2.2.6.
Section 5.2 Study plan
This section was changed as a result of Modifications 1, 2, and 4.
Old text:
….
The screening period begins after TAVR. Subjects who have successfully undergone a 
TAVR procedure of a native aortic valve stenosis by iliofemoral or subclavian access with 
any approved/marketed device type available in the participating countries are potentially 
eligible for inclusion in the study. ….
….
Randomization must take place within 2-7 days post-TAVR and before hospital discharge. 
Randomization is performed by an Interactive Web or Voice Response System (IxRS) and 
stratified by site. Stratification by site is performed to ensure balance across potential local 
differences in treatment practices.
….
The assigned treatment strategy is implemented after randomization without any undue delay
(please refer to Section 7.4).


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Subjects randomized to rivaroxaban-based strategy: In the rivaroxaban-based strategy, 
rivaroxaban is started at the time of randomization if the subject is not on clopidogrel. If the 
subject is treated with clopidogrel, clopidogrel is stopped immediately after randomization 
and rivaroxaban is started within 24-72 hours after the last intake of clopidogrel. ….
New text:
….
The screening period begins after TAVR. Subjects who have successfully undergone a 
TAVR procedure of an aortic valve stenosis (either native or valve-in-valve) by iliofemoral 
or subclavian access with any approved/marketed device type available in the participating 
countries are potentially eligible for inclusion in the study. ….
….
Randomization must take place within 1-7 days post-TAVR and before hospital discharge. 
Randomization is performed by an Interactive Web or Voice Response System (IxRS) and 
stratified by site. Stratification by site is performed to ensure balance across potential local 
differences in treatment practices.
….
The assigned treatment strategy is implemented after randomization (please refer to Section 
7.4).
Subjects randomized to rivaroxaban-based strategy: In the rivaroxaban-based strategy, 
rivaroxaban is started at the time of randomization if the subject is not on clopidogrel. If the 
subject is treated with clopidogrel, clopidogrel is stopped immediately after randomization 
and rivaroxaban is started within 1-3 days after the last intake of clopidogrel. In case study 
medication is started the next day post-TAVR, study medication should not be started earlier 
than the time the TAVR was done on the previous day and the subject should be stabilized 
and complication or bleedings should have been excluded carefully. ….
15.2.2.7.
Section 5.3.3  Other variable(s)
This section was changed as a result of Modification 12.
Old text:
….
The primary completion event for this study occurs when the 440th subject experiences a 
positively adjudicated primary efficacy endpoint. The efficacy cut-off date is defined as the 
date of the primary completion event.
For practical purposes, the anticipated efficacy cut-off date is set based on a projection of the 
date of the primary completion event after 400 subjects have experienced a positively 
adjudicated primary efficacy endpoint. When the anticipated efficacy cut-off date is set, an
on-site visit will be scheduled for all subjects within 6 weeks. 
….


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New text:
….
The primary completion event for this study occurs when the 440th subject experiences a 
positively adjudicated primary efficacy endpoint or earlier if the event rate is unexpectedly 
low. The efficacy cut-off date is defined as the date of the primary completion event.
For practical purposes, the anticipated efficacy cut-off date is set based on a projection of the 
date of the primary completion event before 400 subjects have experienced a positively 
adjudicated primary efficacy endpoint. When the anticipated efficacy cut-off date is set, on-
site visit will be scheduled for all subjects within 6 weeks. 
….
15.2.2.8.
Section 6.1  Inclusion criteria
This section was changed as a result of Modification 2.
Old text:
Potential subjects must satisfy the following criteria to be enrolled in the study:
….

Have a successful TAVR of a native aortic valve stenosis
….
Successful TAVR (29) is defined:
….
2. Intended performance of the prosthetic heart valve - presence of all 3 conditions post-
TAVR:
a.
mean aortic valve gradient < 20 mmHg
b. peak transvalvular velocity < 3.0 m/s
c.
no severe or moderate aortic valve regurgitation
3. Absence of periprocedural complications, such as:
a.
Any type of stroke
….
New text:
Potential subjects must satisfy the following criteria to be enrolled in the study:
….

Have a successful TAVR of an aortic valve stenosis (either native or valve-in-
valve)
….


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Successful TAVR (29) is defined:
….
2. Intended performance of the prosthetic heart valve - presence of all 3 conditions post-
TAVR:
a.
mean aortic valve gradient < 20 mmHg
b. peak transvalvular velocity (aortic valve maximum velocity) < 3.0 m/s
c.
no severe or moderate aortic valve regurgitation
3. Absence of periprocedural complications, such as:
a.
Any type of periprocedural stroke
….
15.2.2.9.
Section 6.2  Exclusion criteria
This section was changed as a result of Modifications 3 and 6.
Old text:
Subjects are NOT eligible to participate in this trial if they meet ANY of the following 
exclusion criteria:
….
Concomitant and study medication
4. Any indication for dual-antiplatelet therapy (DAPT) for more than 3 months after 
randomization (such as coronary, carotid or peripheral stent implantation)
….
Concomitant conditions
….
15. Active malignancy (diagnosed within 5 years) except for adequately treated non-
melanoma skin cancer or other non-invasive or in situ neoplasm (e.g., cervical cancer in 
situ that has been successfully treated)
New text:
Subjects are NOT eligible to participate in this trial if they meet ANY of the following 
exclusion criteria:
….
Concomitant and study medication
4. Any ongoing absolute indication for dual-antiplatelet therapy (DAPT) at time of 
screening that is unrelated to the TAVR procedure
….


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Concomitant conditions
….
15. Active malignancy (diagnosed within 5 years) except for adequately treated non-
melanoma skin cancer or other non-invasive or in situ neoplasm (e.g., cervical cancer in 
situ that has been successfully treated or non-active prostate cancer)
15.2.2.10. Section 7.1.1  Rivaroxaban-based strategy (experimental strategy)
This section was changed as a result of Modification 1.
Old text:
….
The first dose of rivaroxaban is given immediately after randomization
or within 24-72 hours after the last intake of clopidogrel. ….
New text:
….
The first dose of rivaroxaban is given at the time of randomization if 
the subject is not on clopidogrel or within 1-3 days after the last intake 
of clopidogrel. In case study medication is started the next day post-
TAVR, study medication should not be started earlier than the time the 
TAVR was done on the previous day and the subject should be 
stabilized and complication or bleedings should have been excluded 
carefully.….
15.2.2.11. Section 7.6  Drug logistics and accountability
This section was changed as a result of Modifications 14 and 16.
Old text:
Rivaroxaban will be stored at the investigational site in accordance with GCP and GMP 
requirements and according to the instructions given by the clinical supplies department of 
the sponsor (or its affiliate/CRO), and will be inaccessible to unauthorized personnel. Special 
storage conditions and a complete record of batch numbers and expiry dates can be found in 
the sponsor’s study file; the site-relevant elements of this information will be available in the 
investigator site file.  On the day of receipt, the responsible site personnel will confirm 
receipt of rivaroxaban via IxRS.  The study personnel will use rivaroxaban only within the 
framework of this clinical study and in accordance with this protocol. Receipt, distribution, 
return, and destruction (if any) of rivaroxaban must be properly documented according to the 
sponsor’s agreed and specified procedures.  Re-supply of rivaroxaban can be initiated 
through the IxRS module in the eCRF.
New text:
Rivaroxaban will be stored at the investigational site in accordance with GCP and GMP 
requirements and according to the instructions given by the clinical supplies department of 
the sponsor (or its affiliate/CRO/academic research organization [ARO]), and will be 
inaccessible to unauthorized personnel. Special storage conditions and a complete record of 


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batch numbers and expiry dates can be found in the sponsor’s study file; the site-relevant 
elements of this information will be available in the investigator site file.  On the day of 
receipt, the responsible site personnel will confirm receipt of rivaroxaban via IxRS.  The 
study personnel will use rivaroxaban only within the framework of this clinical study and in 
accordance with this protocol. Receipt, distribution, return, and destruction (if any) of 
rivaroxaban must be properly documented according to the sponsor’s agreed and specified 
procedures.  Re-supply of rivaroxaban is automatically initiated through the IxRS module in 
the eCRF.
15.2.2.12. Section 8.1  Prior and concomitant therapy
This section was changed as a result of Modification 7.
Old text:
All medications (prescription and over-the-counter), including adjunct therapy or medical 
devices, will be recorded in the appropriate section of the eCRF throughout the study.  
….

Medicines that reduce gastric acid (e.g., H-2 antagonists or proton pump inhibitors 
[PPIs]) may reduce the incidence of GI bleeding in subjects’ post-TAVR who are 
treated with antithrombotics and unless contraindicated their use is recommended. 
The choice of gastric protection drugs (such as pantoprazole) is at the discretion of 
the treating physician. PPIs that interact with cytochrome P450 2C19 (such as 
omeprazole or esomeprazole) are disallowed.
Concomitant use (with study treatment strategies) of the following therapies is disallowed
during the study:

Single or dual antiplatelet therapy other than assigned study strategy

In the rivaroxaban-based strategy use of P2Y12 inhibitors in combination with 
rivaroxaban.

In the antiplatelet-based strategy, the use of a P2Y12 inhibitor for > 3 months (> 
90 days) after randomization.

VKA other than the assigned study strategy and low molecular weight or 
unfractionated heparin if used for reasons other than short-term bridging of VKA 
therapy until the target INR is established.

Factor IIa inhibitors and factor Xa inhibitors other than the study medication

Systemic treatment with drugs that are strong inhibitors of both CYP 3A4 and P-gp 
(azole antimycotics such as ketoconazole and itraconazole or HIV protease 
inhibitors such as ritonavir). The azole antimycotic fluconazole, a moderate CYP 
3A4 inhibitor, has however less effect on rivaroxaban exposure and can be co-
administered.

Systemic treatment with drugs that are strong CYP3A4 inducers (e.g. 
carbamazepine, phenytoin, rifampin, St. John’s wort).


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
Concomitant therapy with omeprazole or esomeprazole that cannot be switched to 
an alternative medication.
….
New text:
All ongoing medications at screening and used during the study (prescription and over-the-
counter), including adjunct therapy or medical devices, will be recorded in the appropriate 
section of the eCRF throughout the study.  Use of ASA and clopidogrel or any other P2Y12 
inhibitor prior and during TAVR procedure should also be recorded.
….

Medicines that reduce gastric acid (e.g., H-2 antagonists or proton pump inhibitors 
[PPIs]) may reduce the incidence of GI bleeding in subjects’ post-TAVR who are 
treated with antithrombotics and unless contraindicated their use is recommended. 
The choice of gastric protection drugs (such as pantoprazole) is at the discretion of 
the treating physician. PPIs that interact with cytochrome P450 2C19 (such as 
omeprazole or esomeprazole) are disallowed in the antiplatelet-based strategy, 
during concomitant use of clopidogrel.
Concomitant use (with study treatment strategies) of the following therapies is disallowed
during the study:

Single or dual antiplatelet therapy other than assigned study strategy

VKA other than the assigned study strategy and low molecular weight or 
unfractionated heparin if used for reasons other than short-term bridging of VKA 
therapy until the target INR is established

Factor IIa inhibitors and factor Xa inhibitors other than the study medication

In the rivaroxaban-based strategy concomitant use of 
o
P2Y12 inhibitors in combination with rivaroxaban 
o
During concomitant use of rivaroxaban systemic treatment with drugs that 
are strong inhibitors of both CYP 3A4 and P-gp (azole antimycotics such 
as ketoconazole and itraconazole or HIV protease inhibitors such as 
ritonavir). The azole antimycotic fluconazole, a moderate CYP 3A4 
inhibitor, has however less effect on rivaroxaban exposure and can be co-
administered. 
o
During concomitant use of rivaroxaban systemic treatment with drugs that 
are strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampin, St. 
John’s wort)

In the antiplatelet-based strategy concomitant use of
o
P2Y12 inhibitor for > 3 months (> 90 days) after randomization
o
Omeprazole or esomeprazole that cannot be switched to an alternative 
medication during concomitant use of clopidogrel 


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15.2.2.13. Section 9.1  Tabular schedule of evaluations
This section was changed as a result of Modifications 4, 9, 10, 11, 12, and 14.
Old text:


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Table 1: Schedule of evaluations
Visit number
1
2
3
4
5
6, 7, (n)
Period
Screening
Planned treatment
Post-
treatment
Visit
Screening
Baseline / 
Randomizationb
On-site 
visit
On-site 
visit
Phone 
call
On-site 
visit
On-site 
visit
On-site 
visit
Phone call
Day
2-7 days a
prior to 
randomization
0
30
90
180 c
360 c
540,720c, z
every 180d 
EOT d
EOT+30d e
Window (day[s])
± 7d
± 15d
± 15d
± 30d
± 30d
d
± 7d
Study Assessments
Informed consent a
X
Demographics f
X
Medical history
X
Prior medication
X
TAVR assessment
X
In /exclusion criteria
X
X
Concomitant medication
X
X
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
Vital signs g
X
X
X
X
X
X
Echocardiogram (TTE 
or TEE) h
X
X
12-lead ECG
X
X
X
X
X
X
Study Medication
Prescribing/dispensing
assigned strategy
X i
X
X
X
X
Treatment strategy 
adjustment j
X


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Visit number
1
2
3
4
5
6, 7, (n)
Period
Screening
Planned treatment
Post-
treatment
Visit
Screening
Baseline / 
Randomizationb
On-site 
visit
On-site 
visit
Phone 
call
On-site 
visit
On-site 
visit
On-site 
visit
Phone call
Day
2-7 days a
prior to 
randomization
0
30
90
180 c
360 c
540,720c, z
every 180d 
EOT d
EOT+30d e
Window (day[s])
± 7d
± 15d
± 15d
± 30d
± 30d
d
± 7d
Transition to other 
therapy
X
Laboratory Assessments (local labs)
Hematology k
X
Liver tests L
X
Renal function m
X
Ongoing study assessments
Efficacy endpoints
X
X
X
X
X
X
X
X
Safety endpoints
X
X
X
X
X
X
X
X
NOAF assessment and 
adjustment of treatment n
X
X
X
X
X
X
X
X
(Serious) AEs o
X
X
X
X
X
X
X
X
X


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a Consenting subjects must be randomized within 2-7 calendar days post-TAVR and before hospital discharge.
b Once randomized, a subject has entered the study and all randomized subjects will be followed until the efficacy cut-off date when the predefined number of 
efficacy endpoints is anticipated, even if they did not take assigned study medication or prematurely discontinued study medication. In case of early 
permanent discontinuation of study medication, all relevant information must be captured in the eCRF as soon as possible after stopping the assigned study 
medication. The timing of on-site visits and of telephone contacts must be kept unchanged.
….
L Liver tests include transaminases (AST/ALT), total bilirubin and its components (conjugated and unconjugated fractions), and alkaline phosphatase.
….
o For details, see Section 9.6.1.4 and 9.6.1.6. Only SAEs or AEs that lead to permanent discontinuation of the assigned study medication are to be reported. The 
investigator must report immediately (within 24 hours of the investigator’s awareness) all (S)AEs as described in Figure 3.


