Conditions: Prevention & Control
Keywords: Cardiovascular events Rivaroxaban Xarelto Anticoagulant Blood thinner Aspirin ASA Coronary artery disease CAD Peripheral artery disease PAD Artery disease Coronary artery bypass graft Stroke Heart attack Angina Arterial vascular disease Myocardial infarction MI Cardiovascular Death CV Death Heart disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27395
Healthy volunteers: no

Brief summary:
The primary objectives of this study are:

* To determine whether rivaroxaban 2.5 mg twice daily (bid) + aspirin 100 mg once daily (od) compared with aspirin 100 mg od reduces the risk of a composite of myocardial infarction, stroke, or cardiovascular death in subjects with coronary artery disease (CAD) or peripheral artery disease (PAD);
* To determine whether rivaroxaban 5 mg bid compared with aspirin 100 mg od reduces the risk of a composite of myocardial infarction, stroke or cardiovascular death in subjects with CAD or PAD.

Detailed description:

Arms:
arm 1: Participants received rivaroxaban 2.5 mg twice daily (bid) and aspirin 100 mg once daily (od). All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a proton pump inhibitor (PPI), were additionally randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part. arm 2: Participants received rivaroxaban 5 mg bid and aspirin placebo od. All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a PPI, were additionally randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part. arm 3: Participants received rivaroxaban placebo bid and aspirin 100 mg od. All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a PPI, were randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.

Interventions: intervention 1: Rivaroxaban (Xarelto, BAY59-7939) intervention 2: Rivaroxaban (Xarelto, BAY59-7939) intervention 3: Aspirin intervention 4: Aspirin placebo intervention 5: Rivaroxaban placebo intervention 6: Pantoprazole intervention 7: Pantoprazole placebo
Intervention descriptions: intervention 1: Tablet, 2.5 mg, twice daily, oral intervention 2: Tablet, 5 mg, twice daily, oral intervention 3: Tablet, 100 mg, once daily, oral intervention 4: Aspirin matching placebo, once daily, oral intervention 5: Rivaroxaban matching placebo, twice daily, oral intervention 6: Tablet, 40 mg, once daily, oral, for participants who were not on a PPI and who were randomized to pantoprazole intervention 7: Pantoprazole matching placebo, once daily, oral, for participants who were not on a PPI and who were randomized to pantoprazole placebo

Protocol document:
Prot_002.pdf: 
 
Document Type: Study Protocol 
Official Title: 
A randomized controlled trial of rivaroxaban for the prevention 
of major cardiovascular events in patients with coronary or 
peripheral artery disease (COMPASS - Cardiovascular OutcoMes 
for People using Anticoagulation StrategieS) 
NCT Number: 
NCT01776424 
Document Date: 
12-SEP-2017 
 
 


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Cover page of the integrated protocol
A randomized controlled trial of rivaroxaban for the prevention of major 
cardiovascular events in patients with coronary or peripheral artery disease
(COMPASS - Cardiovascular OutcoMes for People using Anticoagulation StrategieS)
This protocol version is an integration of the following documents / sections:
Revised protocol, Version 1.1, dated 28 NOV 2012
Amendment no. 6 (global) (described in Section 13.1) forming integrated protocol 
Version 2.0, dated 03 JUL 2014
Amendment no. 8 (global) (described in Section 13.2) forming integrated protocol 
Version 3.0, dated 19 AUG 2015
Amendment no. 11 (global) (described in Section 13.3) forming integrated protocol 
Version 4.0, dated 12 SEPT 2017
Amendments not included in the consecutive numbering of amendments are 
local amendments not forming part of this integrated global protocol. Local amendments 
were as filed in Japan (Amendments 1, 2, 7, 9 and 10), Sweden (Amendment 3), Germany 
(Amendment 4), and United Kingdom (Amendment 5).
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Title page - amended
A randomized controlled trial of rivaroxaban for the prevention of major cardiovascular 
events in patients with coronary or peripheral artery disease (COMPASS - Cardiovascular 
OutcoMes for People using Anticoagulation StrategieS)
Rivaroxaban for the prevention of major cardiovascular events in CAD or PAD
(COMPASS)
Test drug:
BAY 59-7939 / Rivaroxaban / Xarelto®
Study purpose:
Comparative combination drug study for new indication
Clinical study phase:
III
Date:
12 SEPT 2017
EudraCT no.:
2012-004180-43
Version no.: 4.0
Study no.:
BAY 59-7939/15786 
Coordinating center
 
Canada
Sponsor
Non-US territory: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer 
Boulevard, P.O. Box 915, Whippany NJ 07981-0915, USA
Coordinating center:
 Canada
Tel: 
Sponsor Clinical Leader1:
Bayer U.S. LLC
Development, Pharmaceuticals
Thrombosis & Hematology Therapeutic Area
11 Waterview Blvd., Location 2095B
Parsippany, New Jersey 07054 USA
Tel:
The study will be conducted in compliance with the protocol, International Conference on 
Harmonization – Good Clinical Practice (ICH-GCP) and any applicable regulatory 
requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether in 
part or in full - to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed.  Hence, 
the appearance of product names without these symbols does not imply that these names are not protected.
                                                
changed as per Amendment 11. (See Section 13.3.1)
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Signature of principal investigators 
The signatories agree to the content of the fmal clinical study protocol as presented. 
Name: 
Role: 
Date: 
Name:
Role: 
Date 
Signature: 
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Signature of site investigators
The signatories agree to the content of the final clinical study protocol as presented.
Name:
Role:  
Site investigator
Date:
Signature:
Name:
Role:  
Site investigator  
Date:
Signature:
Signed copies of this signature page are stored in 
 
 and the sponsor’s study files and in the respective center’s investigator site file.
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Signature of the sponsor's medically responsible person -amended 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
Role: 
changed as per Amendment I l. (See Section 13.3 .2) 
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Synopsis - amended
Title
A randomized controlled trial of rivaroxaban for the prevention of major 
cardiovascular events in patients with coronary or peripheral artery disease
(COMPASS - Cardiovascular OutcoMes for People using Anticoagulation 
StrategieS)
Short title
Rivaroxaban for the prevention of major cardiovascular events in CAD or 
PAD (COMPASS)
Clinical study phase
III
Study objectives
Primary objectives for rivaroxaban randomization

To determine whether rivaroxaban 2.5 mg twice daily (bid) + 
aspirin 100 mg once daily (od) compared with aspirin 100 mg od 
reduces the risk of a composite of myocardial infarction, stroke, or 
cardiovascular death in subjects with CAD or PAD

To determine whether rivaroxaban 5 mg bid compared with 
aspirin 100 mg od reduces the risk of a composite of myocardial 
infarction, stroke or cardiovascular death in subjects with CAD or 
PAD
Secondary objectives for rivaroxaban randomization

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 
100 mg od and rivaroxaban 5 mg bid alone reduces the risk of the 
composite of major thrombotic events: (1) coronary heart disease 
death, myocardial infarction, ischemic stroke, acute limb ischemia;
(2) cardiovascular death, myocardial infarction, ischemic stroke, 
acute limb ischemia compared with aspirin 100 mg od in subjects 
with CAD or PAD3

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 
100 mg od and rivaroxaban 5 mg bid alone reduces the risk of 
mortality in subjects with CAD or PAD
Objective for pantoprazole randomization

To determine whether pantoprazole 40 mg od compared with 
placebo reduces the risk of upper gastrointestinal bleeding, 
ulceration, and gastrointestinal obstruction or perforation in 
subjects with CAD or PAD receiving antithrombotic medications
Objective for Long-Term Open-Label Extension (LTOLE)

To make rivaroxaban 2.5 mg twice daily (bid) + aspirin 100 mg 
once daily (od) available to COMPASS trial subjects until the 
rivaroxaban treatment is commercially available for this indication
or for approximately 3 years from regulatory approval of LTOLE4
in a country, whichever comes first.5
                                                
3 Text revised as per Amendments 6 and 8. (See Sections 13.1.2 and 13.2.2)
4 The protocol amendment with the LTOLE addition.
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Test drugs
Rivaroxaban, aspirin, and pantoprazole
Name of active ingredient
Rivaroxaban, aspirin, and pantoprazole
Dose(s)

Rivaroxaban 2.5 mg, bid

Rivaroxaban 5.0 mg, bid

Aspirin 100 mg, od

Pantoprazole 40 mg, od
LTOLE

Rivaroxaban 2.5 mg bid + aspirin 100 mg od6
Route of administration
Per oral
Duration of treatment
Estimated average of 3-4 years
LTOLE: approximately 3 years 7
Reference drugs
Rivaroxaban placebo, aspirin placebo, and pantoprazole placebo
LTOLE: no reference drug8
Name of active ingredient
Not applicable
Dose(s)
Not applicable
Route of administration
Per oral
Duration of treatment
Estimated average of 3-4 years
Indication
Coronary or peripheral artery disease
Diagnosis and main criteria for 
inclusion
Subjects are eligible for  inclusion if they:

Meet criteria for CAD* and/or PAD9
*Subjects with CAD must also meet at least one of the following criteria:

Age 65 years, or

Age 65 years and documented atherosclerosis or 
revascularization involving at least 2 vascular beds§, or at least 2
additional cardiovascular risk factors:
1)
Current smoker (within 1 year of randomization)
                                                                                                                                                        
5 Text added as per Amendment 11. (See Section 13.3.1) 
6 Text added as per Amendment 11. (See Section 13.3.1)
7 Text added as per Amendment 11. (See Section 13.3.1)
8 Text added as per Amendment 11. (See Section 13.3.1)
9 Text added/deleted as per Amendment 6. (See Section 13.1.2)
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2)
Diabetes mellitus
3)
Renal dysfunction with estimated glomerular filtration rate 
60 ml/min
4)
Heart failure
5)
Non-lacunar ischemic stroke 1 month ago
§ Because CAD involves disease in the coronary vasculature, only one 
additional vascular bed is required: e.g. the aorta and arterial supply to the 
brain, gastro-intestinal tract, lower limbs, upper limbs, or kidneys.
LTOLE: all subjects randomized to the COMPASS trial willing to consent 
to LTOLE are eligible unless the subjects developed a condition considered 
by the investigator as exclusionary.10
Study design
Randomized, double-blind, controlled trial with a 3 x 2 partial factorial 
design
LTOLE: open label uncontrolled study11
Methodology
The study will comprise 4 periods:  screening, run-in, follow-up, and 
washout.
During the screening period, informed consent will be obtained and 
evaluations of subject eligibility will be performed.  The run-in period will 
occur during the 28 days 12 prior to initiation of study treatment, with the 
exception of subjects randomized Day 4-712 after coronary artery bypass 
surgery who will not require a run-in.  During run-in, subjects will 
discontinue any current anticoagulant therapy and will begin rivaroxaban 
placebo and 100 mg aspirin.  Treatment of subjects who comply with the 
run-in treatment and who remain committed to the study, as well as those 
who are randomized Day 4-712 after coronary artery bypass graft surgery 
will begin on Day 0, which will also signal the initiation of the follow-up 
period.  Subjects will be randomized 1:1 to pantoprazole or pantoprazole 
placebo and then will be randomized 1:1:1 to rivaroxaban and aspirin or 
their matching placebos as shown in the treatment regimen design below:
Randomized study treatments* 
Rivaroxaban 2.5 mg bid +
Aspirin 100 mg od +
Pantoprazole 40 mg od
Rivaroxaban 2.5 mg bid +
Aspirin 100 mg od +
Pantoprazole placebo
Rivaroxaban 5 mg bid + 
Aspirin placebo + 
Pantoprazole 40 mg od
Rivaroxaban 5 mg bid + 
Aspirin placebo +
Pantoprazole placebo
Rivaroxaban placebo + 
Aspirin 100 mg od +
Pantoprazole 40 mg od
Rivaroxaban placebo + 
Aspirin 100 mg od + 
Pantoprazole placebo
*Subjects who have a continuous need for use of a proton pump inhibitor at 
                                                
10 Text added as per Amendment 11. (See Section 13.3.1)
11 Text added as per Amendment 11. (See Section 13.3.1)
12 Text modified as per Amendments 6 and 8. (See Sections 13.1.2 and 13.2.2)
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baseline will undergo only a single randomization (to rivaroxaban 2.5 mg 
bid + aspirin 100 mg od, rivaroxaban 5 mg bid + aspirin placebo or 
rivaroxaban placebo + aspirin 100 mg od)
Subjects will be followed for the duration of the study irrespective of 
whether they are receiving study treatment or whether they experience an 
outcome event.  A final visit (Final Follow-up Visit) will mark the end of 
the follow-up period and will occur when a minimum of 2,200 subjects 
experience an event for the primary efficacy outcome. A final washout 
period visit (End of Washout Telephone Visit) will be conducted by 
telephone (performed 30 days after the Final Follow-up Visit).
LTOLE: initiation visit and a follow-up period13
Type of control
For rivaroxaban: active control (aspirin).  For pantoprazole: placebo
LTOLE: none14
Number of subjects12
Enrolled = approximately 29,940; randomized = approximately 27,400 in 
approximately 33 countries worldwide
Approximately 29,940 subjects will be enrolled; approximately 28,300 will 
be admitted to the run-in period and 2000 subjects will undergo coronary 
artery bypass graft but no run-in.  A non-compliance rate of 10% is 
anticipated for those subjects in the run-in period; thus, approximately 
27,400 subjects will be randomized (of which approximately 2000 subjects 
who underwent coronary artery bypass graft would be randomized without 
run-in) in approximately 33 countries worldwide.
LTOLE: COMPASS trial subjects are potentially eligible.15
Primary variable
The primary efficacy variable will be the time from randomization to the 
first occurrence of the primary efficacy outcome, the composite of 
myocardial infarction, stroke, or cardiovascular death.
The primary safety variable will be the time from randomization to the first 
occurrence of the primary safety outcome, a modified International Society 
on Thrombosis and Haemostasis major bleeding.
LTOLE: the same primary safety and efficacy variables will be collected in 
LTOLE.16
Plan for statistical analysis
Analysis of the primary efficacy variable for rivaroxaban or aspirin 
randomization will be based on the intention-to-treat principle. Primary 
hypotheses will be tested using stratified log-rank tests.  Relative risk 
reduction will be estimated with stratified Cox proportional hazards 
models.
LTOLE: all statistical analyses will be descriptive.17
                                                
13 Text added as per Amendment 11. (See Section 13.3.1)
14 Text added as per Amendment 11. (See Section 13.3.1)
15 Text added as per Amendment 11. (See Section 13.3.1)
16 Text added as per Amendment 11. (See Section 13.3.1)
17 Text added as per Amendment 11. (See Section 13.3.1)
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Table of contents
Cover page of the integrated protocol .................................................................................... 1
Title page - amended ................................................................................................................ 2
Signature of principal investigators........................................................................................ 3
Signature of site investigators ................................................................................................. 4
Signature of the sponsor’s medically responsible person – amended.................................. 5
Synopsis - amended .................................................................................................................. 6
Table of contents..................................................................................................................... 10
Table of Tables........................................................................................................................ 13
Table of Figures...................................................................................................................... 14
List of abbreviations - amended............................................................................................ 14
1.
Introduction ..................................................................................................................... 16
1.1
Background – amended.................................................................................................. 16
1.2
Study rationale ............................................................................................................... 17
1.2.1
Rivaroxaban - amended.............................................................................................. 17
1.2.2
Aspirin and anticoagulants - amended........................................................................ 18
1.2.3
Proposed rivaroxaban evaluation - amended.............................................................. 21
1.2.4
Long-Term Open-Label Extension - amended........................................................... 21
1.3
Benefit-risk assessment – amended ............................................................................... 22
2.
Study objectives – amended ........................................................................................... 23
3.
Investigators and other study participants................................................................... 24
3.1
Study committees - amended......................................................................................... 24
3.2
Study coordination......................................................................................................... 25
3.3
Other study personnel and administrative functions...................................................... 26
4.
Study design..................................................................................................................... 26
4.1
Design overview – amended.......................................................................................... 26
4.1.1
Subjects randomized after CABG surgery - amended................................................ 28
4.2
Primary efficacy and safety variables − amended ......................................................... 29
4.3
Justification of the design .............................................................................................. 29
4.3.1
Overall design rationale – amended ........................................................................... 29
4.3.2
Design rationale for Long-Term Open-Label Extension − amended......................... 30
4.4
Final follow-up visit and end of study-amended ........................................................... 30
5.
Study population - amended........................................................................................... 31
5.1
Eligibility − amended..................................................................................................... 32
5.1.1
Inclusion criteria - amended ....................................................................................... 32
5.1.2
Exclusion criteria - amended ...................................................................................... 33
5.1.3
Long-Term Open-Label Extension − amended.......................................................... 34
5.1.3.1
Inclusion criteria...................................................................................................... 34
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5.1.3.2
Exclusion criteria..................................................................................................... 34
5.2
Discontinuation of subjects from study treatment - amended........................................ 34
5.2.1
Replacement ............................................................................................................... 35
5.2.2
Long-Term Open-Label Extension − amended.......................................................... 35
5.3
Subject identification ..................................................................................................... 35
6.
Treatments ....................................................................................................................... 35
6.1
Treatments to be administered - amended ..................................................................... 35
6.1.1
Run-in - amended ....................................................................................................... 35
6.1.2
Randomization - amended.......................................................................................... 35
6.1.3
Treatment in Long-Term Open-Label Extension − amended .................................... 36
6.2
Identity of study treatment - amended ........................................................................... 36
6.3
Treatment assignment - amended .................................................................................. 36
6.4
Dosage and administration - amended........................................................................... 37
6.4.1
Dose modifications - amended ................................................................................... 37
6.4.2
Dose modifications and treatment guidance - amended............................................. 37
6.4.2.1
Guidance for the treatment of subjects who require an invasive procedure -
amended................................................................................................................... 38
6.4.2.2
Guidance for the treatment of subjects who require coronary artery bypass graft 
surgery – amended................................................................................................... 38
6.4.2.3
Guidance for the treatment of subjects who develop an acute coronary syndrome 
and those who require percutaneous coronary intervention with stenting –
amended................................................................................................................... 39
6.4.2.4
Guidance for the treatment of subjects who overdose on study 
rivaroxaban/rivaroxaban placebo – amended.......................................................... 40
6.4.2.5
Guidance for the treatment of subjects who experience a major bleed –amended . 40
6.4.2.6
Guidance for the treatment of subjects who develop a stroke and who are being 
considered for reperfusion therapy – amended ....................................................... 41
6.5
Blinding.......................................................................................................................... 41
6.6
Drug logistics and accountability - amended................................................................. 42
6.7
Treatment compliance.................................................................................................... 43
6.8
Post-study therapy - amended........................................................................................ 43
6.9
Prior and concomitant therapy - amended ..................................................................... 43
6.9.1
Combined CYP 3A4 and p-glycoprotein inhibitors and CYP 3A4 inducers -
amended...................................................................................................................... 44
6.9.2
Clopidogrel (or any other non-study antiplatelet treatment) - amended..................... 44
6.9.3
Anticoagulant treatment - amended............................................................................ 45
6.9.4
Proton pump inhibitor treatment - amended............................................................... 46
7.
Procedures and variables................................................................................................ 46
7.1
Schedule of procedures − amended ............................................................................... 46
7.1.1
Tabulated overview - amended................................................................................... 48
7.1.2
Timing of assessments................................................................................................ 55
7.1.2.1
Pre-screening visit ................................................................................................... 55
7.1.2.2
Screening and run-in visit(s) - amended.................................................................. 55
7.1.2.3
Randomization visit (Day 0 ± 5 days) - amended................................................... 56
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7.1.2.4
Follow-up visits....................................................................................................... 57
7.1.2.4.1
Routine follow-up visits (Visits 3, 5, and 7-15+) - amended............................... 57
7.1.2.4.2
Non-clinic assessments (Months 3 and 9 ± 4 weeks) .......................................... 58
7.1.2.4.3
Final Follow-up Visit (± 4 weeks) ....................................................................... 58
7.1.2.5
End of washout telephone visit (30 days post Final Follow-up Visit ± 5 days)...... 59
7.1.2.6
Long-Term Open-Label Extension − amended....................................................... 59
7.1.2.6.1
Initiation of Long-Term Open-Label Extension − amended ............................... 59
7.1.2.6.2
Follow-up of Long-Term Open-Label Extension − amended ............................. 60
7.1.2.6.3
Final visit of Long-Term Open-Label Extension................................................. 60
7.2
Population characteristics .............................................................................................. 60
7.2.1
Demographics............................................................................................................. 60
7.2.2
Medical history........................................................................................................... 61
7.2.3
Other baseline characteristics - amended ................................................................... 61
7.3
Efficacy - amended ........................................................................................................ 61
7.4
Pharmacokinetics / pharmacodynamics......................................................................... 62
7.5
Safety − amended........................................................................................................... 62
7.5.1
E6 Definition of (serious) adverse event - amended .................................................. 63
7.5.2
Causal relationship - amended.................................................................................... 63
7.5.3
Protocol-specific adverse event definitions................................................................ 63
7.5.3.1
Protocol-specific exceptions to SAE reporting - amended ..................................... 63
7.5.3.2
Reporting of (S)AEs - amended .............................................................................. 65
7.5.3.3
Adverse events of special safety interest - amended............................................... 65
7.5.3.4
Non-serious adverse events..................................................................................... 67
7.5.3.5
Pregnancies - amended............................................................................................ 67
7.5.4
Reporting of events to Bayer by 
 and compliance with regulatory authorities’ 
reporting requirements - amended.............................................................................. 67
7.6
Other procedures and variables...................................................................................... 67
7.7
Appropriateness of procedures / measurements............................................................. 68
8.
Statistical methods and determination of sample size ................................................. 68
8.1
General considerations................................................................................................... 68
8.2
Analysis sets and data scopes......................................................................................... 68
8.2.1
Analysis sets ............................................................................................................... 68
8.2.2
Data scopes................................................................................................................. 68
8.3
Variables – amended...................................................................................................... 69
8.3.1
Primary efficacy outcome........................................................................................... 69
8.3.2
Secondary efficacy outcomes - amended ................................................................... 69
8.3.3
Tertiary and other efficacy outcomes - amended ....................................................... 70
8.3.4
Primary safety outcome.............................................................................................. 70
8.3.5
Outcome for pantoprazole randomization - amended ................................................ 70
8.3.6
Subgroup variables - amended.................................................................................... 71
8.4
Statistical and analytical plans - amended ..................................................................... 71
8.4.1
Analysis of the primary efficacy outcome - amended................................................ 72
8.4.2
Analysis of the secondary efficacy outcomes - amended........................................... 74
8.4.3
Analysis of the tertiary efficacy outcomes ................................................................. 74
8.4.4
Analysis of the primary safety outcome..................................................................... 74
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8.4.5
Analysis of the outcome for pantoprazole randomization - amended........................ 74
8.4.6
Subgroup analyses - amended .................................................................................... 75
8.4.7
Handling of missing data............................................................................................ 76
8.4.8
Long-Term Open-Label Extension – amended .......................................................... 76
8.5
Planned interim analyses - amended.............................................................................. 77
8.6
Determination of sample size - amended....................................................................... 78
9.
Data handling and quality assurance ............................................................................ 80
9.1
Data recording................................................................................................................ 80
9.2
Monitoring ..................................................................................................................... 80
9.3
Data processing – amended............................................................................................ 81
9.4
Audit and inspection ...................................................................................................... 82
9.5
Archiving ....................................................................................................................... 83
10. Premature termination of the study .............................................................................. 83
11. Ethical and legal aspects................................................................................................. 83
11.1
Ethical and legal conduct of the study........................................................................... 83
11.2
Subject information and consent.................................................................................... 84
11.3
Publication policy- amended.......................................................................................... 85
11.4
Compensation for health damage of subjects / insurance.............................................. 85
11.5
Confidentiality ............................................................................................................... 85
12. Reference list - amended................................................................................................. 87
13. Protocol amendments...................................................................................................... 91
13.1
Amendment 6................................................................................................................. 91
13.1.1
Overview changes to the study................................................................................... 91
13.1.2
Changes to protocol text........................................................................................... 102
13.2
Amendment 8............................................................................................................... 145
13.2.1
Overview changes to the study................................................................................. 145
13.2.2
Changes to protocol text........................................................................................... 151
13.3
Amendment 11............................................................................................................. 180
13.3.1
Overview changes to the study................................................................................. 180
13.3.2
Changes to protocol text........................................................................................... 182
14. Appendices ..................................................................................................................... 202
14.1
COMPASS MIND substudy - amended ...................................................................... 202
Table of Tables
Table 4–1.  Randomized study treatments* ............................................................................. 27
Table 7–1.  Schedule of evaluations......................................................................................... 48
Table 7–2 Schedule of evaluations after DSMB recommendation in Feb 2017...................... 52
Table 7–3 Schedule of LTOLE Procedures ............................................................................. 54
Table 7–4.  Adverse events of special interest ......................................................................... 66
Table 8–1.  Events calculations................................................................................................ 79
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Table of Figures
Figure 8–1: Hypothesis testing problem .................................................................................. 72
Figure 14–1: Covert brain infarct (arrow) on MR imaging (T-1 sequence) .......................... 202
List of abbreviations - amended
ACE
Angiotensin converting enzyme
AE
Adverse event
bid
Twice daily
BP
Blood pressure
bpm
Beats per minute
CABG
Coronary artery bypass graft
CAD
Coronary artery disease
CI
Confidence interval
cm
Centimeter
CRF
Case report form (either paper or electronic)
CT
Computed tomography
CV
Cardiovascular
dL
Deciliter
DNA
Deoxyribonucleic acid
DSMB
Data Safety Monitoring Board 
DSS
Digit Symbol Substitution
DVT
Deep vein thrombosis
e.g.
Exempli gratia, for example
eGFR
Estimated glomerular filtration rate
EQ-5D
European Quality of Life-5 Dimensions
EU
European Union
FLAIR
Fluid Attenuated Inversion Recovery
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
GPV
Global Pharmacovigilance
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
i.e.
Id est, that is
IEC
Independent ethics committee
in
Inch
INR
International normalized ratio
IRB
Institutional review board
IT
Information technology
Hb
Hemoglobin
HIV
Human immunodeficiency virus
HR
Hazard ratio
ISTH
International Society on Thrombosis and Haemostasis
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kg
Kilogram
Lb
LTOLE
Pound
Long-term open-label extension18
MACE
Major adverse cardiac event19
MD
Medical director/doctor
MI
Myocardial infarction
min
Minute
mg
Milligram
mL
Milliliter
mmHg
Millimeter of mercury
MRI
Magnetic resonance imaging
MoCA
Montreal Cognitive Assessment
MRU
Medical resource utilization
NL
National Leaders
NYHA
New York Heart Association
od
Once daily
PAD
Peripheral artery disease
PASS
Power Analysis and Sample Size software
PCI
Percutaneous coronary intervention
PE
Pulmonary embolism
P-gp
P-glycoprotein
PPI
Proton pump inhibitor20
OR
Odds ratio
QA
Quality assurance
RRR
Relative risk reduction
SAE
Serious adverse event
SAGE
Standard Assessment of Global-Activities in the Elderly
SAP
Statistical analysis plan
SAS
Statistical Analysis System
SUSAR
Serious unexpected suspected adverse reaction 
USA
United States of America
US FDA
United States Food and Drug Administration
Xa
Activated coagulation factor X
                                                
18 Text added as per Amendment 11. (See Section 13.3.1)
19 Text added as per Amendment 11. (See Section 13.3.1)
20 Text added as per Amendment 11. (See Section 13.3.2)
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1.
Introduction
1.1
Background – amended
Globally an estimated 17.5 million people died from cardiovascular disease in 2005 (30% of 
all deaths) and this number is projected to increase to 20 million by 2015.(1)
Coronary artery disease (CAD) is the most common cause of cardiovascular disease.  One-
third to one-half of middle-aged males and females in high income countries are expected to 
develop manifestations of CAD during their lifetime and the number of patients with chronic 
CAD is rising globally.  Although CAD mortality rates have declined in high income 
countries over the past few years they have risen sharply in Asia, Latin America, the Middle 
East, and in India and China. Coronary heart disease remains responsible for about one-third 
of deaths in persons over the age of 35.(1,2)  
Peripheral artery disease (PAD) of the lower extremities while often undiagnosed is a 
powerful risk marker of cardiovascular disease.(3)  The global prevalence of PAD is less well 
studied than that of CAD but screening studies suggest that approximately 20% of adults older 
than 55 years have objective evidence of PAD.(4)  The disease prevalence is strongly age-
related and like CAD the numbers of affected patients is rising because of the aging of the 
population.  Best available estimates suggest that 27 million individuals in Europe and North 
America have PAD and it is likely that this number can be multiplied by at least 3- to 6-fold to 
estimate the global burden of disease.(5) The severity of PAD is a major determinant of 
subsequent risk of cardiovascular events and mortality.  
Aspirin, statins, and angiotensin converting enzyme (ACE) inhibitors are effective and widely 
used for the prevention of cardiovascular events in patients with CAD and PAD but the risk of 
vascular events remains high despite these treatments.   A new, safe, and convenient 
antithrombotic therapy that further improves efficacy when it is added to or replaces aspirin 
could have a major impact in reducing the individual, community, and global burden of 
disability and death due to cardiovascular disease.  
Rivaroxaban is an orally active anticoagulant that selectively targets activated coagulation 
factor X (Xa), thereby inhibiting thrombin generation and thrombus formation.  Rivaroxaban 
has been demonstrated in large phase 3 randomized controlled trials to be a highly effective 
antithrombotic treatment for the prevention and treatment of venous thromboembolism, the 
prevention of stroke and systemic embolism in patients with atrial fibrillation, and the 
prevention of major cardiovascular events in patients with a recent acute coronary syndrome. 
The evidence of efficacy of rivaroxaban for the prevention of atherothrombotic events on a 
background of dual antiplatelet therapy in patients with recent acute coronary syndrome 
supports the hypothesis that it may also be effective for prevention of atherothrombotic events 
in patients with established CAD or PAD, receiving usual care.21  
                                                