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New text:
Table 1:  Schedule of evaluations
Visit number
1
2
3
4
5
6, 7, (n)
Period
Screening
Planned treatment
Post-
treatment
Visit
Screening
Baseline / 
Randomizationb
On-site 
visit
On-
site 
visit
Phone 
call
On-site 
visit
On-site 
visit
On-site 
visit
Phone 
call
Day
1-7 days a
post-TAVR
30
90
180 c
360 c
540,720c, z
every 180d 
EOT d
EOT+30d e
Window (day[s])
±7d
± 15d
± 15d
± 30d
± 30d
d
± 7d
Study Assessments
Informed consent a
X
Demographics f
X
Medical history
X
Prior medication
X
TAVR assessment
X
In /exclusion criteria
X
X
Concomitant medication
X
X
X
X
X
X
X
X
Physical exam p
X
X
X
X
X
X
Vital signs g
X
X
X
X
X
X
Echocardiogram (TTE 
or TEE) h
X
X
12-lead ECG
X
X
X
X
X
X
Study Medication


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Prescribing/dispensing
assigned strategy
X i
X
X
X
X
Treatment strategy 
adjustment j
X
Transition to other 
therapy
X
Laboratory Assessments (local labs)
Hematology k
X
Liver tests L
X
Renal function m
X
Ongoing study assessments
Efficacy endpoints
X
X
X
X
X
X
X
X
Safety endpoints
X
X
X
X
X
X
X
X
NOAF assessment and 
adjustment of treatment n
X
X
X
X
X
X
X
X
(Serious) AEs o
X
X
X
X
X
X
X
X
X
Vital status
a Consenting subjects must be randomized within 1-7 days post-TAVR and before hospital discharge.
b Once randomized, a subject has entered the study and all randomized subjects will be followed until the efficacy cut-off date when the predefined number of 
efficacy endpoints is anticipated or earlier if the event rate is unexpectedly low, even if they did not take assigned study medication or prematurely discontinued 
study medication. In case of early permanent discontinuation of study medication, all relevant information must be captured in the eCRF as soon as possible 
after stopping the assigned study medication. The timing of on-site visits and of telephone contacts must be kept unchanged.
….
L Liver tests include transaminases (AST/ALT), total bilirubin and its components (conjugated and/or unconjugated fractions) in case of elevated total bilirubin, 
and alkaline phosphatase if available as current standard of care.  Liver test results collected before TAVR procedure can be used as long as performed as 
part of the standard of care for the index-TAVR procedure.
o For detail, See section 9.6.1.4 and 9.6.1.6. Only SAEs, AE of special interest (even if classified as non-serious), or AEs that lead to permanent discontinuation 
of the assigned study medication are to be reported. The investigator must report immediately (within 24 hours of the investigator’s awareness) all (S)AEs as
described in Figure 3.
p  Physical examination aims to investigate any occurrence of a safety or efficacy outcome.


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Added text:
Figure 2: Study treatment flow diagram.
15.2.2.14. Section 9.2.1  Screening period (screening and randomization)
This section was changed as a result of Modifications 4, 10, 14, and 15.
Old text:
…. Please note that if screening procedures are performed as part of routine medical practice 
(e.g. laboratory parameters) these are not required to be repeated as long as they are within 
the screening window.
Screening evaluations are performed after the index-TAVR procedure (between 2 and 7 
calendar days after the subject index-TAVR procedure). All screening procedures are 
completed before randomization on Day 0. Before the IC form is obtained the inclusion and 
exclusion criteria are reviewed to assess the subjects’ eligibility. All clinical laboratory 
results performed during screening are used to confirm eligibility for randomization. 
….
Randomization by IxRS, must take place within 2-7 days post-TAVR, and before hospital 
discharge. The allocated treatment strategy is implemented after randomization without any 
undue delay.
If allowed by the subject, his/her general practitioner (GP) will be informed of the subject’s 
participation in the trial by means of a letter from the investigator. Information will be 
included on the treatment strategies as well as on specific clinical assessments that must come 
to the attention of the investigational study center before subject’s treatment is modified 
(such as, if NOAF is detected).


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Screening (2-7 days prior to randomization)
The following procedures will be performed 2-7 calendar days after the index-TAVR and 
prior to randomization:
….
Visit 1 – Baseline / Randomization - Study Day 0
….

12-lead electrocardiogram (ECG) 
….
The following procedures will be performed 2-7 calendar days after the index-TAVR, after 
randomization and before discharge:
….
New text:
…. Please note that if screening procedures are performed as part of routine medical practice 
(e.g. laboratory parameters) these are not required to be repeated as long as they meet the 
protocol requirements described below.
Hematology tests and renal function results from standard of care can be used as long as 
collected after the index-TAVR procedure and before randomization.  Liver test results 
collected before TAVR procedure can be used as long as performed as part of the standard of 
care for the index-TAVR procedure. Before the IC form is obtained the inclusion and 
exclusion criteria are reviewed to assess the subjects’ eligibility. 
….
Randomization by IxRS, must take place within 1-7 days post-TAVR, and before hospital 
discharge. The allocated treatment strategy is implemented after randomization.
If allowed by the subject or for local legal requirements, his/her general practitioner (GP) will 
be informed of the subject’s participation in the trial by means of a letter from the 
investigator. Information will be included on the treatment strategies as well as on specific 
clinical assessments that must come to the attention of the investigational study center before 
subject’s treatment is modified (such as, if NOAF is detected).
Screening (1-7 days post-TAVR)
The following procedures will be performed 1-7 days after the index-TAVR and prior to 
randomization:
….


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Visit 1 – Baseline / Randomization 
….

12-lead electrocardiogram (ECG) or any other method documenting heart rhythm 
(e.g. ECG strip) able to exclude atrial fibrillation
….
The following procedures will be performed 1-7 days after the index-TAVR, after 
randomization and before discharge:
….
15.2.2.15. Section 9.2.2  Planned treatment period 
This section was changed as a result of Modifications 4 and 12.
Added text:
The duration of the planned treatment period for a given subject will depend on the time 
needed to reach the efficacy cut-off date, i.e. to collect the predefined number of primary 
adjudicated efficacy endpoints in the total study population or earlier if the event rate is 
unexpectedly low. The expected duration of the treatment period is 720 days but may be 
longer or even shorter depending upon the rate of subject recruitment and efficacy event 
rates. Visits are scheduled at 30, 90, 180 days after randomization, and every 180 days 
thereafter until the anticipated efficacy cut-off date is set (see Section 9.1 Tabular schedule of 
evaluations (Table 1)) at which time a final on-site visit will be scheduled. 
15.2.2.16. Section 9.2.3  Post-treatment period 
This section was changed as a result of Modification 9.
Added text:
End of study visit
This visit takes place within 6 weeks of the announcement of the anticipated efficacy cut-off 
date.  
This visit will be performed for subjects who early permanent discontinue the study 
medication and had the expectation to keep the regular scheduled visits as planned by the 
time of study drug discontinuation. This visit will also be performed for subjects who 
withdraw consent and allow collection of further information.
The following procedures will be performed during this visit:

Assess if any efficacy and/or safety endpoints occurred

Vital status, if applicable

Assessment of (S)AEs


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15.2.2.17. Section 9.6.3.1  Laboratory evaluation 
This section was changed as a result of Modification 10.
Old text:
The following local routine laboratory measurements need to be performed post-TAVR and
before randomization.
….

Liver tests
o
Transaminases (AST/ALT)
o
Total bilirubin and components (conjugated and unconjugated 
fractions) 
o
Alkaline phosphatase
New text:
The following local routine laboratory measurements need to be evaluated before 
randomization.
….

Liver tests
o
Transaminases (AST/ALT)
o
Total bilirubin and components (conjugated and/or unconjugated 
fractions in case of elevated total bilirubin)
o
Alkaline phosphatase, if available as current standard of care
….
Laboratory tests results done as part of standard of care can be used.  Hematology tests and 
renal function results from standard of care can be used as long as collected after the index-
TAVR procedure and before randomization. Liver test results collected before TAVR 
procedure can be used as long as performed as part of the standard of care for the index-
TAVR procedure.
15.2.2.18. Section 10.2.2  Data scope 
This section was changed as a result of Modification 12.
Deleted text:
….
Data scope after NOAF (post-NOAF analysis)
The post-NOAF data scope includes all outcome events observed between the treatment 
switch precipitated by NOAF until the efficacy cut-off date (i.e. EOT visit performed).


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15.2.2.19. Section 10.3.4  Subgroup variables
This section was changed as a result of Modification 12.
Added text:
…

Valve-in-valve procedure
15.2.2.20. Section 10.3.5  Planned statistical analysis
This section was changed as a result of Modification 12.
Deleted  text:
10.3.5  Planned statistical analysis
The primary efficacy and safety endpoints are analyzed as a time-to-event endpoint, using the 
Cox proportional hazards model. The validity of the proportional hazards assumption will be 
assessed prior to carrying out the analysis. Kaplan-Meier curves are used to describe the 
occurrence of the primary efficacy endpoint over time.
15.2.2.21. Section 10.3.5  Analysis of the primary efficacy variable
This section was changed as a result of Modification 12.
Old text:
10.3.5.1  Analysis of the primary efficacy variable
The analysis of the primary efficacy variable is performed on the Full Analysis Set (FAS)
under the ITT scope – that is, events are analyzed irrespective of their time of occurrence 
relative to termination of assigned study treatment strategy.  Follow-up is censored at the last 
date of known outcome status or at the efficacy cut-off date, whichever comes first.
New text:
10.3.5  Analysis of the primary efficacy variable
The analysis of the primary efficacy variable is performed on the Full Analysis Set (FAS). 
For superiority analysis the follow-up is censored at the last date of known outcome status or 
at the efficacy cut-off date, whichever comes first. Non-inferiority analysis is carried out 
under the OT data scope, i.e. follow-up is censored at two days after permanent 
discontinuation of the randomized treatment strategy. Censoring is assumed independent of 
the treatment group assignment.
15.2.2.22. Section 10.3.5.1.1  Test for validity of the proportional hazard 
assumption
This section was changed as a result of Modification 12.
Deleted text:
10.3.5.1.1  Test for validity of the proportional hazard assumption


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The validity of the proportional hazards assumption is assessed with the use of the test 
proposed by Grambsch and Therneau on the Schoenfeld residuals (estat ph test) (60).
If the assumption of proportional hazards holds, superiority of the rivaroxaban-based strategy 
for the primary outcome is tested with the use of the Hazard Ratio (HR) and the Cox 
proportional hazards model. The test for superiority is hierarchically preceded by a test for 
non-inferiority with a non-inferiority boundary of 1.20 for the hazard ratio.
In case of rejection of the assumption of proportional hazards for the primary efficacy 
endpoint, superiority of the rivaroxaban-based strategy for the primary outcome is tested with 
the use of the log rank methodology, without any (preceding) testing for non-inferiority.
15.2.2.23. Section 10.3.5.1  Testing for superiority 
This section was changed as a result of Modification 12.
Old text:
10.3.5.1.2  Testing for superiority under the proportional hazards assumption
If the assumption of proportional hazards holds, superiority of the rivaroxaban-based strategy 
for the primary outcome is tested with the use of the hazard ratio (HR) and the Cox
proportional hazards model. The HR(t) at time t is defined as:
HR(t) =  λ(t)rivaroxaban / λ(t)antiplatelet, where λ(t) is the hazard of the primary 
efficacy endpoint, respectively in subjects randomized to the rivaroxaban-based 
strategy and in subjects randomized to the antiplatelet-based strategy.
Under the proportional hazards assumption, λ(t) may vary over time, but the ratio of the two 
hazards is constant.
The following null hypothesis (H0) is tested at a one-sided significance level of 0.025%:
H0: HR(t) = 1 for all time points t ≥ 0, (i.e. “there is no difference between the 
rivaroxaban-based treatment group and the antiplatelet-based control group regarding 
to the hazard (= instantaneous risk) for the primary efficacy endpoint at all time 
points”)
The one-sided alternative hypothesis (H1) is:
H1: HR(t) < 1 for all time points t ≥ 0, (i.e. “there is difference in favor of the 
rivaroxaban-based treatment group for the primary efficacy endpoint at all time 
points”)
The parameter estimate β (=ln(HR), its standard error, p-value, and 95% Confidence Limits 
are calculated according to the maximum partial likelihood method (ML), with Breslow’s 
approximation for ties (phreg).
The following decision rule to test the null hypothesis is applied:
If the z value from the one-sided test for the HR (βML/SE(β)ML) is smaller than the 
critical quantile from the normal distribution (z0.025 = -1.96), the null hypothesis is 
rejected in favor of the alternative hypothesis.


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Or, equivalently, if the 95% Confidence Interval for HR falls below 1.00.
This test is carried out under the ITT data scope (i.e. all events are counted irrespective of the 
actual treatment at the time of the event).
New text: 
10.3.5.1  Testing for superiority
In order to evaluate whether the rivaroxaban-based strategy is superior to the antiplatelet-
based strategy in prolonging the time to primary efficacy outcome event in patients with post-
TAVR patients, the following null hypothesis (H0) is tested at the significance level of 2.5%:
H0: SRIV(t) = SAPT(t) for all time points t ≥ 0, (i.e. “there is no difference between the 
rivaroxaban-based treatment group and the antiplatelet-based control group regarding the 
primary efficacy outcome for all time points”)
The one-sided alternative hypothesis is:
H1: SRIV(t) > SAPT(t) for at least one time point t ≥ 0, and SRIV(t) ≥ SAPT(t) for all time 
points t ≥ 0, (i.e. “there is a difference between the two groups in favor of the rivaroxaban-
based treatment group regarding the primary efficacy outcome for at least one time point“)
where SRIV denotes the event-free survival function of the rivaroxaban-based treatment group 
and SAPT denotes the event-free survival function of the antiplatelet-based treatment group.
The following decision rule to test the null hypothesis is applied:
According to the size of this study, it is justified to assume under H0 a sufficiently close 
approximation of the one-sided log-rank test to the normal distribution. If the z-value from 
the one-sided log-rank test (for the difference SRIV(t) - SAPT(t)) is larger than the critical 
quantile from the normal distribution (z0.975 =1.96), the null hypothesis is rejected in favor 
of the alternative hypothesis.
Kaplan-Meier estimates of cumulative risk and cumulative hazard functions are 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 and corresponding two-sided 95% confidence intervals are estimated based on a 
Cox proportional hazards models. The parameter estimate β (=ln(HR)), its standard error, p-
value, and 95% Confidence Limits are calculated according to the maximum partial 
likelihood method, with Breslow’s approximation for ties (phreg).
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. If there is strong 
evidence of non-proportionality, the estimation of time-dependent hazard ratios will be 
considered.
All of the above analyses are carried out under the ITT data scope (i.e. all events are counted 
irrespective of the actual treatment at the time of the event).
Further details will be specified in SAP.


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15.2.2.24. Section 10.3.5.2  Testing for non-inferiority
This section was changed as a result of Modification 12.
Old text:
10.3.5.1.3  Testing for non-inferiority under the proportional hazards assumption
If the assumption of proportional hazards holds, testing for superiority of the rivaroxaban-
based strategy for the primary efficacy outcome is preceded by testing for non-inferiority 
tested with the use of the hazard ratio (HR) and the Cox proportional hazards model.
The following an (inferiority) null hypothesis (H0) is tested at a one-sided significance level 
of 2.5%:
H0: HR(t) ≥ 1.20 for all time points t ≥ 0, (i.e. “the hazard for the primary efficacy 
endpoint in the rivaroxaban-based treatment group is more than 20% larger than that 
in the antiplatelet-based control group regarding”)
The one-sided alternative hypothesis (H1) is:
H1: HR(t) < 1.20 for all time points t ≥ 0, (i.e. “the hazard in the rivaroxaban-based 
treatment group for the primary efficacy endpoint is such that the HR is below 1.20”)
The following decision rule to test the null hypothesis of inferiority is applied:
If the upper boundary of 95% confidence interval (CI) for HR falls below 1.20, the 
null--hypothesis of inferiority (H0) is rejected and non-inferiority of the rivaroxaban-
based strategy (relative to the antiplatelet-based strategy) with regard to the primary 
efficacy endpoint can be claimed.
In order to preserve the type I error rate for efficacy testing, the two tests for the primary 
efficacy endpoint are technically placed in a hierarchical order, (1) testing for non-inferiority 
as described in this section followed by (2) testing for superiority as described in the previous 
section.
This test is carried out under the OT data scope (i.e. follow-up is censored at two days after 
permanent discontinuation of the randomized treatment strategy; in other words, only those 
events that occurred between randomization and two days after permanent discontinuation of 
the randomized treatment strategy are analyzed). 
New text:
10.3.5.2  Testing for non-inferiority 
Using a log rank test adapted to non-inferiority testing the following (inferiority) null 
hypothesis (H0) is tested at a one-sided significance level of 2.5%:
H0: HR(t) ≥ 1.2 for all time points t ≥ 0, (i.e. “the hazard for the primary efficacy 
endpoint in the rivaroxaban-based treatment group is more than 20% larger than that 
in the antiplatelet-based control group regarding”)
The one-sided alternative hypothesis (H1) is:


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H1: HR(t) < 1.2 for all time points t ≥ 0, (i.e. “the hazard in the rivaroxaban-based 
treatment group for the primary efficacy endpoint is such that the HR is below 1.20”)
The following decision rule to test the null hypothesis of inferiority is applied:
If the upper boundary of 95% confidence interval (CI) for HR falls below 1.20, the 
null-hypothesis of inferiority (H0) is rejected and non-inferiority of the rivaroxaban-
based strategy (relative to the antiplatelet-based strategy) with regard to the primary 
efficacy endpoint can be claimed.
Hazard ratio and corresponding two-sided 95% confidence intervals are estimated based on a 
Cox proportional hazards model. 
In order to preserve the type I error rate for efficacy testing, the two tests for the primary 
efficacy endpoint are technically placed in a hierarchical order, (1) testing for non-inferiority 
as described in this section followed by (2) testing for superiority as described in the previous 
section.
15.2.2.25. Section 10.3.5.1.4 Testing for superiority in case of rejection of the 
proportional hazards assumption
This section was changed as a result of Modification 12.
Deleted text:
10.3.5.1.4 Testing for superiority in case of rejection of the proportional hazards 
assumption
In case of rejection of the assumption of proportional hazards for the primary efficacy 
endpoint, superiority of the rivaroxaban-based strategy for the primary outcome is tested with 
the use of the log rank methodology, without any (preceding) testing for non-inferiority.
The following null hypothesis (H0) is tested one-sided at the significance level of 2.5%:
H0: SR(t) = SA(t) for all time points t ≥ 0, (i.e. “there is no difference between the 
rivaroxaban-based treatment group and the ASA-based control group regarding the 
primary efficacy outcome for all time points”)
The one-sided alternative hypothesis is:
H1:  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 is applied:
According to the size of this study, it is justified to assume under H0 a sufficiently 
close approximation of the one-sided stratified 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) ) is 


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larger than the critical quantile from the normal distribution (z0.975 =1.96), the null 
hypothesis is rejected in favor of the alternative hypothesis.
This test is carried out under the ITT data scope (i.e. all events are counted irrespective of the 
actual treatment at the time of the event).
15.2.2.26. Section 10.3.5.3 Exploratory analyses of the primary efficacy variable
This section was changed as a result of Modification 12.
Old text:
10.3.5.1.5 Exploratory analyses of the primary efficacy variable
New text:
10.3.5.3 Exploratory analyses of the primary efficacy variable
15.2.2.27. Section 10.3.6 Analysis of secondary and other efficacy variable
This section was changed as a result of Modification 12.
Old text:
10.3.5.2 Analysis of secondary and other efficacy variable
New text:
10.3.6 Analysis of secondary and other efficacy variable
15.2.2.28. Section 10.3.7  Analysis of safety variables
This section was changed as a result of Modification 12.
Old text: 
10.3.5.3  Analysis of safety variables
The analysis of the primary safety variable is performed on the Full Analysis Set (FAS) under 
the ITT data scope — that is, events are analyzed irrespective of their time of occurrence 
relative to termination of assigned study treatment strategy. Follow-up is censored at the last 
date of known outcome status or at the efficacy cut-off date, whichever comes first.
The analysis of primary safety variable is that of a non-inferiority design with a non-
inferiority boundary of 1.50. Hypotheses and analytic methods are similar to those described 
in Section 10.3.5.2. Non-inferiority for the primary safety variable is established if the upper-
bound of the 95% confidence interval for the hazard ratio for the primary safety variable falls 
below 1.50.
On treatment analyses, pre-NOAF and post-NOAF analyses of the primary safety variable are 
performed as exploratory analyses.
The analyses of secondary safety variables are similar to those for secondary efficacy 
variables, without any sequential order. 
New text: 


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10.3.7  Analysis of the safety variables
The analysis of the primary safety variable is performed on the Full Analysis Set (FAS) under 
the ITT data scope — that is, events are analyzed irrespective of their time of occurrence 
relative to termination of assigned study treatment strategy. Follow-up is censored at the last 
date of known outcome status or at the efficacy cut-off date, whichever comes first.
Kaplan-Meier estimates of cumulative risk and cumulative hazard functions for the primary 
safety variable are 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.
If the proportional hazards assumption holds for the primary safety variable, hazard ratio and 
corresponding two-sided 95% confidence intervals are estimated based on a Cox proportional 
hazards models.
On treatment analyses, pre-NOAF and post-NOAF analyses of the primary safety variable are 
performed as exploratory analyses.
All of the above analyses of the primary safety variable are descriptive, without formal 
statistical tests being performed.
The analyses of secondary safety variables are similar to those for secondary efficacy 
variables, without any sequential order. 
15.2.2.29. Section 10.3.8  Subgroup analysis
This section was changed as a result of Modification 12.
Old text:
10.3.5.4  Subgroup analysis
New text:  
10.3.8  Subgroup analysis
15.2.2.30. Section 10.4  Determination of sample size
This section was changed as a result of Modification 12.
Old text:
….
A sample size of sample size of 2 x 760 subjects allows for an attrition rate of 2.63%. The 
study is event driven and the number of randomized subjects is estimated to be required to 
collect 440 primary efficacy events. The study is planned to run until this number of events 
has been reached.
….
The final sample size will depend on multiple factors including the rate of accrual of the 
primary endpoint events. Therefore, the sample size may be increased if planning 
assumptions are modified based on blinded data review. The Steering Committee of the trial 
will monitor the aggregate (blinded) event rate and may increase the sample size or duration 
of follow-up to achieve the planned target number of events in consultation with the sponsor.