21 Text modified as per Amendment 6. (See Section 13.1.2)
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Further information concerning the results of the rivaroxaban trials is provided in 
Section 1.2.1.  Details concerning the pharmacology of rivaroxaban are provided in the 
investigator's brochure, located in the Manual of Operations. 
The trial described herein, Cardiovascular OutcoMes for People using Anticoagulation 
StrategieS (COMPASS), is a randomized double-blind trial utilizing a 3 x 2 partial factorial 
design that will evaluate the efficacy and safety of rivaroxaban 2.5 mg twice daily (bid) + 
aspirin 100 mg once daily (od) versus aspirin 100 mg od and rivaroxaban 5 mg bid versus 
aspirin 100 mg od for the prevention of myocardial infarction, stroke, and cardiovascular 
death in patients with established CAD or PAD, who are receiving usual care.  In the (partial 
factorial) randomization, patients who do not have a continuous need for use of a proton pump 
inhibitor (PPI) will be randomized to receive pantoprazole 40 mg od or placebo for the 
prevention of major upper gastrointestinal complications, and then randomized to receive 
rivaroxaban in combination with aspirin, rivaroxaban alone, or aspirin alone.22
Long-Term Open-Label Extension – amended
On February 6, 2017, the COMPASS Data Safety Monitoring Board (DSMB) recommended 
discontinuation of the rivaroxaban/aspirin arms of the COMPASS trial because of a clear 
benefit of one of the two rivaroxaban-containing arms. The DSMB recommendation was 
made because for rivaroxaban 2.5 mg bid + aspirin 100 mg od, the z-value (test statistic of the 
log-rank test) for efficacy had crossed the critical value for early efficacy as outlined in the 
DSMB charter consistently over a 3-month period, and the z-value for rivaroxaban 5 mg bid 
had reached conventional significance for efficacy. The Steering Committee concurred with 
the recommendation of the DSMB, and the sponsor decided to stop the rivaroxaban/aspirin 
arms of the study based on the recommendation of the DSMB and the Steering Committee. 
The sponsor is making rivaroxaban 2.5 mg bid + aspirin 100 mg od available early for 
COMPASS trial subjects as part of a long-term open-label extension (LTOLE) protocol 
amendment. The dedicated LTOLE sections in this document describe LTOLE activities only; 
activities related to the pantoprazole/placebo arm remain unchanged with the exception of the 
removal of the washout visit. LTOLE activities will be coordinated with those of the ongoing 
pantoprazole/placebo arms of the trial where possible until pantoprazole/placebo part of the 
trial is completed.23
1.2
Study rationale
1.2.1
Rivaroxaban - amended
Rivaroxaban has been tested in randomized controlled trials involving more than 80,00024
patients and has been used by millions of patients worldwide.  
A pooled analysis of 4 trials comprising the RECORD program involving 12,729 patients 
undergoing hip or knee arthroplasty demonstrated that rivaroxaban given at a dose of 10 mg 
                                                
22 Text modified as per Amendment  6. (See Section 13.1.2)
23 Text added as per Amendment 11. (See Section 13.3.1)
24 Text modified as per Amendments 6 and 8.  (See Sections 13.1.2 and 13.2.2)
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od compared with enoxaparin given at a dose of 30 mg bid or 40 mg od, significantly reduced 
the risk of symptomatic venous thromboembolism and mortality (odds ratio [OR] 0.48; 95% 
confidence interval [CI]: 0.30 to 0.76), without increasing the risk of major or clinically 
relevant non-major bleeding (OR 1.17; 95% CI: 0.93 to 1.46).(6)  
The EINSTEIN venous thromboembolism treatment trials involving 9,447 patients with 
venous thromboembolism demonstrated that rivaroxaban 15 mg bid for 3 weeks followed by 
20 mg od compared with initial low-molecular-weight heparin followed by warfarin 
(International Normalized Ratio [INR] 2.0 to 3.0) was associated with a similar or reduced 
risk of recurrent venous thromboembolism (deep venous thrombosis [DVT] trial, hazard ratio
[HR] 0.68; 95% CI: 0.44 to 1.04; pulmonary embolism [PE] trial, HR 1.12; 95% CI: 0.75 to 
1.68) with a similar or reduced rate of major bleeding during up to 12 months (DVT trial, HR 
0.65; 95% CI: 0.33 to 1.30; PE trial, HR 0.49; 95% CI: 0.31 to 0.79).(7,8)  In the EINSTEIN 
extension study, rivaroxaban compared with placebo reduced the risk of recurrent venous 
thromboembolism by more than 80% (HR 0.18; 95% CI 0.09-0.39) at the expected cost of an 
increase in major bleeding (4 versus 0 events).(8)
The ROCKET AF trial involving 14,264 patients with atrial fibrillation at high risk of stroke 
demonstrated that rivaroxaban 20 mg od (15 mg od in patients with an estimated glomerular 
filtration rate of 30 to 49 ml/min) compared with warfarin (INR 2.0 to 3.0) was non-inferior 
for the prevention of stroke or systemic embolism (HR 0.79; 95% CI: 0.66-0.96), with a 
significant reduction in life-threatening, intracranial, and fatal bleeding and a favorable effect 
on mortality.(9)
The ATLAS TIMI-51 study demonstrated that rivaroxaban 2.5 mg or 5 mg bid compared with 
placebo reduced the risk of myocardial infarction, stroke, or cardiovascular death by 16% (HR 
0.84, 95% CI 0.74-0.96, p=0.008) in patients with a recent myocardial infarction, most of 
whom (92%) were also receiving dual antiplatelet therapy.  The reduction in the primary 
efficacy outcome was driven by a reduction in both cardiovascular death and myocardial 
infarction, and rivaroxaban was also associated with 31% reduction in stent thrombosis (HR 
0.69; 95% CI: 0.61-0.93).  Rivaroxaban increased major and intracranial bleeding, but not 
fatal bleeding. (10)  On a background of aspirin alone, rivaroxaban compared with placebo 
produced consistent benefits and appeared to be associated with no excess of major bleeding, 
although this was based on modest numbers of patients.
1.2.2
Aspirin and anticoagulants - amended
A large body of evidence from randomized controlled trials has established the efficacy of 
antithrombotic therapies for the prevention of cardiovascular events in high risk individuals. 
Data from the Antithrombotic Trialists Collaboration meta-analysis demonstrate the efficacy 
of antiplatelet therapy for prevention of cardiovascular events.(11) Aspirin reduced the risk of 
myocardial infarction, stroke, or cardiovascular death by about one-quarter in patients with 
established coronary, cerebral, and PAD.  A similar magnitude of benefit was evident across 
the different vascular beds. 
Aspirin has also been demonstrated to be effective for the prevention of graft failure following 
coronary artery bypass graft (CABG) surgery.(11) Despite these results, however 1 in 3 
patients undergoing CABG surgery with the placement of two or more graft have at least one 
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blocked graft at 1 year of follow-up.(12)  Graft failure is an independent predictor of 
myocardial infarction and death following CABG surgery.  
The CAPRIE trial demonstrated that clopidogrel compared with aspirin reduced the risk of 
myocardial infarction, stroke, or cardiovascular death by additional 10% in patients with 
coronary, cerebral, or PAD.(13)  Increasing the intensity of antiplatelet therapy by using the 
combination of aspirin and clopidogrel (dual antiplatelet therapy) compared with aspirin alone 
further reduced the risk of major cardiovascular events by 20% to 30% in patients with a 
recent acute coronary syndrome and in those undergoing percutaneous coronary intervention 
with stent insertion.(14)  The replacement of clopidogrel by more potent P2Y(12) receptor 
antagonists such as prasugrel and ticagrelor has provided even greater benefit during the first 
12 to 18 months after an acute coronary event.(15,16)  However, a benefit of long term dual 
antiplatelet therapy (beyond the first 12-18 months) has not been demonstrated. The 
CHARISMA trial did not demonstrate a benefit of long-term aspirin and clopidogrel therapy 
(median 28 months) in patients with stable coronary, cerebral, or PAD or in those at high risk 
of atherothrombotic vascular events, although a benefit was suggested in the subgroup of 
patients with symptomatic cardiovascular disease.(17)
Other studies have investigated the potential benefits of combined antiplatelet therapy for 
long-term prevention of cardiovascular disease. The TRA 2 P-TIMI 50 study demonstrated 
that the platelet protease-activated receptor 1 antagonist, vorapaxar added to standard therapy 
that included aspirin and clopidogrel, compared with standard therapy alone reduced the risk 
of myocardial infarction, stroke, or cardiovascular death by 13% at 3 years25 in patients with a 
history of myocardial infarction, ischemic stroke, or PAD, but at the cost of an increase in 
major and intracranial bleeding.(18)  The PEGASUS trial demonstrated that 33 months of 
treatment with ticagrelor (90 mg twice-daily or 60 mg twice-daily) compared with placebo 
reduced the risk of cardiovascular death, myocardial infarction, or stroke by 15-16% 
(ticagrelor 90 mg: 7.85%, ticagrelor 60 mg: 7.77%, placebo 9.04%; p=0.008 and p=0.004, 
respectively) in patients with a history of myocardial infarction 1 to 3 years earlier. This came 
at the cost of a 2-3 fold increase in major bleeding (ticagrelor 90 mg: 2.60%, ticagrelor 60 mg: 
2.30%, placebo 1.06%; p<0.01 for each dose vs. placebo), and there was no reduction in total 
mortality (ticagrelor 90 mg: 5.15%, ticagrelor 60 mg: 4.69%, placebo 5.16%; p=0.99 and 
p=0.14, respectively). (43)26
The DAPT trial randomized 9,961 patients with a history of coronary stenting with a drug 
eluting stent who had completed 12 months of dual antiplatelet therapy with a thienopyridine 
and aspirin to receive continuing clopidogrel 75 mg once daily or prasugrel 10 mg once daily 
or placebo for another 18 months. All patients continued receiving aspirin. Continuing 
treatment with a thienopyridine as compared with placebo reduced the rates of stent 
thrombosis by 71% (0.4% vs. 1.4%, p<0.001) and the composite, death, MI or stroke by 29% 
(4.3% vs. 5.9%, p<0.001) but at the cost of excess moderate or severe bleeding (2.5% vs. 
                                                
25 Text modified as per Amendment 6. (See Section 13.1.2)
26 PEGASUS trial data added as per Amendment 8. (See Section 13.2.2)
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1.6%, p=0.001) and a borderline significant 36% increase in all-cause death from any cause 
(2.0% vs. 1.5%, p=0.05). (44)27
Excess mortality seen with extended dual antiplatelet therapy in the DAPT trial was 
confirmed in a subsequent meta-analysis of 10 randomized trials including 31,666 patients 
who had undergone coronary artery stenting comparing different durations of dual antiplatelet 
therapy. Shorter duration dual antiplatelet therapy was associated with an 18% reduction in 
all-cause mortality (HR 0.82, 95% CI 0.69-0.98; p=0.02), predominantly due lower non-
cardiac mortality (HR 0.67, 0.51-0.89; p=0.006), with similar cardiac mortality (HR 0.93, 
0.73-1.17; p=0.52). Shorter duration dual antiplatelet therapy was also associated with a lower 
risk of major bleeding (HR 0.58, 0.47-0.72; p<0.001), but a higher risk of myocardial 
infarction (HR 1.51, 1.28-1.77; p<0.001) and stent thrombosis (HR 2.04, 1.48-2.80; 
p<0.001).(45)27
Anticoagulation with warfarin and the combination of warfarin and single agent antiplatelet 
therapy are also effective for the secondary prevention of cardiovascular events. A 
meta-analysis of randomized controlled trials involving more than 20,000 patients with CAD
demonstrated that moderate intensity (INR 2.0 to 3.0) and high intensity (INR >2.8) warfarin 
compared with control reduced the risk of major cardiovascular events by 16% to 42%, 
establishing the efficacy of anticoagulant therapy for this indication.(19)
Direct randomized comparisons between anticoagulant and antiplatelet therapy have
established the superior efficacy of warfarin for the prevention of major cardiovascular events 
in patients with established CAD but at the cost of increased bleeding.  Thus, moderate 
intensity (INR 2.0 to 3.0) or moderate to high intensity (INR 2.5 to 3.5) warfarin compared 
with aspirin reduces the risk of myocardial infarction, stroke or cardiovascular death by 21% 
compared with aspirin (OR 0.79; 95% CI: 0.67 to 0.94), but this was at the cost of a more than 
2-fold increase in major bleeding (OR 2.1; 95% CI 1.7 to 2.7).(19) A subsequent meta-
analysis of randomized controlled trials involving 25,307 patients with established CAD
demonstrated that the combination of warfarin (INR 2.0 to 3.0) and aspirin compared with 
aspirin alone reduced the risk of myocardial infarction, ischemic stroke, and all-cause 
mortality by 27% (OR 0.73; 95% CI: 0.63 to 0.84).(20) Once again the reduction in major 
cardiovascular events with warfarin-based therapy was accompanied by a more than 2-fold 
excess of major bleeding (OR 2.32; 95% CI: 1.63 to 3.29). 
Warfarin has not been as extensively evaluated in patients with PAD but limited data suggest 
that it also offers benefits in this setting.  The WAVE trial did not find a benefit of warfarin 
(INR 2.0 to 3.0) plus aspirin compared with aspirin alone for the prevention of myocardial 
infarction, stroke, or cardiovascular death in patients (n=2,161) with PAD (HR 0.92; 95% CI: 
0.73-1.16).(21)  However, the combination was associated with a more than 3-fold excess of 
life-threatening bleeding, and an exploratory post-hoc analysis excluding patients with major 
bleeding suggested an 18% relative risk reduction (HR 0.82; 95% CI: 0.62 to 1.05). 
data on file)  
                                                
27 Paragraphs added as per Amendment 8. (See Section 13.2.2)
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Additional25 evidence for the efficacy and safety of oral factor Xa inhibitors for the prevention 
of major cardiovascular events comes from the recently completed AVERROES trial which 
demonstrated that the oral factor Xa inhibitor, apixaban, compared with aspirin not only 
reduced the risk of stroke but was also associated with numerically fewer myocardial 
infarctions with no significant increase in major bleeding.(22)  
In summary, the randomized trials of antithrombotic therapy in patients with established 
atherothrombotic vascular disease have demonstrated the efficacy of single agent antiplatelet 
therapy (with aspirin or clopidogrel), anticoagulant therapy (warfarin), and the combination of 
single agent antiplatelet and anticoagulant therapy (aspirin and warfarin) for the long term 
secondary prevention of major cardiovascular events.  Warfarin alone is substantially more 
effective than aspirin alone, and the combination of warfarin and aspirin provides even greater 
benefits, but is limited by excess of bleeding.  Furthermore, because of the challenges of 
adjusting the dose of warfarin based on the results of routine laboratory monitoring, it is 
uncommonly used for long-term prevention of cardiovascular events. 
The data summarized above support the hypothesis that when given in combination with, or 
instead of aspirin, a new anticoagulant such as rivaroxaban has the potential to yield 
substantial benefits for the prevention of cardiovascular events in patients with established 
CAD or PAD.  
1.2.3
Proposed rivaroxaban evaluation - amended
Based on the demonstrated efficacy and safety profile of rivaroxaban, rivaroxaban will be 
tested at a dose of 2.5 mg twice daily plus aspirin compared with aspirin alone, and at a dose 
of 5 mg twice daily compared with aspirin alone, in a 3-arm study.  We hypothesize that the 
combination of rivaroxaban and aspirin compared with aspirin alone will substantially reduce 
the risk of myocardial infarction, stroke, or cardiovascular death and that this benefit will 
readily outweigh any potential28 increase in bleeding.  We also hypothesize that rivaroxaban 
compared with aspirin will reduce the risk of myocardial infarction, stroke, or cardiovascular 
death and that this benefit will not be accompanied by a clinically relevant increase in major 
bleeding. 
1.2.4 Long-Term Open-Label Extension - amended29
As described in Section 1.1, due to the clinical effect of rivaroxaban 2.5 mg bid + aspirin 
100 mg od over existing standard treatment with aspirin, the sponsor will offer the 
rivaroxaban 2.5 mg bid + aspirin 100 mg od to trial subjects in a long-term open-label 
extension (LTOLE) until the rivaroxaban treatment is commercially available for this 
indication or for approximately 3 years from regulatory approval of LTOLE in a country, 
whichever comes first. The same efficacy and safety variables as in COMPASS will be 
collected in LTOLE in a descriptive way.
In COMPASS, the combination rivaroxaban 2.5mg bid + aspirin 100mg od compared to 
aspirin 100mg alone:
                                                
28 Text added as per Amendment 6. (See Section 13.1.2)
29 Text added as per Amendment 11. (See Sections 13.3.1 and 13.3.2)
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
Reduced the relative risk for the primary composite of stroke, myocardial infarction 
and cardiovascular death by 24% (p<0.0001)

Increased the risk of ISTH modified major bleeding significantly (HR 1.70, 95% CI 
1.40-2.05, p<0.00001)

No significant increase was found in intracranial or fatal bleeds

Reduced the risk for pre-specified net clinical benefit, a composite of outcomes of 
irreversible harm, significantly (HR 0.80, 95% CI 0.70-0.91, p=0.00052)
Rivaroxaban 5.0 mg BID alone compared to 100 mg aspirin alone:

Did not significantly reduce the hazard for the primary outcome (HR 0.90, 95% CI 
0.79-1.03, p=0.11), but increased major bleeding
Findings were consistent across the majority regions and subgroups.
1.3
Benefit-risk assessment – amended
Considering the use of a new treatment for the prevention of cardiovascular disease, potential 
benefits need to be balanced against the risk.  Bleeding is the most common complication of 
antithrombotic therapy and upper gastrointestinal bleeding accounts for the majority of 
bleeding complications.  The risk of gastrointestinal bleeding increases with increasing 
intensity of antithrombotic therapy.  When used for the prevention of cardiovascular disease, 
aspirin compared with placebo/no aspirin is associated with a 50 to 60% relative excess and a 
0.5 to 1% absolute excess risk of major gastrointestinal bleeding.(23,24)  In the ROCKET-AF 
trial, the 20 mg od dose was associated with an annualized rate of International Society on 
Thrombosis and Haemostasis (ISTH) major and non-major gastrointestinal (GI) combined 
bleeding rate of 3.2/100 patient years. (46)30
Major bleeding is an independent predictor of risk of death and other major cardiovascular 
events.(25,26)  This excess risk may in part be explained by confounding, because patients 
who are more ill are more likely to experience adverse outcomes and are also more likely to 
bleed.  However, even minor bleeding leads to discontinuation of effective antithrombotic 
therapies, thereby potentially compromising the efficacy of cardiovascular prevention and 
providing another possible explanation for the excess cardiovascular risk associated with 
bleeding.  Effective strategies for the prevention of gastrointestinal bleeding have the potential 
to reduce morbidity and mortality directly caused by bleeding, but more importantly may also 
reduce ischemic cardiovascular events resulting from temporary or permanent interruption in 
patients treated with rivaroxaban.  
Among patients taking aspirin or the combination of aspirin and clopidogrel, treatment with a 
PPI significantly reduces the risk of dyspepsia and peptic ulcer disease.(27)  The United States 
Food and Drug Administration (US FDA) has issued a warning concerning the use of 
omeprazole but not pantoprazole in combination with clopidogrel.  In the COMPASS trial, the 
efficacy of pantoprazole will be compared with placebo for the prevention of upper 
                                                
30 The bleeding rate was updated as per Amendment 8 (was 2.23/100 patient years) and the reference was added.
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gastrointestinal bleeding, ulceration, obstruction or perforation in subjects randomized to the 
combination of rivaroxaban and aspirin, rivaroxaban alone, or aspirin alone, using a partial 
factorial design.
Long-Term Open-Label Extension – amended
Rivaroxaban 2.5mg bid + aspirin 100mg od has demonstrated superior efficacy on reducing
major adverse cardiac event (MACE) in patients with CAD/PAD as compared to aspirin alone
and reduced the risk for pre-specified net clinical benefit significantly (refer to Section 1.2.4).
Therefore, the sponsor aims to make rivaroxaban 2.5 mg bid + aspirin 100 mg od available in 
a long-term open-label extension. 31
2.
Study objectives – amended
Primary objectives for rivaroxaban randomization

To determine whether rivaroxaban 2.5 mg bid + aspirin 100 mg od compared with 
aspirin 100 mg od reduces the risk of a composite of myocardial infarction, stroke, or 
cardiovascular death in subjects with CAD or PAD

To determine whether rivaroxaban 5 mg bid compared with aspirin 100 mg od reduces 
the risk of a composite of myocardial infarction, stroke, or cardiovascular death in 
subjects with CAD or PAD
Secondary objectives for rivaroxaban randomization

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and 
rivaroxaban 5 mg bid alone reduces the risk of the composite of major thrombotic 
events (coronary heart disease death, myocardial infarction, ischemic stroke, acute 
limb ischemia; cardiovascular death, myocardial infarction, ischemic stroke, acute 
limb ischemia) compared with aspirin 100 mg od in subjects with CAD or PAD32

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and 
rivaroxaban 5 mg bid alone reduces the risk of mortality in subjects with CAD or PAD
Tertiary objective for rivaroxaban randomization

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and 
rivaroxaban 5 mg bid alone preserves the ability to perform everyday activities 
independently in subjects with CAD or PAD

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and 
rivaroxaban 5 mg bid alone reduces the incidence of hospitalization for any cause in 
subjects with CAD or PAD

To collect medical resource utilization data to be incorporated in economic modeling 
for subjects with CAD or PAD
                                                
31 Text added as per Amendment 11. (See Section 13.3.1)
32 Text revised as per Amendments 6 and 8. (See Sections 13.1.2 and 13.2.2)
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Objective for pantoprazole randomization

To determine whether pantoprazole 40 mg od compared with placebo reduces the risk 
of upper gastrointestinal bleeding, ulceration, or gastrointestinal obstruction or 
perforation in subjects with CAD or PAD receiving antithrombotic medications
Objectives for Day 4-7 post-CABG randomization33

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and 
rivaroxaban 5 mg bid alone reduces the risk of bypass graft failure compared with 
aspirin 100 mg od33

To determine the association between post CABG graft failure and risk of a composite 
of myocardial infarction, stroke, or cardiovascular death in subjects with CAD or 
PAD33
Substudy objectives
The COMPASS-MIND substudy will examine the effect of the antithrombotic therapies being 
tested in COMPASS on covert cerebral ischemia, thereby providing additional information 
about mechanisms of disease and treatment benefits. 34   COMPASS-MIND will be conducted 
concurrently with the main study in a subset of subjects at selected centers.  A detailed 
description is included in Section 14.1.
Objective for Long-Term Open-Label Extension – amended
The objective of LTOLE is to make rivaroxaban 2.5 mg bid + aspirin 100 mg od available to 
COMPASS trial subjects until the treatment is commercially available or for approximately 3 
years from regulatory approval of LTOLE in a country, whichever comes first.
Primary, secondary and tertiary efficacy and safety outcomes as described above will be 
collected in the LTOLE.35
3.
Investigators and other study participants
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 and will be identified on the respective 
country-specific signature pages.
The COMPASS trial will be carried out in accordance with Good Clinical Practice (GCP) in 
close collaboration between Bayer and 
3.1
Study committees - amended
An Operations Committee will be responsible for ensuring that study execution and 
management of the study are of the highest quality.  This committee is a subcommittee of the 
Steering Committee and will convene regularly to discuss and report on the ongoing 
supervision of the study.  The committee will consist of the study chair and principal 
                                                
33 Text added as per Amendment 6. (See Section 13.1.2)
34 Sentence was revised as per Amendment 8.  (See Section 13.2.2)
35 Text added as per Amendment 11. (See Section 13.3.1)
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investigators, project leader, senior study coordinator, 2-3 sponsor representatives, and 3-4 
National Leaders (NL). 
A Steering Committee comprising members of the Operations Committee, university-based 
and sponsor-based scientists with clinical and methodological expertise, and NL from each 
country, has overall responsibility for the study. The Steering Committee will be responsible 
for producing and conducting a scientifically sound study design and ensuring accurate 
reporting of the study.  The Steering Committee will meet periodically to address and resolve 
scientific and practical issues encountered during the study. 
An Events Committee consisting of members with clinical and methodological expertise will 
oversee the process of event adjudication. The process of event adjudication is detailed in the 
Event Adjudication Plan.36
An independent Data Safety Monitoring Board (DSMB) will be formed, comprising a chair, 
co-chair, and members who have recognized expertise in clinical trials, cardiovascular 
disease, and biostatistics, and who are not members of the Steering Committee or involved in 
the routine conduct of the COMPASS trial.  The DSMB will be responsible for:

monitoring efficacy and safety of the studied medications based on periodic updates 
throughout the study 

giving recommendations to the Steering Committee as to whether to continue, modify,
or stop the study
The DSMB plays a key role in monitoring all aspects of the study.  This committee will 
review aggregate data by treatment group in an unblinded fashion and thus are tasked with 
assessing risk and benefit for the study subjects. 
At the first meeting of the DSMB, the DSMB charter and the frequency of meetings will be 
agreed upon. The DSMB will be supported at meetings by the designated 
 biostatistician 
(unblinded for the purpose of preparing reports for the DSMB).  The study chair and/or the 
principal investigators will attend the open portion of the meeting to provide reports and 
respond to questions concerning the study.
Long-Term Open-Label Extension − amended
Outcome events for LTOLE will be collected in a descriptive way, and no adjudication will be 
performed. 
The DSMB will not monitor the LTOLE and will conclude responsibilities when the 
pantoprazole/placebo treatment is completed.37
3.2
Study coordination
The study will be coordinated by 
 in Canada, 
whose primary function is to facilitate and oversee the execution of the study in collaboration 
with the sponsor.  
 will keep the Operations and Steering Committees appraised of the 
                                                
36 The first 3 paragraphs of this section were revised as per Amendment 8. (See Section 13.2.2)
37 Text added as per Amendment 11. (See Section 13.3.1)
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progress and conduct of the study and will provide ongoing methodological and 
administrative support to the DSMB and will make available appropriate study data and/or 
documentation for these committees. 
The NL are responsible for the conduct of the study within their respective countries.  The NL 
are physicians with experience in both clinical management of cardiovascular disease and 
conduct of clinical studies in this field.  Additional information is provided in the Manual of 
Operations.
The Site Investigators are responsible for the conduct of the study within their respective 
centers.  Additional information is provided in the Manual of Operations.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained, and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature sheet before subject 
recruitment may start at the respective center.  Likewise, all protocol amendments/integrated 
protocols must be signed and dated by the principal investigator before coming into effect at 
the respective center.
3.3
Other study personnel and administrative functions
All other study personnel not included in Section 3 are identified in a separate personnel list 
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.
A complete list of all participating centers and their investigators, as well as all required 
signature documents and other required documents, will be maintained in the trial master file.
4.
Study design
4.1
Design overview – amended
This Phase 3, event-driven (at least 2,200 primary efficacy outcome events), randomized 
controlled trial will have a 3 x 2 partial factorial design and will randomize at least 27,40038
subjects who will receive treatment for an expected average duration of 3 to 4 years.  The 
COMPASS trial will involve 4 periods: screening, run-in, follow-up, and washout.
Prescreening procedures may require informed consent in some countries.  In all other study 
sites, informed consent will be obtained prior to the initiation of any screening procedures 
(Section 7.1.2.1).38  Screening will be performed to determine subject eligibility and will 
include the review of inclusion and exclusion criteria, physical measurements, laboratory 
evaluations, etc. (Section 7.1.2.2).39
The run-in period will occur during the 2839 days prior to initiation of randomized study 
treatment, with the exception of subjects who are randomized after CABG surgery, who will 
                                                
38 Text modified as per Amendments 6 and 8. (See Sections 13.1.2 and 13.2.2)
39 Text modified/added as per Amendment 6. (See Section 13.1.2)
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not undergo a run-in phase (Section 4.1.1).  During run-in, subjects will discontinue any 
antithrombotic39 therapy and will begin study rivaroxaban placebo and study aspirin 100 mg.  
Subjects who successfully complete the run-in period and who remain committed to the study 
as well as those who are being randomized after CABG will be randomized and begin study 
treatments on Day 0, which will also signal the initiation of the follow-up period.  Subjects 
without a continous39 need for treatment with a PPI will be randomized 1:1 to the 
pantoprazole or pantoprazole placebo and all subjects (including those subjects who entered 
the study while already receiving a PPI) will then be randomized 1:1:1 to rivaroxaban alone, 
the combination of rivaroxaban and aspirin or aspirin alone, and their matching placebos as 
shown in Table 4–1:
Table 4–1.  Randomized study treatments* 
Study Arm
Treatment Assignments
A
Rivaroxaban 2.5 mg bid +
Aspirin 100 mg od +
Pantoprazole 40 mg od
Rivaroxaban 2.5 mg bid +
Aspirin 100 mg od +
Pantoprazole placebo od
B
Rivaroxaban 5 mg bid + 
Aspirin placebo od + 
Pantoprazole 40 mg od
Rivaroxaban 5 mg bid + 
Aspirin placebo od +
Pantoprazole placebo od
C
Rivaroxaban placebo + 
Aspirin 100 mg od +
Pantoprazole 40 mg od
Rivaroxaban placebo + 
Aspirin 100 mg od + 
Pantoprazole placebo od
*Subjects who have a continuous need for use of39 a proton pump inhibitor at baseline will undergo only a single 
randomization (to rivaroxaban 2.5 mg bid + aspirin 100 mg od, rivaroxaban 5 mg bid + aspirin placebo or 
rivaroxaban placebo + aspirin 100 mg od)
Subjects will be seen in the clinic at 1 month and at 6 months after randomization and at 
6 month intervals thereafter in order to collect information on treatment adherence, treatment 
interruption, outcomes, and adverse events (AEs).  Validated questionnaires (Standard 
Assessment of Global-Activities in the Elderly [SAGE], Montreal Cognitive Assessment 
[MoCA], Digital Symbol Substitution [DSS], European Quality of Life-5 Dimensions [EQ-
5D]) will be administered at screening/run-in or randomization, or as soon as possible 
thereafter, as well as at Month 24 and at the Final Follow-Up visit to collect data on subject 
health and quality of life.  The SAGE, MoCA, DSS, and EQ-5D will also be administered at 
the next study clinic visit after each outcome event. The Interheart Diet Questionnaire and the 
International Physical Activity Questionnaire will be administered at screening/run-in or
randomization, or as soon as possible thereafter, and at Month 24.  All subjects will be 
followed for the duration of the study, irrespective of whether they are receiving study 
treatments or whether an event has occurred. Additional follow-up visits will be conducted by 
telephone at Months 3 and 9.  The Final Follow-up Visit will occur as soon as possible after 
the required pre-specified number of subjects experience a primary efficacy outcome event for 
the antithrombotic randomization (close out is expected to occur over a period of about 
3 months).  A final washout period visit (End of Washout Telephone Visit) will be conducted 
by telephone (performed 30 days after the Final Follow-up Visit) to collect information on 
outcomes and protocol specific AEs.  Adverse events will continue to be collected up to 
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30 days post study drug treatment.  Bayer Global Pharmacovigilance will continue to follow 
the reported AEs until stabilized or resolved. 40
Amended after early termination of rivaroxaban/aspirin arms
There will be no washout visit following the completion of the final pantoprazole/placebo 
follow-up visit, due to the short half-life of pantoprazole.41
4.1.1
Subjects randomized after CABG surgery - amended
42Subjects randomized Day 4-7 after CABG surgery will undergo the same screening, follow-
up, and washout as other COMPASS trial subjects but not run-in. Subjects are to sign 
informed consent before or after the surgery.  Randomization will occur between Day 4-7
after surgery, at least 24 hours following the removal of chest tubes.  The first dose of study 
drug should not be administered until at least 12 hours after last administration of any 
anticoagulant (including DVT prophylaxis) (Section 7.1.1 Tabulated overview).
Subjects randomized Day 4-7 after CABG surgery will undergo computed tomography (CT)  
angiography at 1 year or later as part of the study protocol to assess graft patency unless they 
have a specific contraindication for CT angiography (e.g., contrast allergy, estimated 
glomerular filtration rate <30 ml/min). In the event the subject undergoes an invasive 
coronary angiography at approximately 1 year or later post CABG for any reason, a CT 
angiogram may not be required.
Long-Term Open-Label Extension −amended
The long-term open-label extension (LTOLE) will provide open-label rivaroxaban 2.5mg bid
+ aspirin 100mg od to COMPASS subjects until it is commercially available or for 
approximately 3 years from regulatory approval of LTOLE in a country, whichever comes 
first. The implementation of LTOLE is an amendment to the COMPASS trial. 
For inclusion and exclusion criteria, see Section 5.1.3; for treatment related details, see 
Section 6.1.3 (Treatment to be administered), Section 6.6 (Drug logistics and accountability), 
and Section 6.8 (Post-study therapy). 
The LTOLE will involve an initiation visit and a follow-up period. 
Treatment initiation visits can be scheduled as soon as the LTOLE has received regulatory 
and ethics approvals, the site has signed a contract amendment, and the drug is available at the 
site. Before entering LTOLE, informed consent is needed. 
For detailed procedures and variables, see Section 7.1.1 (Tabulated overview of LTOLE) and 
Section 7.1.2.6 (Timing of assessments in LTOLE).The same efficacy and safety outcomes as 
in the COMPASS trial will be collected in the LTOLE. All statistical analyses will be 
descriptive.43
                                                
40 Paragraph revised as per Amendments 6 and 8. (See Sections 13.1.2 and 13.2.2)
41 Text added as per Amendment 11. (See Sections 13.3.1 and 13.3.2)
42 This section was revised as per Amendments 6 and 8.  (See Sections 13.1.2 and 13.2.2)
43 Text added as per Amendment 11. (See Section 13.3.1)
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4.2
Primary efficacy and safety variables − amended
The primary efficacy outcome for the rivaroxaban randomization is a composite of myocardial 
infarction, stroke, or cardiovascular death.
The primary safety outcome for the rivaroxaban randomization is a composite of: 

fatal bleeding, and/or 

symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with 
compartment syndrome, or bleeding into the surgical site requiring re-operation, 
and/or 

bleeding leading to hospitalization
Long-Term Open-Label Extension −amended
The same primary efficacy and safety outcomes collected in the COMPASS trial will be 
collected during the LTOLE visits.44
4.3
Justification of the design
4.3.1 Overall design rationale – amended
The primary objective of the COMPASS trial is to determine whether rivaroxaban 2.5 mg bid 
+ aspirin 100 mg od (Arm A) compared with aspirin 100 mg od (Arm C) reduces the risk of 
the composite of myocardial infarction, stroke, or cardiovascular death in subjects with CAD 
or PAD and, similarly, to determine whether rivaroxaban 5.0 mg bid + aspirin placebo od 
(Arm B) compared with aspirin 100 mg od (Arm C) reduces the risk of the composite of 
myocardial infarction, stroke, or cardiovascular death in subjects with CAD or PAD.  The 
event-driven, double-blinded, 3 x 2 partial factorial design was selected for this study to 
support a rigorously controlled approach that would minimize study bias while focusing on 
the effects of treatment on the composite of the expected outcomes (myocardial infarction, 
stroke, or cardiovascular death) in this study population. 
The benefit of increased45 intensity of antithrombotic therapy for the prevention of recurrent 
thrombotic cardiovascular events by adding a second agent to aspirin has been established in 
trials of dual antiplatelet therapy after an acute coronary syndrome when compared with 
aspirin alone.  Additionally, a benefit has been shown in trials of combined warfarin and 
aspirin after myocardial infarction compared with aspirin alone. 
The potential for the combination of rivaroxaban and aspirin to prevent thrombotic 
cardiovascular events after an acute coronary syndrome compared with aspirin alone has been 
investigated in previous rivaroxaban trials.  A pooled post hoc analysis of the data from 
patients with an acute coronary syndrome in the Phase 2 and Phase 3 trials (ATLAS TIMI 46 
and ATLAS TIMI 51) suggests  that the effect size of rivaroxaban plus aspirin compared to 
aspirin alone for the composite outcome of CV death, myocardial infarction, and stroke (HR 
                                                
44 Text added as per Amendment 11. (See Section 13.3.1)
45 Text modified as per Amendment 6. (See Section 13.1.2)
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0.66, 95% CI 0.46-0.96,  p=0.026) (data on file) is at least double the effect size seen in the 
primary analysis of the ATLAS 51 trial (HR 0.84, 95% CI (0.74-0.96, p=0.008).  For patients 
who do not have an ongoing indication for dual antiplatelet therapy but have a residual risk of 
cardiovascular events, it is expected that the addition of rivaroxaban 2.5 mg bid to standard 
dose of aspirin 100 mg will provide additional benefit compared to aspirin alone.  
Not all trials of combined antithrombotic therapy have shown a benefit, but where there was a 
lack of benefit it could be explained either by the risk profile of the patients included in the 
trial (e.g., in the CHARISMA trial, clopidogrel plus aspirin was effective for secondary 
prevention in the subgroup of patients with established vascular disease but not in those 
without a history of symptomatic vascular disease) or by an excess of bleeding of the 
experimental treatment (e.g., in the WAVE trial, warfarin plus aspirin was associated with a 
substantial excess of bleeding compared with aspirin which substantially attenuated the 
benefits).
To date, no trials have directly compared a new anticoagulant with aspirin for long-term 
secondary prevention of cardiovascular disease.  Prior efforts to identify more effective 
antithrombotic treatments than aspirin have focused on new antiplatelet therapies (terutroban, 
a platelet thromboxane receptor antagonist; clopidogrel, prasugrel, and ticagrelor, P2Y1245
antagonists; and vorapaxar, a PAR-1 receptor antagonist) and warfarin.  In most cases, the 
benefit of the experimental treatment has either been of insufficient magnitude to warrant a 
switch in treatment (e.g., clopidogrel, prasugrel) or has been accompanied by a substantial 
excess of bleeding (e.g., vorapaxar, ticagrelor46, warfarin).  The promise of a new 
anticoagulant such as rivaroxaban (rivaroxaban 5.0 mg as explored in Arm B) is highlighted 
by the results of the AVERROES study which demonstrated superior efficacy of apixaban 
compared with aspirin for stroke prevention in patients with atrial fibrillation as well as 
numerically fewer myocardial infarctions and no significant excess in bleeding.(22)
The use of aspirin-alone antiplatelet therapy for atherosclerotic CAD and PAD is widely 
accepted.47 As such, most patients will be candidates for aspirin monotherapy.  This is in line 
with current practice guidelines and the current prescribing information for secondary 
prevention.   The dose of aspirin being tested in COMPASS is 100 mg/d.  
4.3.2 Design rationale for Long-Term Open-Label Extension −amended48
Due to the clinical efficacy of rivaroxaban 2.5mg bid + aspirin 100mg od (see Section 1.2.4), 
participation in the LTOLE will be offered to all subjects who meet the LTOLE 
Inclusion/Exclusion criteria defined in Section 5.1.3.
4.4
Final follow-up visit and end of study-amended
The primary analysis will be based on the events that occur between randomization and the 
Final Follow-up Visit.  The date of the Final Follow-up Visit cannot be pre-determined as this 
study is event-driven but the visit will occur when at least 2,200 subjects experience an event 
                                                
46 “ticagrelor” added as per Amendment 8 based upon the recently published PEGASUS trial.
47 Sentence revised as per Amendment 8.  (See Section 13.2.2.)
48 Text added as per Amendment 11. (See Section 13.3.1)
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for the primary efficacy outcome.  All subjects will remain in follow-up until this minimum 
number of primary outcome events has been reached, irrespective of whether they are still 
taking study treatments or whether they have experienced an outcome.  The Final Follow-up 
Visit and the subsequent 30-day washout period will occur nearly simultaneously (as 
scheduling permits) for all study subjects.  
For each participating European Union (EU) country, the end of the study according to the EU 
Clinical Trial Directive will be reached when the telephone call at the end of the 30 day 
washout period for the last subject for all centers in the respective country has occurred.  The 
end of the study as a whole will be reached as soon as the end of the study according to the 
above definition has been reached in all participating countries (EU and non-EU).
Long-Term Open-Label Extension − amended
The final visits of LTOLE will begin, per country, when the duration reaches 3 years from the 
regulatory approval of LTOLE or the rivaroxaban treatment is commercially available for this 
indication in the respective country, whichever comes first. The subject should be called in for 
the final visit within approximately 3 months or at latest the final visit may be conducted at 
the next scheduled visit.49  
5.
Study population - amended
Multiple strategies will be employed to identify subjects potentially eligible for this study.  
These will include (but are not restricted to) database screening, chart screening, and patient 
screening at physician offices and at internal medicine, cardiology, and vascular 
disease/imaging clinics.  The approach at individual centers will vary according to physician, 
office, or hospital environment, and ethical considerations. 
Approximately 28,300 eligible subjects will be admitted to the run-in period and an additional 
2000 will be enrolled post CABG and without run-in.  Approximately 10% of run-in subjects 
are expected to either be non-compliant with treatment or to decline further interest in 
participating; thus, the study will randomize approximately 27,400 men and women with 
objectively confirmed CAD or PAD from approximately 33 countries worldwide.50
Subjects with high risk of incident cardiovascular disease will be enrolled in the study. 
Subjects will be treated with rivaroxaban, the combination of rivaroxaban and aspirin, or 
aspirin on top of usual care. Investigators in the study are selected based on their 
qualifications and ability to enroll and treat these subjects in accordance with the protocol and 
applicable standard of care.51
For the purpose of determining eligibility for this trial, subjects meeting criteria for CAD must 
have one or more of the following:51

Myocardial infarction within the last 20 years51, or
                                                
49 Text added as per Amendment 11. (See Section 13.3.1)
50 Text modified/added as per Amendments 6 and 8. (See Sections 13.1.2 and 13.2.2.)
51 Text modified as per Amendment 6. (See Section 13.1.2)
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
Multi-vessel coronary disease* with symptoms or history of stable or unstable angina, 
or51

Multi-vessel percutaneous coronary intervention (PCI), or

Multi-vessel CABG surgery 
*Refers to stenosis of greater than or equal to 50% in 2 or more coronary arteries, 
confirmed by invasive coronary angiography, or non-invasive imaging or stress studies 
(e.g. exercise or pharmacologic) suggestive of significant ischemia in 2 or more coronary 
territories; or in 1 coronary territory if at least one other territory has been revascularized51
For the purpose of determining eligibility for this trial, subjects meeting criteria for PAD must 
have one or more of the following: 51

Previous aorto-femoral bypass surgery, limb bypass surgery, or percutaneous 
transluminal angioplasty revascularization51 of the iliac, or infrainguinal arteries, or

Previous limb or foot amputation for arterial vascular disease (i.e., excludes trauma), 
or

History of intermittent claudication and one or more of the following: 1) 51 an 
ankle/arm blood pressure (BP) ratio < 0.90, or 2) 51 significant peripheral artery 
stenosis (≥50%)51 documented by angiography, or by duplex ultrasound, or

Previous carotid revascularization (e.g., endarterectomy, stenting) or51 asymptomatic 
(i.e., no ipsilateral stroke or transient ischemic attack within 6 months) carotid artery 
stenosis ≥50%51 as diagnosed by duplex ultrasound or angiography.
5.1
Eligibility − amended
In order to be eligible for study entry, potential subjects must meet all of the inclusion criteria 
and none of the exclusion criteria listed below.
5.1.1
Inclusion criteria - amended

Willing and able to provide written informed consent

Meet criteria for CAD* and/52or PAD

*Subjects with CAD must also meet at least one of the following criteria52:

Age ≥65, or 

Age <65 and documented atherosclerosis or revascularization involving at least 2
vascular beds§,52 or at least 2 additional risk factors:
1)
Current smoker (within 1 year of randomization)52
2)
Diabetes mellitus
3)
Renal dysfunction with estimated glomerular filtration rate 
<60 ml/min 
                                                
52 Text modified/added as per Amendment 6. (See Section 13.1.2)
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4)
Heart failure 
5)
Non-lacunar ischemic stroke ≥1 month ago
§ Because CAD involves disease in the coronary vasculature, only one additional vascular bed 
is required: e.g. the aorta and arterial supply to the brain, gastro-intestinal tract, lower limbs, 
upper limbs, or kidneys.52
5.1.2
Exclusion criteria - amended

High risk of bleeding

Stroke within 1 month or any history of hemorrhagic or lacunar stroke 

Severe heart failure with known ejection fraction <30% or New York Heart 
Association (NYHA) class III or IV symptoms 

Estimated glomerular filtration rate (eGFR)<15 mL/min

Need for dual antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral 
anticoagulant therapy

Known non-cardiovascular disease that is associated with poor prognosis (e.g., 
metastatic cancer) or that increases the risk of an adverse reaction to study 
interventions.

History of hypersensitivity or known contraindication for rivaroxaban, aspirin, 
pantoprazole, or excipients, if applicable.52

Systemic treatment with strong inhibitors of both CYP 3A4 and p-glycoprotein (P-gp) 
(e.g., systemic azole antimycotics, such as ketoconazole, and human 
immunodeficiency virus [HIV]-protease inhibitors, such as ritonavir), or strong 
inducers of CYP 3A4, i.e. rifampicin, rifabutin, phenobarbital, phenytoin, and 
carbamazepine53

Any known hepatic disease associated with coagulopathy

Subjects who are pregnant, breastfeeding, or are of childbearing potential, and53
sexually active and not practicing an effective method of birth control (e.g. surgically 
sterile53, prescription oral contraceptives, contraceptive injections, intrauterine device, 
double-barrier method, contraceptive patch, male partner sterilization) 

Previous assignment to treatment during this study

Concomitant participation in another study with investigational drug53

Known contraindication to any study related procedures53
An additional exclusion for the pantoprazole randomization is:

Need for continuous53 treatment with a PPI
                                                
53 Text modified as per Amendment 6. (See Section 13.1.2)
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5.1.3
Long-Term Open-Label Extension −amended54
All subjects from COMPASS trial will be invited to join LTOLE as long as they continue to 
meet the COMPASS eligibility criteria (refer to sections 5.1.1 and 5.1.2) plus the specific 
ones for LTOLE (refer to sections 5.1.3.1 and 5.1.3.2). All LTOLE subjects must provide 
written informed consent to participate in LTOLE.
5.1.3.1
Inclusion criteria

All subjects randomized to the COMPASS trial willing to consent to LTOLE are 
eligible unless the subjects developed a condition considered by the investigator as 
exclusionary.

Subjects who have given their written informed consent to participate in the LTOLE 
after having received adequate information prior to any LTOLE specific procedures.
5.1.3.2
Exclusion criteria

Subjects should not be included if, in the judgement of the investigator, they have 
developed a condition which should exclude them from receiving LTOLE study 
medication. For example if the subject has developed atrial fibrillation or had a severe 
allergic rash while in the study, which subsided when drug was stopped and returned 
when drug was reinitiated.
5.2
Discontinuation of subjects from study treatment - amended
All subjects will be encouraged to remain on treatment and under observation for the full 
duration of the study.  However, at any time during the study and without giving reasons, 
subjects may withdraw from the study at their own request or at the request of their legally 
acceptable representative.  The subject will not suffer any disadvantage as a result.  In all 
cases, the reason for permanent discontinuation of study treatments (including “at the 
subject’s request”) must be recorded in the case report form (CRF) and in the subject's 
medical records.  
It is important to note that discontinuation of study treatment is not the equivalent to 
withdrawal of informed consent.  Additionally, withdrawal of consent does not withdraw 
permission to collect vital status.  Withdrawal of this consent must be made separately.  In 
cases where subjects indicate they do not want to “continue”, investigators must determine 
whether this refers to discontinuation of study treatment (the most common expected 
scenario), unwillingness to attend follow-up visits, unwillingness to have telephone contact, 
unwillingness to have any contact with study personnel, or unwillingness to allow contact 
with a third party (e.g., family member, doctor).  In all cases, including the subjects who
have had any of the primary study outcome events, every effort must be made to 
continue to follow the subject at regular study visits.55 Additionally, survival status and 
outcome information must be determined for all subjects.53
                                                
54 Text added as per Amendment 11. (See Section 13.3.1)
55 Sentence revised as per Amendment 8.  (See Section 13.2.2)
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5.2.1
Replacement
No subject replacements are permitted in this study.
5.2.2
Long-Term Open-Label Extension −amended56
In case of permanent discontinuation of LTOLE treatment, the subject should come for a final 
visit within approximately 3 months, but follow the PPI visit schedule if applicable.
5.3
Subject identification
Each subject will receive a unique identification number, which will represent both the 
assigned study center number and subject number.  The center number will be pre-assigned by 
  The subject identification number, consisting of center number and subject number 
must be entered in the 
 randomization and drug management system to obtain the 
assignment of study treatment.  Once assigned to a subject, the subject identification number 
will not be re-used. 
6.
Treatments
6.1
Treatments to be administered - amended
The study drugs to be administered in this trial include the antithrombotic drugs, rivaroxaban 
and enteric-coated57 aspirin; the PPI pantoprazole; and their matching placebos.  
6.1.1 Run-in - amended
During the run-in period, Day -2857 to Day -158, eligible subjects (excluding those who are 
randomized58 Day 4-757 after CABG surgery) who have signed informed consent and stopped 
non-study anticoagulants and aspirin will receive rivaroxaban placebo bid and aspirin 100 mg 
od.  Study pantoprazole or pantoprazole placebo will not be administered during the run-in 
period. 
All doses will be provided in tablet form for oral administration.
6.1.2 Randomization - amended
Subjects who have completed the run-in period with adherence to treatment with rivaroxaban 
placebo bid and aspirin 100 mg od of at least 80% except for extenuating circumstances,57 and 
who wish to continue in the study will be randomized.  Subjects being randomized after run-
in57 and those who are being randomized  Day 4-757  after CABG surgery (Section 7.1.1
Tabulated overview) and who do not have a continuous57 need to take a PPI, will initially be 
randomized 1:1 to receive pantoprazole 40 mg od or matching placebo od, stratified by center.  
All subjects will then be randomized 1:1:1 to anticoagulant therapy stratified by center and by 
PPI use (randomized to pantoprazole, randomized to pantoprazole placebo, not randomized 
because subject is already taking a PPI as shown below:
                                                
56 Text added as per Amendment 11. (See Section 13.3.1)
57 Text modified/added  as per Amendment 6. (See Section 13.1.2)
58 Text deleted as per Amendment 6. (See Section 13.1.2)
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Arm A:  rivaroxaban 2.5 mg bid + aspirin 100 mg od
Arm B:  rivaroxaban 5.0 mg bid + aspirin placebo od
Arm C:  rivaroxaban placebo bid + aspirin 100 mg od
All doses will be provided in tablet form for oral administration.
Follow-up will continue until a minimum of 2,200 subjects experience an event for the 
primary efficacy outcome for the rivaroxaban randomization.  These events are expected to 
accumulate over approximately 4-5 trial years after randomization of the first subject.   
6.1.3 Treatment in Long-Term Open-Label Extension −amended59
The LTOLE treatment will be open-label rivaroxaban 2.5 mg bid + aspirin 100 mg od.
6.2
Identity of study treatment - amended
All study drugs will be labeled in the local language according to the requirements of local 
law and legislation and will include no information about the subject except for the
medication number.  Label text will be approved according to the sponsor’s agreed 
procedures, and a copy of the labels will be made available to the study site upon request. For 
the purpose of this study, the term “aspirin” is used interchangeably with the term “acetyl 
salicylic acid”.60
For all study drugs, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk ware of the ingredients.  Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies quality assurance (QA) group. 
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor study file.
6.3
Treatment assignment - amended
For subjects who successfully complete the run-in period, the investigator or delegate will 
access the 
 randomization and drug management system to confirm eligibility and 
compliance to run-in rivaroxaban placebo bid and aspirin od and to obtain the randomized 
treatment allocation.61
The 
 randomization and drug management system will assign the subject a unique 
number for each medication that corresponds to one of the treatments listed in Table 4–1.
Long-Term Open-Label Extension − amended
All subjects in the LTOLE will receive the same treatment of rivaroxaban 2.5 mg bid + 
aspirin 100 mg od.62
                                                
59 Text added as per Amendment 11. (See Section 13.3.1)
60 Text added as per Amendment 6. (See Section 13.1.2)
61 Sentence revised as per Amendment 8. (See Section 13.2.2)
62 Text added as per Amendment 11. (See Section 13.3.1)
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6.4
Dosage and administration - amended
Study medication will be taken orally.  Study rivaroxaban/rivaroxaban placebo is taken twice 
daily (generally morning and evening, approximately 12 hours apart) and study aspirin/aspirin 
placebo and study pantoprazole/pantoprazole placebo are taken once daily, generally in the 
morning.  The first doses of study drug should be administered on the day of randomization,
or at least 12 hours after the last dose of antithrombotic medication if being randomized post-
CABG.63   
If a dose of study rivaroxaban/rivaroxaban placebo is missed and less than 6 hours have 
elapsed since the time that the missed dose was due, it should be taken immediately.  If more 
than 6 hours have elapsed since the missed dose was due, the dose should be skipped and the 
next dose of study rivaroxaban should be taken according to schedule.
If a dose of study aspirin/aspirin placebo or study pantoprazole/pantoprazole placebo is 
missed it should be taken as soon as the subject becomes aware that the dose has been missed. 
6.4.1 Dose modifications - amended
The investigator should interrupt study drug for a given subject if continuation is deemed to 
be detrimental to the subject’s well-being.  All subjects who interrupt study drug should 
resume treatment when possible.  If there is concern that the subject may be intolerant of 
study treatments or if the subject is reluctant to take the full dose of study treatments, a 
possible approach to restarting study medications is to reduce the frequency of dosing (eg, to 
once-daily or alternate-daily).64 Irrespective of whether or not treatment is resumed, all 
subjects must be followed according to the study protocol until the end of the study.  
Permanent study drug interruption should be recorded on the corresponding follow-up case 
report form, giving the date and primary reason for stopping the study drug.  If one of the 
study treatments needs to be discontinued65, other study treatments must be continued.  For 
example, if study rivaroxaban/rivaroxaban placebo is interrupted, study aspirin/aspirin 
placebo and study pantoprazole/pantoprazole placebo should be continued.
Long-Term Open-Label Extension − amended
No dose modifications will be conducted in the LTOLE.66
6.4.2 Dose modifications and treatment guidance - amended
This section provides a general guide for investigators on the management of subjects who 
develop intercurrent illnesses or bleeding during the course of the COMPASS trial.  The 
guidance provided in this section does not replace clinical judgment nor usual care65 in 
determining the appropriate management strategy for individual subjects. For specific 
treatment guidance with study pantoprazole/pantoprazole placebo see Section 6.9.465  
                                                
63 Sentence revised as per Amendment 8.  (See Section 13.2.2)
64 Sentence revised as per Amendment 8.  (See Section 13.2.2)
65 Text modified/added as per Amendment 6. (See Section 13.1.2)
66 Text added as per Amendment 11. (See Section 13.3.1)
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6.4.2.1
Guidance for the treatment of subjects who require an invasive 
procedure - amended
If the subject requires an invasive procedure that is associated with a standard or high risk of 
bleeding (i.e., any procedure that is not considered “minor”), study rivaroxaban/rivaroxaban 
placebo must be interrupted.  Study aspirin/aspirin placebo may also be interrupted, at the 
discretion of the investigator.  If study aspirin/aspirin placebo is interrupted, non-study aspirin 
may be used.67
Dosing recommendations before and after invasive procedures and surgical intervention
If an invasive procedure or surgical intervention is required, rivaroxaban/rivaroxaban placebo 
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/rivaroxaban 
placebo 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.
If surgery is urgent or needed in an emergency situation, the risk of bleeding must be weighed 
against the risk of delaying surgery.  The total daily dose of rivaroxaban in subjects 
randomized to receive 5 mg bid is equivalent to the prophylactic dose that was tested in major 
orthopedic surgery trials and this dose of rivaroxaban is not expected to substantially increase 
the risk of bleeding.  The total daily dose of rivaroxaban in subjects randomized to receive 
rivaroxaban 2.5 mg bid is only half that of the orthopedic thromboprophylaxis dose although 
these subjects will also be receiving treatment with aspirin.  If there is a concern about the risk 
of bleeding in a subject who requires urgent or emergency surgery, unblinding may be 
considered but should only be performed if knowledge of randomized treatment allocation 
will influence clinical management (Section 6.5).  A two-unit single donor platelet transfusion 
in subjects treated with the combination of aspirin and rivaroxaban may restore the capacity to 
generate thromboxane and thereby overcome the antiplatelet effects of aspirin.(29)
Long-Term Open-Label Extension − amended
The same guidance will apply to LTOLE.68
6.4.2.2
Guidance for the treatment of subjects who require coronary artery 
bypass graft surgery – amended
CABG surgery can occur immediately prior to randomization or it may occur in randomized 
subjects who later develop a need for the surgery.   
Subjects who are scheduled to be randomized  Day 4-7 after CABG surgery will not 
participate in the run-in phase (Section 4.1.1).  Randomization should only be performed 
between Day 4-7 post-CABG and at least 24 hours following the removal of chest tubes.  
                                                
67 Text deleted as per Amendment 6. (See Section 13.1.2)
68 Text added as per Amendment 11. (See Section 13.3.1)
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Study drug should not be administered until at least 12 hours after last administration of any 
anticoagulant (including DVT prophylaxis).69
Subjects who are scheduled for CABG surgery during the course of the trial ideally should 
interrupt study rivaroxaban/rivaroxaban placebo at least 24 hours before CABG surgery in 
order to minimize the risk of bleeding.  Study aspirin/aspirin placebo may be interrupted 
and/or non-study aspirin may be used or at the discretion of the investigator.  The timing of 
resumption of study antithrombotic therapy after surgery is at the discretion of the investigator 
but, in general, study rivaroxaban/rivaroxaban placebo or study aspirin/aspirin placebo should 
be resumed once the chest tubes are removed and hemostasis is secure.  Study 
rivaroxaban/rivaroxaban placebo should be interrupted if subjects require in-hospital 
anticoagulant thromboprophylaxis.  In all cases, the goal should be to resume study 
antithrombotic drugs within 1473 days and prior to being discharged from hospital.70  
Long-Term Open-Label Extension − amended71
The same guidance will apply to LTOLE. For subjects who are scheduled to undergo CABG, 
LTOLE treatment can be initiated four days after CABG and at least 24 hours after the 
removal of chest tubes. LTOLE treatment should not be administered until at least 12 hours 
after last administration of any anticoagulant (including DVT prophylaxis).72
6.4.2.3
Guidance for the treatment of subjects who develop an acute coronary 
syndrome and those who require percutaneous coronary intervention 
with stenting – amended
Study rivaroxaban/rivaroxaban placebo should be interrupted in subjects who require 
anticoagulant or dual antiplatelet therapy because of an acute coronary syndrome or need for 
percutaneous coronary intervention with stenting.  Standard antiplatelet therapy, including 
loading doses of aspirin and clopidogrel (or prasugrel or ticagrelor) can be administered 
according to usual practice.  Study aspirin/aspirin placebo may be continued. Standard 
anticoagulant therapy can be used without regard to the timing of the most recent dose of 
study rivaroxaban/rivaroxaban placebo because the doses of rivaroxaban being tested in the 
COMPASS trial are lower than the 1573 or 20 mg dose given for stroke prevention in atrial 
fibrillation and the half-life is short, 5-13 hours.  
Subjects who remain on long term dual antiplatelet therapy may commence “interim study 
rivaroxaban/rivaroxaban placebo” once any non-study anticoagulant therapy is stopped. 
Study aspirin/placebo may be continued. 74 The difference between interim study 
rivaroxaban/rivaroxaban placebo and study rivaroxaban/rivaroxaban placebo is that during the 
period of dual antiplatelet therapy all subjects will receive rivaroxaban at a dose of 2.5 mg bid 
(i.e., the dose of rivaroxaban in those previously allocated 5 mg bid will be reduced to 2.5 mg 
bid). Subjects previously allocated 2.5 mg bid will continue on the same dose whereas those 
                                                