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….
Taking into consideration both the historical NI margins used in TAVR trials together with 
the expected high event rates and the considerable proportion of subjects with NOAF after 
randomization, a conservative non-inferiority margin of 1.20 was chosen for this study.
Power analysis for safety
The expected 540 days event rate of the primary safety endpoint is 12.0% (5, 7, 12, 15, 62-
64). With 2 x 740 fully analyzable subjects and the accrual assumptions defined under 
Section 10.4 the study has 85% power to show non-inferiority with a non-inferiority margin 
of 1.50 for the hazard ratio at a one-sided significance level of 2.5%. The non-inferiority 
margin of 1.50 has been selected on basis of both clinical appropriateness and relevant 
studies (52).
The power calculation was based on a test using the Cox proportional hazards model and was 
performed with PASS version 12.0.6, with the module for two survival curves using Cox’s 
proportional hazards model.
New text:
….
A sample size of sample size of 2 x 760 subjects allows for an attrition rate of 2.63%. The 
study is event driven and the number of randomized subjects is estimated to be required to 
collect 440 primary efficacy events. The study is planned to run until this number of events 
has been reached or to stop earlier if the event rate is unexpectedly low.
….
The final sample size will depend on multiple factors including the rate of accrual of the 
primary endpoint events. The Steering Committee of the trial will monitor the aggregate 
(blinded) event rate and may increase the sample size or duration of follow-up to achieve the 
planned target number of events in consultation with the sponsor.
….
Taking into consideration both the historical NI margins used in TAVR trials together with 
the expected high event rates and the considerable proportion of subjects with NOAF after 
randomization, a non-inferiority margin of 1.20 was chosen for this study.
15.2.2.31.
Section 10.5  Planned interim analyses 
This section was changed as a result of Modification 13.
Old text:
A planned interim analysis for futility will be performed when the last randomized subject
reaches 270 days of follow-up or when 300 primary efficacy events have occurred.
The interim analysis will be performed based on adjudicated primary efficacy endpoints by 
treatment groups, if needed supplemented by best available information. The conditional 
power for the primary efficacy endpoint will be calculated. The DSMB may recommend 


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immediate termination of the trial if the calculated conditional power for the trial does not 
exceed 50%.
There will be no adjustment for type I error level for the final analysis.
The DSMB recommendation will be based on an overall assessment of benefit and harm 
given the observed rates of efficacy and safety endpoints at that time.
New text:
No formal interim analysis is planned.
15.2.2.32. Section 11.1  Data recording
This section was changed as a result of Modification 16.
Added text:
….
Data required according to this protocol are recorded by investigational site personnel via 
data entry into the internet based eCRF system, which Cardialysis (CRO) licenses from 
XClinical. MARVIN is validated by XClinical and Cardialysis for use in its clinical studies. 
MARVIN allows for the application of software logic to set-up data entry screens and data 
checks to ensure the completeness and accuracy of the data entered by the site personnel. 
Cardialysis extensively applies the logic to ensure data are complete and reflect the clinical 
data requirements of the study. Data queries resulting from the application of the software 
logic are resolved by the site personnel. The data are stored at a secure host facility 
maintained by XClinical and will be downloaded by Cardialysis each night. All access to the 
MARVIN system is through a password-protected security system that is part of the 
MARVIN software.
All internal Cardialysis, internal Mount Sinai (ARO), Bayer, and external investigator site 
personnel seeking access must go through a MARVIN training process before they are 
granted access to MARVIN for use in Bayer's clinical studies. Training records are 
maintained.
….
15.2.2.33. Section 11.2  Monitoring
This section was changed as a result of Modification 16.
Added text:
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s/ARO’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.  ….
15.2.2.34. Section 12 Premature termination of study
This section was changed as a result of Modification 13.
Deleted text:


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-
Results of any interim analysis
15.2.2.35. Section 16.2  Definition of terms
This section was changed as a result of Modification 14.
Added text:
Non-active prostate cancer
No current or planned diagnostic measures, chemotherapy, surgical treatment or a reduced 
life expectancy.


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16.
Appendices
16.1.
Endpoint definitions
16.1.1.Death or first adjudicated thromboembolic event (DTE)
Defined as the composite of all-cause death and adjudicated stroke, myocardial infarction 
(MI), symptomatic valve thrombosis, pulmonary embolism (PE), deep vein thrombosis 
(DVT) or non-CNS systemic embolism.
The components of this primary efficacy endpoint are adjudicated according to the latest
valve academic research consortium (VARC) definitions (29) available.
Death is classified according to the VARC definitions.
All-cause death

All deaths from any cause. This includes all cardiovascular and non-cardiovascular deaths.
Cardiovascular death
Death fulfilling any of the following criteria:

Death due to proximate cardiac cause (e.g. myocardial infarction, cardiac tamponade, worsening 
heart failure)

Death caused by non-coronary vascular conditions such as neurological events, pulmonary 
embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular disease

All procedure-related deaths, including those related to a complication of the procedure or 
treatment for a complication of the procedure (e.g. reintervention on the operated valve)

All valve-related deaths including structural or non-structural valve dysfunction or other valve-
related adverse events (e.g. valve thrombosis, embolism, bleeding event, or implanted valve 
endocarditis)

Sudden death or unwitnessed death

Death of unknown cause
Non-cardiovascular death

Any death in which the primary cause of death is clearly related to another condition (e.g. trauma, 
cancer, suicide)
Stroke is classified according to the VARC definitions.
Diagnostic criteria

Acute episode of a focal or global neurological deficit with at least one of the following: change 
in the level of consciousness, hemiplegia, hemiparesis, numbness, or sensory loss affecting one 
side of the body, dysphasia or aphasia, hemianopia, amaurosis fugax, or other neurological signs 
or symptoms consistent with stroke

Stroke – duration of a focal or global neurological deficit >24 h; OR <24 h if available 
neuroimaging documents, a new haemorrhage or infarct; OR the neurological deficit results in 
death

No other readily identifiable non-stroke cause for the clinical presentation (e.g. brain tumour, 


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Stroke is classified according to the VARC definitions.
trauma, infection, hypoglycemia, peripheral lesion, pharmacological influences), to be determined 
by or in conjunction with the designated neurologist*

Confirmation of the diagnosis by at least one of the following: neurologist or neurosurgical 
specialist; neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed on 
clinical grounds alone
Stroke classification

Ischemic: an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of 
the central nervous system tissue

Hemorrhagic: an acute episode of focal or global cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular, or subarachnoid hemorrhage

A stroke may be classified as undetermined if there is insufficient information to allow 
categorization as ischemic or hemorrhagic
Stroke definitions

Disabling stroke: an modified Rankin Scale (mRS) score of 2 or more at 90 days and an increase 
in at least one mRS category from an individual’s pre-stroke baseline

Non-disabling stroke: an mRS score at <2 at 90 days or one that does not result in an increase in 
at least one mRS category from an individual’s pre-stroke baseline
NB: Modified Rankin Scale assessments should be made by qualified individuals according to a certification process.
* Patients with non-focal global encephalopathy will not be reported as stroke without unequivocal evidence of cerebral infarction-based 
upon neuroimaging studies (CT scan or brain MRI).
Myocardial infarction (MI) is classified according to the VARC definitions.
Peri-procedural MI (<72 h after the index procedure)

New ischemic symptoms (e.g. chest pain or shortness of breath), or new ischemic signs 
(e.g. ventricular arrhythmias, new or worsening heart failure, new ST-segment changes, 
hemodynamic instability, new pathological Q-waves in at least two contiguous leads,
imaging evidence of new loss of viable myocardium or new wall motion abnormality) 
AND

Elevated cardiac biomarkers (preferable CK-MB) within 72h after index procedure, 
consisting of at least one sample post-procedure with a peak value exceeding 15x as the 
upper reference limit (URL) for troponin or 5x for CK-MB. 
Spontaneous MI (> 72h after index procedure)
Any one of the following criteria:

Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one 
value above the 99th percentile URL, together with the evidence of myocardial ischemia 
with at least one of the following:
o
Symptoms of ischemia
o
ECG changes indicative of new ischemia [new ST-T changes or new left bundle 
branch block (LBBB)]
o
New pathological Q-waves in at least two contiguous leads


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Myocardial infarction (MI) is classified according to the VARC definitions.
o
Imaging evidence of a new loss of viable myocardium or new wall motion 
abnormality

Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST elevation, or 
new LBBB, and/or evidence of fresh thrombus by coronary angiography and/or at 
autopsy, but death occurring before blood samples could be obtained, or at a time before 
the appearance of cardiac biomarkers in the blood.

Pathological findings of an acute myocardial infarction.
Symptomatic valve thrombosis (29, 65)
Symptomatic valve thrombosis is defined as any thrombus attached to or near an implanted 
valve that occludes part of the blood flow path, interferes with valve function, or is 
sufficiently large to warrant treatment.
Note that valve-associated thrombus identified at autopsy in a patient whose cause of death 
was not valve-related should not be reported as valve thrombosis. The most common clinical 
presentation of valve thrombosis is progressive dyspnea. The most commonly observed 
echocardiographic features are: increasing transvalvular gradients, thickened valve leaflets 
with impaired mobility and visualization of thrombus formation on the valve.
Pulmonary embolism (PE) (66)
Symptomatic PE was defined as objectively documented PE with one of the following 
findings:

new intraluminal filling defect in segmental or more proximal branches on sCT,

A new intraluminal filling defect or an extension of an existing defect or a new sudden 
cut-off of vessels more than 2.5 mm in diameter on the pulmonary angiogram,

A new perfusion defect of at least 75% of a segment with a local normal ventilation result 
(high-probability) on ventilation/perfusion lung scintigraphy

Inconclusive sCT, pulmonary angiography or lung scintigraphy with demonstration of 
DVT in the lower extremities by compression ultrasound or venography.

Fatal PE based on objective diagnostic testing, autopsy, or

Death which cannot be attributed to a documented cause and for which PE/DVT cannot
be ruled out (unexplained death).
Deep-vein thrombosis (DVT) (66)
Symptomatic DVT was defined as objectively documented deep-vein thrombosis with one of 
the following findings:

A new non-compressible venous segment or a substantial increase (4 mm or more) in the 
diameter of the thrombus during full compression in a previously abnormal segment on 
ultrasonography


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
An intraluminal filling defect on venography.
Non-central nervous system (CNS) systemic embolism
Non-CNS systemic embolism is defined as abrupt vascular insufficiency of an extremity or 
organ associated with clinical or radiological evidence of arterial occlusion in the absence of 
other likely mechanisms, (e.g., trauma, atherosclerosis, instrumentation). In the presence of 
atherosclerotic peripheral vascular disease, diagnosis of embolism to the lower extremities 
should be made with caution and requires angiographic demonstration of abrupt arterial 
occlusion.
16.1.2.
Primary bleeding event (PBE)
Bleeding events are primarily adjudicated according to the VARC definitions, following the 
BARC classification (67).
The components of this primary efficacy endpoint are adjudicated according to the latest 
valve academic research consortium (VARC) definitions available.
VARC Bleeding
Life-threatening or disabling bleeding

Fatal bleeding (BARC type 5) OR

Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial 
necessitating pericardiocentesis, or intramuscular with compartment syndrome (BARC type 3b 
and 3c) OR

Bleeding causing hypovolaemic shock or severe hypotension requiring vasopressors or surgery 
(BARC type 3b) OR

Overt source of bleeding with drop in hemoglobin > 5 g/dL or whole blood or packed red blood 
cells (RBCs) transfusion >4 units * (BARC type 3b)
Major bleeding (BARC type 3a)

Overt bleeding either associated with a drop in the hemoglobin level of at least 3.0 g/dl or 
requiring transfusion of two or three units of whole blood/RBCs, or causing hospitalization or 
permanent injury, or requiring surgery AND

Does not meet the criteria of life-threatening or disabling bleeding
Minor bleeding (BARC type 2 or 3a, depending on the severity)

Any bleeding worthy of clinical mention (e.g. access site hematoma) that does not qualify as life-
threatening, disabling, or major
Bleeding Academic Research Consortium (BARC).
* Given that one unit of packed RBC typically will raise the n by 1 g/dl, an estimate decrease in hemoglobin will be calculated.


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BARC Bleeding Classification
Type 0 No Bleeding
Type 1 Bleeding that is not actionable and does not cause the patient to seek unscheduled 
performance of studies, hospitalization, or treatment by a health care professional.
Type 2 Any overt, actionable sign of hemorrhage (e.g. more bleeding than would be expected for a 
clinical circumstance; including bleeding found by imaging alone) that does not fit the criteria for 
Types 3, 4, or 5, but does meet at least one of the following criteria:
1) Requiring non-surgical, medical intervention by a health care professional
2) Leading to hospitalization or increased level of care 3) Prompting evaluation
Type 3
Type 3a

Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL (provided hemoglobin drop is related to 
bleed)
Any transfusion with overt bleeding
Type 3b

Overt bleeding plus hemoglobin drop ≥ 5 g/dL (provided hemoglobin drop is related to bleed)

Cardiac tamponade

Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid)

Bleeding requiring intravenous inotropes
Type 3c

Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation; does 
include intraspinal). 

Subcategories; Confirmed by autopsy or imaging or LP

Intra-ocular bleed compromising vision
Type 4 - CABG–related bleeding

Perioperative intracranial bleeding within 48 hrs

Reoperation following closure of sternotomy for the purpose of controlling bleeding

Transfusion of ≥ 5 units of whole blood or packed red blood cells within a 48 period*. 

Chest tube output ≥ 2L within a 24 hour period
If a CABG - related bleed is not adjudicated as at least a Type 3 severity event, it will be classified as 
‘not a bleeding event’
Type 5 - Fatal Bleeding
Type 5a

Definite fatal bleeding: overt bleeding or autopsy or imaging confirmation
Type 5b

Probable fatal bleeding: no autopsy or imaging confirmation, but clinically suspicious
Platelet transfusions should be recorded and reported but are not included in these definitions until further information is obtained about the 
relationship to outcomes.
If a CABG-related bleed is not adjudicated as at least a type 3 severity event, it will be classified as not a bleeding event. If a bleeding event 
occurs with a clear temporal relationship to CABG (i.e., within a 48-h time frame) but does not meet type 4 severity criteria, it will be 
classified as not a bleeding event.
*Corrected for transfusion (1 U packed red blood cells or 1 U whole blood = 1 g/dL hemoglobin).
†Cell saver products are not counted. 
CABG indicates coronary artery bypass graft.