69 Text modified as per Amendments 6 and 8. (See Sections 13.1.2 and 13.2.2)
70 Text deleted as per Amendment 6. (See Section 13.1.2)
71 Text added as per Amendment 11. (See Section 13.3.1)
72 Text modified as per Amendments 6 and 8. (See Sections 13.1.2 and 13.2.2)
73 Text modified/added as per Amendment 6. (See Section 13.1.2)
74 The first sentence was revised and the second sentence was added as per Amendment 8.  (See Section 13.2.2)
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previously allocated rivaroxaban placebo will remain on placebo.  Interim study rivaroxaban 
will be allocated via the 
 randomization and drug management system. All subjects 
should resume originally allocated study rivaroxaban/rivaroxaban placebo once non-study 
dual antiplatelet therapy is stopped and they are not being treated with non-study 
anticoagulants.  When switching back to originally allocated study anticoagulant, interim 
study anticoagulant therapy should be stopped.70
Long-Term Open-Label Extension − amended
Study rivaroxaban should be interrupted in subjects who require anticoagulant or dual 
antiplatelet therapy because of an acute coronary syndrome or need for percutaneous coronary 
intervention with stenting. Standard antiplatelet therapy, including loading doses of aspirin 
and clopidogrel (or prasugrel or ticagrelor) can be administered according to usual practice.  
Study aspirin may be continued. All subjects should resume rivaroxaban 2.5 mg bid + aspirin
od once non-study dual antiplatelet therapy is stopped and they are not being treated with non-
study anticoagulants.75
6.4.2.4
Guidance for the treatment of subjects who overdose on study 
rivaroxaban/rivaroxaban placebo – amended
If rivaroxaban overdose is suspected, the use of activated charcoal up to 8 hours after 
overdose to reduce absorption may be considered.  Due to its low solubility, rivaroxaban 
absorption plateaus at doses of 50 mg and above, thus limiting exposure in the majority of 
subjects. Gastrointestinal absorption of rivaroxaban is reduced in subjects exposed to high 
oral doses and thus the anticoagulant effect of an overdose of rivaroxaban is expected to be 
limited. If available, consideration may be given to the use of a specific reversal agent. 76
Long-Term Open-Label Extension − amended
The same guidance will apply to LTOLE.77
6.4.2.5
Guidance for the treatment of subjects who experience a major bleed –
amended
Temporary discontinuation of rivaroxaban is expected to be sufficient to control bleeding in 
most cases because the drug half-life is only 5-13 hours.  Local measures should be applied if 
needed to control bleeding (e.g., local pressure, endoscopy and injection of a bleeding vessel, 
embolization) and intravenous fluids and blood transfusion support should be provided as 
indicated.  In the rare case of life-threatening bleeding, the investigator may consider 
obtaining advice from a hematologist.  Animal studies suggest that both prothrombin complex 
concentrates and recombinant factor VIIa partially restore hemostasis following treatment 
with factor Xa inhibitors such as rivaroxaban and a randomized trial involving healthy 
subjects treated with rivaroxaban has demonstrated that prothrombin concentrates reverse 
prolongation of the prothrombin time.(30)  Rivaroxaban cannot be dialyzed as it is highly 
                                                
75 Text added as per Amendment 11. (See Section 13.3.1)
76 This paragraph was revised as per Amendment 8.  (See Section 13.2.2)
77 Text added as per Amendment 11. (See Section 13.3.1)
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protein bound. If available, consideration may be given to the use of a specific reversal 
agent.78
Long-Term Open-Label Extension − amended
The same guidance will apply to LTOLE.79
6.4.2.6
  Guidance for the treatment of subjects who develop a stroke and who 
are being considered for reperfusion therapy – amended
The decision to use reperfusion therapies (including intravenous, intra-arterial thrombolysis,
or mechanical endovascular approaches) in acute ischemic stroke should follow local practice, 
experience, and guidelines. At present there are limited data to guide treatment in this setting 
in subjects taking rivaroxaban. The following guidance is intended to aid clinical decision 
making in this setting. 
At or around the time of the peak drug levels (we suggest in the first 6 hours after a dose), 
clinicians may choose to unblind and to avoid thrombolysis if the subject is taking 
rivaroxaban. Alternatively, if it is possible to obtain a rivaroxaban anti-Xa level in this time 
period, clinicians may use this information to decide on the appropriateness of starting 
thrombolysis. Endovascular therapy with clot extraction can proceed whether or not the 
subject is receiving rivaroxaban without the need to unblind.80
Long-Term Open-Label Extension − amended81
The decision to use reperfusion therapies (including intravenous, intra-arterial thrombolysis, 
or mechanical endovascular approaches) in acute ischemic stroke should follow local practice, 
experience, and guidelines. At present there are limited data to guide treatment in this setting 
in subjects taking rivaroxaban. The following guidance is intended to aid clinical decision 
making in this setting. 
At or around the time of the peak drug levels (we suggest in the first 6 hours after a dose), 
clinicians may consider to avoid thrombolysis. If it is possible to obtain a rivaroxaban anti-Xa 
level in this time period, clinicians may use this information to decide on the appropriateness 
of starting thrombolysis. 
6.5
Blinding
Subjects, site personnel, sponsor personnel, 
 staff (with the exceptions mentioned 
below), persons performing the assessments, and data analysts will remain blinded to the 
identity of the treatment from the time of randomization until database lock.  Randomization 
data are to be kept strictly confidential until the time of unblinding and will not be accessible 
by anyone else involved in the study with the following exceptions: (1) 
 information 
technology (IT) computer programmers who work on the 
 randomization and drug 
management system; and (2) the 
 unblinded biostatistician who prepares reports for the 
                                                
78 This paragraph was revised as per Amendment 8.  (See Section 13.2.2)
79 Text added as per Amendment 11. (See Section 13.3.1)
80 Section was added with Amendment 8.  (See Section 13.2.2)
81 Text added as per Amendment 11. (See Section 13.3.1)
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DSMB and provides unblinded information to Bayer for required regulatory reporting 
(suspected unexpected serious adverse reactions [SUSAR] reporting).  These individuals will 
not be involved in the day-to-day running of the study.
In compliance with applicable regulations, in the event of a SUSAR that was believed to be 
related to study treatment, the subject’s treatment code will usually be unblinded before 
reporting to the health authorities, ethic committees and investigators.
Emergency unblinding by the investigator
Emergency unblinding should only be undertaken when it is essential for subject safety and 
will only be provided for the treatment that requires unblinding.  Most often, study drug 
interruption and knowledge of the possible treatment assignments are sufficient to treat a 
study subject who presents with an emergency condition. Detailed information concerning 
unblinding procedures is provided in the Manual of Operations.  In case of unblinding, only 
those individuals who are required to know treatment allocation may be given this 
information.  All others must remain blinded to treatment, including the subject.  All subjects 
should resume study treatments after recovery if it is medically appropriate to do so and 
should be followed until the end of the study.
Long-Term Open-Label Extension – amended
The LTOLE is open label and no blinding procedures are applicable to the LTOLE.82
6.6
Drug logistics and accountability - amended
Each study site will be supplied with study medication kits for the run-in (2 pill bottles) and 
additional study supply for the follow-up phase (and will be re-supplied throughout the study, 
as needed).  The study medication supply will have appropriately labeled packaging according 
to national law and GMP ruling.  The study medication packaging has a 2-part tear-off label.  
A unique medication number will be printed on each part of this label, which corresponds to 
one of the unique treatment arms for the blinded randomized treatment period.  Investigator 
staff will identify the study drug package(s) to dispense to the subject by accessing the 
 
randomization and drug management system and obtaining the medication number(s).  At the 
time of dispensing, one part of the 2-part label will be removed and affixed to the subject’s 
drug dispensing log and the other will remain on the study medication package.  
All study drugs will be stored at the investigational site in accordance with GCP and Good 
Manufacturing Practices (GMP) requirements and the instructions given by the clinical 
supplies department of the sponsor (or its affiliate), 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 study file; the site-relevant elements of this information will 
be available in the investigator site file.  The responsible site personnel will confirm the date83
of receipt of study drug and will use the study drug only within the framework of this clinical 
study and in accordance with this protocol.  Receipt, distribution, return and destruction (if 
any) of the study drug must be properly documented according to the agreed and specified 
                                                
82 Text added as per Amendment 11. (See Section 13.3.1)
83 Text deleted as per Amendment 6. (See Section 13.1.2)
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procedures.  Specific instructions for the study drug recordkeeping are provided in the Study 
Operations Manual.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
Long-Term Open-Label Extension - amended
Investigator staff will continue to access the 
 randomization and drug management 
system to dispense study medication. LTOLE treatment will be provided in appropriately 
labelled medication kits that identify the treatment. All LTOLE treatment will be stored at the 
site in accordance with GCP and Good Manufacturing Practices (GMP) requirements and the 
instructions given by the clinical supplies department of the sponsor or its affiliates. Receipt, 
distribution, return and destruction (if any) of the study drug must be properly documented 
according to the agreed and specified procedures.84
6.7
Treatment compliance
The investigator should promote compliance by counseling the subject to take the study drug 
as prescribed.  The subject should be instructed to contact the investigator if unable for any 
reason to take the study drug as prescribed.
Treatment compliance will be assessed by confirmatory pill counts to be conducted at each 
study visit.
6.8
Post-study therapy - amended
At the conclusion of treatment with study medication, the study staff should encourage the 
subject to resume treatment with open-label aspirin as indicated.85
Long-Term Open-Label Extension − amended86
At the conclusion of LTOLE treatment, subject’s will be directed to their usual care physician
for appropriate treatment.  
6.9
Prior and concomitant therapy - amended
As described in Section 5.1.2, Exclusion criteria, the use of the following agents is not 
permitted at study entry:  systemic treatment with strong inducers of CYP 3A4 (e.g. 
rifampicin) and inhibitors of both87 CYP 3A4 and P-gp (e.g., systemic azole antimycotics, 
such as ketoconazole, and HIV-protease inhibitors, such as ritonavir) (see Section 6.9.1)88.  
Additionally, subjects with a need for dual antiplatelet therapy or oral anticoagulant therapy 
are not eligible for inclusion in COMPASS.
                                                
84 Text added as per Amendment 11. (See Section 13.3.1)
85 Text revised as per Amendment 8.  (See Section 13.2.2)
86 Text added as per Amendment 11. (See Section 13.3.1)
87 Text modified/added as per Amendment 6. (See Section 13.1.2)
88 The cross-reference to Section 6.9.1 was added as per Amendment 8.
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During the study, all randomized subjects should continue to receive any ongoing 
medications, with the exception of the subject’s own aspirin, which must be discontinued at 
the time of commencing the run-in, and treatments that are contraindicated in combination 
with rivaroxaban.  Subjects may receive all medications that their treating physicians believe 
are necessary.  If subjects develop a need for treatments that may interfere with the efficacy or 
safety of study drugs or for treatments that are taken in place of study drug, they must 
temporarily discontinue the relevant study drug (study rivaroxaban/rivaroxaban placebo, 
aspirin/aspirin placebo, or pantoprazole/pantoprazole placebo) until such time that the 
interacting treatment is discontinued.  Study aspirin/aspirin placebo may be continued 89
irrespective of the need for aspirin or dual antiplatelet therapy.  
Long-Term Open-Label Extension − amended
During the LTOLE, all subjects should continue to receive any ongoing medications, with the 
exception of the subject’s own aspirin and treatments that are contraindicated in combination 
with rivaroxaban. Subjects may receive all medications that their treating physicians believe 
are necessary. If subjects develop a need for treatments that may interfere with the efficacy or 
safety of LTOLE treatment or for treatments that are taken in place of LTOLE treatment, they 
must temporarily discontinue the relevant study drug (rivaroxaban or aspirin or both) until 
such time that the interacting treatment is discontinued.90
6.9.1 Combined CYP 3A4 and p-glycoprotein inhibitors and CYP 3A4 inducers -
amended
Strong inhibitors of both CYP 3A4 and p-glycoprotein increase plasma concentrations of 
rivaroxaban and are contraindicated in subjects taking rivaroxaban. These include systemic 
azole antifungal drugs (e.g. ketoconazole, itraconazole, posaconazole, etc.), and HIV protease 
inhibitors.  Additionally, strong inducers of CYP 3A4 such as rifampicin, rifabutin, 
phenobarbital, phenytoin, and carbamazepine can reduce the plasma concentrations of 
rivaroxaban. If any of these treatments are needed, randomized study 
rivaroxaban/rivaroxaban placebo must be temporarily discontinued and open-label aspirin 
should be begun.91  
Long-Term Open-Label Extension − amended
The same guidance applies to LTOLE. No placebo will be used.92
6.9.2 Clopidogrel (or any other non-study antiplatelet treatment) - amended
Subjects who develop a need for treatment with non-study dual antiplatelet therapy, such as 
aspirin plus clopidogrel (e.g., subjects who experience an acute coronary syndrome, those 
who undergo percutaneous coronary intervention with stent insertion) must interrupt87 study 
treatment of87 rivaroxaban/rivaroxaban placebo.  Study rivaroxaban/rivaroxaban placebo must 
                                                
89 Prior to Amendment 8, this sentence had read: “…should be continued…”  (See Section 13.2.2)
90 Text added as per Amendment 11. (See Section 13.3.1)
91 Section revised as per Amendments 6 and 8.  (See Sections 13.1.2 and 13.2.2)
92 Text added as per Amendment 11. (See Section 13.3.1)
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be restarted once dual antiplatelet therapy is stopped (i.e., after completion of an adequate 
duration of dual antiplatelet treatment).  Additional guidance is provided in Section 6.4.2.3.  
Long-Term Open-Label Extension − amended
The same guidance applies to LTOLE. No placebo will be used.93
6.9.3 Anticoagulant treatment - amended
Subjects who develop a need for anticoagulant therapy (e.g., thromboprophylaxis in subjects 
undergoing major orthopedic surgery, acute venous thromboembolism, atrial fibrillation, 
mechanical aortic valve replacement) must interrupt study rivaroxaban/rivaroxaban placebo.  
Study rivaroxaban/rivaroxaban placebo must be restarted in subjects who no longer have a 
need for non-study anticoagulant therapy (e.g., after completion of anticoagulant 
thromboprophylaxis or anticoagulant treatment for venous thromboembolism).  In subjects 
who develop a need for anticoagulant therapy, study aspirin/aspirin placebo may also be 
interrupted, at the discretion of the investigator.94  
If prophylactic anticoagulation is required, subjects should start the first dose of open 
prophylactic anticoagulation at the time that the next dose of study rivaroxaban/rivaroxaban 
placebo is due.  If study drug is interrupted and the subject is transitioned to an anticoagulant 
with a slow onset of action, bridging therapy may be needed.
If therapeutic anticoagulation is required, subjects should start therapeutic anticoagulation 
immediately, irrespective of the timing of the last dose of study rivaroxaban.  
Long-Term Open-Label Extension − amended95
Subjects who develop a need for anticoagulant therapy (e.g., thromboprophylaxis in 
subjects undergoing major orthopedic surgery, acute venous thromboembolism, atrial 
fibrillation, mechanical aortic valve replacement) must discontinue LTOLE medication. 
Guidance for converting see below:

Converting from rivaroxaban to oral anti-coagulants
Rivaroxaban affects INR, so INR measurements made during co-administration with oral 
anticoagulant may not be useful for determining the appropriate dose of oral anticoagulant. 
One approach is to discontinue rivaroxaban and begin both a parenteral anticoagulant and oral 
VKA at the time the next dose of rivaroxaban would have been taken.

Converting from rivaroxaban to parenteral anti-coagulants
Discontinue rivaroxaban and give the first dose of parenteral anticoagulant at the time that 
the next rivaroxaban dose would be taken.
Study rivaroxaban can be restarted at the discretion of the investigator in subjects who 
no longer have a need for non-study anticoagulant therapy (e.g., after completion of 
                                                
93 Text added as per Amendment 11. (See Section 13.3.1)
94 Text deleted as per Amendment 6. (See Section 13.1.2)
95 Text added as per Amendment 11. (See Section 13.3.1)
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anticoagulant thromboprophylaxis or anticoagulant treatment for venous thromboembolism). 
Guidance for restarting see below:

Converting patients from VKAs to rivaroxaban
When converting patients from VKAs to rivaroxaban, INR values will be falsely elevated 
after the intake of rivaroxaban. The INR is not valid to measure the anticoagulant activity 
of rivaroxaban, and therefore should not be used. 

Converting patients from parenteral anticoagulant to rivaroxaban
For patients currently receiving a parenteral anticoagulant, start rivaroxaban 0 to 2 hours 
before the time of the next scheduled administration of the parenteral drug (e.g. LMWH) 
or at the time of discontinuation of a continuously administered parenteral drug (e.g. 
intravenous unfractionated heparin). 
6.9.4 Proton pump inhibitor treatment - amended
Subjects who develop a continuous96 need for treatment with a PPI during the study96 (e.g., 
gastroduodenal ulcer) should discontinue study pantoprazole/pantoprazole placebo while 
receiving non-study PPI treatment.  Study pantoprazole/pantoprazole placebo should96 be 
restarted in all subjects who no longer have a continuous96 need for PPI therapy. 
7.
Procedures and variables
7.1
Schedule of procedures − amended
The study schedule comprises 4 periods:  screening, run-in, follow-up, and washout.  The trial 
will require clinic visits at screening (in most cases this visit is expected to coincide with the 
run in visit), run-in, randomization, 1 and 6 months after randomization, and at least every 6
months thereafter until the end of the study.  Study staff will contact subjects by phone at 
Month 3, Month 9 and at the End of Washout Telephone Visit (30 days post Final Follow-up 
Visit).  Some centers may also perform pre-screening visits.  Further details are provided in 
the Manual of Operations.  
A tabulated overview (Table 7–1) of the procedures conducted in each of these periods is 
provided in Section 7.1.1 and the procedures and their timing are described in more detail in 
Section 7.1.2. 
Early termination of rivaroxaban/aspirin arms of COMPASS − amended
On February 6, 2017, the COMPASS Data Safety Monitoring Board (DSMB) recommended 
discontinuation of the rivaroxaban/aspirin arms of the COMPASS trial. The PPI comparison 
of pantoprazole versus pantoprazole placebo is continuing. 
                                                
96 Text modified/added as per Amendment 6. (See Section 13.1.2)
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Another update has been added to the revised schedule of evaluation. Specifically, the 
pantoprazole/placebo washout call previously included in the table was removed as shown in 
Table 7–2.97
Long-Term Open-Label Extension − amended98
A tabulated overview of the procedures conducted during the LTOLE is provided in Table 7–
3, and the procedures and their timing are described in more detail in Section 7.1.2.6.
                                                
97 Text added as per Amendment 11. (See Sections 13.3.1 and 13.3.2)
98 Text added as per Amendment 11. (See Section 13.3.1)
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7.1.1
Tabulated overview - amended
Table 7–1.  Schedule of evaluations
Pre-Screeninga
Screening/
Run-in
Randomizations,99
Follow-up
Washout
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15n
Final
Wash
out
Timing
-4w
0
1 m 3mm 6m 9mm
1y
1.5y
2y
2.5y
3y
3.5y
4y
4.5y
5y
1 m post 
Finalm
Windowsq,99
± 5d ± 7d ± 2w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w
± 5d
Informed consent (if required for 
pre-screening)
X
Informed consent
Xr,99
Inclusion/exclusion criteria
X
X
X99
Demographics
X
Medical history
X
Physical measurementsb
X
X
X
Concomitant medications
X
X
X
X
Pregnancy test if pre-
menopausal
X
Laboratory testsc
Xd
Xe
Blood/DNA collection and 
storage
Xf
Xf
Diet and activity questionnaires
Xo
Xo Xp100
X
                                                
99 Added as per Amendment 6. (See Section 13.1.2)
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Pre-Screeninga
Screening/
Run-in
Randomizations,99
Follow-up
Washout
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15n
Final
Wash
out
Timing
-4w
0
1 m 3mm 6m 9mm
1y
1.5y
2y
2.5y
3y
3.5y
4y
4.5y
5y
1 m post 
Finalm
Windowsq,99
± 5d ± 7d ± 2w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w
± 5d
MoCA, DSS, and SAGE t, 101
Xo
Xo Xp,100
X
X
EQ-5Dg
Xo
Xo Xp,100
X
X
Health Care Costs
X
Driving Status
X
EuroSCORE for subjects 
randomized post CABG surgery
X
CT coronary angiographyh
Xh
MRI braini
X
X
Outcomes
X100
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug dispensed
Xk
Xl
X
X
X
X
X
X
X
X
X
X
Study drug adherence
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations:  w = week; m = month; y = year; d = day; DNA = deoxyribonucleic acid; MoCA = Montreal Cognitive Assessment; DSS = Digit Symbol 
Substitution test; SAGE = Standard Assessment of Global-Activities in the Elderly; EQ-5D = European Quality of Life-5 Dimensions questionnaire; CT = 
computed tomography; MRI = magnetic resonance imaging; CABG = coronary artery bypass graft
                                                                                                                                                                                                                       
100 Added as per Amendment 6. (See Section 13.1.2)
101 Footnote t added as per Amendment 8 (See Section 13.2.2)
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a. Pre-screening visit is not mandatory and will be conducted only in some centers and for some subjects. Subjects who will be randomized Day 4-7102 after 
CABG surgery do not require pre-screening.
b. Weight, height, waist and hip circumference, heart rate, ankle-brachial blood pressure index
c. Serum creatinine, total cholesterol
d. If not available within 1 year102 prior. 
e. Repeat serum creatinine in patients being enrolled Day 4-7 102 post CABG surgery. For other, non-CABG subjects, the blood results of creatinine and total 
cholesterol should be available within 3 months of this visit. 102
f.
Collection of blood & DNA samples for central evaluation in subjects participating in the COMPASS-MIND substudy is optional. If collected, obtain 
samples102 at randomization, before starting the study drug102, and at 1 month, or as close to one month after randomization as possible. 102 If the first blood 
sample is not collected before start of study drug, it is not required. Irrespective of whether the first blood sample is obtained, collect the second blood 
sample at 1 month. If either the DNA sample or second blood sample is missed, it should be collected at the next visit.102
g. Using the European Quality of Life-5 Dimensions questionnaire and to be performed at screening/run-in or randomization (see “o”), year 2 and Final Follow-
up Visit  as well as at the next study clinic visit after each outcome event103
h. CT angiography will be performed at 1 year or later in all subjects who are randomized Day 4-7102 after CABG to evaluate graft patency  (except in subjects 
those with specific contraindications). In the event the subject undergoes an invasive coronary angiography at 1 year or later post CABG for any reason, a 
CT angiogram may not be required.102, 103
i.
MRI of the brain will be performed only in COMPASS-MIND substudy subjects after randomization102,103 and near the end of the follow-up
j.
Adverse events will be assessed from time of consent to 30 days post last dose of study treatment
k. Stop treatment with non-study aspirin.102  Dispense run-in medications. CABG surgery patients will be randomized Day 4-7102 after CABG surgery and will 
not be dispensed run-in study drug; however, the Screening/Run-In Visit CRFs are still required to be completed for these subjects.  
l.
Stop run-in medication and begin randomized treatment assignment
m. Telephone visits
n. Visits will continue every 6 months until the required number of primary efficacy outcomes has been collected
o. It is optional to administer all or some of the questionnaires (SAGE, DSS, MoCA, EQ-5D, Diet, and Physical Activity) at Screening/Run-in instead of at the 
Randomization Visit, or as soon as possible thereafter (with the exception of patients randomized Day 4-7 post CABG; see “p”).102   
p. For patients randomized Day 4-7 post CABG, questionnaires (SAGE, DSS, MoCA, EQ-5D, Diet, and Physical Activity) should be performed at the 1 month 
visit.102
q. Clinic visits should be scheduled as close to the specified interval as possible, and preferably within the defined window.  If it is not possible for the subject to 
return within the visit "window," especially due to unforeseen circumstance beyond the control of the subject or the study center, then the visit should be 
scheduled as close to the interval as is convenient for the subject and study center.102
                                                
102 Text modified/added as per Amendment 6. (See Section 13.1.2)
103 Text modified/added as per Amendment 8. (See Section 13.2.2)
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r.
CABG subjects can sign the informed consent before or after surgery.102
s. CABG subjects should be randomized between Day 4-7 after the surgery. In the event that a subject is unable to be randomized within this time range for 
medical and logistical reasons, the subject can be randomized, up to Day 14 post-CABG.
t.
Also to be administered at the next study clinic visit after each outcome event.
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Table 7–2 Schedule of evaluations after DSMB recommendation in Feb 2017104
Follow-up
Rivaroxaban/ Aspirin
Pantoprazole/placebo
Pantoprazole/placeboj
Visitj
Final Rivaroxaban/ 
Aspirin Follow-up
Rivaroxaban/ Aspirin 
Washout
Pantoprazole/ Placebo Follow-up
Final Pantoprazole/ 
Placebo Follow-up 
Timing
1 m post Rivaroxaban/ 
Aspirin Finalf
6 m post Rivaroxaban/ Aspirin Final
Follow-up and 6 monthly thereafter
Expected in  2018, 
endpoint dependent
Windowsg
Mar – 15 May 2017 ± 5d
± 4w
± 4w
Complete outstanding re-consents X
Physical measurementsa
X
X
Concomitant medications
X
X
Diet and activity questionnaires
MoCA, DSS, and SAGEh
X
X
X
EQ-5Db
X
X
CT coronary angiographyc
X if 1yr not done yet
MRI braind
X
Outcomes
X
X
X
X
Adverse eventse
X
X
X
X
Study drug dispensedi
Xi
X
Study drug adherence
X
X
X
Study drug accountability
X
X
X
Abbreviations:  w = week; m = month; y = year; d = day; DNA = deoxyribonucleic acid; MoCA = Montreal Cognitive Assessment; DSS = Digit Symbol 
Substitution test; SAGE = Standard Assessment of Global-Activities in the Elderly; EQ-5D = European Quality of Life-5 Dimensions questionnaire; CT = 
computed tomography; MRI = magnetic resonance imaging; CABG = coronary artery bypass graft
a.
Weight, height, waist and hip circumference, heart rate, ankle-brachial blood pressure index
b.
Using the European Quality of Life-5 Dimensions questionnaire and to be performed at year 2 and Final Follow-up Visit  as well as at the next study clinic 
visit after each outcome event
c.
CT angiography will be performed at 1 year or later in all subjects who are randomized Day 4-7 after CABG to evaluate graft patency  (except in subjects 
those with specific contraindications). In the event the subject undergoes an invasive coronary angiography at 1 year or later post CABG for any reason, a 
CT angiogram may not be required. 
d.
MRI of the brain will be performed only in COMPASS-MIND substudy subjects after randomization and near the end of the follow-up
e.
Adverse events will be assessed from time of consent to last dose of study treatment
f.
Telephone visits
                                                
104 Text added as per Amendment 11. (See Section 13.3.1)
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g.
Clinic visits should be scheduled as close to the specified interval as possible, and preferably within the defined window.  If it is not possible for the subject to 
return within the visit "window," especially due to unforeseen circumstance beyond the control of the subject or the study center, then the visit should be 
scheduled as close to the interval as is convenient for the subject and study center. 
h.
Also to be administered at the next study clinic visit after each outcome event
i.
Applicable only for subjects ongoing with pantoprazole/placebo
j.
For subjects from the PPI part, follow up visits will continue regardless of early stoppage of the rivaroxaban/aspirin treatment arms, and there will be no 
washout visit.
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Table 7–3 Schedule of LTOLE Procedures105
Visita
1
2
3
4
5
6
Final LTOLE visite
Timingb
0
6m
1y
1.5y
2y
2.5y
3y/
commercial availablef
Windows
± 4w ± 4w ± 4w
± 4w
± 4w
± 4w
Informed consent
X
Inclusion/exclusion criteria
X
Concomitant medications
X
X
Pregnancy test if pre-menopausal
X
Serum creatinine c
X
Outcomes
X
X
X
X
X
X
Adverse events d
X
X
X
X
X
X
Study drug dispensed
X
X
X
X
X
X
Study drug accountability
X
X
X
X
X
X
Study drug adherence
X
X
X
X
X
X
Questionnaires (MoCA, DSS, SAGE, EQ-5D)
X
a. LTOLE visits may be combined with PPI visits as long as both are ongoing, and the visit window may be adjusted accordingly.
b. Clinic visits should be scheduled as close to the specified interval as possible, and preferably within the defined window.  If it is not possible for the subject to 
return within the visit "window," especially due to unforeseen circumstance beyond the control of the subject or the study center, then the visit should be 
scheduled as close to the interval as is convenient for the subject and study center. 
c.
If not available in the 1 year prior.
d. Adverse events will be assessed from the start of LTOLE treatment to final visit.
e. Subject is on LTOLE treatment and will stop it at this visit and will be suggested to start non-study antithrombotic treatment at physician’s discretion.
f.
If the commercial availability in a country is achieved earlier than 3 years, the subject should be called in for final assessment within approximately 3 months 
or latest at the next scheduled visit; if a participant stops LTOLE treatment, a final visit should be scheduled immediately.
                                                
105 Text added as per Amendment 11. (See Section 13.3.1)
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7.1.2
Timing of assessments
7.1.2.1
Pre-screening visit 
Pre-screening visits are optional but when performed will generally be conducted during the 
1-2 months prior to screening and run-in. The aim of the pre-screening visit is to establish 
subject eligibility.  Some centers may be required by the local ethics committee to obtain 
informed consent prior to conducting pre-screening events.  If this is the case, pre-screening 
activities will include:

Obtain written informed consent for pre-screening (if required) 

Review inclusion and exclusion criteria and evaluate subject willingness to participate 
in the study

Record adverse events if informed consent was obtained
7.1.2.2
Screening and run-in visit(s) - amended
The aim of the screening visit is to confirm eligibility.  Laboratory results of creatinine and 
total cholesterol performed within a year of this visit can be used to assess eligibility. 
Otherwise, obtain relevant laboratory tests.106  For subjects who are randomized Day 4-7106
after CABG surgery, the screening visit may be performed prior to or after106 surgery 
(Section 4.1.1).107  Screening/run-in activities include:

Obtain written informed consent  

Review inclusion and exclusion criteria and evaluate subject willingness for 
participation in the study

Collect demographic data:  gender, date of birth, race/ethnicity

Measure body weight (kg or lb), height (cm or in), waist circumference (cm or in), hip 
circumference (cm or in), heart rate (bpm), ankle-brachial blood pressure index (mm 
Hg) 

Record concomitant medications

It is optional to administer all or some of the questionnaires (SAGE, DSS, MoCA, EQ-
5D, Diet, and Physical Activity) at Screening/Run-in instead of at the Randomization 
Visit.  (In patients randomized Day 4-7 post CABG, the questionnaires should be 
performed at the 1 month visit).108  

Conduct pregnancy test (serum or urine) for premenopausal subjects

Record adverse events

Stop treatment with non-study aspirin
                                                
106 Text modified/added as per Amendment 6. (See Section 13.1.2)
107 Text deleted as per Amendment 6. (See Section 13.1.2)
108 Text modified/added as per Amendment 6. (See Section 13.1.2)
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
Obtain medication code for run-in study treatment and dispense run-in study 
medications (not applicable for subjects who are randomized Day 4-7108 after CABG 
surgery) 
A subject can be re-screened/re-run-in, if not previously randomized to study treatment:108

Obtain written informed consent, if applicable108

Repeat/complete the rest of the screening/run-in activities, where applicable.108
7.1.2.3
Randomization visit (Day 0 ± 5 days) - amended
The aim of the randomization visit is to assign blinded study treatment.  Subjects may be 
randomized if they fulfill all study inclusion and exclusion criteria, have the blood results of 
the serum creatinine and total cholesterol available within 3 months of this visit, have at 
least108 80% adherence (except for extenuating circumstances)108 to both run-in study 
treatments and remain committed to participate in the trial and randomization activities 
including: 

Perform run-in drug accountability; assess adherence to run-in drug (not applicable for 
subjects who are randomized Day 4-7108after CABG surgery)

Record disease and surgical history

Record concomitant medications

Administer diet and activity questionnaires (may be administered at Screening/Run-in 
instead of Randomization)

Administer MoCA, DSS, and SAGE questionnaires (may be administered at 
Screening-Run-in instead of Randomization). 

Administer EQ-5D questionnaire (may be administered at Screening/Run-in instead of 
Randomization). 

In patients randomized day 4-7 post CABG perform questionnaires (SAGE, DSS, 
MoCA, EQ-5D, Diet, and Physical Activity)  at 1 month visit109  

Collect health care costs information

Assess driving status

Assess local laboratory results of creatinine and total cholesterol109

Collect blood for local laboratory assessment of creatinine in subjects being 
randomized post CABG 

Collect EuroSCORE for subjects being randomized post CABG surgery (if score is not 
available in medical chart, calculate EuroSCORE)

Collect blood (DNA) sample for storage and central evaluation in COMPASS MIND 
substudy subjects, if applicable109
                                                
109 Text modified/added as per Amendment 6. (See Section 13.1.2)
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
MRI of the brain will be performed only in COMPASS-MIND substudy subjects after 
randomization110

Record outcomes109

Record adverse events 

Randomize subject by accessing the 
 randomization and drug management 
system 

Dispense assigned study treatments.  Study treatments should be started on the day of 
randomization or, if study aspirin has already been administered on the day of 
randomization, study treatment should be started the day thereafter.  
7.1.2.4
Follow-up visits
7.1.2.4.1
Routine follow-up visits (Visits 3, 5, and 7-15+) - amended
Subjects will be seen in the clinic at Month 1 (7 days), Month 6 (± 4 weeks), and thereafter 
at 6 month intervals (± 4 weeks) post-randomization until Visit 15. Thereafter, subjects will 
continue to be seen at the clinic every 6 months until the required number of primary efficacy 
outcomes has been collected.  During the first year, subjects will be phoned at Month 3 and 
Month 9 to assess and encourage adherence to study treatments, and a further phone call (End 
of Washout Telephone Visit) will be made 30 days after the Final Follow-up Visit to assess 
outcomes and adverse events.  Follow-up assessments include:

Record outcomes 

Record adverse events (if appropriate, complete the Hospitalization CRF to allow 
collection of medical resource utilization [MRU] data)

In patients randomized day 4-7 post CABG perform questionnaires (SAGE, DSS, 
MoCA, EQ-5D, Diet, and Physical Activity) (1 month).111  

Collect blood sample for storage and central evaluation in COMPASS MIND substudy 
subjects at Visit 3 (1 month)

Dispense study drug at Visits 5 and 7-15 by obtaining medication numbers through the 
 randomization and drug management system.

Assess adherence to study drug

Perform study drug accountability (pill count) at each in-clinic visit

Perform CT angiography only at Visit 7 (1 year or later if not performed at 1 year) in 
all subjects who are randomized during the first week after CABG to evaluate graft 
patency (except in subjects with specific contraindications). In the event the subject 
undergoes an invasive coronary angiography at 1 year or later post CABG for any 
reason, a CT angiogram may not be required.111
                                                
110 “after randomization” was added as per Amendment 8.  (See Section 13.2.2)
111 Text added as per Amendments 6 and 8. (See Sections 13.1.2 and 13.2.2)
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
Additional assessments to be performed only at Visit 9 (2 years) include:
o
Physical measurements: body weight (kg or lb), height (cm or in), waist 
circumference (cm or in), hip circumference (cm or in), heart rate (bpm), ankle-
brachial blood pressure index (mm Hg)
o
Record concomitant medications
o
Administer diet and activity questionnaires at Visit 9112
o
Administer MoCA, DSS, and SAGE questionnaires 
o
Administer EQ-5D questionnaire
While every effort should be made for the subject to attend those visits that are meant to be in 
person, infrequently it may not be possible to conduct the visit in person in which case the  
visit may occur by telephone instead.113
7.1.2.4.2
Non-clinic assessments (Months 3 and 9 ± 4 weeks)
At Months 3 and 9, the study staff will contact the study subject by telephone to collect the 
following data:

Record outcomes 

Record adverse events

Discuss study drug adherence 
Additional interim phone calls or visits may occur as required to appropriately manage 
subjects during the study.  Further details are included in the Manual of Operations.
7.1.2.4.3
Final Follow-up Visit (± 4 weeks)
When the required number of primary efficacy outcomes have been collected, the study 
termination will be announced and subjects will return to the clinic for a Final Follow-up 
Visit.  Final follow-up assessments include:

Physical measurements:  body weight (kg or lb), height (cm or in), waist 
circumference (cm or in), hip circumference (cm or in), heart rate (bpm), 
ankle-brachial blood pressure index (mm Hg)

Record concomitant medications

Administer MoCA, DSS, and SAGE questionnaires 

Administer EQ-5D questionnaire 

MRI of the brain will be performed only in COMPASS-MIND substudy subjects

Record outcomes 
                                                
112 Text deleted as per Amendment 6. (See Section 13.1.2)
113 Sentence added as per Amendment 8. (See Section 13.2.2)
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
Record adverse events (if appropriate, complete the Hospitalization CRF to allow 
collection of MRU data)

Assess adherence to study drug

Perform study drug accountability (pill count)
7.1.2.5
End of washout telephone visit (30 days post Final Follow-up Visit ± 5 
days)
The washout visit will be conducted by study staff via telephone interview.  Washout visit 
assessments include:

Record outcomes 

Record adverse events (if appropriate, complete the Hospitalization CRF to allow 
collection of MRU data)
Amended after early termination of rivaroxaban/aspirin arms114
No washout will be scheduled for PPI treatment groups.
7.1.2.6
Long-Term Open-Label Extension −amended115
The LTOLE protocol amendment requires clinic visits at initiation and every 6 months 
thereafter. For the COMPASS trial subjects continuing in the pantoprazole versus placebo 
randomization, LTOLE visits are recommended to coincide with the ongoing visits for 
pantoprazole comparison. If regulatory and ethics approval is obtained shortly after a 
pantoprazole versus placebo follow-up visit, an additional visit is recommended to evaluate 
eligibility and, if appropriate, initiation of LTOLE treatment.
7.1.2.6.1
Initiation of Long-Term Open-Label Extension − amended116
The COMPASS trial subjects will be invited to participate in the LTOLE. Eligibility for 
LTOLE is defined in Section5.1.3. 
The objective of the LTOLE initiation visit is to evaluate eligibility of COMPASS trial 
subjects for LTOLE. Initiation activities include:

Obtain written informed consent 

Review inclusion and exclusion criteria 

Record concomitant medications

Conduct pregnancy test (serum or urine) for premenopausal subjects

Obtain results of serum creatinine (if not available in within prior 1 year)

Dispense study drug
                                                
114 Text added as per Amendment 11. (See Section 13.3.1)
115 Text added as per Amendment 11. (See Section 13.3.1)
116 Text added as per Amendment 11. (See Section 13.3.1)
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7.1.2.6.2
Follow-up of Long-Term Open-Label Extension − amended117
Subjects will be seen in the clinic every 6 months. Follow-up visit assessments include:

Record outcomes 

Record adverse events

Assess adherence to study drug

Perform study drug accountability (pill count)

Dispense study medication
7.1.2.6.3
Final visit of Long-Term Open-Label Extension118
The final visits of LTOLE will begin, per country, when the duration reaches 3 years from the 
regulatory approval of LTOLE or the LTOLE treatment is commercially available in the 
respective country, whichever occurs first. If the commercial availability in a country is 
achieved earlier than 3 years, the subject should be called in for final visit within 
approximately 3 months or at latest the final visit may be conducted at the next scheduled 
visit. The final visit assessments include:

Record outcomes

Record adverse events

Assess adherence to study drug

Perform study drug accountability (pill count)

Record concomitant medication

Administer questionnaires (MoCA, DSS, SAGE, EQ-5D)
In the case of permanent discontinuation of LTOLE treatment, the subject will be called in for 
a final visit.
7.2
Population characteristics
7.2.1
Demographics
Demographic data will be collected at the Screening Visit.  These data will include:

Gender

Date of birth

Race/ethnicity
                                                
117 Text added as per Amendment 11. (See Section 13.3.1)
118 Text added as per Amendment 11. (See Section 13.3.1)
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7.2.2
Medical history
Medical history (i.e. previous diagnoses, diseases or surgeries) meeting all criteria listed 
below will be collected:

Not pertaining to the study indication

Start before signing of the informed consent 

Considered relevant to the study.
Medical history parameters to be collected at randomization will include, e.g.:

Disease history associated with CAD or PAD (myocardial infarction, angina, 
intermittent claudication, diabetes, renal dysfunction, heart failure, transient ischemic 
attack, stroke, liver disease, hypertension, cancer, bleeding requiring transfusion, 
tobacco use) or associated with gastrointestinal disease (bleeding, erosions, ulceration, 
obstruction, perforation) 

Surgical history associated with CAD or PAD (coronary percutaneous transluminal 
coronary angioplasty, atherectomy, percutaneous coronary intervention, coronary 
artery bypass graft, peripheral artery bypass surgery, peripheral percutaneous 
transluminal angioplasty, limb or foot amputation) or associated with gastrointestinal 
disease (bleeding, erosions, ulceration, obstruction, perforation)
7.2.3
Other baseline characteristics - amended
Validated health and quality of life questionnaires (SAGE, MoCA, DSS, and EQ-5D) will be 
administered at screening/run-in or randomization, or as soon as possible thereafter, at Month 
24 and at the Final Follow-up Visit, and at the next study clinic visit after each outcome event 
to measure the effect of randomized treatment on functional outcomes and quality of life.  
Diet and activity questionnaires will also be administered at screening/run-in or 
randomization, or as soon as possible thereafter, and at Month 24 in order to explore the 
determinants and consequences of cognitive decline in patients with CAD and PAD. These 
inventories may be administered at the beginning of each of these study visits prior to meeting 
with the physician and prior to the conduct of any other visit-related procedures. 119
7.3
Efficacy - amended
The primary efficacy outcome is a composite of myocardial infarction, stroke, or 
cardiovascular death.
The secondary efficacy outcomes are: 120
a) A composite of coronary heart disease death, myocardial infarction, ischemic stroke or 
acute limb ischemia 
b) A composite of cardiovascular death, myocardial infarction, ischemic stroke or acute limb 
ischemia
                                                
119 Section was modified as per Amendments 6 and 8.  (See Sections 13.1.2 and 13.2.2)
120 Revised with Amendments 6 and 8.  (See Sections 13.1.2 and 13.2.2)
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c) Mortality by any cause
Other efficacy outcomes include the evaluation of responses recorded for the SAGE, MoCA, 
DSS, and EQ-5D inventories and the following:  individual components of the primary and 
secondary outcomes, hospitalization, revascularization, amputation, stent thrombosis, unstable 
angina, worsening angina, new angina, heart failure, resuscitated cardiac arrest, venous 
thromboembolism, new diagnosis of cancer, MRU, coronary artery bypass graft failure.120
Hospitalization data will be collected on the CRF to permit the analysis of MRU. These data 
will be analyzed and reported to the sponsor separately and will include:

Total days length of stay

Emergency room visits

Intensive care unit /cardiac care unit days 

Rehabilitation and skilled nursing facilities

Reason for medical resource use, i.e., major adverse cardiovascular event or bleeding
MRU data will be incorporated into economic modeling, which will be performed and 
reported separately from this study. 
The outcome for the pantoprazole randomization is a composite of overt bleeding of 
gastroduodenal origin confirmed by endoscopy or radiography, overt upper gastrointestinal 
bleeding of unknown origin, bleeding of presumed occult gastrointestinal origin with 
documented decrease in Hb of 2 g/dL, symptomatic gastroduodenal ulcer, gastrointestinal 
pain with underlying multiple gastroduodenal erosions, and gastrointestinal obstruction, or
perforation. 121
Long-Term Open-Label Extension − amended
The same primary, secondary and tertiary efficacy outcomes collected during the COMPASS 
trial will be collected during the LTOLE.122
7.4
Pharmacokinetics / pharmacodynamics
No measures of pharmacokinetics or pharmacodynamics will be performed for this study.
7.5
Safety − amended
The primary safety outcome is Modified ISTH major bleeding, defined as:  i) fatal bleeding, 
and/or ii) symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment 
syndrome, or bleeding into the surgical site requiring re-operation and/or iii) bleeding leading 
to hospitalization.
                                                
121 Text deleted as per Amendment 6. (See Sections 13.1.2)
122 Text added as per Amendment 11. (See Section 13.3.1)
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The known side effect profile of rivaroxaban can be found in the Investigator Brochure (IB),
which is updated on a regular basis.  Any new, relevant information about side effects of 
rivaroxaban will be provided to the subject by the investigator or designate.
Long-Term Open-Label Extension − amended
The safety collection requirements for the COMPASS trial will remain unchanged for the 
LTOLE.123
7.5.1 E6 Definition of (serious) adverse event - amended
An AE is any untoward medical occurrence including an exacerbation of a pre-existing 
condition or abnormal laboratory finding in a clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. 
A serious adverse event (SAE) is classified as any untoward medical occurrence that, at any 
dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of 
existing hospitalization, results in persistent or significant disability / incapacity is a 
congenital anomaly / birth defect and/or is another medically important serious event 
representing a significant hazard, which is comparable to the aforementioned criteria.124
Note:  If a subject is hospitalized or has a procedure that was planned or anticipated prior to 
the subject signing the informed consent, the hospitalization/procedure is considered part of 
medical  history or a therapeutic intervention and is not the result of an (S)AE unless the 
severity has worsened or changed unexpectedly. Additionally, a procedure is not an (S)AE, 
but the reason for the procedure may be an (S)AE.125
7.5.2
Causal relationship - amended
The assessment of the causal relationship between an AE and the administration of study drug 
is a clinical decision based on all available information at the time of the completion of the 
CRF. The causality assessment should be done separately for each study treatment as detailed 
in the CRF. The assessment is based on the question whether there was a “reasonable causal 
relationship” to the study drug in question.126
7.5.3 Protocol-specific adverse event definitions
7.5.3.1
Protocol-specific exceptions to SAE reporting - amended
Rivaroxaban has been extensively studied in Phase 2 and 3 clinical studies involving more 
than 80,000124 patients and its overall adverse event profile has been well described.  
Appropriate information concerning adverse events will be systematically collected and 
submitted to regulatory authorities and all data on safety and outcomes will be reviewed 
regularly by an unblinded Data and Safety Monitoring Board.
                                                
123 Text added as per Amendment 11. (See Section 13.3.1)
124 Text modified as per Amendments 6 and 8. (See Sections 13.1.2 and 13.2.2)
125 Paragraph added with Amendment 8.  (See Section 13.2.2)
126 Section 7.5.2 and text within was added in Amendment 6.
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For the purposes of this trial, the following events will be captured on the CRF as study 
outcome events only and will be waived from unblinding and will be exempted from the 
expedited reporting but will be included in the final study report. 

Primary efficacy127 outcomes:
o
Cardiovascular death
o
Myocardial infarction
o
Stroke

Secondary and tertiary efficacy128 outcomes
o
Coronary heart disease death
o
Ischemic stroke
o
Acute limb ischemia
o
Cardiovascular hospitalization
o
Venous thromboembolism
o
Revascularization
o
Amputation
o
Stent thrombosis129
o
Angina pectoris (unstable, worsening or new)129
o
Heart failure
o
Resuscitated cardiac arrest
o
New diagnosis of cancer 
o
Coronary artery bypass graft failure129

Primary safety outcomes:129
As bleeding, including fatal bleeding, from all tissues and organs is a known side effect of 
rivaroxaban, bleeding events, including those resulting in hospitalization, will not be reported 
as (S)AEs, but will be captured on the CRF only, and will be reported as outcomes.

Expected Events:129
In addition, events that are expected to occur with high frequency in the population under 
study and for which no safety signal arose from more than 80,000129, 130 patients already 
studied in clinical trials with rivaroxaban will be captured on the CRF only, will be waived 
from unblinding, and be will be exempted from expedited reporting.  These include:
                                                
127 Text modified/added as per Amendment 6.  (See Section 13.1.2)
128 Text revised as per Amendments 6 and 8. (See Sections 13.1.2 and 13.2.2)
129 Text modified/added as per Amendment 6. Section 7.5.3.2 added. (See Section 13.1.2)
130 Number changed from 70,000 to 80,000 as per Amendment 8.
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
Planned hospitalizations (e.g., for surgery, respite care) 

Non-cardiovascular SAEs (including unplanned hospitalizations) that are expected to 
occur with high frequency in the population under study (depression, pneumonia, 
trauma, chronic obstructive pulmonary disease, diabetes mellitus)
7.5.3.2
Reporting of (S)AEs - amended
The following events are to be reported to 
 on the SAE/ESI CRF within 24 hours of the 
investigator becoming aware of the event/diagnosis.129 Bayer HealthCare 
Pharmacovigilance129 is responsible for reporting these events to the health authority: 129

Any non-cardiovascular death of a subject occurring after signing informed consent or 
prior to the end of monitoring for adverse events. (note: fatal bleeding events are 
primary safety outcomes and are exempted)129

Any non-cardiovascular SAEs not listed in Section 7.5.3.1

Any non-cardiovascular AE that recurs when the subject is restarted on study drug 
(positive re-challenge).129
In addition, any AEs of particular concern to the investigator may be recorded on the CRF to 
bring them to the attention of the sponsor.
7.5.3.3
Adverse events of special safety interest - amended
For ongoing pharmacovigilance, the large COMPASS trial is an opportunity to identify rare 
events in the population that may or may not be drug-related.  The following events have, to 
date, not been observed with increased frequency with rivaroxaban, but are considered AEs of 
special safety interest. These events must be reported to 
 independent of their 
seriousness, but within the same timelines as an SAE (within 24 hours) by reporting them on 
the SAE page of the CRF. Bayer HealthCare Pharmacovigilance may decide to upgrade the 
event based on the information received.

Pregnancy outcome and any congenital anomaly131

Events currently under observation by Bayer HealthCare Pharmacovigilance and 
which may be unusual in the absence of drug therapy in the study population.  The 
types of events that fall into this category are listed in Table 7–4.

Events of special interest that are mild or moderate do not need to be reported in 
expedited fashion
                                                
131 Text deleted as per Amendment 6. (See Section 13.1.2)
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Table 7–4.  Adverse events of special interest
System Organ Class
Example
Blood and lymphatic system
Pancytopenia, aplastic anemia
Red cell aplasia
Agranulocytosis
Severe leukopenia
Severe neutropenia
Severe thrombocytopenia (<50 x 109/L)
Thrombotic thrombocytopenic purpura
Immune thrombocytopenic purpura
Heparin-induced thrombocytopenia
Hemolytic anemia
Severe megaloblastic anemia
Disseminated intravascular coagulation
Skin and subcutaneous disorders
Severe exfoliative dermatitis 
Severe bullous skin reactions
Erythema multiforme
Stevens Johnson Syndrome
Toxic epidermal necrolysis
Epidermolysis
Anaphylaxis
Angioedema requiring hospitalization
Angioneurotic oedema (not otherwise explained e.g. by ACE-
inhibition)
Allergic vasculitis
Hepatobiliary disorders
Hepatic failure (incl. fulminant hepatitis, hepatic necrosis) and 
associated disorders (like hepatorenal syndrome, encephalopathy)
Severe hepatocellular damage and hepatitis
Jaundice (if unrelated to gallstones)
Gastrointestinal disorders
Pancreatitis
Retroperitoneal fibrosis
Pseudomembraneous colitis
Renal and urinary disorders
Acute nephritis (not caused by infection)
Nephrotic syndrome
Acute renal failure (only if not related to cardiovascular event or 
bleeding)
Nervous system disorders
Acute polyneuropathies 
Muscle disorders
Rhabdomyolysis
Toxic myopathy
Respiratory disorders
Alveolitis
Acute interstitial pneumonia
Infections 
Severe sepsis
Endocrine disorders
Adrenal insufficiency
Addison’s disease
Eye and ear disorders
Acute, sudden vision loss or acute reduced visual acuity (only if not 
related to stroke)
Sudden hearing loss
Cardiac disorders
Torsades de pointe
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7.5.3.4
Non-serious adverse events
With the exception of the events of special interest defined in Section 7.5.3.3, AEs which are 
not serious but which lead to permanent discontinuation of study medication will be captured 
in the CRF but do not require expedited reporting.  
Non-serious AEs which do not lead to discontinuation of study medication will not be 
collected.
7.5.3.5
Pregnancies - amended
The investigator must report to the sponsor any pregnancy occurring in a study subject, or in 
the study subject’s partner, during the subject’s participation in this study.  The report should 
be submitted within the same timelines as an SAE, although a pregnancy per se is not 
considered an SAE.
For a study subject, the outcome of the pregnancy should be followed up carefully, and any 
outcome of the mother or the child should be reported. Abnormal  pregnancy outcomes (eg, 
spontaneous abortion, stillbirth, and congenital anomaly) are considered serious adverse 
events and must be reported using the Serious Adverse Event Form.132  For the pregnancy of a 
study subject’s partner, all efforts should be made to obtain similar information on course and 
outcome, subject to the partner’s consent.
For all pregnancy reports, the forms provided by 
 are to be used.133
7.5.4 Reporting of events to Bayer by 
 and compliance with regulatory 
authorities’ reporting requirements - amended
Adverse events that require expedited reporting described in Sections 7.5.3.2, 7.5.3.3, and 
7.5.3.5132 (protocol-specific adverse event reporting) are to be recorded on the appropriate 
SAE CRF page and are to be forwarded to 
 within 24 hours of the investigator having 
been made aware of the event. In this trial, exempted outcomes are to be recorded on the 
appropriate outcome CRF page, not the SAE CRF page.132  Upon receipt of an SAE CRF 
page132 this form will be reported to Bayer Global Pharmacovigilance by 
 within 
24 hours, or 3 calendar days for weekends or public holidays, or next working day whichever 
is earlier. 
All required information will be listed on the SAE page in the CRF.  If the required 
information is not immediately available, 
 will query the center to obtain the information 
once it becomes available.  In the rare circumstances that additional information is needed, 
 will work with Bayer and the site investigators to obtain additional information in a 
timely manner to enable Bayer to comply with regulatory authorities’ reporting requirements. 
7.6
Other procedures and variables
No other procedures will be conducted and no other variables will be explored in this trial.
                                                
132 Text modified/added as per Amendment 6. (See Section 13.1.2)
133 Section ‘Data Safety Monitoring Board’ was deleted in Amendment 6. (See Section 13.1.2)
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7.7
Appropriateness of procedures / measurements
With the exception of routine laboratory assessments performed at screening, imaging studies 
performed in subjects randomized post CABG, and blood and imaging studies in those 
participating in the COMPASS MIND substudy, no invasive procedures are planned for this 
study.  All study visits will be used to collect safety and outcome data, which are appropriate 
measures for this events-driven trial.  
8.
Statistical methods and determination of sample size
8.1
General considerations
General description of the statistical methods is outlined below. A more detailed statistical 
analysis plan (SAP) will be provided in a separate document.
The core SAP document will provide a more technical and detailed elaboration of the 
principal features of the planned analyses, e.g. censoring schemes for time-to-event variables. 
The core SAP will be finalized ideally prior to study enrollment, at the latest before any 
substantial information in the trial has accumulated.
Amendments and/or appendices to the core SAP will provide more details on the coding 
guidelines, data-handling, and output tables and figures. These SAP associated documents 
will be finalized ideally 6 months before planned study end to take into account emerging data 
external to the trial becoming available during conduct of the trial that could influence study 
interpretation. All SAP associated documents will be finalized without knowledge of any 
emerging results from the trial.
Analyses will be performed using SAS software (SAS Institute Inc, Cary, NC, USA).
8.2
Analysis sets and data scopes
8.2.1 Analysis sets
Intention-to-treat analysis set
The intention-to-treat analysis set, also termed full analysis set in the International Conference 
on Harmonization (ICH) E9 guideline,(31) will include all randomized subjects. 
Safety analysis set (for secondary safety analyses)
The safety analysis set will include all randomized subjects who received at least one dose of 
study medication. 
8.2.2 Data scopes
Data scope according to intention-to-treat principle
Analyses according to the intention-to-treat principle will be based on the intention-to-treat 
analysis set and will include all outcome events observed from randomization until the date of 
the Final Follow-up Visit for each subject.  For subjects who are unable to attend the Final 
Follow-up Visit within the acceptable closeout time-window (range of dates depending on 
date of announcement of study termination), a calendar date will be chosen after which events 
will not be counted for primary analysis before unblinding.  Subjects will be kept in the study 
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group to which they were randomized and the follow-up period for each subject will be as 
long and complete as possible. 
Additional data scopes for secondary safety analyses
Additional analyses of safety outcomes will be based on the safety analysis set. Subjects will 
be kept in the study group to which they were randomized. The outcome events will include:

All outcome events observed from randomization until the date of the Final Follow-up 
Visit or a chosen calendar date described above for each subject

All outcome events observed from randomization until 2 days following permanent 
discontinuation of the study drug (“treatment emergent outcomes” analysis)

All outcome events observed from randomization up to 30 days following permanent 
discontinuation of the study drug

All outcome events observed from randomization during the entire follow-up and 
wash-out periods
8.3
Variables – amended
Time (in days) from randomization to the first occurrence of 

the primary, secondary, tertiary efficacy outcomes (except SAGE, MoCA, DSS, and 
EQ5D, and MRU) for the antithrombotic treatment randomization (Sections 8.3.1, 
8.3.2, 8.3.3),

the primary safety outcome for the antithrombotic treatment randomization 
(Section 8.3.4), and

the outcome for the pantoprazole randomization (Section 8.3.5) 
will be analyzed as time-to-event variables. 
8.3.1
Primary efficacy outcome
The primary efficacy outcome is the composite of the following outcomes:

Myocardial infarction 

Stroke 

Cardiovascular death 
8.3.2
Secondary efficacy outcomes - amended
134The secondary efficacy outcomes are (in the following order):

The composite of outcomes --- coronary heart disease death, myocardial infarction, 
ischemic stroke, acute limb ischemia

The composite of outcomes --- cardiovascular death, myocardial infarction, ischemic 
stroke, acute limb ischemia
                                                
134 Text modified/added as per Amendments 6 and 8. (See Sections 13.1.2 and 13.2.2)
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
Mortality (all-cause)
8.3.3
Tertiary and other efficacy outcomes - amended
The tertiary efficacy outcomes are:

Subject-reported SAGE, MoCA, DSS, and EQ-5D

Individual components of the primary and secondary outcomes

Hospitalization for cardiovascular reasons135

Hospitalization

Revascularization135

Amputation136

Stent thrombosis134

Unstable angina 

Worsening angina 

New angina 

Heart failure 

Venous thromboembolism135

Resuscitated cardiac arrest

New diagnosis of cancer

MRU

Coronary artery bypass graft failure137
8.3.4
Primary safety outcome
The primary safety outcome is modified ISTH major bleeding, defined as:
fatal bleeding, and/or 
symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with 
compartment syndrome, or bleeding into the surgical site requiring reoperation, and/or
bleeding leading to hospitalization
8.3.5
Outcome for pantoprazole randomization - amended
The outcome for the pantoprazole randomization is the composite of the following outcomes: 

Overt bleeding of gastroduodenal origin confirmed by endoscopy or radiography 

Overt upper gastrointestinal bleeding of unknown origin 
                                                
135 Added as per Amendment 8.  (See Section 13.2.2)
136 Text deleted as per Amendment 6. (See Section 13.1.2)
137 Text modified as per Amendment 6. (See Section 13.1.2)
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
Bleeding of presumed occult gastrointestinal origin with documented decrease in Hb 
of 2 g/dL138

Symptomatic gastroduodenal ulcer 

Gastrointestinal pain with underlying multiple gastroduodenal erosions, obstruction or 
perforation
8.3.6
Subgroup variables - amended
Homogeneity of treatment effect will be examined for the following subgroup variables:

CAD137 (yes, no)

PAD137 (yes, no)

CAD and PAD (yes, no)

CAD only, PAD only, CAD and PAD 

CABG days 4-7 before randomization137 (yes, no)

Any prior CABG (yes, no), further subdivided as CABG days 4-7 before 
randomization and other prior CABG139   

Region (North America, Western Europe, Eastern Europe, Asia Pacific and other, and 
South America)

History of a prior heart failure (yes, no)

History of non-lacunar ischemic stroke ≥1 months ago (yes, no)

Sex (male, female)

Age (<55, 55 - <65, 65 - 75, >75 years)

Race (White or Caucasian, Black or African American, Asian, other)

Baseline renal function (estimated glomerular filtration rate <60, ≥60 mL/min)

Baseline diabetes (yes, no)