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TIMI Bleeding Criteria (68, 69)
Non-CABG related bleeding

Major
o
Any intracranial bleeding (excluding microhemorrhages < 10mm evident only on 
gradient-echo MRI)
o
Clinically overt signs of hemorrhage associated with a drop in hemoglobin of 
≥5g/dL
o
Fatal bleeding (bleeding that directly results in death within 7 days

Minor
o
Clinically overt (including imaging), resulting in hemoglobin drop of 3 to < 5g/dL

Requiring medical attention
o
Any overt sign of hemorrhage that meets one of the following criteria and does not 
meet criteria for a major or minor bleeding event, as defined above
o
Requiring intervention (medical practitioner-guided medical or surgical treatment 
to stop or treat bleeding, including temporarily or permanently discontinuing or 
changing the dose of a medication or study drug)
o
Leading to or prolonging hospitalization
o
Prompting evaluation (leading to an unscheduled visit to a healthcare professional 
and diagnostic testing, either laboratory or imaging)

Minimal
o
Any overt bleeding event that does not meet the criteria above


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ISTH Bleeding Criteria (70)
Major bleeding

Clinically overt bleeding that is associated with:
o
A fall in hemoglobin of 2 g/dL or more, or
o
A transfusion of 2 or more units of packed red blood cells or whole blood, or
o
A critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, 
intramuscular with compartment syndrome, retroperitoneal, or 
o
A fatal outcome
Non-major clinically relevant bleeding

Overt bleeding event not meeting the criteria for a major bleeding event but associated with 
medical intervention, unscheduled contact (visit or telephone call) with a physician, (temporary) 
cessation of study drug treatment, or associated with discomfort for the subject such as pain or 
impairment of activities of daily life. Examples include:
o
Epistaxis if it lasts for more than 5 minutes, if it is repetitive (i.e., 2 or more 
episodes of true bleeding, i.e., no spots on a handkerchief, within 24 hours), or 
leads to an intervention (packing, electrocautery, etc.)
o
Gingival bleeding if it occurs spontaneously (i.e., unrelated to tooth brushing or 
eating), or if it lasts for more than 5 minutes
o
Hematuria if it is macroscopic, and either spontaneous or lasts for more than 24 
hours after instrumentation (e.g., catheter placement or surgery) of the urogenital 
tract
o
Macroscopic GI hemorrhage: at least 1 episode of melena or hematemesis, if 
clinically apparent
o
Rectal blood loss, if more than a few spots
o
Hemoptysis, if more than a few speckles in the sputum, or
o
Intramuscular hematoma
o
Subcutaneous hematoma if the size is larger than 25 cm2 or larger than 100 cm2 if 
provoked
o
Multiple source bleeding events
Minimal

All other overt bleeding episodes not meeting the criteria for major or clinically relevant non-
major bleeding.
16.2.
Definitions of terms
This section was modified with Amendment 3. For details, see Section 15.2.
Acute kidney injury
Acute kidney injury is define according to the VARC-2 definitions (29), following the AKIN 
Classification (71). The timing for diagnosis of AKI is up to 7 days and subjects who 
experience AKI should have follow-up renal assessments after 7 days until stabilization.


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Acute Kidney Injury (AKIN Classification)
Stage 1
Increase in serum creatinine to 150-199 % (1.50-1.99 x increase compared with 
baseline) OR increase of > 0.3 mg/dl (> 26.4 mmol/l) OR
Urine output < 0.5 ml/kg/h for > 6 but < 12h
Stage 2
Increase in serum creatinine to 200-299% (2.00-2.99 x increase compared with 
baseline) OR
Urine output < 0.5 ml/kg/h for > 12 but < 24h
Stage 3
Increase in serum creatinine to > 300% (> 3 x increase compared with baseline) OR
serum creatinine of > 4.0 mg/dl (> 354 mmol/l) with an acute increase of at least 0.5 
mg/dl (44 mmol/l) OR
Urine output < 0.3 ml/kg/h for > 24h OR
Anuria for > 12h
Patients receiving renal replacement therapy.
The increase must occur within 48 hours.
Aortic stenosis (AS)
Aortic stenosis (AS) typically refers to a narrowing, stiffening or obstruction of flow at the 
level of the native aortic valve. The recently released AHA/ACC heart disease guidelines 
define the stages for AS (33).
Child-Pugh Classification of Severity of Liver Disease (72, 73)
Modified Child-Pugh classification of severity of liver disease according to the degree of 
ascites, the plasma concentrations of bilirubin and albumin, the prothrombin time, and the 
degree of encephalopathy.
Parameter
Points assigned
1
2
3
Ascites
Absent
Slight
Moderate
Bilirubin, mg/dL
≤2
2-3
>3
Albumin, g/dL
>3.5
2.8-3.5
<2.8
Prothrombin time
- Seconds over control
- INR
1-3
<1.8
4-6
1.8-2.3
>6
>2.3
Encephalopathy
None
Grade 1-2
Grade 3-4
Grade
Points
A: well-compensated disease
5-6
B: significant functional compromise
7-9
C: decompensated disease
10-15


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Moderate renal impairment
Kidney damage or glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 for ≥3 months or 
with estimated creatinine clearance <50 mL/min. Kidney damage is defined as pathologic 
abnormalities or markers of damage, including abnormalities in blood or urine test or imaging 
studies.
Non-active prostate cancer
No current or planned diagnostic measures, chemotherapy, surgical treatment or a reduced 
life expectancy.
New-onset atrial fibrillation (NOAF) or new-onset atrial flutter (74)
NOAF or atrial flutter is diagnosed as a common supraventricular arrhythmia that is 
characterized by an uncoordinated contraction of the atrium. An electrocardiogram (ECG) 
recording is necessary to diagnose AF or atrial flutter. Any arrhythmia that has the ECG 
characteristics of AF and lasts sufficiently long for a 12-lead ECG to be recorded, or for at 
least 30 seconds on a rhythm strip is considered to be either AF or atrial flutter. The 
therapeutic approach to NOAF (spontaneous conversion, electrical or medical cardioversion, 
initiation of oral anticoagulation, and rate control), should be considered an AF episode. The 
diagnosis requires an ECG or rhythm strip and any clinical consequences should be 
thoroughly documented in the case report form.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
Global multicenter, open-label, randomized, event-driven, active-
controlled study comparing a rivaroxaban-based antithrombotic 
strategy to an antiplatelet-based strategy after transcatheter aortic 
valve replacement (TAVR) to optimize clinical outcomes. 
NCT Number: 
NCT02556203 
Document Date: 
15-Dec-2016 
 


 
Statistical Analysis Plan 
 
 
Study No.: BAY59-7939-17938 
Page:
1 of
31
 
 
Reference Number: BPD-SOP-060 
Supplement Version: 6 
Global multicenter, open-label, randomized, event-driven, active controlled 
study comparing a rivaroxaban-based antithrombotic strategy to an  
antiplatelet-based strategy after transcatheter 
aortic valve replacement (TAVR) to optimize clinical outcomes. 
(GALILEO) 
[Global study comparing a rivAroxaban-based antithrombotic strategy to an 
antipLatelet-based strategy after transcatheter aortIc vaLve rEplacement to Optimize 
clinical outcomes.] 
Bayer study drug 
BAY 59-7939 / JNJ-39039039 / Rivaroxaban 
 
[Study purpose:] 
Exploratory study in a specific population after TAVR 
Clinical study 
phase: 
III 
Date: 
15 December 2016 
Study No.: 
 
17938 
Version: 
1.0 (final) 
Author: 
  
 
 
 
 
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


 
Statistical Analysis Plan 
 
 
Study No.: BAY59-7939-17938 
Page:
2 of
31
 
 
Reference Number: BPD-SOP-060 
Supplement Version: 6 
Table of Contents 
 
1. 
Introduction ................................................................................................................... 5 
2. 
Study Objectives ............................................................................................................ 6 
2.1 
Primary Objective(s) .................................................................................................... 6 
2.2 
Secondary Objectives ................................................................................................... 6 
2.3 
Other Objectives ........................................................................................................... 6 
3. 
Study Design .................................................................................................................. 7 
3.1 
Study flow diagram ...................................................................................................... 7 
3.2 
Study plan .................................................................................................................... 7 
4. 
General Statistical Considerations ................................................................................ 9 
4.1 
General Principles ........................................................................................................ 9 
4.2 
Handling of Dropouts ................................................................................................... 9 
4.3 
Handling of Missing Data ............................................................................................. 9 
4.4 
Interim Analyses and Data Monitoring ....................................................................... 10 
4.5 
Data Rules .................................................................................................................. 10 
4.6 
Validity Review ......................................................................................................... 10 
5. 
Analysis Sets................................................................................................................. 11 
5.1 
Assignment of analysis sets ........................................................................................ 11 
5.2 
Data scopes ................................................................................................................ 11 
5.2.1 
Data scopes according to intention-to-treat principle (ITT analysis) ......................... 11 
5.2.2 
Data scope according to on-treatment (OT analysis) ................................................ 11 
5.2.3 
Data scope pre-NOAF analysis ................................................................................ 12 
5.2.4 
Data scope post-NOAF analysis .............................................................................. 12 
Only subjects that start OAC treatment as described in the protocol section 7.1.1.1 and 
7.1.2.1 are included from the post-NOAF analysis. .................................................. 12 
6. 
Statistical Methodology ............................................................................................... 13 
6.1 
Population characteristics ........................................................................................... 13 
6.1.1 
Disposition .............................................................................................................. 13 
6.1.2 
Demographics ......................................................................................................... 13 
6.1.3 
Medical history ....................................................................................................... 14 
6.1.4 
TAVR details .......................................................................................................... 14 
6.1.5 
Randomization timing ............................................................................................. 15 
6.1.6 
Protocol deviations .................................................................................................. 15 
6.1.7 
Prior and concomitant medications .......................................................................... 15 
6.1.8 
Extent of exposure and Compliance ........................................................................ 15 
6.2 
Efficacy ...................................................................................................................... 15 
6.2.1 
Analysis of the efficacy endpoints ........................................................................... 16 
6.3 
Pharmacokinetics / pharmacodynamics ....................................................................... 20 
6.4 
Safety ......................................................................................................................... 20 
6.4.1 
Analysis of the safety endpoints .............................................................................. 21 
6.5 
Other analysis ............................................................................................................. 21 


 
Statistical Analysis Plan 
 
 
Study No.: BAY59-7939-17938 
Page:
3 of
31
 
 
Reference Number: BPD-SOP-060 
Supplement Version: 6 
6.6 
Subgroup analysis ...................................................................................................... 22 
6.6.1 
Analysis of the subgroups........................................................................................ 23 
7. 
Document history and changes in the planned statistical analysis ............................ 25 
8. 
Appendix I Flowcharts ................................................................................................ 26 
8.1 
Flowchart 1: Primary efficacy ..................................................................................... 26 
8.2 
Flowchart 2: Secondary efficacy, secondary safety and other variables ....................... 27 
8.3 
Flowchart 3: Primary safety ........................................................................................ 28 
8.4 
Flowchart 4: Primary efficacy and primary safety in other data scopes ....................... 29 
8.5 
Flowchart 5: Subgroups .............................................................................................. 30 
9. 
References .................................................................................................................... 31 
 
 
 
 


 
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Abbreviations 
 
AE 
Adverse event 
IC 
Informed consent 
AF 
Atrial fibrillation 
INR 
International normalized ratio 
AS 
Aortic stenosis 
ISTH 
International Society on Thrombosis and 
Haemostasis 
ASA 
Acetylsalicylic acid 
ITT 
Intention-to-treat 
ATC 
Anatomical Therapeutic Chemical 
(ATC) Classification System 
IxRS 
Interactive Web or Voice Response System 
BARC 
Bleeding academic research 
consortium 
ln 
Natural Logarithm 
CAD 
Coronary artery disease 
mg 
Miligram 
CEC 
Clinical Event Committee 
MI 
Myocardial infarction 
CI 
Confidence interval 
min 
Minutes 
CNS 
Central nervous system 
ML 
Maximum partial likelihood method 
COPD 
Chronic Obstructive Pulmonary 
Disease 
N/A 
Not applicable 
CRF 
Case report form 
NI 
Non-inferiority 
CSP 
Clinical study protocol 
NOAC 
Non-vitamin K oral anticoagulants 
DAPT 
Dual-antiplatelet therapy 
NOAF 
New-onset atrial fibrillation 
DSMB 
Data safety monitoring board 
od 
Once-daily 
DTE 
Death or first adjudicated 
thromboembolic event 
OT 
On-treatment 
DVT 
Deep vein thrombosis 
PBE 
Primary bleeding event 
e.g. 
Exempli gratia (for example) 
PE 
Pulmonary embolism 
eCRF 
Electronic case report form 
SAP 
Statistical analysis plan 
eGFR 
Estimated glomerular filtration rate 
TAVR 
Transcatheter aortic valve replacement 
EOT 
End-of-treatment 
TEE 
Transesophageal echocardiogram 
et al. 
Et alii (and others) 
TIA 
Transient ischemic attack 
etc. 
Et cetera  (and so on) 
TIMI 
Thrombolysis in Myocardial Infarction 
FAS 
Full analysis set 
TTE 
Transthoracic echocardiogram 
H0 
Null Hypothesis 
US(A) 
United States (of America) 
H1 
Alternative Hypothesis 
VARC 
Valve academic research consortium 
HR 
Hazard ratio 
VKA 
Vitamin K antagonists 
i.e. 
Id est  (that is) 
VRM 
Validity Review Meeting 
 