Smoking status at baseline (smoker, nonsmoker)

Baseline PPI use (yes, no)
Additional subgroup variables, if identified, will be specified in the SAP prior to unblinding 
of the treatment assignment.
8.4
Statistical and analytical plans - amended
Summaries by randomized group using appropriate descriptive statistics will be provided for 
all study variables including demographic and baseline characteristics. Mean, median, 
standard deviation, minimum, and maximum will be used to summarize continuous variables. 
Counts and percentages will be used to summarize categorical variables.
Testing strategy140
                                                
138 Text deleted as per Amendment 6. (See Section 13.1.2)
139 Bullet was added as per Amendment 8.  (See Section 13.2.2)
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Each of the rivaroxaban-based treatment groups will first be compared to the common aspirin 
control group on the primary efficacy outcome, followed by the same comparisons on the 
three ordered secondary efficacy outcomes.  Figure 8–1 illustrates the hypothesis testing 
problem with ordered hypotheses. The null hypotheses of no effect corresponding to different 
efficacy outcomes will be grouped into four separate families. Standard logical restrictions 
will be imposed, i.e., the null hypotheses will be split into two branches corresponding to the 
tests for rivaroxaban 2.5 mg plus aspirin (hypotheses H1A, H2A, H3A, H4A) and to the tests for 
rivaroxaban 5.0 mg (hypotheses H1B, H2B, H3B, H4B).  A null hypothesis within each branch 
can be tested if and only if the immediately preceding null hypothesis is rejected, e.g., 
hypothesis H2A, is “testable” if and only if hypothesis H1A is rejected. In Figure 8–1, these 
logical restrictions are represented by arrows.
Figure 8–1: Hypothesis testing problem
Multiple hypotheses testing will be performed according to a mixture gatekeeping procedure 
based on the Hochberg test with a truncation fraction of γ = 0.9, which controls the 
familywise error rate at the pre-assigned level of significance α = 5% in the strong sense.  The 
Hochberg-based gatekeeping procedure based on an extension of the general mixture 
methodology developed in Dmitrienko and Tamhane (33,34) was recently proposed in 
Brechenmacher et al. (32)  Details for the setting of this study will be described in the SAP.  
8.4.1
Analysis of the primary efficacy outcome - amended
Analysis of the primary efficacy outcome will be based on the intention-to-treat principle 
(Section 8.2).  Two comparisons will be performed to compare each of the rivaroxaban-based 
treatment groups to the common aspirin control group to evaluate:

Superiority of rivaroxaban 2.5 mg bid + aspirin 100 mg od over 
rivaroxaban placebo + aspirin 100 mg od (control)
                                                                                                                                                        
140 Testing strategy text added as per Amendment 8.  (See Section 13.2.2)
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
Superiority of rivaroxaban 5 mg bid + aspirin placebo over 
rivaroxaban placebo + aspirin 100 mg od (control).
Each of the primary null hypotheses H0;riva2.5 and H0;riva5 stating that “there is no difference 
between the considered rivaroxaban-based treatment group and the aspirin control group in
the probability of the primary efficacy outcome for all time points” will be tested against the 
respective alternative hypotheses H1;riva2.5 and H1;riva5 stating that “there is a difference 
between the two groups in the probability of the primary efficacy outcome for at least one 
time point”.
The 2 comparisons will be performed using 2 separate stratified log-rank tests. Following the 
mixture gatekeeping procedure as mentioned in Section 8.4, a truncated Hochberg test with 
the pre-specified truncation parameter γ = 0.9 at =0.05 will be used. Further details will be 
described in the SAP.  PPI use (3 strata levels: not randomized to a PPI; pantoprazole 40 mg 
od; pantoprazole placebo) will be used as a stratification factor.  Study center will not be used 
as a stratification factor.  There will be no formal comparison between the rivaroxaban 2.5 mg 
bid + aspirin 100 mg od and rivaroxaban 5 mg bid + aspirin placebo groups.141
Kaplan-Meier estimates of cumulative risk and cumulative hazard functions will be provided 
to evaluate the timing of event occurrence in the 3 antithrombotic study groups and the 
consistency of the respective treatment effects for all time points (the two survival curves in 
each comparison do not cross). 
Hazard ratio, relative risk reduction, and corresponding 2-sided 95% confidence intervals will 
be estimated based on 2 separate stratified Cox proportional hazards models. Censoring will 
be assumed independent of the randomized group assignment. The plausibility of the 
proportional hazards assumption will be assessed by visually examining both the plot of the 
log of the negative log of Kaplan-Meier estimates of the survival function versus the log of 
time for evidence of non-parallelism and the smoothed plot of the scaled Schoenfeld residuals 
to directly visualize the log hazard ratio,(33) and by including a time-treatment interaction 
term in the Cox model (time log transformed).  The significance of the interaction will be 
tested at the 5% type I error level. If the interaction is significant and there is strong evidence 
of non-proportionality from the plots, time-dependent hazard ratios will be estimated with the 
model that includes the interaction term.  Further details will be specified in SAP.
The trial success will be determined based on the totality of evidence for significance, 
magnitude, and direction of treatment effect from the analysis of primary and secondary 
efficacy outcomes. 142
Analysis of the joint effect and/or interaction between rivaroxaban-based anti-thrombotic 
therapy and PPI use on the primary efficacy outcome will be performed as described in 
Section 8.4.5.  Further details of this analysis will be specified in SAP.
                                                
141 Paragraph was revised as per Amendment 8.  (See Section 13.2.2)
142 Text was deleted from this paragraph as per Amendment 8.  (See Section 13.2.2)
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8.4.2
Analysis of the secondary efficacy outcomes - amended
Analysis of the secondary efficacy outcomes will be based on the intention-to-treat principle 
(Section 8.2) and will use a similar approach as described in Section 8.4.1. The family-wise 
error rate will be controlled using the truncated and/or regular Hochberg tests as described in 
Section 8.4 and more detailed in the SAP.143
8.4.3
Analysis of the tertiary efficacy outcomes
Analysis of the tertiary efficacy outcomes will be based on the intention-to-treat principle 
(Section 8.2) and will use a similar approach as described in Section 8.4.1 (except for SAGE, 
MoCA, DSS, and EQ5D).  Analysis of subject reported SAGE, MoCA, DSS, and EQ5D will 
be described in the SAP. Both comparisons of the rivaroxaban-based treatment groups to the 
common aspirin control group will be performed at the 2-sided 5% type I error level.  
Additional exploratory analyses will be conducted, as described in the SAP.
The MRU data will be incorporated into economic modeling, which will be performed and 
reported separately from this study. 
8.4.4
Analysis of the primary safety outcome
The principal analysis of the primary safety outcome will be based on the intention-to-treat 
principle (Section 8.2). The analysis will follow similar methodology as the analysis of the 
primary efficacy outcome described in Section 8.4.1.
In addition, the primary safety outcome will be analyzed based on the other data scopes 
defined in Section 8.2.2.  
8.4.5
Analysis of the outcome for pantoprazole randomization - amended
Analysis of the outcome for pantoprazole randomization will be based on the intention-to-
treat principle (Section 8.2) and will include all subjects randomized to receive pantoprazole 
40 mg od or pantoprazole placebo.
Pantoprazole 40 mg od treatment group and pantoprazole placebo control group will be 
compared. The null hypothesis H0;panto40 stating that “there is no difference between the 
pantoprazole treatment and control groups in the probability of the outcome144 for 
pantoprazole randomization for all time points” will be tested against the alternative 
hypothesis H1;panto40 stating that “there is a difference between the two groups in the 
probability of the outcome144 for at least one time point”.
The comparison will be performed using a log-rank test stratified by antithrombotic therapy 
study group (3 strata levels: rivaroxaban 2.5 mg bid + aspirin 100 mg od; rivaroxaban 5 mg 
bid + aspirin placebo; rivaroxaban placebo + aspirin 100 mg od), conducted at the 2-sided 5% 
type I error level. There will be no interim analyses for the pantoprazole randomization.
Kaplan-Meier estimates of cumulative risk and cumulative hazard functions will be provided 
to evaluate the timing of event occurrence in the 2 PPI study groups and the consistency of the 
treatment effect for all time points (the 2 survival curves do not cross).
                                                
143 Paragraph was revised as per Amendment 8.  (See Section 13.2.2)
144 Text deleted as per Amendment 6. (See Section 13.1.2)
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Hazard ratio, relative risk reduction, and corresponding 2-sided 95% confidence intervals will 
be estimated based on a Cox proportional hazards model stratified by antithrombotic therapy 
study group.  Censoring will be assumed independent of the treatment group assignment. 
Similar strategies to those outlined in Section 8.4.1 will be used for assessing the plausibility 
of the proportional hazards assumption.
In addition, joint effect and interaction between the antithrombotic and pantoprazole study 
groups will be explored based on the intention-to-treat principle in subjects randomized to 
receive pantoprazole 40 mg od or pantoprazole placebo.  The analysis will use 2 separate Cox 
proportional hazards models, one for the comparison of rivaroxaban 2.5 mg bid + aspirin 
100 mg od vs. rivaroxaban placebo + aspirin 100 mg od, and one for the comparison of 
rivaroxaban 5 mg bid + aspirin placebo vs. rivaroxaban placebo + aspirin 100 mg od.  The 
models will include:

a covariate for the effect of the considered rivaroxaban-based treatment group vs. the 
aspirin control group,

a covariate for the effect of pantoprazole 40 mg od treatment group vs. pantoprazole 
placebo control group,

an interaction term of these 2 factors.
If the interaction term is significant at the 5% type I error level, then the interaction ratio test
(36) will be performed to assess synergy and sub-additivity of the two treatment effects.  
Additional exploratory analyses, e.g. a comparison of subjects who used PPI at baseline (and 
therefore were not randomized to receive pantoprazole 40 mg od or pantoprazole placebo) 
with subjects randomized to pantoprazole placebo group, will be conducted as described in 
the SAP.
8.4.6
Subgroup analyses - amended
Subgroup analyses for the primary efficacy and safety outcomes, and the outcome145 for 
pantoprazole randomization will be performed based on the same analysis sets and data 
scopes as in the main analyses of the study outcomes (Sections 8.4.1, 8.4.2, 8.4.3, 8.4.4, and 
8.4.5). 
Homogeneity of treatment effect in subgroups, both in magnitude and direction, will be 
assessed by adding a covariate for the subgroup variable (Section 8.3.6) and the corresponding 
treatment-subgroup interaction to the respective stratified Cox proportional hazards model 
used in the main analysis.  Cox proportional hazards regression model (not stratified) will be 
used for baseline PPI use (yes, no) variable.
As the number of subgroup analyses may be large, the probability of observing at least one 
statistically significant but spurious interaction is high despite the lack of a biological or 
pharmacological basis for expecting an interaction.  Thus any significant interactions in the 
analysis of primary outcomes will be interpreted as “flags” to prompt further investigation.
                                                
145 Text deleted as per Amendment 6. (See Section 13.1.2)
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No interactions with any of the subgroup variables are expected.  If the interaction term is 
significant at the 5% type I error level in the analysis of the primary efficacy outcome, 
secondary and tertiary efficacy outcomes will be investigated to evaluate the plausibility of 
such an effect.  Furthermore, in the analysis of all outcomes if the interaction term is 
significant at the 5% type I error level the likelihood ratio test proposed by Gail and 
Simon(37) will be performed to test the hypothesis that there is no crossover or qualitative 
interaction at the 1% type I error level (H0: The direction of treatment effect is the same for all 
levels of a subgroup variable vs. H1:  The direction of treatment effect is different for at least 
one level of a subgroup variable).  As was shown by Li et al (2007),(38) the probability of 
observing the treatment effect in the opposite direction to the true overall treatment effect for 
at least one subgroup level is not negligible. The contributing factors may be small subgroup 
sizes, imbalance of randomized groups within the subgroups, and small true overall treatment 
effect.(38)
Following the test of interaction, hazard ratio and relative risk reduction for the treatment 
effect will be estimated separately within each level of a subgroup variable using the stratified 
Cox proportional hazards models that were used in the main analyses of study outcomes.
8.4.7
Handling of missing data
All efforts will be made to collect complete data for all subjects randomized in this study.  
Subjects will be followed to the study end and will complete all required data collection, 
regardless of their compliance with study medications or visits. 
When an event date is not known, the site investigator will be asked to provide a best estimate 
as to when the event occurred.  Even though the exact date of an event is unknown, the 
investigator often does know some information that would indicate the approximate date, such 
as the first week of a month, in the fall of a year, or the middle of a particular year, or at least 
the date when the subject was last seen or contacted.  This information can be meaningfully 
incorporated into the estimated date recorded, as this is likely to be closer to the true date than 
any produced by an uninformed computer program.  This estimated date should be the middle 
date within the period that the event is known to have occurred.  If the event is known to have 
occurred in the first week of a month, then the date in the middle of that week should be 
recorded as the estimate.  If it occurred in the fall of a year, then the middle date in the fall is 
the appropriate estimate.  If no information is known then the date in the middle of the 
plausible time period should be given, based on the last contact with the subject prior to the 
event and the date of contact when information about the event was known.  This method for 
date estimation has been used in many studies and is recommended by Dubois and Hebert
(2001).(39)
8.4.8
Long-Term Open-Label Extension – amended146
All primary, secondary, tertiary efficacy outcomes and safety outcomes will be summarized 
using frequency table in a descriptive way. Further details will be included in a separate SAP.
The same subgroup variables as in the COMPASS trial will apply to LTOLE.
                                                
146 Text added as per Amendment 11. (See Section 13.3.1)
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8.5
Planned interim analyses - amended
Interim assessments and study monitoring for efficacy and safety will be done by an 
independent DSMB, which will review unblinded event rates. An independent statistician 
within 
, who is not involved with any study conduct, will perform interim data analyses 
to support the DSMB.
Two formal interim analyses are planned when 50% and 75% of the expected number of 
accumulated primary efficacy outcome events accrue. 
If the interim analyses show clear and consistent benefit in both treatment arms, the DSMB 
may recommend early study termination.  The Haybittle-Peto rule will be used to guide the 
decision regarding early stopping:  a reduction of 4 standard deviations in the analysis of the 
primary efficacy outcome at the first interim analysis or 3 standard deviations at the second 
interim analysis.  If the monitoring boundary is crossed at either of the 2 interim analyses, a 
second look will be done after at least 4-6 months to confirm the boundary remains crossed 
and that the trend in treatment effect is not temporary.
For a lack of efficacy, a futility approach will be utilized at the time of planned interim 
analysis. If the conditional probability of rejecting the null hypothesis for either primary 
comparisons, given current trends, falls to an unacceptably low level (i.e. <5%), the DSMB 
may consider recommending early termination of the study.
Given these conservative monitoring boundaries and only 2 interim analyses, the type I error 
level adjustment for the final analysis will be negligible.  If the results are clear with one 
intervention, but not for the second intervention, the DSMB may decide to continue 
evaluation of both or one rivaroxaban treatment arms.  If the study is continued with both 
interventions, then the type I error levels specified in Section 8.4.1 will be used in the final 
analysis; if the decision is made to continue with only one intervention, the final comparison 
will be made as follows: 147

If one intervention was stopped early for efficacy, the multiple testing procedure for 
the final analysis will be performed as described in Section 8.4 with the assumption 
that the p-value for the primary efficacy outcome of the arm that was stopped early for 
overwhelming efficacy is smaller than 0.025. For secondary outcomes, the p-values 
will be obtained from log-rank tests based on all available data for the stopped arm 
(data from confirmation analysis 6 months after respective interim look) and the 
complete data from the comparator arm.

If one intervention was stopped early for futility, the final analysis will be performed 
when at least 1,513148 subjects in the 2 remaining arms have experienced an event.
                                                
147 The details in the bulleted paragraphs were added as per Amendment 8.  (See Section 13.2.2)
148 The whole study was planned to be stopped when at least 2,200 subjects had experienced a primary outcome 
event. Under the planning assumptions that both alternative hypotheses are true, observed randomization times 
and estimated overall incidence rates based on preliminary data, and projected study duration after sample size 
increase, it is expected that 826 subjects in the control arm and each 687 subjects in the rivaroxaban intervention 
arms will experience a primary outcome event. Dropping one intervention arm early but still expecting that for 
the other comparison the alternative hypothesis holds true, the study needs to be continued until at least 826 + 
687 = 1,513 subjects in the remaining arms have experienced a primary event.
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The final analysis will be performed according to the multiple testing strategy as 
described in Section 8.4. P-values for the primary and secondary hypotheses for the 
intervention stopped early will be obtained from the log-rank tests based on all 
available data for the stopped arm and the complete data from the comparator arm. It 
can be assumed that for the stopped intervention the corresponding p-value of the 
primary efficacy outcome will be greater than 0.05. Thus, for the intervention stopped 
early for futility the primary and none of the secondary outcomes can achieve 
statistical significance at the overall type I error level of 5%.
The Steering Committee will review overall blinded event rates to ensure that they meet 
protocol projections.  If overall event rates are lower than expected, consideration will be 
given to increasing the sample size or extending the study duration without knowledge of any 
treatment effect.  The trial will aim to enroll about one-quarter149 subjects with PAD; this will 
be monitored during the trial and steps may be taken to adjust the proportion during the trial.
8.6
Determination of sample size - amended
150In this trial, it is planned to randomize at least 27,400 subjects and to continue the study 
until a minimum of 2,200 subjects experience an event for the primary efficacy outcome.
The aim is to achieve at least 90% power to detect a 20% relative risk reduction (RRR) for 
each of the 2 rivaroxaban-based treatment groups vs. the common aspirin control group.  The 
total number of events needed is shown in Table 8–1 for different scenarios depending on the 
assumed annual incidence rate for the primary outcome in the aspirin group based on the 
assumptions modified according to Amendment 6 (integrated protocol Version 2.0), dated 
03 JUL 2014.  Due to the event-driven study design, the number of randomized subjects, 
length of enrollment and total study duration may vary.  If recruitment is going extremely 
well, a larger number of subjects may be recruited.  All numbers below refer to the minimum 
number of events to be observed after successful completion of the run-in period.  For the 
total number of subjects to be enrolled in the run-in period, at least 10% must be added to the 
total number below.
Original assumptions for antithrombotic treatment randomization were:

3-arm study with 1:1:1 randomization

In total, a minimum of 21,400 subjects are randomized (approximately 7,134 subjects 
per treatment group) according to a 1:2:3:4:4 pattern within 2.5 years

2-sided type I error level of 2.7% for each of the two comparisons to control the 
overall type I error level of 5%

Constant annual incidence rate in aspirin control group between 3.0% and 4.0%

Effect size: 20% relative risk reduction to be detected for each comparison
                                                
149 Prior to Amendment 8, this was one-third subjects with PAD.
150 This section was revised as per Amendments 6 and 8.  (See Sections 13.1.2 and 13.2.2)
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
Intention-to-treat analysis: all subjects randomized are included in the analysis as 
randomized and the follow-up period for each subject is as long as possible from 
randomization until the date of the Final Follow-up Visit for each subject

Length of recruitment period about 2.5 years 

Early discontinuation of study drug: about 6% and 4% in the 1st and 2nd 6-month 
periods, and 3% in the 6-month periods thereafter
The expected total number of observed events and the estimated power for each of the two 
comparisons are displayed in Table 8–1. 
Table 8–1.  Events calculations
Assumed annual 
incidence rate in 
aspirin control group
Expected total study 
duration (years)
Estimated power for one 
comparison
Expected total number 
of events
3.0%
4.5
85.1%
1,642
5.0
89.2%
1,909
3.5%
4.5
90.2%
1,907
5.0
93.4%
2,215
4.0%
4.5
93.7%
2,171
5.0
96.0%
2,517 
Based on these estimates and the aim to detect a true relative risk reduction of 20% in each of 
the rivaroxaban arms with at least 90% power, it was planned to randomize at least 21,400 
subjects and to continue the study until a minimum of 2,200 subjects experience an event for 
the primary efficacy outcome.  In this multi-center study, each center is expected to 
randomize at least 50 subjects.
The originally planned sample size of 21,400 and 5 year study duration was based on an 
annual primary incidence rate in the control group of 3.5% and 90% power to detect a relative 
risk reduction of 20% in each of the rivaroxaban arms. Based on an observed incidence rate of 
2.9% as of July 2015, it is now planned to randomize at least 27,400151 subjects. This new 
sample size will maintain current study timelines and 90% power to detect a 20% relative risk 
reduction in each of the rivaroxaban arms, based on the following revisions to the original 
assumptions:  

Overall length of recruitment period about 3 to 3.5 years and taking observed 
randomization times up to July 2015 into account

2-sided overall type I error level of 5% using a truncated Hochberg test (γ = 0.9) for 
the testing of the two primary hypotheses

Constant overall incidence rate of about 2.9% per year, resulting in a constant 
incidence rate of about 3.3% per year for the aspirin control group assuming a 20% 
relative risk reduction for both hypotheses

Censoring due to non-CV death at an event rate of almost 1% per year
                                                
151 Text modified as per Amendment 6. (See Section 13.1.2)
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Assumptions for pantoprazole randomization are: 

Annual incidence rate for major upper gastrointestinal complications (overt or occult 
bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction or perforation) 
in the range of 1.6% to 2.2%

At least 16,440 subjects included in the study are not PPI users and they are 
randomized to pantoprazole treatment and control groups in 1:1 ratio

2-sided type I error level of 5%

Effect size: 50% relative risk reduction to be detected

Intention-to-treat analysis: all subjects randomized are included in the analysis as 
randomized and the follow-up period for each subject is as long as possible from 
randomization until the date of the Final Follow-up Visit for each subject
Under these assumptions, the expected total number of major upper gastrointestinal 
complications is between 570 and 780, depending on the observed event rates and the total 
study duration. The estimated power for the detection of the true relative risk reduction of 
about 50% for major upper gastrointestinal complications for pantoprazole 40 mg od vs. 
pantoprazole placebo is close to 100% for all scenarios considered.
Sample size estimation was based on the method by Lakatos(40) implemented in Power 
Analysis and Sample Size (PASS) software, version 11.0.7, and on a Statistical Analysis 
System (SAS) macro provided by J. Shih (1995).(41)  In addition, simulations were 
performed to confirm that the mixture gatekeeping procedure as described in Section 8.4 for 
the analysis of the primary efficacy outcome keeps the overall type I error level of 5%.  SAS 
calculations and simulations were performed using SAS software, version 9.2 (SAS Institute 
Inc, Cary, NC, USA).
9.
Data handling and quality assurance
9.1
Data recording
All data will be managed centrally at the 
 
 
Canada.  Case report forms will be completed electronically using 
iDataFax or will be collected on paper CRF and faxed to 
 for integration into iDataFax.  
All data will be kept secure and confidentiality of all study subjects will be carefully 
protected.
Further details are included in the Manual of Operations.
9.2
Monitoring
In accordance with applicable regulations, GCP, and
 procedures, Site Management 
Coordinators and 
 project office staff 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. 
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The sponsor will develop a Study Oversight Plan to ensure appropriate oversight of the study.  
Additionally, risk-based monitoring will be implemented for this study and further details will 
be included in the Site Management Coordination Plan.  
 is responsible for the monitoring of the study. The purpose of monitoring is to verify
that the data and study procedures have been conducted as described in this protocol and to 
ensure the validity of the study results.  Study monitors will follow the Site Management 
Coordination Plan to verify that: 

Data are authentic, accurate and complete 

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 
Monitoring will encompass a variety of methods at the central, national, and site levels; 
incorporate central data verification, national event verification, and local site monitoring; 
focus on key aspects of the study; and involve multiple levels of oversight to enable rapid and 
efficient identification and correction of issues that arise. Both the NL and 
 will perform 
central monitoring with close communication between 
 the NL, the Sponsor, and the 
sites. Additionally, the NL will also oversee focused on-site monitoring visits to maintain the 
quality and integrity of the data. Signed informed consent will be verified to ensure that 
consent has been obtained and a sample of the cases will be reviewed to ensure that study 
procedures have been followed. 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor, auditors, and inspectors direct access to all relevant documents.
Long-Term Open-Label Extension – amended
The same details will apply to LTOLE. Any specific considerations for LTOLE will be 
detailed in the Site Management Coordination Plan.152
9.3
Data processing – amended
Data that may be directly recorded on the CRFs (ie., no prior written or electronic record of 
data) and can be considered to be source data are: 

Medical history (excluding eligibility criteria)

Adherence

Demographic data

Vital signs

Anthropometric measurements
                                                
152 Text added as per Amendment 11. (See Section 13.3.1)
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
Concomitant medications

Visit attendance153

Pill counts

Dietary and exercise assessment

SAGE questionnaire responses

Adverse events
All other data entered into the CRFs (including all data associated with the primary endpoints 
for the rivaroxaban and pantoprazole randomizations, as well as SAEs) must be supported by 
source documentation whether entered at the same time that it is collected by the person 
performing the assessment, or at a later time following the visit.  
The CRFs and iDataFax software will be provided for each participating center along with the 
study aids. Some sites will complete a paper CRF (instead of the electronic CRF) and submit 
the data to 
 by fax transmission.  At each subject visit, the investigator or research nurse 
will submit the data to 
 for data management.
Clinical data management will be performed in accordance with agreed standards and data 
cleaning procedures.  This is applicable for data recorded on CRF as well as for data from 
other sources (e.g., the 
 randomization and drug management system, laboratory, events 
committees).
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used.
9.4
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s QA
department may arrange to conduct an audit to assess the performance of the study at the 
study site and of the study documents originating there.  A representative from the 
 QA
department may join the audit. The investigator/institution will be informed of the audit 
outcome.  In addition to sponsor audits, with prior agreement from the sponsor, 
 may 
choose to also conduct audits and will coordinate with the sponsor to select appropriate sites 
for audit. 
In addition, inspections by regulatory health authority representatives and independent ethics 
committees/institutional review boards (IECs/IRBs) are possible.  The investigator should 
notify 
 (or 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.  
The investigator/institution will permit study-related monitoring, audits, IEC/IRB review, and 
regulatory inspection, providing direct access to all related source data/documents.  Case 
report forms and all source documents, including informed consent forms and copies of 
                                                
153 Added with Amendment 8.  (See Section 13.2.2)
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laboratory and medical test results must be available at all times for review by the authorized 
clinical study monitor and inspection by health authorities. 
9.5
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
The confidentiality of all subjects will be protected at both the local centers and at 
 and 
Bayer.  Data at 
 will be kept secure during the study, and for the time that is required by 
local regulatory requirements after the study.  A duplicate copy of the data will be stored 
securely in a bank vault.  At the end of the study, a copy of the data will be provided to the 
sponsor.
The investigator site file is not to be destroyed without 
 and the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
10.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time for the following reasons: 
If risk-benefit ratio becomes unacceptable owing to, for example,
- Safety findings from this study (e.g. SAEs)
- Results of any interim analysis
- 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; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame as agreed upon by the Steering Committee.
Long-Term Open-Label Extension – amended
The same premature termination reasons will apply to LTOLE with the exception of the
interim analysis.154
11.
Ethical and legal aspects
11.1
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
                                                
154 Text added as per Amendment 11. (See Section 13.3.1)
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GCP guidelines and under the guiding principles detailed in the Declaration of Helsinki.  The 
study will also be carried out in keeping with applicable local law(s) and regulation(s).
Documented approval from appropriate IECs/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the Sponsor.  The responsible unit (e.g. 
IEC/IRB, head of the study center/medical institution) must supply to the Sponsor, upon 
request, a list of the IEC/IRB members involved in the vote and a statement to confirm that 
the IEC/IRB is organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.  
Modifications to the study protocol will not be implemented by either 
 or the sponsor 
without agreement by both parties.  However, 
 and 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 10.
11.2
Subject information and consent
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form provided by the sponsor or the study center.  A sample 
subject information and informed consent 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 each subject / legal representative or proxy consenter (if the subject is 
under legal protection), prior to his/her entry into the study (i.e. before any examinations and 
procedures associated with the selection for the study are performed or any study-specific data 
are recorded on study-specific forms).
The investigator will also mention that written approval of the IEC/IRB has been obtained.
Each subject / legal representative or proxy consenter will have ample time and opportunity to 
ask questions and will be informed about the right to withdraw from the study at any time 
without any disadvantage and without having to provide reasons for this decision.
Only if the subject / legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study.  Additionally, the 
investigator and other information provider (if any) will personally sign and date the form.  
The subject / legal representative or proxy consenter will receive a copy of the signed and 
dated form.
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The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the subject’s note/file of the medical institution.  Any other handling and storage 
of the signed informed consent statement will be detailed in the ICF.
The informed consent form and any other written information provided to subjects / legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an amendment to 
the protocol that necessitates a change to the content of the subject information and / or the 
written informed consent form.  The investigator will inform the subject / legal representative 
or proxy consenter of changes in a timely manner and will ask the subject to confirm his/her 
participation in the study by signing the revised informed consent form.  Any revised written 
informed consent form and written information must receive the IEC/IRB`s approval / 
favorable opinion in advance of use.
Long-Term Open-Label Extension − amended
Documented informed consent will be required for the LTOLE.155
11.3
Publication policy- amended
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. The study results will be reported irrespective of the outcome of the 
study.  The Operations Committee which will also serve as a Publication Committee,156 will 
decide on the authorship of all papers.  The main study results will be written by a writing 
group led by members of the Operations Committee, and may include additional individuals 
who have made substantial and sustained contributions and will be on behalf of the whole 
study group.
11.4
Compensation for health damage of subjects / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
11.5
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Only the subject number and patient initials or ‘dummy’ initials will be recorded in the CRF, 
and all efforts will be made to obliterate subject names that appears on any other document 
(e.g. pathologist report), before a copy of the document is supplied to 
 or the sponsor.  
Study findings stored on a computer will be stored in accordance with local data protection 
laws.  As part of the informed consent process, the 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 
                                                