 
 
 


 
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1. 
Introduction 
Calcific aortic valve stenosis (AS) is characterized by an increased thrombogenic and 
inflammatory profile1. Long-term oral antithrombotic treatment after transcatheter aortic 
valve replacement (TAVR) aims to prevent complications, notably ischemic stroke and 
myocardial infarction (MI) as well as thromboembolism related to deep vein thrombosis, 
pulmonary embolism, valve thrombosis, or systemic embolism while minimizing bleeding 
risk. The baseline risk for ischemic and thromboembolic complications is determined by 
comorbidities such as concomitant coronary artery disease (CAD), which is present in 20–
70% of patients eligible for TAVR. Furthermore, in-hospital atrial fibrillation (AF) may occur 
in about one-third of patients referred for TAVR2. 
Therefore, dual-antiplatelet therapy (DAPT) is not optimal in targeting the underlying 
pathophysiological mechanisms in the actual standard of care after TAVR due to severe AS. 
Rivaroxaban, through the inhibition of the pathways underlying the increased 
thrombogenicity, may effectively prevent thrombotic complications after TAVR without 
exposing this elderly3 population to an increased bleeding risk. 
Stroke and transient ischemic attack (TIA) are estimated to occur in 5% of patients at 30 days 
and 10% of patients at 1 year after TAVR, based on the PARTNER cohorts, on the CoreValve 
trial, and on a large meta-analysis by Athappan et al4, 5, 6. Approximately half of the strokes 
within 30 days post TAVR occur within the first 24 hours7. 
The investigation of anticoagulation in the medical management of patients following TAVR 
is further justified by the fact that the incidence of new-onset atrial fibrillation (NOAF) after 
TAVR may be underestimated. Dumont and his group reported that one-third of patients with 
no prior history of AF had NOAF after TAVR and this was associated with a higher rate of 
stroke/systemic embolism at 30 days and 1 year2 . Thus, despite the number of mechanisms 
that may be involved in stroke after TAVR, there is a particularly strong relationship between 
post procedural AF and stroke occurring after 24 hours suggesting that cardioembolic origin 
might significantly contribute to stroke after TAVR. Finally, the clustering of 
thromboembolic risk factors in TAVR populations such as renal impairment (close to 80%), 
severe chronic obstructive pulmonary disease (COPD) (15%), coronary artery disease (70%), 
peripheral vascular disease (30%), and moderate to severe mitral regurgitation (30%), could 
indicate that long-term anticoagulation therapy (beyond 12 months) after TAVR can be of 
value. 
For further information see the Clinical Study protocol 2015-001975-30 version 3.0 dated 
17 August 2016 where upon this SAP is based. 
 
 


 
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2. 
Study Objectives 
2.1 
Primary Objective(s) 
The aim of this study is to assess whether a rivaroxaban-based anticoagulation strategy, 
following successful TAVR, compared to an antiplatelet-based strategy, is superior in 
reducing death or first thromboembolic events (DTE). This comparison is preceded by a non-
inferiority test that must be satisfied. 
A second aim of this study is to assess the primary bleeding events (PBE) of the rivaroxaban-
based strategy, following TAVR, compared to an antiplatelet-based strategy. PBE is defined 
as the composite of life-threatening, disabling, or major bleeding events and is classified 
according to the VARC definitions following the BARC classification. 
2.2 
Secondary Objectives 
The secondary efficacy objectives are to compare the effects of the rivaroxaban-based 
strategy and antiplatelet-based strategy with respect to the net-clinical-benefit, defined as the 
composite of death or first thromboembolic events and life-threatening, disabling, or major 
bleeding events classified according to the VARC definitions following the BARC 
classification. 
Whereas the secondary safety objectives are safety criteria with respect to bleeding 
(Thrombolysis in myocardial infarction [TIMI] major or minor bleeds, International society 
on thrombosis and haemostasis [ISTH] major bleeding, and BARC 2, 3, or 5 bleeds). 
2.3 
Other Objectives 
Other secondary efficacy and safety objectives are to compare the effects of a rivaroxaban 
based strategy and an antiplatelet-based strategy with respect to the individual components of 
the composite of DTE and of the composite of life threatening, disabling, or major bleeding, 
respectively. 
The effect of rivaroxaban-based strategy, following successful TAVR, compared to an 
antiplatelet-based strategy, on the mean transaortic valve pressure gradient at 360 days as 
measured by echocardiography will be assessed as an exploratory study endpoint. 
 
 
 


 
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3. 
Study Design 
3.1 
Study flow diagram 
The study design is detailed in Figure 1 and in section 3.2 
 
Figure 1: Study flow diagram. 
Successful transcatheter aortic valve replacement (TAVR)  
§ The duration of the planned treatment period will depend on the time needed to reach the efficacy 
cut-off date, i.e. to collect the predefined number of efficacy endpoints or earlier if the event rate is 
unexpectedly low. The expected duration of the treatment is 720 days but may be adjusted depending 
upon the rate of subject recruitment and efficacy event rates.  
R, randomization; ASA, acetylsalicylic acid; OD, once-daily. 
 
3.2 
Study plan 
This is an event-driven, randomized, open-label with blinded endpoint evaluation, parallel-
group, active-controlled, and multicenter study comparing the efficacy and safety of a 
rivaroxaban-based strategy versus a standard antiplatelet-based strategy for the prevention of 
ischemic and thromboembolic complications while minimizing the bleeding risk in subjects 
who successfully underwent TAVR. 
The study is divided into a screening period, a planned treatment period, and an observational 
post-treatment period. 
The screening period begins after TAVR. Subjects who have successfully undergone a TAVR 
procedure of an aortic valve stenosis (either native of valve-in-valve) are included. All 
inclusion and exclusion criteria should be reviewed before IC is signed. Subjects with an 


 
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ongoing/continued indication for oral anticoagulation at the time of randomization are 
excluded from this study. 
Once IC has been obtained and eligibility has been confirmed, subjects are randomized (1:1), 
to a rivaroxaban-based strategy or to an antiplatelet-based strategy. Randomization must take 
place within 1-7 days post-TAVR and before hospital discharge. Stratification by site is 
performed to ensure balance across potential local differences in treatment practices. 
The assigned treatment strategy is implemented after randomization.  
In each strategy, one antiplatelet therapy agent is dropped after 90 days. This means that in 
the rivaroxaban-based strategy, ASA is discontinued after 90 days and rivaroxaban 10 mg is 
to be continued alone. Whereas, in the antiplatelet-based strategy, clopidogrel must be 
discontinued after 90 days and ASA is to be continued alone. 
Study treatments are continued until the efficacy cut-off date , i.e. when 440 subjects are 
anticipated to have experienced a positively adjudicated primary efficacy endpoint, when 
subjects will be transitioned from the assigned strategy to an appropriate therapy, as per the 
clinical site standard of care. This is anticipated to occur approximately 720 days after the 
first patient is randomized, but may vary depending on the recruitment rate as well as the on 
the primary efficacy event rate. One on-site visit will be scheduled for each patient when the 
efficacy cut-off date is anticipated. 
In the event of NOAF, study treatments are changed as follows: 
Subjects randomized to rivaroxaban-based strategy: Subjects randomized to the rivaroxaban-
based strategy should be switched to rivaroxaban 20 mg once-daily (or 15 mg once-daily dose 
for moderate renal impairment with eGFR < 50 and ≥ 30 mL/min/1.73m2). 
Subjects randomized to antiplatelet-based strategy: Subjects randomized to the antiplatelet-
based strategy are switched to treatment with VKA with a target INR 2-3. 
In case NOAF is diagnosed within the first 90 days after randomization, ASA 75-100 mg 
once-daily will be continued in both treatment arms in addition to oral anticoagulation with 
rivaroxaban 20 mg/ 15 mg once-daily or VKA, respectively. ASA 75-100 mg once-daily will 
be discontinued at 90 days after randomization and anticoagulation continued alone with 
rivaroxaban 20 mg/ 15 mg once-daily or VKA, respectively. NOAF subjects remain in the 
study, the timing of on-site visits and/or phone assessments will be kept unchanged until the 
efficacy cut-off date when an on-site visit and remaining study closure activities take place. 
Subject contacts are planned to take place at least at 30, 90, and 180 days after randomization 
and from 180 days onward, every 180 days until the efficacy cut-off date is anticipated, and 
the study medication is stopped. Thirty days after the permanent discontinuation of the 
assigned study medication, a telephone assessment will be performed. 
All randomized subjects should be followed until the efficacy cut-off date. 
 
 
 


 
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4. 
General Statistical Considerations 
4.1 
General Principles 
The statistical evaluation will be performed by using the software package SAS release 9.3 or 
higher (SAS Institute Inc., Cary, NC, USA).  
All variables will be analyzed by descriptive statistical methods. The number of data available 
and missing data, mean, standard deviation, minimum, maximum, median and quartiles will 
be calculated for metric data. Frequency tables will be generated for categorical data.  
Tabulation of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place.  
In general, these summaries will be calculated separately for each treatment group but jointly 
for all study centers.  
If not stated otherwise, all efficacy and safety analyses will be based on findings as confirmed 
by the Clinical Event Committee (CEC). 
Events occurring on the day of randomization will be considered post-randomization, since 
the CEC is guided to not confirm events pre-randomization. 
The validity of subjects for allocation to various populations and data scopes (FAS, pre-
NOAF, post-NOAF and on-treatment) will be assessed during one or more interim and a final 
Validity Review Meetings (VRM) and decisions will be documented in the Validity Review 
Report. This SAP might be updated based on the results of the validity review meeting. 
All subjects randomized will analyzed as randomized. 
  
4.2 
Handling of Dropouts 
A subject who withdraws IC before randomization or who develops a violation of the 
selection criteria before randomization is defined as a screening failure. No follow-up of 
screening failures is performed. These screening failures will be excluded from the analyses. 
Only the number of screening failures and the reason for failure will be presented. 
Subjects discontinuing study participation prematurely after the subject has been randomized 
will not be excluded from the analyses.  
 
4.3 
Handling of Missing Data 
No imputation of data will be performed, with the following exceptions:. 
Missing or incomplete AE or efficacy/safety event dates will be imputed according to: 
• If only the day is missing the date will be set to first day of the recorded month  


 
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• If the day and the month are missing the date will be set to the first of January of the 
recorded year 
• If the imputed date is prior to the date of the randomization the date will be set equal 
to the date of the randomization 
Medication dates used for the Data Scopes (see paragraph 5.2) will not be missing or 
incomplete, since the Study Drug Exposure form in the eCRF does not allow missing or 
incomplete start and stop dates. 
All other missing or incomplete dates will not be imputed. 
All missing or incomplete data will be presented in the subject data listing as they are 
recorded in the eCRF.  
4.4 
Interim Analyses and Data Monitoring 
No formal interim analysis is planned. 
The Data Safety Monitoring Board (DSMB) will assess the benefit and harm given the 
observed rates of efficacy and safety endpoints at that time. Detailed information on the roles 
and responsibilities of the DSMB are described in the DSMB charter. 
4.5 
Data Rules 
For event data, the number of days from randomization will be used. For each subject, each 
assessment (event) will be assigned a study day with respect to the trial reference start date, 
which is the date of randomization of the subject. 
If assessment date is on or after the trial reference start date: 
Study Day = Assessment day – trial reference start date +1.  
If assessment date before the trial reference start date : 
Study Day = Assessment date – trial reference start date. 
So Study Day 1 will indicate the event occurred at the same day the randomization was 
performed, Study Day 2 will indicate the event occurred the day following the day of the 
randomization and Study Day -1 indicates the day before randomization.   
4.6 
Validity Review 
The results of the validity review meeting will be documented in the validity review report 
and may comprise decisions and details relevant for statistical evaluation. Any changes to the 
statistical analysis prompted by the results of the validity review meeting will be documented 
in an amendment and, if applicable, in a supplement to this SAP. 
 
 
 


 
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5. 
Analysis Sets 
5.1 
Assignment of analysis sets 
Full analysis set (FAS) 
This subject set includes all randomized subjects, whether treated or not. 
5.2 
Data scopes  
5.2.1 
 Data scopes according to intention-to-treat principle (ITT analysis) 
Efficacy cut-off date 
When the anticipated efficacy cut-off date is set, the sponsor informs each investigational site 
and all subjects must return to the clinic within 6 weeks in order to have a final assessment. 
This assessment will coincide with the EOT visit for the subjects under treatment. The 
efficacy cut-off date is the date when the study treatments are discontinued. This date will be 
determined by the Executive Committee (see protocol 5.3.3). From this day onwards subjects 
will be transitioned from the assigned strategy to an appropriate therapy, as per the clinical 
site standard of care.  
Censoring of follow-up in ITT analysis 
Censoring of follow-up for patients is on the efficacy cut-off date, or date of last known 
clinical status collected from Last Clinical Status form, or date of death (by CEC 
adjudication) whichever comes first. 
 
5.2.2 
Data scope according to on-treatment (OT analysis) 
Date of permanent discontinuation of the randomized treatment strategy  
Date of permanent discontinuation of the randomized treatment strategy is defined as follows: 
For subjects randomized to rivaroxaban-based strategy:  
• two days after last known ingestion of study rivaroxaban. This date is derived from 
study drug exposure form, as are the other medication start/stop dates in this 
section.  
 
For subjects randomized to antiplatelet-based strategy:  
• two days after last known ingestion of clopidogrel, ASA, or VKA (after  NOAF 
only), whichever comes last. 
Censoring of follow-up for subjects in OT analysis 
Censoring of follow-up for patients is the efficacy cut-off date, the date of last know clinical 
status or date of permanent discontinuation of the randomized treatment strategy + 2 days, 
whichever comes first. 


 
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5.2.3 
Data scope pre-NOAF analysis 
Date of NOAF requiring treatment with high dose oral anticoagulation 
Date NOAF is defined as the date where treatment with high dose oral anticoagulation for 
NOAF is started. Information is derived from study drug exposure form for Rivaroxaban or 
VKA  in combination with ECG evidence of NOAF.  
Censoring of follow-up in pre-NOAF analysis 
Censoring of follow-up for subjects is on the efficacy cut-off date, date of last known visit or 
NOAF date, whichever comes first. 
 
5.2.4 
Data scope post-NOAF analysis 
Date of NOAF requiring treatment with high dose oral anticoagulation 
Date NOAF is defined as the date where treatment with high dose oral anticoagulation for 
NOAF is started. Information is derived from study drug exposure form for Rivaroxaban or 
VKA  in combination with ECG evidence of NOAF.  
Start of follow-up in post-NOAF analysis 
Day 1 in post NOAF analysis is the date of NOAF as defined above. 
Censoring of follow-up in post-NOAF analysis 
Censoring of follow-up for subjects is on the efficacy cut-off date, or date of last known visit, 
whichever comes first. 
Only subjects that start OAC treatment as described in the protocol section 7.1.1.1 and 7.1.2.1 
are included from the post-NOAF analysis. 
 


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6.
Statistical Methodology
6.1 
Population characteristics 
6.1.1 
Disposition 
The following will be tabulated overall and/or by treatment group: 
•
Study sample size (FAS)
•
Study sample size by region, country and site (FAS)
Region is defined as follows:
North America: Canada, USA 
Eastern Europe: Czech Republic, Poland 
Western Europe: Austria, Belgium, Denmark, France, Germany, Italy, 
Netherlands, Norway, Spain, Sweden, Switzerland, UK 
•
Number of subjects by primary reason for screening failure (overall only, subjects
screened)
•
Number of subjects with permanent discontinuation of randomized treatment strategy
(FAS)
•
Number of subjects and primary reason for discontinuation from the study (FAS)
6.1.2 
Demographics 
The following demographic and baseline characteristics will be summarized by treatment 
group in FAS. Summary statistics will be presented for metric variables and frequency tables 
will be presented for categorical variables. 
•
Sex (% male)
•
Age (continuous, year)
•
Age (categorical <median, ≥median, ≤75 year, >75 year, ≤85 year, >85 year)
•
Weight (continuous, kg)
•
BMI (continuous, kg/m2)
•
Ethnicity (categorical as specified in eCRF)
•
Race (categorical as specified in eCRF)
•
Current/recent smoker (<1 year) (% yes)
•
Diabetes mellitus (% yes, )
•
eGFR at screening (<30 ml/min/1.73m2,  ≥30 to ≤50 ml/min/1.73m2,  >50 to ≤80
ml/min/1.73m2,  >80 ml/min/1.73m2)
Other baseline characteristics may be added. 


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6.1.3 
Medical history 
Medical history data will be evaluated by treatment group in FAS. Frequency tables, showing 
the number if subjects with medical history findings that started before signing of the 
informed consent and that are considered relevant to the study. 
Medical history findings, of the pre-specified CRF items as listed, will be coded by Medical 
Dictionary for Regulatory Activities (MedDRA) codes. Medical history will be presented for 
each MedDRA Primary System Organ Class (SOC) and Preferred Term (PT) by treatment 
group and overall based on FAS. Medical History of the category “Other” will be presented if 
the frequency of PT is 5% or higher.  In addition, medical history will be presented by the 
pre-specified terms as listed in the CRF: 
•
Arterial hypertension (% yes)
•
Congestive heart failure (left ventricular dysfunction) (% yes)
•
Myocardial infarction (% yes)
•
Percutaneous Coronary Intervention (% yes)
•
Coronary Artery Bypass Graft (% yes)
•
Stroke (% yes)
•
Transient Ischemic Attack (% yes)
•
Peripheral artery disease (% yes)
•
Non-CNS systemic embolism (% yes)
•
Venous thromboembolism (% yes)
•
COPD (% yes)
6.1.4 
TAVR details 
The following TAVR details will be summarized by treatment group in FAS. Summary 
statistics will be presented for metric variables and frequency tables will be presented for 
categorical variables as specified in 4.1 
•
TAVR due to subjects frailty (% yes)
•
EuroScore II (final) (continuous)
•
STS score (final) (continuous)
•
Brand name of aortic valve (categorical as specified in eCRF)
•
Size of aortic valve (continuous)
•
Valve in valve procedure (% yes)


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6.1.5 
Randomization timing 
Timing of randomization (number of days post TAVR) is summarized by treatment group in 
FAS. 
6.1.6 
Protocol deviations 
Protocol deviations will be summarized by treatment group in FAS. Frequency tables will be 
presented by type of deviation. 
6.1.7 
Prior and concomitant medications 
Frequency tables by ATC code will be provided for prior medications prior to randomization 
and for concomitant medication post-randomization. The summaries will be by treatment 
group and overall based on FAS. 
6.1.8 
Extent of exposure and Compliance 
All summaries related to intake of study medication will be by treatment group based on FAS. 
The treatment duration (date of last study medication – date of start first study medication +1) 
will be summarized descriptively. 
The time on study medication (treatment duration excluding days off study medication) will 
be calculated and summarized descriptively. 
6.2 
Efficacy 
The primary efficacy endpoint is death or first adjudicated thromboembolic event (DTE), 
defined as the adjudicated composite of 
•
All-cause death
•
Any stroke
•
Myocardial infarction (MI)
•
Symptomatic valve thrombosis
•
Pulmonary embolism (PE)
•
Deep vein thrombosis (DVT)
•
Non-central nervous system (CNS) systemic embolism
The endpoint definitions are located in sections 16.1 and 16.2 of the protocol. 
The secondary efficacy endpoints, analyzed hierarchically, are 


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•
The adjudicated composite of cardiovascular death (including unknown of
unexplained death), any stroke, myocardial infarction, symptomatic valve
thrombosis, pulmonary embolism, deep vein thrombosis, or non-CNS systemic
embolism
•
The net-clinical-benefit defined as the adjudicated composite of all-cause death,
any stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary
embolism, deep vein thrombosis, non-CNS systemic embolism (efficacy); life-
threatening, disabling and major bleeds (safety).
6.2.1 
Analysis of the efficacy endpoints
The analysis of the primary efficacy endpoint (DTE) and the secondary efficacy endpoints are 
performed on the FAS under the ITT scope. See chapter 5 for details.  
In order to preserve the type I error rate for efficacy testing, there is a hierarchy in testing for 
the efficacy endpoints, first a non-inferiority testing of the primary efficacy endpoint (DTE) is 
performed. If non-inferiority can be claimed for the rivaroxaban-based strategy a superiority 
testing of the primary efficacy endpoint (DTE) is performed. If superiority can be declared for 
the rivaroxaban-based strategy the secondary efficacy and net-benefit variables are tested 
sequentially in a hierarchical order, first the composite of cardiovascular death, any stroke, 
myocardial infarction, symptomatic valve thrombosis, pulmonary embolism, deep vein 
thrombosis, or non-CNS systemic embolism, second the net-clinical-benefit defined as the 
adjudicated composite of all-cause death, any stroke, myocardial infarction, symptomatic 
valve thrombosis, pulmonary embolism, deep vein thrombosis, non-CNS systemic embolism 
(efficacy); life-threatening, disabling and major bleeds (safety). These are tested at a one-sided 
significance level of 2.5% 
If there is strong evidence of non-proportionality, the estimation of time-dependent hazard 
ratios will be considered. 
The analysis of the primary efficacy endpoint is visualized in flowchart 1 in appendix I, the 
analysis of the secondary efficacy endpoints are visualized in flowchart 2 in appendix I. 
Details of the tests in the following sections. 
6.2.1.1 
Testing for non-inferiority 
Testing for superiority of the rivaroxaban-based strategy for the primary efficacy outcome is 
preceded by testing for non-inferiority, in the OT data scope, tested with the non-inferiority 
log rank test8. 
Using an  non-inferiority log rank test the following (inferiority) null hypothesis (H0) is tested 
at a one-sided significance level of 2.5%: 
H0: 
 (t) ≥ 1.20 for all time points t ≥ 0, (i.e. “the hazard for the primary efficacy
endpoint in the rivaroxaban-based treatment group is more than 20% larger than that 
in the antiplatelet-based control group regarding”) 
The one-sided alternative hypothesis (H1) is: 


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H1: 
 (t) < 1.20 for all time points t ≥ 0, (i.e. “the hazard in the rivaroxaban-based
treatment group for the primary efficacy endpoint is such that the 
  is below 1.20”)
The following decision rule to test the null hypothesis of inferiority is applied: 
With the estimated drift parameter   = / where Z is the LR statistic with its
Variance V (note that V ≈ events/4) and 
 = exp	(−), the upper 97.5% limit of the
confidence interval for 
  is calculated as
	
.	
  = exp − −
.
√ 	and will be compared with the NIM of 1.2. The
null hypothesis  :	 ≥1.2 will be rejected if	
.	
  < 1.2
If the null-hypothesis of inferiority (H0) is rejected and non-inferiority of the 
rivaroxaban-based strategy (relative to the antiplatelet-based strategy) with regard to 
the primary efficacy endpoint can be claimed, proceed to section 6.2.1.2. 
The following SAS code can be used to obtain the LR statistic: 
ods output LogRankHomCov=work.LRHC HomStats=work.HomStats ; 
proc  lifetest data=work.infile alpha=0.025 method=km notable ; 
time d2fDTE * DTE(0); 
strata treat /test=(logrank); 
run; 
*from ODS datasets to needed variables, and calculations;
data work.logrank (drop=treat);
merge work.lrhc (where=(treat='0') keep=treat _0 rename=(_0=V))
work.homstats (where=(treat='0') rename=(LogRank=Z) keep=LogRank 
treat); 
q=Z/V; 
HR=exp(-q); 
UL=exp (-(q-(1.96/sqrt(V)))); 
label 
Z="LR statistic" 
V="Variance of LR statistic" 
q="q" 
HR="HR" 
UL="Upper limit 0.975" 
; 
%put "on purpose no by statement for merge, 1 record per input dataset"; 
run; 
/* 
where 
work.infile = name of source dataset 
treat 
= randomization code 
DTE 
= death and thromboembolitic event 
d2fDTE 
= days to first DTE (since randomization) 
*/


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6.2.1.2 
Testing for superiority 
If, for the primary efficacy endpoint (DTE), non-inferiority of the rivaroxaban-based strategy 
can be claimed, superiority of the rivaroxaban-based strategy for the primary efficacy 
endpoint (DTE) is tested with the following hypothesis (H0) at the significance level of 2.5% 
H0: SRIV(t) = SAPT(t) for all time points t ≥ 0, (i.e. “there is no difference between the
rivaroxaban-based treatment group and the antiplatelet-based control group regarding 
the primary efficacy endpoint at all time points”) 
The one-sided alternative hypothesis (H1) is: 
H1: SRIV (t) > SAPT(t) for at least one time point t ≥ 0, and SRIV (t) ≥ SAPT(t) for all time
points ≥ 0 (i.e. “there is difference between the two groups in favor of the rivaroxaban-
based treatment group for the primary efficacy endpoint at all time points”) 
where SRIV denotes the event-free survival function of the rivaroxaban-based treatment group 
and SAPT denotes the event-free survival function of the antiplatelet-based treatment group.  
The following decision rule to test the null hypothesis is applied: 
According to the size of this study, it is justified to assume under H0 a sufficiently 
close approximation of the one-sided log-rank test to the normal distribution. If the z 
value from the one-sided log-rank test (for the difference SRIV(t) - SAPT(t)) is larger 
than the critical quantile from the normal distribution (z0.975 = 1.96), the null 
hypothesis is rejected in favor of the alternative hypothesis. 
Kaplan-Meier curves, one-sided log rank p-value, number of patients with event and 
incidence rate are 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. 
The following SAS code may be used: 
proc lifetest data=work.infile  notable; 
 time d2fDTE*DTE(0); 
 strata treat /test=(logrank); 
run; 
/* 
where 
work.infile = name of source dataset 
treat 
= randomization code 
DTE 
= death and thromboembolitic event 
d2fDTE 
= days to first DTE (since randomization) 
*/
If, for the primary efficacy endpoint (DTE), non-inferiority of the rivaroxaban-based strategy 
can be claimed and the assumption of proportional hazards is plausible (see section 6.2.1.3), 
Hazard ratio and corresponding two-sided 95% confidence intervals are estimated. This is 
based on a Cox proportional hazards model, and will be reported descriptively. The parameter 
estimate β (=ln(HR)), its standard error, p-value, and 95% Confidence Limits are calculated
according to the maximum partial likelihood method (ML), with Breslow’s approximation for 
ties (phreg). 


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The following SAS code may be used: 
proc phreg data=work.infile  ; 
model d2fDTE*DTE(0)=treat /risklimits ; 
run; 
/* 
where 
work.infile = name of source dataset 
treat 
= randomization code 
DTE 
= death and thromboembolitic event 
d2fDTE 
= days to first DTE (since randomization) 
*/
If superiority of DTE can be declared for the rivaroxaban-based strategy the secondary 
efficacy and net-benefit variables are tested for superiority sequentially in a hierarchical order, 
first the composite of cardiovascular death, any stroke, myocardial infarction, symptomatic 
valve thrombosis, pulmonary embolism, deep vein thrombosis, or non-CNS systemic 
embolism, second the net-clinical-benefit defined as the adjudicated composite of all-cause 
death, any stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary 
embolism, deep vein thrombosis, non-CNS systemic embolism (efficacy); life-threatening, 
disabling and major bleeds (safety).  
The superiority analysis are carried out under the ITT data scope. 
6.2.1.3 
Assessment plausibility of the proportional hazards assumption 
If the hypothesis of non-inferiority is accepted the plausibility of the proportional hazards 
assumption will be assessed by visually comparing the plot of the log of cumulative hazard , 
in the ITT data scope, between treatments. The following SAS code may be used: 
proc phreg data=work.infile (where=(treat=1)); 
model d2fDTE*DTE(0)=treat; 
baseline out=work.ch_t1 cumhaz=ch; 
run; 
proc phreg data=work.infile (where=(treat=0)); 
model d2fDTE*DTE(0)=treat; 
baseline out=work.ch_t0 cumhaz=ch; 
run; 
data work.log_ch; 
set 
work.ch_t1 
work.ch_t0; 
if ch ne 0 then log_ch=log(ch); 
run; 
proc sgrender data=work.log_ch template=comp_log_CH; 
dynamic xvar="d2fDTE" yvar="log_ch" groupvar="treat"; 
run; 
/* 
where 


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work.infile = name of source dataset 
treat 
= randomization code 
DTE 
= death and thromboembolitic event 
d2fDTE 
= days to first DTE (since randomization) 
comp_log_ch = proc template for a log of cumulativehazards plot 
*/ 
By additionally adding a time-varying covariate, an interaction between the predictor and the 
time the plausibility of proportional hazards is assessed, the following SAS code may be used: 
proc phreg data= work.infile; 
model d2fDTE * DTE (0)=treat treat_time; 
treat_time = treat*log(d2fDTE); 
proportionality_test: test treat_time; 
run; 
/* 
where 
work.infile = name of source dataset 
treat 
= randomization code 
DTE 
= death and thromboembolitic event 
d2fDTE 
= days to first DTE (since randomization) 
*/
6.3 
Pharmacokinetics / pharmacodynamics 
Not applicable. 
6.4 
Safety 
The primary safety endpoint 
The primary safety endpoint is primary bleeding event (PBE), defined as the composite of 
life-threatening, disabling or major bleeds classified according to the VARC definitions 
following the BARC classification. This is: Life-threatening or disabling bleeds; BARC type 
3b, 3c or 5 and for Major bleeds; BARC type 3a. 
The secondary safety endpoints 
The secondary safety endpoints are bleeding complications according to: 
•
The composite of TIMI major or minor bleeds
•
ISTH major bleeding
•
The composite of BARC 2, 3 or 5 bleeds
Investigator reported events 
•
Serious adverse events (SAEs)


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•
Adverse events of special interest
o Pericardial bleedings
o Pulmonary alveolar bleedings/pulmonary bleeding
•
Non-serious Adverse Events
6.4.1 
Analysis of the safety endpoints 
6.4.1.1 
Analysis of the primary safety endpoint 
The descriptive analysis of the primary safety endpoint (PBE) and the secondary safety 
endpoints are performed on the FAS under the ITT scope  
Kaplan-Meier curves, one-sided log rank p-value, number of patients with event and 
incidence rate are 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.. 
This is done analogue to the primary efficacy endpoint as described in section  6.2.1.2 
If the assumption of proportional hazards is plausible (see section 6.2.1.3), Hazard ratio and 
corresponding two-sided 95% confidence intervals are estimated.. This is done analogue to 
the primary efficacy endpoint as described in section 6.2.1.2.  
The analysis of the primary safety endpoint is visualized in flowchart 3 in appendix I. 
6.4.1.2 
Analysis of the secondary safety endpoints 
The secondary safety endpoints are descriptively analyzed similar to those for secondary 
efficacy variables, without any sequential order. 
The analysis of the secondary safety endpoints are visualized in flowchart 2 in appendix I. 
6.4.1.3 
Analysis of the investigator reported endpoints 
SAEs are descriptively reported (frequencies of events and frequencies of patients with any 
event) by MedDRA SOC and PT. 
Adverse events of special interest (pericardial bleedings and pulmonary alveolar 
bleedings/pulmonary bleedings) are descriptively reported (frequencies of events and 
frequencies of patients with any event) 
Non-serious AEs, are descriptively reported (frequencies only) by MedDRA SOC, outcome 
of event, reasonable causal relationship to ASA, -clopidogrel, -rivaroxaban and -VKA, and 
Action taken with ASA, - clopidogrel, -rivaroxaban and –VKA. 
6.5 
Other analysis 
Pre-NOAF and post-NOAF analysis are carried out as an exploratory analysis for the primary 
efficacy variable (DTE). On treatment, pre-NOAF and post-NOAF analysis are carried out as 
an exploratory analysis for the primary safety (PBE) variable. The analyses are done analogue 
to the superiority HR analysis as described in 6.2.1.2 and are visualized in flowchart 4. 


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The separate components of the adjudicated primary efficacy and safety endpoint are 
analyzed exploratory and analogue to the superiority HR analysis as described in 6.2.1.2. The 
separate components of the adjudicated primary efficacy and safety endpoint are:, 
•
All-cause death
•
Any stroke
•
Myocardial infarction
•
Symptomatic valve thrombosis
•
Pulmonary embolism
•
Deep vein thrombosis
•
Non-CNS systemic embolism
•
Life-threatening or disabling bleeds (BARC type 3b, 3c or 5)
•
Major bleeds (BARC type 3a).
The following details of NOAF are summarized by treatment: 
•
Subjects with NOAF reported on ECG but without medication switch
•
Subjects with medication switch but without ECG evidence of NOAF
•
Subjects with both ECG evidence and medication switch
Medication switch here means: requiring treatment with high dose oral anticoagulation as 
specified in 3.2. 
Mean transaortic valve pressure gradient is measured by echocardiogram (TTE or TEE) at 
screening and at approximately 360 days after randomization. The difference between 360 
days and screening is derived and analyzed exploratory by using a t-test. 
The analysis the other variables are visualized in flowchart 2 in appendix I. 
6.6 
Subgroup analysis 
The following subgroup variables based on baseline demographics are planned according to 
the subgroup analysis:  
•
Region (Northern America, Eastern Europe, Western Europe)
•
Sex (male, female)
•
Age (< Median, ≥ Median)
•
Weight (< Median, ≥ Median)
•
BMI (Underweight (<18.5), Normal (≥18.5 & <25), Overweight (≥25 & <30),
Obese (≥30)


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•
Valve type (balloon-expandable, self-expandable)
•
Valve-in-valve procedure
•
Surgical Risk Scores:
o Society of Thoracic Surgeons’ (STS) risk score (Low  (STS<3), Intermediate
(3<=STS<=8), High (STS>8))
o EuroSCORE II (low risk (<5 %), intermediate risk (≥5% & ≤ 10%), high risk
(>10%)
•
Renal function (Estimated Glomerular Filtration Rate):
o <30 mL/min/1.73 m2
o ≥30 & <50 mL/min/1.73 m2
o ≥50 & <80 mL/min/1.73 m2
o ≥80 mL/min/1.73 m2
•
Hypertension (yes, no)
•
Diabetes mellitus (yes, no)
•
History of a prior stroke (ischemic or unknown type) or non-CNS systemic
embolism (yes, no)
•
Prior MI (yes, no)
•
Previous revascularization (CABG or PCI)
•
CHADS2 and CHA2DS2-VASc scores (< Median, ≥ Median)
•
HAS-BLED (< Median, ≥ Median)
•
TAVR done because of subjects frailty (yes/no)
6.6.1 
Analysis of the subgroups 
Subgroup analysis is done outside the scope of the main analysis. 
Subgroups analysis for the primary efficacy and safety variables are based on the ITT data 
scope. The subgroup analyses are presented descriptively without formal hypotheses testing. 
Homogeneity of treatment effect in subgroups, both in magnitude and direction, is 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. The 
following SAS code may be used (using subgroup male as example): 
proc phreg data= work.infile; 
model d2fDTE * DTE (0)=treat male treat*male; 
run; 
/* 
where 
work.infile = name of source dataset 


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treat 
= randomization code 
DTE 
= death and thromboembolitic event 
d2fDTE 
= days to first DTE (since randomization) 
male = 1 for male and 0 for female 
*/ 
For subgroups the HR per subgroup is derived and the accompanying  p-value for interaction. 
The following SAS code may be used: 
proc phreg data=work.infile2; 
where male = 1; 
model d2fDTE*DTE(0) = treat /risklimits; 
run; 
proc phreg data=work.infile2; 
where male = 0; 
model d2fDTE*DTE(0) = treat /risklimits; 
run; 
/* 
where 
work.infile = name of source dataset 
treat 
= randomization code 
DTE 
= death and thromboembolitic event 
d2fDTE 
= days to first DTE (since randomization) 
male = 1 for male and 0 for female 
*/ 
The p-value for interaction can also be obtained from the first phreg statement  in this section 
(with the interaction term). 
A forest plot will be created to visualize the results.  
The analysis of the subgroups are visualized in flowchart 5 in appendix I. 
As the number of subgroup analyses is 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 variables will be interpreted as “flags” to prompt further 
investigation. This further investigation may include the likelihood ratio test proposed by Gail 
and Simon to test for qualitative interaction. 9,10


 
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7. 
Document history and changes in the planned statistical analysis 
None. 
 
 
 
 
 


 
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8. 
Appendix I Flowcharts 
8.1 
Flowchart 1: Primary efficacy 
 
 
 
 


 
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8.2 
Flowchart 2: Secondary efficacy, secondary safety and other variables 
 
 
 


 
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8.3 
Flowchart 3: Primary safety 
 
 
 
 


 
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8.4 
Flowchart 4: Primary efficacy and primary safety in other data scopes 
 
 
 
 


 
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8.5 
Flowchart 5: Subgroups 
 
 
 
 
 


 
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9. 
References 
                                               
1 Otto CM, Prendergast B. Aortic-valve stenosis--from patients at risk to severe valve obstruction. N Engl J Med. 
2014;371(8):744-56. 
2 Amat-Santos IJ, Rodes-Cabau J, Urena M, DeLarochelliere R, Doyle D, Bagur R, et al. Incidence, predictive 
factors, and prognostic value of new-onset atrial fibrillation following transcatheter aortic valve implantation. J 
Am Coll Cardiol. 2012;59(2):178-88. 
3 Green P, Woglom AE, Genereux P, Daneault B, Paradis JM, Schnell S, et al. The impact of frailty status on 
survival after transcatheter aortic valve replacement in older adults with severe aortic stenosis: a single-center 
experience. JACC Cardiovasc Interv. 2012;5(9):974-81. 
4 Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, et al. Transcatheter versus surgical 
aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364(23):2187-98. 
5 Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al. Transcatheter aortic-valve 
implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363(17):1597-607. 
6 Athappan G, Gajulapalli RD, Sengodan P, Bhardwaj A, Ellis SG, Svensson L, et al. Influence of transcatheter 
aortic valve replacement strategy and valve design on stroke after transcatheter aortic valve replacement: a meta-
analysis and systematic review of literature. J Am Coll Cardiol. 2014;63(20):2101-10. 
7 Tay EL, Gurvitch R, Wijesinghe N, Nietlispach F, Wood D, Cheung A, et al. A highrisk period for 
cerebrovascular events exists after transcatheter aortic valve implantation. JACC Cardiovasc Interv. 
2011;4(12):1290-7. 
8 Sin-ho Jung , Sun J. Kang , Linda M. McCall & Brent Blumenstein 
(2005) Sample Size Computation for Two-Sample Noninferiority Log-Rank Test, Journal of 
Biopharmaceutical Statistics, 15:6, 969-979, DOI: 10.1080/10543400500265736 
9 Gail M., Simon R. Testing for qualitative interactions between treatment effects and patient 
subsets.  Biometrics. 1985 Jun, 41(2):361-72. 
10 Dmitrienko A., Molenberghs G., Chuang-Stein C., and Offen W. Analysis of Clinical Trials Using SAS:  A 
Practical Guide. Cary, NC,  SAS Institute Inc., 2005