155 Text added as per Amendment 11. (See Section 13.3.1)
156 Text added as per Amendment 6. (See Section 13.1.2)
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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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12.
Reference list - amended
1.
Fact sheet: Cardiovascular diseases (CVDs): World Health Organization; 2013. 
Available from http://www.who.int/mediacentre/factsheets/fs317/en/157
2.
WHO. The global burden of disease: 2004 update. Geneva: World Health 
Organization; 2008b.157
3.
Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW et 
al. Peripheral arterial disease detection, awareness, and treatment in primary care. 
JAMA 2001 September 19;286(11):1317-24.
4.
Hankey GJ, Norman PE, Eikelboom JW. Medical treatment of peripheral arterial 
disease. JAMA 2006 February 1;295(5):547-53.
5.
Belch JJ, Topol EJ, Agnelli G, Bertrand M, Califf RM, Clement DL et al. Critical 
issues in peripheral arterial disease detection and management: a call to action. Arch 
Intern Med 2003 April 28;163(8):884-92.
6.
Turpie AG, Lassen MR, Eriksson BI, Gent M, Berkowitz SD, Misselwitz F et al. 
Rivaroxaban for the prevention of venous thromboembolism after hip or knee 
arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011 
March;105(3):444-53.
7.
Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E et al. Oral 
rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 
2012 April 5;366(14):1287-97.
8.
Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS et al. 
Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010 
December 23;363(26):2499-510.
9.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W et al. Rivaroxaban 
versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011 September 
8;365(10):883-91.
10.
Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C et al. 
Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012 
January 5;366(1):9-19.
11.
Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention 
of death, myocardial infarction, and stroke in high risk patients. BMJ 2002 January 
12;324(7329):71-86.
12.
Alexander JH, Hafley G, Harrington RA, Peterson ED, Ferguson TB, Jr., Lorenz TJ 
et al. Efficacy and safety of edifoligide, an E2F transcription factor decoy, for 
prevention of vein graft failure following coronary artery bypass graft surgery: 
PREVENT IV: a randomized controlled trial. JAMA 2005 November 
16;294(19):2446-54.
                                                
157 Reference modified as per Amendment 6. (See Section 13.1.2)
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13.
A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of 
ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996 November 
16;348(9038):1329-39.
14.
Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of 
clopidogrel in addition to aspirin in patients with acute coronary syndromes without 
ST-segment elevation. N Engl J Med 2001 August 16;345(7):494-502.
15.
Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C et al. 
Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J 
Med 2009 September 10;361(11):1045-57.
16.
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S et al.
Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J 
Med 2007 November 15;357(20):2001-15.
17.
Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE et al. Clopidogrel 
and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl 
J Med 2006 April 20;354(16):1706-17.
18.
Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP et al. 
Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 
2012 April 12;366(15):1404-13.
19.
Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J 
Am Coll Cardiol 2003 February 19;41(4 Suppl S):62S-9S.
20.
Andreotti F, Testa L, Biondi-Zoccai GG, Crea F. Aspirin plus warfarin compared to 
aspirin alone after acute coronary syndromes: an updated and comprehensive meta-
analysis of 25,307 patients. Eur Heart J 2006 March;27(5):519-26.
21.
Anand S, Yusuf S, Xie C, Pogue J, Eikelboom J, Budaj A et al. Oral anticoagulant 
and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007 July 
19;357(3):217-27.
22.
Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S et al. Apixaban 
in patients with atrial fibrillation. N Engl J Med 2011 March 3;364(9):806-17.
23.
Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of 
aspirin: meta-analysis. BMJ 2000 November 11;321(7270):1183-7.
24.
Lanas A, Wu P, Medin J, Mills EJ. Low doses of acetylsalicylic acid increase risk of 
gastrointestinal bleeding in a meta-analysis. Clin Gastroenterol Hepatol 2011 
September;9(9):762-8.
25.
Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of 
bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006 
August 22;114(8):774-82.
26.
Rao SV, Eikelboom JA, Granger CB, Harrington RA, Califf RM, Bassand JP. 
Bleeding and blood transfusion issues in patients with non-ST-segment elevation 
acute coronary syndromes. Eur Heart J 2007 May;28(10):1193-204.
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27.
Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, et al; COGENT 
Investigators. Clopidogrel with or without omeprazole in coronary artery disease.N 
Engl J Med. 2010 Nov 11;363(20):1909-17
28.
Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Paolasso E, et al.
CORONARY Investigators.  Off-pump or on-pump coronary-artery bypass grafting 
at 30 days. N Engl J Med 2012 Apr;19;366(16):1489-97. 
29.
Li C, Hirsh J, Xie C, Johnston MA, Eikelboom JW. Reversal of the anti-platelet 
effects of aspirin and clopidogrel. J Thromb Haemost 2012 April;10(4):521-8.
30.
Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. 
Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a 
randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011 
October 4;124(14):1573-9.
31.
ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. 
International Conference on Harmonisation E9 Expert Working Group. Stat Med. 
1999;18(15):1905-42.
32.
Brechenmacher, T, Xu, J, Dmitrienko, A, Tamhane, AC. A mixture gatekeeping 
procedure based on the Hommel test for clinical trial applications. Journal of 
Biopharmaceutical Statistics, 2011; 21: 748-767.
33.
Dmitrienko, A, Tamhane, AC. Mixtures of multiple testing procedures for 
gatekeeping applications in clinical trials. Statistics in Medicine, 2011; 30: 1473-
1488.
34.
Dmitrienko, A, Tamhane, AC. General theory of mixture procedures for gatekeeping. 
Biometrical Journal, 2013; 55: 402-419.
35.
Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on 
weighted residuals. Biometrika 1994, 81(3):515-526.
36.
McAlister FA, Straus SE, Sackett DL, Altman DG. Analysis and reporting of 
factorial trials: a systematic review. JAMA 2003; 289(19):2545-53.
37.
Gail M., Simon R. Testing for qualitative interactions between treatment effects and 
patient subsets. Biometrics 1985 41:361-372.
38.
Li Z., Chuang-Stein C., Hoseyni C. The probability of observing negative subgroup 
results when the treatment effect is positive and homogeneous across all subgroups. 
Drug Information Journal 2007 41:47-56.
39.
Dubois MF, Hébert R. Imputation of missing dates of death or institutionalization for 
time-to-event analyses in the Canadian Study of Health and Aging. Int Psychogeriatr. 
2001;13 Supp 1:91-7. 
40.
Lakatos, Edward. Sample sizes based on the log-rank statistic in complex clinical 
trials. Biometrics 1988 44:229-241.
41.
J. Shih. Sample size calculation for complex clinical trials with survival. Controlled 
Clinical Trials 1995 16:395-407
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42.
Vermeer SE, Longstreth WT, Jr., Koudstaal PJ. Silent brain infarcts: a systematic 
review. Lancet Neurol 2007 July;6(7):611-9.
43.
Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al.  Long-term 
use of ticagrelor in patients with prior myocardial infarction.  N Engl J Med 2015; 
372:1791-1800. 158
44.
Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlio DE, Steg PG, et al.  
Twelve of 30 months of dual antiplatelet therapy after drug-eluting stents.  N Engl J 
Med 2014;371:2155-66. 158
45.
Palmerini T, Benedetto U, Bacchi-Reggiani L, Della Riva D, Biondi-Zoccai G, Feres 
F, et al.  Mortality in patients treated with extended duration dual antiplatelet therapy 
after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis 
of randomised trial.  Lancet 2015;385;2371-82.158
46.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al.  Rivaroxaban 
versus warfarin in nonvalvular atrial fibrillation.  N Engl J Med 2011;Sep 
8;365(10):883-91.158
                                                
158 References  added as per Amendment 8.
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13.
Protocol amendments
Protocol version history
Original Protocol Version 1.0 – Approved 19 OCT 2012
Revised Protocol Version 1.1 – Approved 28 NOV 2012
The revised protocol contains some additional clarifications on data collection. The changes to 
the protocol are not substantial and do not affect the study design, but must be done for 
consistency with the CRFs.
The word “primary” has been removed when linked to the outcome for the pantoprazole 
randomization, and similarly a paragraph describing the “primary” outcome for the 
pantoprazole randomization has been removed from the protocol sections where they are not 
applicable. Rationale and implications: Although the outcome of the composite of GI bleeding 
is the “primary” objective of the pantoprazole randomization, it is not part of the primary 
objective of the trial and, thus, not a primary variable of the trial. Therefore, the word 
“primary” has been removed. The intent and the analysis plan remains the same.
A consistent use of the terms “outcome” and “variable” has been ensured. While the term 
“outcome” is used to describe a clinical event to be observed in the trial, e.g. stroke, the term 
“variable” refers to the statistical variable to be analyzed, e.g. the time to the first occurrence 
of the outcome since randomization. The wording in section 4.2 has been adapted to 
consistently reflect this throughout the protocol.
The timing of the study questionnaires have been further clarified in respective protocol 
sections. Collection of two additional questionnaires (health care costs information and 
assessment of the driving status) and additional information relative to the CABG surgery for 
subjects randomized post CABG surgery (EuroSCORE) have been added to the respective 
study visit section.  Collection of two questionnaires (Diet and Activity) has been removed 
from the Final Follow-up Visit. Collection of blood sampling relevant for COMPASS MIND 
study has been included in the relevant study visit section.
13.1
Amendment 6
The eligibility criteria for study population of subjects with coronary artery disease (CAD) 
and peripheral artery disease (PAD) have been simplified and clarified.  Despite the improved 
language and adjustment of the criteria, the target population remains largely unchanged. 
Additionally, there is an increase in the overall sample size of the study by 1900, from 19,500 
to 21,400 randomized subjects, of which 900 will be enrolled in Japan.
There are otherwise other minor changes, and logistical improvements or clarifications 
throughout the protocol.
13.1.1
Overview changes to the study
The following changes are made to Original Protocol Version 1.1. 
Administrative, editorial and typographical corrections were made throughout the document 
including Table 7-1 and the list of abbreviations. These changes do not affect the overall study 
concept.
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Modification 1: Name of the sponsor clinical leader has been updated.
Rationale: 
 replaces 
 as the sponsor’s 
 
for the COMPASS study.
Sections affected:

Title page

Signature of the sponsor’s medically responsible person
Modification 2: Minor clarifications for the secondary and  tertiary efficacy outcomes
Rationale: The following sections now contain minor clarifications to address either the terms 
that were omitted  in the previous protocol or to reflect the changes in the associated sections 
of this protocol amendment. These clarifications are as follows:  1) addition of 
revascularization to the secondary composite outcomes, and 2) addition of the stent 
thrombosis and coronary artery bypass graft failure to the tertiary outcomes. These additions 
do not affect the analysis of the corresponding statistical variables.
Sections affected:

Synopsis: Study objectives

Section 2: Study objectives

Section 7.3 Efficacy 

Section 7.5.3.1 Protocol-specific exceptions to SAE reporting (new section)

Section 8.3.2 Secondary efficacy outcomes

Section 8.3.3 Tertiary and other efficacy outcomes
Modification 3: Clarifications in the main criteria for inclusion
Rationale: Originally, the protocol mandated that subjects with PAD under the age of 65 have 
documented atherosclerosis in at least two vascular beds or at least two additional 
cardiovascular risk factors.  This requirement was based on the general observation that 
cardiovascular risk is closely correlated with increasing age.  Thus, subjects under the age of 
65 with either coronary or peripheral artery disease would have a substantially lower rate of 
cardiovascular death, myocardial infarction, or stroke than those over the age of 65.  
However, further scrutiny of the recent data from the On-Target (1) and Transcend (2) trials 
demonstrated that event rates in subjects under the age of 65 with PAD are about 50% higher 
than those with CAD and are well over 4%. This observation prompted the removal of the 
requirement for two additional risk factors or disease in at least two vascular beds for PAD 
subjects under the age of 65; such subjects are at high risk even without additional risk factors 
and will potentially benefit from a more effective rivaroxaban-based treatment. 
Based on the questions received from the sites, it became evident that additional clarifications 
regarding definition of vascular beds were required. The definition is now specified in the 
protocol amendment.
References:
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1. The ONTARGET Investigators. Telmisartan, Ramipril, or Both in Patients at High Risk for 
Vascular Events. N Engl J Med 2008; 358:1547-1559
2. The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with 
cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor 
blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-
converting enzyme inhibitors: a randomised controlled trial. Lancet. Published on-line 29 
August 2008; 372(9644):1174-83.
Sections affected:

Synopsis: Diagnosis and Main Criteria for Inclusion

Section 5.1.1 Inclusion criteria
Modification 4: Minor clarifications for consistency
Minor, consistency and logistical clarifications were made throughout the document. These 
changes do not affect the overall study concept.
Sections affected:

Synopsis: Methodology

List of abbreviations

Section 1.1 Background

Section 1.2.1 Rivaroxaban

Section 1.2.2 Aspirin and anticoagulants

Section 1.2.3 Proposed rivaroxaban evaluation

Section 4.1 Design overview

Section 4.1.1 Subjects randomized after CABG surgery

Section 4.3.1 Overall design rationale

Section 5 Study population

Section 6.1 Treatments to be administered

Section 6.1.1 Run-in

Section 6.1.2 Randomization

Section 6.4.1 Dose modification

Section 6.4.2 Dose modification and treatment guidance

Section 6.4.2.1 Guidance for the treatment of subjects who require an invasive 
procedure

Section 6.4.2.2 Guidance for the treatment of subjects who require coronary artery 
bypass graft surgery
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
Section 6.4.2.3 Guidance for the treatment of subjects who develop an acute coronary 
syndrome and those who require percutaneous coronary intervention with stenting

Section 6.6 Drug logistics and accountability

Section 6.9 Prior and concomitant therapy

Section 6.9.2 Clopidogrel (or any other non-study antiplatelet treatment)

Section 6.9.4 Proton pump inhibitor treatment

Section 7.2.3 Other baseline characteristics

Section 7.3 Efficacy

Section 8.3.5 Outcome of pantoprazole randomization

Section 8.3.6 Subgroup variables

Section 8.4.5 Analysis of the outcome for pantoprazole randomization

Section 8.4.6 Subgroup Analysis

Section 14.1 COMPASS MIND Substudy
Modification 5: Clarification about the subjects with the need for the proton pump inhibitor 
(PPI) treatment
Rationale: The initial protocol required that the subjects with a need for PPI should not be 
randomized to the PPI. The clarification in this protocol amendment specifies that the need for 
the PPI refers to subjects who have a continuous need for  treatment with the PPI.
Sections affected:

Synopsis: Methodology

Section 1.1 Background

Section 4.1 Design overview

Section 5.1.2 Exclusion criteria

Section 6.1.2 Randomization

Section 6.9.4 Proton pump inhibitor treatment
Modification 6: The number of subjects in the trial has been increased.
Rationale: The number of subjects in the trial has been increased to: ~23,500 enrolled and 
~21,400 randomized (10% non-compliance rate is anticipated the run-in period). The reason 
for increasing the number of subjects is based on emerging data from the ORIGIN trial (1) 
and the Vorapaxar secondary prevention trial (2), a realistic event rate is 3.5-4% rather than 4-
4.5% which mandates an increase in numbers of subjects or duration of follow up to maintain 
study power. 
References:
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1. The ORIGIN Trial Investigators. Basal Insulin and Cardiovascular and Other Outcomes in 
Dysglycemia. N Engl J Med 2012; 367:319-328
2. Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP et al. Vorapaxar 
in the secondary prevention of atherothrombotic events. N Engl J Med 2012 April 
12;366(15):1404-13.
Sections affected:

Synopsis: Number of subjects

Section 4.1 Study design

Section 5 Study population

Section 8.6 Determination of the sample size
Modification 7: Clarification on one of the referenced studies.
Rationale: Some additional clarification regarding the Voraxapar study (TRA 2 P-TIMI 50) is 
now included.
Sections affected:

Section 1.2.2 Aspirin and anticoagulants
Modification 8: Addition of CABG specific objectives
Rationale: In the original protocol, the objectives for the CABG subjects and testing for graft 
patency were not formally outlined.  The protocol amendment now includes these objectives. 
Sections affected:

Section 2 Study Objectives
Modification 9: Clarification on the timing of the administration of the study related 
questionnaires.
Rationale: Considering the older subjects participating in the COMPASS study, it may be 
difficult to have all of the study related questionnaires administered at one visit. Therefore, the 
timing of the administration of the questionnaires now allows some flexibility to when these 
questionnaires should be completed.
Sections affected:

Section 4.1 Design overview

Section 7.1.1 tabulated overview
Modification 10: Changes in the informed consent timing for CABG subjects, and 
requirement for the angiography at 1 year post surgery for CABG subjects
Rationale: CABG subjects can now sign consent for participation in the evaluation of graft 
patency either before or after CABG surgery. Irrespective of the timing of consent, the 
decision to randomize is based on the information available to the investigator on Day 4 or 
later post-op. Surgeons will not randomize if information becomes available post-operatively 
that the treatment is not in the subject’s best interests. Moreover, in some centers, it is not 
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feasible to get the consent before surgery because subjects are admitted the evening before 
surgery.  Thus, for some subjects, it may be more appropriate to approach them once they 
have begun recovering from surgery and are stable and ready to be discharged home or 
transferred to a rehabilitation center. 
Approximately at 1 year post-CABG, certain number of sites routinely perform invasive 
coronary angiography rather than CT angiography; thus, the protocol amendment now allows 
the  invasive angiography as an acceptable alternative to CT angiography.
Sections affected:

Section 4.1.1 Subjects randomized after CABG surgery

Section 7.1.1 tabulated overview

Section 7.1.2.4.1 Routine follow-up visits (Visits 3, 5, and 7-15+)
Modification 11: Clarification on the study population and the study investigators 
qualifications
Rationale: The  new paragraph in the protocol amendment summarizes that COMPASS study 
is enrolling subjects with the high risk of the incident cardiovascular disease. Additionally, 
based on the request from South American regulatory authority, the investigator qualifications 
are now further clarified.
Sections affected:

Section 5 Study population
Modification 12: The section defining eligibility criteria for subjects with coronary artery 
disease has been modified 
Rationale: First, only subjects with a history of previous myocardial infarction (most recent 
episode) within the past 20 years are eligible, if no other CAD criteria are met.  The risk of 
recurrent event in a subject who has been stable without other complications for more than 20 
years is likely to be low, diminishing their potential benefit from a new treatment. 
Second, the emphasis of this protocol with respect to coronary artery disease is subjects with 
multi-vessel disease.  With the increasing use of non-invasive means of screening for 
coronary disease, the potential exists for identification of subjects with positive exercise stress 
test to have only single vessel coronary artery disease. Thus, the requirement for stress studies 
has been further clarified.
Furthermore, with respect to CABG surgery, the protocol previously restricted this to multi-
vessel surgery within one week or at least four years prior to randomization (unless the patient 
had recurrent ischemic events in the first four years after surgery). The recently completed one 
year follow-up of the CORONARY trial (1) and the five year follow-up of the SYNTAX trial 
(2) have shown that event rate in subjects with prior CABG surgery is in the order of 3.5-4% 
per year, even during the first four years after surgery.  Thus, these subjects need to be given 
the opportunity to participate in COMPASS, as they are at substantial risk and could benefit 
from a new treatment that is potentially more effective than aspirin.  
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References:
1. Andre Lamy et al. for CORONARY Investigators. Off-Pump or On-Pump Coronary-Artery 
Bypass Grafting at 30 Days. N Engl J Med 2012; 366:1489-1497
2. Serruys PW et al. for SYNTAX Investigators. Percutaneous Coronary Intervention versus 
Coronary-Artery Bypass Grafting for Severe Coronary Artery Disease. N Engl J Med 2009; 
360:961-972
Sections affected:

Section 5 Study population
Modification 13: Section defining the eligibility criteria for subjects with peripheral artery 
disease has been modified 
Rationale: Asymptomatic carotid disease carries a higher risk of MI than stroke on average 
and carotid endarterectomy (CEA), while reducing the risk of stroke (ARR 0.6% per year) 
does not alter the cardiac risk. So a previous endarterectomy identifies an individual with an 
increased cardiac risk. The original observation was made by John Norris (1). Incidentally, the 
cardiac risk correlates with degree of stenosis and a cutoff of 50% ensures selection of high 
risk asymptomatic disease. 
In the NASCET Trial of surgery for symptomatic carotid stenosis, the rate of MI at 5 years 
was ~19% (2).
References:
1. Chambers BR, Norris JW. Outcome in patients with asymptomatic neck bruits. N Engl J 
Med. 1986 Oct 2;315(14):860-5.
2. Ferguson GG et al for The North American Symptomatic Carotid Endarterectomy Trial 
(NASCET) investigators. The North American Symptomatic Carotid Endarterectomy Trial. 
Stroke. 1999; 30: 1751-1758
Sections affected:

Section 5 Study population
Modification 14: Clarifications in the Exclusion criteria
Rationale: In the section on drug interactions, strong inducers of cytochrome P450 3A4 are 
now excluded. These were not previously listed in the protocol.  
Furthermore, there is an additional clarification on women who are pregnant, breastfeeding, or 
of childbearing potential.  
Participation of subjects who concomitantly participate in another study with an 
investigational drug, or have contraindication to any study procedure is now excluded.
Additionally, it is now clarified that the subjects who a continuous need for treatment with 
PPI should not be randomized to pantoprazole arm.
Sections affected:

Section 5.1.2 Exclusion criteria
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Modification 15: Clarifications in the Discontinuations of subjects from study treatment
Rationale: The protocol now clarifies that even the subjects with study outcomes need to be 
followed at regular study visits until the end of the study. Furthermore, besides collection of 
survival status information throughout the study, the outcome information is also required in 
subjects who prematurely terminate the study/study treatment.
Sections affected:

Section 5.2 Discontinuation of subjects from study treatment
Modification 16: Clarification about the aspirin treatment
Rationale: The protocol amendment clarifies that the aspirin used in the study is enteric 
coated. Furthermore, the clarification is now included that the terms “aspirin” and “acetyl 
salicylic acid” are used interchangeably. 
Sections affected:

Section 6.1 Treatments to be administered

Section 6.2 Identity of study treatment
Modification 17:  Clarification on the treatment compliance during run-in 
Rationale: The intent of the run in is to optimize subject retention in the study. While the 80% 
drug adherence during run-in is still required in the protocol, it is recognized that they may be 
certain circumstances, e.g. outside of subject’s control, where the drug adherence may be 
somewhat affected. Therefore, the target compliance during run-in was amended to “at least 
80% except for extenuating circumstances”.
Sections affected:

Section 6.1.2 Randomization

Section 7.1.2.3 Randomization visit (Day 0 ± 5 days)
Modification 18: Change in the section on treatment guidance with study pantoprazole
Rationale: Compared to the initial protocol, the summary of the treatment guidance with study 
pantoprazole is now found only in one section. This was done to further simplify the protocol. 
Sections affected:

Section 6.4.2 Dose modifications and treatment guidance

Section 6.4.2.1 Guidance for the treatment of subjects who require an invasive 
procedure

Section 6.4.2.2 Guidance for the treatment of subjects who require coronary artery 
bypass graft surgery

Section 6.4.2.3 Guidance for the treatment of subjects who develop an acute coronary 
syndrome and those who require percutaneous coronary intervention with stenting

Section 6.9.1 Combined CYP 3A4 and p-glycoprotein inhibitors

Section 6.9.3 Anticoagulant treatment
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
Section 6.9.4 Proton pump inhibitor treatment
Modification 19: Combined CYP 3A4 and p-Glycoprotein Inhibitors and systemic azole 
antimycotics
Rationale: The title of the relevant protocol sections has been updated to include CYP 3A4 
inducers. Also, the concomitant use of strong CYP 3A4 inducers has now been included in the 
protocol due to the potential for reduction in the rivaroxaban plasma concentrations if used 
concomitantly. Additionally, macrolide antibiotics are now removed: if used concomitantly 
with rivaroxaban, their effect on mean rivaroxaban AUC and Cmax is considered to be 
clinically not relevant (see rivaroxaban IB and Company Core Data sheet). Furthermore, the 
list of systemic antifungal drug provides some examples of the systemic antimycotics that 
should not be taken concomitantly with rivaroxaban.  
Sections affected:

Section 6.9.1 Combined CYP 3A4 and p-glycoprotein inhibitors
Modification 20: Revision of time windows and footnotes under section Tabulated overview
Rationale: Compared to previous protocol, the footnotes under section 7.1.1 Tabulated 
overview are now revised to reflect the changes in the related protocol sections. Specifically, 
this section now clarifies the timing of the clinic visits, especially under unforeseen 
circumstances when the visit time window may be missed.  Similarly, the timing for 
administration of the questionnaires and DNA and blood collection has been further clarified. 
With this protocol amendment, the target is still to include subjects in the first week following 
CABG surgery (4-7 days), but randomization is allowed up to Day 14 post-CABG for medical 
or logistical reasons.
Sections affected:

Section 7.1.1 Tabulated overview
Modification 21: Minor clarifications in timing of the visit assessments
Rationale: These protocol sections now contain minor editorial revisions/updates: A 
specification about the administration of the questionnaires for post-CABG subjects has now 
been included, as well as the allowance for the use of invasive or noninvasive coronary 
angiography for post-CABG subjects. Furthermore, these sections now include the 
specification on the timing of blood collection. Namely, at the start of the run-in period, blood 
samples (for creatinine and cholesterol) up to 1 year old are acceptable to determine the 
subject’s preliminary eligibility. However, at randomization the blood samples should not be 
older than 3 months.
Sections affected:

Section 7.1.2.2 Screening and Run-in visit(s)

Section 7.1.2.3 Randomization visit (Day 0 ± 5 days)

Section 7.1.2.4.1 Routine follow-up visits (Visits 3, 5, and 7-15+)
Modification 22: Changes in the efficacy section
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Rationale: The paragraph on hospitalization data has been moved from the safety section to 
efficacy section. 
Sections affected:

Section 7.3 Efficacy

Section 7.5.3.1 Protocol-specific exceptions to SAE reporting
Modification 23: Changes in the safety section 
Rationale: Due to errors in reporting of the study outcomes as e.g. SAEs, the whole safety 
section has been revised to clarify the requirements for the safety reporting. Namely, few new 
sections were included to specify 1) the categorization of the AEs, 2) to help with 
determination of the casual relationship between the study drug and events, and 3) further 
outline which events are considered as outcomes and should be reported as such.  
Additionally, few sections have been placed in different order to help clarify the AE reporting 
requirements. Data Safety Monitoring Board (DSMB) section is now removed, since the 
details on the DSMB procedures are specified in the respective DSMB charter. Section on 
pregnancy contains requirement(s) for the reporting of the abnormal pregnancies.
Sections affected:

Section 7.5.1 Definition of (Serious) Adverse Event

Section 7.5.2 Causal relationship

Section 7.5.3.1 Protocol Specific Exemptions to SAE Reporting

Section 7.5.3.2 Reporting of (S)AEs

Section 7.5.3.3 Adverse events of special safety interest

Section 7.5.3.5 Pregnancies

Section 7.5.3 Data Safety Monitoring Board

Section 7.5.4 Reporting of events to Bayer by 
 and compliance with regulatory 
authorities’ reporting requirements
Modification 24: Changes in the determination of the sample size
Rationale: Modifications to the event rate assumptions have been inserted, reflecting the 
change in sample size. Sections affected:

Section 8.6 Determination of sample size
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Modification 25: Changes in the Publication policy
Rationale: The clarification that the Operations Committee also serves as Publication 
Committee is now included.
Sections affected:

Section 11.3 Publication policy
Modification 26: Reference update
Rationale: Two references have been updated: 1 and 2.
Sections affected:

Section 12 References
Modification 27: Changes in the MRI sequence and DNA blood collection for the 
COMPASS MIND
Rationale: This protocol section now clarifies the MRI sequences and the timing of the 
DNA/blood collections.
Sections affected:

Section 14.1 COMPASS MIND Substudy
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13.1.2
Changes to protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment. Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”. Corrections of typing errors or omissions are not 
highlighted in this amendment.
Title page
This section was changed as a result of Modification 1. 
Old Text:
Sponsor Clinical Leader:
Global Clinical Development 
Bayer Pharma AG
Aprather Weg 18a, Building 402
42113 Wuppertal, Germany
Tel.:  
New Text:
Sponsor Clinical Leader:
Global Clinical Development
Bayer HealthCare Pharmaceuticals, Inc.
100 Bayer Boulevard, P.O. Box 915
Whippany, NJ  07981-0915
United States
Tel: 
Signature of the sponsor’s medically responsible person
This section was changed as a result of Modification 1. 
Old Text:
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Role:  
New Text:
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Role:  
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Synopsis
This section was changed as a result of Modification 2.
Old Text:
Study objective(s)
Secondary objectives for rivaroxaban randomization

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 
100 mg od and rivaroxaban 5 mg bid alone reduces the risk of the 
composite of major thrombotic events (myocardial infarction, stroke, 
cardiovascular death, and venous thromboembolism) and 
cardiovascular hospitalization compared with aspirin 100 mg od in 
subjects with CAD or PAD
New Text:
Study objective(s)
Secondary objectives for rivaroxaban randomization

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 
100 mg od and rivaroxaban 5 mg bid alone reduces the risk of the 
composite of major thrombotic events (myocardial infarction, stroke, 
cardiovascular death, revascularization, and venous 
thromboembolism) and cardiovascular hospitalization compared with 
aspirin 100 mg od in subjects with CAD or PAD
Synopsis
This section was changed as a result of Modifications 3.
Old Text:
Diagnosis and main criteria for 
inclusion
Patients are eligible for inclusion if they have coronary artery disease or 
peripheral artery disease and meet at least one of the following criteria:

Age 65 years

Age 65 years with disease in two vascular beds or at least 2 
additional cardiovascular risk factors 
Additional cardiovascular risk factors are:

Current smoker

Diabetes mellitus

Renal dysfunction with estimated glomerular filtration rate 
60 ml/min 

Heart failure

Non-lacunar ischemic stroke 1 month ago
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New Text:
Diagnosis and main criteria for 
inclusion
Subjects are eligible for  inclusion if they:

Meet criteria for CAD* and/or PAD
*Subjects with CAD must also meet at least one of the following criteria:

Age 65 years, or

Age 65 years and documented atherosclerosis or revascularization 
involving at least 2 vascular beds§, or at least 2 additional 
cardiovascular risk factors:
1)
Current smoker (within 1 year of randomization)
2)
Diabetes mellitus
3)
Renal dysfunction with estimated glomerular filtration rate 
60 ml/min
4)
Heart failure
5)
Non-lacunar ischemic stroke 1 month ago
§ Because CAD involves disease in the coronary vasculature, only one 
additional vascular bed is required: e.g. the aorta and arterial supply to the 
brain, gastro-intestinal tract, lower limbs, upper limbs, or kidneys.
Synopsis
This section was changed as a result of Modifications 4 and 5. 
Old Text:
Methodology
The study will comprise 4 periods:  screening, run-in, follow-up, and washout. 
During the screening period, informed consent will be obtained and 
evaluations of subject eligibility will be performed.  The run-in period will 
occur during the 30 days prior to initiation of study treatment, with the 
exception of subjects randomized after coronary artery bypass surgery who 
will not require a run-in.  During run-in, subjects will discontinue any current 
anticoagulant therapy and will begin rivaroxaban placebo and 100 mg aspirin.  
Treatment of subjects who comply with the run-in treatment and who remain 
committed to the study, as well as those who are randomized after coronary 
artery bypass graft surgery will begin on Day 0, which will also signal the 
initiation of the follow-up period.  
…
*Subjects already taking a proton pump inhibitor at baseline will undergo only 
a single randomization (to rivaroxaban 2.5 mg bid + aspirin 100 mg od, 
rivaroxaban 5 mg bid + aspirin placebo or rivaroxaban placebo + aspirin 
100 mg od)
New Text:
Methodology
The study will comprise 4 periods:  screening, run-in, follow-up, and washout.
During the screening period, informed consent will be obtained and 
evaluations of subject eligibility will be performed.  The run-in period will 
occur during the 28 days prior to initiation of study treatment, with the 
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exception of subjects randomized Day 4-7 after coronary artery bypass surgery 
who will not require a run-in.  During run-in, subjects will discontinue any 
current anticoagulant therapy and will begin rivaroxaban placebo and 100 mg 
aspirin.  Treatment of subjects who comply with the run-in treatment and who 
remain committed to the study, as well as those who are randomized Day 4-7 
after coronary artery bypass graft surgery will begin on Day 0, which will also 
signal the initiation of the follow-up period.  
…
*Subjects who have a continuous need for use of a proton pump inhibitor at 
baseline will undergo only a single randomization (to rivaroxaban 2.5 mg bid 
+ aspirin 100 mg od, rivaroxaban 5 mg bid + aspirin placebo or rivaroxaban 
placebo + aspirin 100 mg od)
Synopsis
This section was changed as a result of Modification 6. 
Old Text:
Number of subjects
Enrolled = 21,500; randomized = 19500 in approximately 25 to 30 countries 
worldwide
Approximately 21,500 subjects will be enrolled; 19500 will be admitted to the
run-in period and 2000 subjects will undergo coronary artery bypass graft but 
no run-in.  A non-compliance rate of 10% is anticipated for those subjects in 
the run-in period; thus, approximately 19,500 subjects will be randomized 
(approximately 17,500 subjects who completed run-in and 2000 who 
underwent coronary artery bypass graft without run-in) in approximately 25 to
30 countries worldwide.
New Text:
Number of subjects
Enrolled = approximately 23,500; randomized = 21,400 in approximately 30 
countries worldwide
Approximately 23,500 subjects will be enrolled; 21,500 will be admitted to the 
run-in period and 2000 subjects will undergo coronary artery bypass graft but 
no run-in.  A non-compliance rate of 10% is anticipated for those subjects in 
the run-in period; thus, approximately  21,400 subjects will be randomized 
(approximately 19,400 subjects who completed run-in and 2000 who 
underwent coronary artery bypass graft without run-in) in approximately 30 
countries worldwide.
List of abbreviations
This section was changed as a result of Modification 4. 
Old Text:
ECG
Electrocardiogram
SAS
Statistical Analysis Software
New Text:
bpm
Beats per minute
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CAD
Coronary artery disease
cm
Centimeter
CV
Cardiovascular
GPV
Global Pharmacovigilance
in
Inch
IT
Information technology
lb
Pound
mmHg
Millimeter of mercury
SAS
Statistical Analysis System
USA
United States of America
Section 1.1 Background
This section was changed as a result of Modifications 4 and 5. 
Old Text:
Aspirin, statins and angiotensin converting enzyme (ACE) inhibitors are effective and widely 
used for the prevention of cardiovascular events in patients with coronary and PAD but the 
risk of vascular events remains high despite these treatments…
… The evidence of efficacy of rivaroxaban for the prevention of atherothrombotic events on a 
background of dual antiplatelet therapy in patients with recent acute coronary syndrome 
supports the hypothesis that it may also be effective for prevention of atherothrombotic events 
in patients with established coronary or PAD who are not treated with dual antiplatelet 
therapy.  
…
The trial described herein, Cardiovascular OutcoMes for People using Anticoagulation 
StrategieS (COMPASS), is a randomized double-blind trial utilizing a 3 x 2 partial factorial 
design that will evaluate the efficacy and safety of rivaroxaban 2.5 mg twice daily (bid) + 
aspirin 100 mg once daily (od) versus aspirin 100 mg daily and rivaroxaban 5 mg bid versus 
aspirin 100 mg od for the prevention of myocardial infarction, stroke and cardiovascular death 
in patients with established coronary or PAD who are receiving standard prevention therapies.  
In the (partial factorial) randomization, patients randomized to receive rivaroxaban in 
combination with aspirin, rivaroxaban alone or aspirin alone and who do not have a need for a 
PPI will be randomized to receive pantoprazole 40 mg od or placebo for the prevention of 
major upper gastrointestinal complications
New Text:
Aspirin, statins and angiotensin converting enzyme (ACE) inhibitors are effective and widely 
used for the prevention of cardiovascular events in patients with CAD and PAD but the risk of 
vascular events remains high despite these treatments.
…The evidence of efficacy of rivaroxaban for the prevention of atherothrombotic events on a 
background of dual antiplatelet therapy in patients with recent acute coronary syndrome 
supports the hypothesis that it may also be effective for prevention of atherothrombotic events 
in patients with established CAD or PAD, receiving usual care.  
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The trial described herein, Cardiovascular OutcoMes for People using Anticoagulation 
StrategieS (COMPASS), is a randomized double-blind trial utilizing a 3 x 2 partial factorial 
design that will evaluate the efficacy and safety of rivaroxaban 2.5 mg twice daily (bid) + 
aspirin 100 mg once daily (od) versus aspirin 100 mg od and rivaroxaban 5 mg bid versus 
aspirin 100 mg od for the prevention of myocardial infarction, stroke, and cardiovascular 
death in patients with established CAD or PAD, who are receiving usual care.  In the (partial 
factorial) randomization, patients who do not have a continuous need for use of a PPI will be 
randomized to receive pantoprazole 40 mg od or placebo for the prevention of major upper 
gastrointestinal complications, and then randomized to receive rivaroxaban in combination 
with aspirin, rivaroxaban alone or aspirin alone.
Section 1.2.1 Rivaroxaban
This section was changed as a result of Modification 4. 
Old Text:
Rivaroxaban has been tested in randomized controlled trials involving more than 60,000
patients and has been used by millions of patients worldwide.  
New Text:
Rivaroxaban has been tested in randomized controlled trials involving more than 70,000
patients and has been used by millions of patients worldwide.  
Section 1.2.2 Aspirin and anticoagulants
This section was changed as a result of Modifications 4 and 7.
Old Text:
Other studies have investigated the potential benefits of combined antiplatelet therapy for 
long-term prevention of cardiovascular disease. The TRA 2 P-TIMI 50 study demonstrated 
that the combination of the platelet thrombin receptor antagonist, vorapaxar, and aspirin 
compared with aspirin alone and continued for 3 years reduced the risk of myocardial 
infarction, stroke or cardiovascular death by 13% in patients with a history of myocardial 
infarction, ischemic stroke or PAD but at the cost of an increase in major and intracranial 
bleeding and with no reduction in cardiovascular mortality.
…
Preliminary evidence for the efficacy and safety of oral factor Xa inhibitors for the prevention 
of major cardiovascular events comes from the recently completed AVERROES trial which 
demonstrated that the oral factor Xa inhibitor, apixaban, compared with aspirin not only 
reduced the risk of stroke but was also associated with numerically fewer myocardial 
infarctions with no significant increase in major bleeding.
New Text:
Other studies have investigated the potential benefits of combined antiplatelet therapy for 
long-term prevention of cardiovascular disease. The TRA 2 P-TIMI 50 study demonstrated 
that the platelet protease-activated receptor 1 antagonist, vorapaxar added to standard therapy
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that included aspirin and clopidogrel, compared with standard therapy alone reduced the risk 
of myocardial infarction, stroke, or cardiovascular death by 13% at 3 years in patients with a 
history of myocardial infarction, ischemic stroke, or PAD, but at the cost of an increase in 
major and intracranial bleeding.
…
Additional evidence for the efficacy and safety of oral factor Xa inhibitors for the prevention 
of major cardiovascular events comes from the recently completed AVERROES trial which 
demonstrated that the oral factor Xa inhibitor, apixaban, compared with aspirin not only 
reduced the risk of stroke but was also associated with numerically fewer myocardial 
infarctions with no significant increase in major bleeding. 
Section 1.2.3 Proposed rivaroxaban evaluation
This section was changed as a result of Modification 4. 
Old Text:
…We hypothesize that the combination of rivaroxaban and aspirin compared with aspirin 
alone will substantially reduce the risk of myocardial infarction, stroke or cardiovascular 
death and that this benefit will readily outweigh any increase in bleeding.  
New Text:
…We hypothesize that the combination of rivaroxaban and aspirin compared with aspirin 
alone will substantially reduce the risk of myocardial infarction, stroke, or cardiovascular 
death and that this benefit will readily outweigh any potential increase in bleeding.  
Section 2 Study objectives
This section was changed as a result of Modification 8. 
Old Text:
Secondary objectives for rivaroxaban randomization

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and 
rivaroxaban 5 mg bid alone reduces the risk of the composite of major thrombotic 
events (myocardial infarction, stroke, cardiovascular death, and venous 
thromboembolism) and cardiovascular hospitalization compared with aspirin 100 mg 
od in subjects with CAD or PAD
New Text:
Secondary objectives for rivaroxaban randomization

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and 
rivaroxaban 5 mg bid alone reduces the risk of the composite of major thrombotic 
events (myocardial infarction, stroke, cardiovascular death, revascularization, and 
venous thromboembolism) and cardiovascular hospitalization compared with aspirin 
100 mg od in subjects with CAD or PAD
…
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Objectives for Day 4-7 post-CABG randomization

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and 
rivaroxaban 5 mg bid alone reduces the risk of bypass graft failure compared with 
aspirin 100 mg od

To determine the association between post CABG graft failure and risk of a composite 
of myocardial infarction, stroke, or cardiovascular death in subjects with CAD or PAD
Section 4.1 Design overview
This section was changed as a result of Modifications 4, 5, 6 and 9. 
Old Text:
This Phase 3, event-driven (at least 2,200 primary efficacy outcome events), randomized 
controlled trial will have a 3 x 2 partial factorial design and will randomize at least 19,500
subjects who will receive treatment for an expected average duration of 3 to 4 years.  The 
COMPASS trial will involve 4 periods:  screening, run-in, follow-up, and washout. 
Prescreening procedures may require informed consent in some countries.  In all other study 
sites, informed consent will be obtained prior to the initiation of any screening procedures.  
Screening will be performed to determine subject eligibility and will include the review of 
inclusion and exclusion criteria, the collection of medical history, physical measurements, and
laboratory evaluations.  
The run-in period will occur during the 30 days prior to initiation of randomized study 
treatment, with the exception of subjects who are randomized after CABG surgery, who will 
not undergo a run-in phase (Section 4.1.1).  During run-in, subjects will discontinue any 
non-study anticoagulant and non-study aspirin therapy and will begin study rivaroxaban 
placebo and study aspirin 100 mg.  
Subjects who successfully complete the run-in period and who remain committed to the study 
as well as those who are being randomized after CABG will be randomized and begin study 
treatments on Day 0, which will also signal the initiation of the follow-up period.  Subjects 
without an ongoing need for treatment with a PPI will be randomized 1:1 to the pantoprazole 
or pantoprazole placebo and all subjects (including those subjects who entered the study while 
already receiving a PPI) will then be randomized 1:1:1 to rivaroxaban alone, the combination 
of rivaroxaban and aspirin or aspirin alone, and their matching placebos as shown in Table 4-
1:
Table 4-1.  Randomized study treatments* 
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Study Arm
Treatment Assignments
A
Rivaroxaban 2.5 mg bid +
Aspirin 100 mg od +
Pantoprazole 40 mg od
Rivaroxaban 2.5 mg bid +
Aspirin 100 mg od +
Pantoprazole placebo od
B
Rivaroxaban 5 mg bid + 
Aspirin placebo od + 
Pantoprazole 40 mg od
Rivaroxaban 5 mg bid + 
Aspirin placebo od +
Pantoprazole placebo od
C
Rivaroxaban placebo + 
Aspirin 100 mg od +
Pantoprazole 40 mg od
Rivaroxaban placebo + 
Aspirin 100 mg od + 
Pantoprazole placebo od
*Subjects already taking a proton pump inhibitor at baseline will undergo only a single randomization (to 
rivaroxaban 2.5 mg bid + aspirin 100 mg od, rivaroxaban 5 mg bid + aspirin placebo or rivaroxaban placebo + 
aspirin 100 mg od)
Subjects will be seen in the clinic at 1 month and at 6 months after randomization and at 6 
month intervals thereafter in order to collect information on treatment adherence, treatment 
interruption, outcomes, and adverse events (AEs).  Validated questionnaires will be 
administered at randomization and at Month 24 to collect data on subject health and quality of 
life (Standard Assessment of Global-Activities in the Elderly [SAGE], Montreal Cognitive 
Assessment [MoCA], DSS [Digital Symbol Substitution], European Quality of Life-5 
Dimensions [EQ-5D], The Interheart Diet Questionnaire, and The International Physical 
Activity Questionnaire).  
New Text:
This Phase 3, event-driven (at least 2,200 primary efficacy outcome events), randomized 
controlled trial will have a 3 x 2 partial factorial design and will randomize at least 21,400
subjects who will receive treatment for an expected average duration of 3 to 4 years.  The 
COMPASS trial will involve 4 periods:  screening, run-in, follow-up, and washout. 
Prescreening procedures may require informed consent in some countries.  In all other study 
sites, informed consent will be obtained prior to the initiation of any screening procedures
(Section 7.1.2.1).  Screening will be performed to determine subject eligibility and will 
include the review of inclusion and exclusion criteria, physical measurements, laboratory 
evaluations, etc. (Section 7.1.2.2).  
The run-in period will occur during the 28 days prior to initiation of randomized study 
treatment, with the exception of subjects who are randomized after CABG surgery, who will 
not undergo a run-in phase (Section 4.1.1).  During run-in, subjects will discontinue any 
antithrombotic therapy and will begin study rivaroxaban placebo and study aspirin 100 mg.  
Subjects who successfully complete the run-in period and who remain committed to the study 
as well as those who are being randomized after CABG will be randomized and begin study 
treatments on Day 0, which will also signal the initiation of the follow-up period.  Subjects 
without a continuous need for treatment with a PPI will be randomized 1:1 to the pantoprazole 
or pantoprazole placebo and all subjects (including those subjects who entered the study while 
already receiving a PPI) will then be randomized 1:1:1 to rivaroxaban alone, the combination 
of rivaroxaban and aspirin or aspirin alone, and their matching placebos as shown in Table 4-
1:
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Table 4-1.  Randomized study treatments* 
Study Arm
Treatment Assignments
A
Rivaroxaban 2.5 mg bid +
Aspirin 100 mg od +
Pantoprazole 40 mg od
Rivaroxaban 2.5 mg bid +
Aspirin 100 mg od +
Pantoprazole placebo od
B
Rivaroxaban 5 mg bid + 
Aspirin placebo od + 
Pantoprazole 40 mg od
Rivaroxaban 5 mg bid + 
Aspirin placebo od +
Pantoprazole placebo od
C
Rivaroxaban placebo + 
Aspirin 100 mg od +
Pantoprazole 40 mg od
Rivaroxaban placebo + 
Aspirin 100 mg od + 
Pantoprazole placebo od
*Subjects who have a continuous need for use of a proton pump inhibitor at baseline will undergo only a single 
randomization (to rivaroxaban 2.5 mg bid + aspirin 100 mg od, rivaroxaban 5 mg bid + aspirin placebo or 
rivaroxaban placebo + aspirin 100 mg od)
Subjects will be seen in the clinic at 1 month and at 6 months after randomization and at 6 
month intervals thereafter in order to collect information on treatment adherence, treatment 
interruption, outcomes, and adverse events (AEs).  Validated questionnaires will be 
administered before or at the time of randomization, or as soon as possible thereafter, and at 
Month 24 to collect data on subject health and quality of life (Standard Assessment of Global-
Activities in the Elderly [SAGE], Montreal Cognitive Assessment [MoCA], DSS [Digital 
Symbol Substitution], European Quality of Life-5 Dimensions [EQ-5D], The Interheart Diet 
Questionnaire, and The International Physical Activity Questionnaire).  
Section 4.1.1 Subjects randomized after CABG surgery
This section was changed as a result of Modification 4 and 10. 
Old Text:
Subjects randomized after CABG surgery will undergo the same screening, follow-up and 
washout periods as other COMPASS trial subjects but will not undergo a run-in period.  The 
majority of these subjects are expected to undergo screening during the 2-3 weeks before 
surgery.  Subjects randomized post CABG will sign consent prior to surgery and those who 
survive and remain eligible will undergo randomization between Days 4-7 after surgery, at 
least 24 hours following the removal of chest tubes and at least 12 hours after last 
administration of any anticoagulant (including DVT prophylaxis). 
Subjects randomized after CABG surgery will undergo computed tomography (CT) 
angiography at 1 year as part of the study protocol unless they have a specific contraindication 
for CT angiography (e.g., contrast allergy, estimated glomerular filtration rate <30 ml/min). 
New Text:
Subjects randomized Day 4-7 after CABG surgery will undergo the same screening, follow-
up, and washout as other COMPASS trial subjects but not run-in. Subjects are to sign 
informed consent before or after the surgery.  Randomization will occur between Day 4-7 
after surgery,  at least 24 hours following the removal of chest tubes and at least 12 hours after 
last administration of any anticoagulant (including DVT prophylaxis) (Section 7.1.1 
Tabulated overview).
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Subjects randomized Day 4-7 after CABG surgery will undergo computed tomography (CT)  
angiography at 1 year as part of the study protocol to assess graft patency unless they have a 
specific contraindication for CT angiography (e.g., contrast allergy, estimated glomerular 
filtration rate <30 ml/min). In the event the subject undergoes an invasive coronary 
angiography at 1 year post CABG for any reason, a CT angiogram may not be required.
Section 4.3.1 Overall design rationale
This section was changed as a result of Modification 4. 
Old Text:
The benefit of increasing the intensity of antithrombotic therapy for the prevention of 
recurrent thrombotic cardiovascular events by adding a second agent to aspirin has been 
established in trials of dual antiplatelet therapy after an acute coronary syndrome when 
compared with aspirin alone.  
…
To date, no trials have directly compared a new anticoagulant with aspirin for long-term 
secondary prevention of cardiovascular disease.  Prior efforts to identify more effective 
antithrombotic treatments than aspirin have focused on new antiplatelet therapies (terutroban, 
a platelet thromboxane receptor antagonist; clopidogrel, prasugrel and ticagrelor, adenosine 
diphosphate (ADP) receptor antagonists; and vorapaxar, a PAR-1 receptor antagonist) and 
warfarin.  
New Text:
The benefit of increased intensity of antithrombotic therapy for the prevention of recurrent 
thrombotic cardiovascular events by adding a second agent to aspirin has been established in 
trials of dual antiplatelet therapy after an acute coronary syndrome when compared with 
aspirin alone.  
…
To date, no trials have directly compared a new anticoagulant with aspirin for long-term 
secondary prevention of cardiovascular disease.  Prior efforts to identify more effective 
antithrombotic treatments than aspirin have focused on new antiplatelet therapies (terutroban, 
a platelet thromboxane receptor antagonist; clopidogrel, prasugrel and ticagrelor, P2Y12
antagonists; and vorapaxar, a PAR-1 receptor antagonist) and warfarin.  
Section 5 Study population
This section was changed as a result of Modifications 4, 6, 11, 12 and 13. 
Old Text:
Approximately 19,500 eligible subjects will be admitted to the run-in period and an additional 
2000 will be enrolled post CABG and without run-in.  Approximately 10% of run-in subjects 
are expected to either be non-compliant with treatment or to decline further interest in 
participating; thus, the study will randomize approximately 19,500 men and women with 
objectively confirmed CAD or PAD from 25 to 30 countries worldwide.
For the purposes of this trial, the definition of CAD is:
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
Previous myocardial infarction, or

Stable angina or unstable angina with documented multi-vessel CAD, > 50% stenosis 
in at least 2 major coronary arteries on coronary angiography, or positive stress test 
(electrocardiogram (ECG) or nuclear perfusion scintogram), or

Multi-vessel percutaneous coronary intervention (PCI), or

Multi-vessel CABG surgery within 1 week or at least 4 years ago or with recurrent 
angina or ischemia at any time following surgery.1
1
Rationale:  The risk of thrombotic events and graft failure increases during the first year post CABG.12  Following 
a relatively stable period with low event rates between Year 1 and 4, the risk starts to rise again.28
For the purposes of this trial, the definition of PAD is:

Previous aorto-femoral bypass surgery, limb bypass surgery or percutaneous 
transluminal angioplasty of the iliac or infrainguinal arteries, or

Previous limb or foot amputation for arterial vascular disease (i.e., excludes trauma), 
or

History of intermittent claudication and either an ankle/arm blood pressure (BP) ratio 
≤0.90 or significant peripheral artery stenosis (>50%) documented by angiography or 
non-invasive testing by duplex ultrasound, or

Asymptomatic (i.e., no ipsilateral stroke or transient ischemic attack within 6 months) 
carotid artery stenosis >50% as diagnosed by duplex ultrasound or angiography.
New Text:
Approximately 23,500 eligible subjects will be admitted to the run-in period and an additional 
2000 will be enrolled post CABG and without run-in.  Approximately 10% of run-in subjects 
are expected to either be non-compliant with treatment or to decline further interest in 
participating; thus, the study will randomize approximately 21,400 men and women with 
objectively confirmed CAD or PAD from approximately 30 countries worldwide.
Subjects with high risk of incident cardiovascular disease will be enrolled in the study. 
Subjects will be treated with rivaroxaban, the combination of rivaroxaban and aspirin, or 
aspirin on top of usual care. Investigators in the study are selected based on their 
qualifications and ability to enroll and treat these subjects in accordance with the protocol and 
applicable standard of care.  
For the purpose of determining eligibility for this trial, subjects meeting criteria for CAD must 
have one or more of the following:

Myocardial infarction within the last 20 years, or

Multi-vessel coronary disease* with symptoms or history of stable or unstable angina, 
or

Multi-vessel percutaneous coronary intervention (PCI), or

Multi-vessel CABG surgery 
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*Refers to stenosis of greater than or equal to 50% in two or more coronary arteries, 
confirmed by invasive coronary angiography, or non-invasive imaging or stress studies 
(e.g. exercise or pharmacologic) suggestive of significant ischemia in 2 or more coronary 
territories; or in 1 coronary territory if at least one other territory has been revascularized
For the purpose of determining eligibility for this trial, subjects meeting criteria for PAD must 
have one or more of the following:

Previous aorto-femoral bypass surgery, limb bypass surgery, or percutaneous 
transluminal angioplasty revascularization of the iliac, or infrainguinal arteries, or

Previous limb or foot amputation for arterial vascular disease (i.e., excludes trauma), 
or

History of intermittent claudication and one or more of the following: 1) an ankle/arm 
blood pressure (BP) ratio < 0.90, or 2) significant peripheral artery stenosis (≥50%) 
documented by angiography, or by duplex ultrasound, or

Previous carotid revascularization (e.g., endarterectomy, stenting) or asymptomatic 
(i.e., no ipsilateral stroke or transient ischemic attack within 6 months) carotid artery 
stenosis ≥50% as diagnosed by duplex ultrasound or angiography.
Section 5.1.1 Inclusion criteria
This section was changed as a result of Modification 3. 
Old Text:

CAD or PAD plus at least one of the following:
o
Age ≥65
o
Age <65 plus documented atherosclerosis in two vascular beds or at least two
additional risk factors
Additional risk factors are: 

Current smoker

Diabetes mellitus

Renal dysfunction with estimated glomerular filtration rate <60 ml/min 

Heart failure

Non-lacunar ischemic stroke ≥1 month ago
New Text:

Meet criteria for CAD* and/or PAD
*Subjects with CAD must also meet at least one of the following criteria:

Age ≥65, or

Age <65 and documented atherosclerosis or revascularization involving at least 2
vascular beds§, or at least 2 additional risk factors:
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1)
Current smoker (within 1 year of randomization)
2)
Diabetes mellitus
3)
Renal dysfunction with estimated glomerular filtration rate 
<60 ml/min 
4)
Heart failure 
5)
Non-lacunar ischemic stroke ≥1 month ago
§ Because CAD involves disease in the coronary vasculature, only one additional vascular bed 
is required: e.g. the aorta and arterial supply to the brain, gastro-intestinal tract, lower limbs, 
upper limbs, or kidneys.
Section 5.1.2 Exclusion criteria
This section was changed as a result of Modification 5 and 14. 
Old Text:

History of hypersensitivity or known contraindication for rivaroxaban, aspirin, or
pantoprazole

Systemic treatment with strong CYP 3A4 and p-glycoprotein (P-gp) inhibitors (e.g., 
systemic azole antimycotics, such as ketoconazole, and human immunodeficiency 
virus [HIV]-protease inhibitors, such as ritonavir) 

Any known hepatic disease associated with coagulopathy

Female subjects, premenopausal who are not surgically sterile, or, if sexually active 
not practicing an effective method of birth control (e.g., prescription oral 
contraceptives, contraceptive injections, intrauterine device, double-barrier method, 
contraceptive patch, male partner sterilization) before entry and throughout the study; 
and, for those of childbearing potential, who have a positive pregnancy test at 
screening

Previous assignment to treatment during this study
An additional exclusion for the pantoprazole randomization is:

Need for treatment with a PPI
New Text:

History of hypersensitivity or known contraindication for rivaroxaban, aspirin, 
pantoprazole, or excipients, if applicable.

Systemic treatment with strong inhibitors of both CYP 3A4 and p-glycoprotein (P-gp) 
(e.g., systemic azole antimycotics, such as ketoconazole, and human 
immunodeficiency virus [HIV]-protease inhibitors, such as ritonavir), or strong 
inducers of CYP 3A4, i.e. rifampicin, rifabutin, phenobarbital, phenytoin, and 
carbamazepine

Any known hepatic disease associated with coagulopathy

Subjects who are pregnant, breastfeeding or are of childbearing potential, and sexually 
active and not practicing an effective method of birth control (e.g. surgically sterile, 
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prescription oral contraceptives, contraceptive injections, intrauterine device, double-
barrier method, contraceptive patch, male partner sterilization) 

Previous assignment to treatment during this study

Concomitant participation in another study with investigational drug

Known contraindication to any study related procedures
An additional exclusion for the pantoprazole randomization is:

Need for continuous treatment with a PPI
Section 5.2 Discontinuation of subjects from study treatment
This section was changed as a result of Modification 15. 
Old Text:
…In all cases, every effort must be made to continue to follow the subject and survival 
status information must be determined for all subjects at the end of the study.
New Text:
…In all cases, including the subjects with the study outcome, every effort must be made 
to continue to follow the subject at regular study visits. Additionally, survival status and 
outcome information must be determined for all subjects. 
Section 6.1 Treatments to be administered
This section was changed as a result of Modifications 4 and 16. 
Old Text:
The study drugs to be administered in this trial include the antithrombotic drugs, rivaroxaban 
and aspirin; the PPI pantoprazole; and their matching placebos.  
New Text:
The study drugs to be administered in this trial include the antithrombotic drugs, rivaroxaban 
and enteric-coated aspirin; the PPI pantoprazole; and their matching placebos.  
Section 6.1.1 Run-in
This section was changed as a result of Modification 4. 
Old Text:
During the run-in period, Day -30 to Day -1 (± 5 days), eligible subjects (excluding those who 
are randomized during the first week after CABG surgery) who have signed informed consent 
and stopped non-study anticoagulants and aspirin will receive rivaroxaban placebo bid and 
aspirin 100 mg od.  
New Text:
During the run-in period, Day -28 to Day -1, eligible subjects (excluding those who are 
randomized Day 4-7 after CABG surgery) who have signed informed consent and stopped 
non-study anticoagulants and aspirin will receive rivaroxaban placebo bid and aspirin 100 mg 
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od.  
Section 6.1.2 Randomization
This section was changed as a result of Modifications 4, 5 and 17. 
Old Text:
Subjects who have completed the run-in period with at least 80% adherence to treatment with 
rivaroxaban placebo bid and aspirin 100 mg od and who wish to continue in the study, and 
those who are being randomized during the first week after CABG surgery and who do not 
have a need to take a PPI, will initially be randomized 1:1 to receive pantoprazole 40 mg od or 
matching placebo od, stratified by center.  
New Text:
Subjects who have completed the run-in period with adherence to treatment with rivaroxaban 
placebo bid and aspirin 100 mg od of at least 80% except for extenuating circumstances, and
who wish to continue in the study will be randomized.  Subjects being randomized after run-in 
and those who are being randomized  Day 4-7 after CABG surgery (Section 7.1.1 Tabulated 
overview) and who do not have a continuous need to take a PPI, will initially be randomized 
1:1 to receive pantoprazole 40 mg od or matching placebo od, stratified by center.  
Section 6.2 Identity of study treatment
This section was changed as a result of Modification 16. 
Old Text:
…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.
New Text:
…Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request. For the purpose of this study, the 
term “aspirin” is used interchangeably with the term “acetyl salicylic acid”.
Section 6.4.1 Dose modifications
This section was changed as a result of Modification 4. 
Old Text:
Permanent study drug interruption should be recorded on the corresponding follow-up case 
report form, giving the date and primary reason for stopping the study drug.  If one of the 
study treatments needs to be interrupted, other study treatments must be continued.  
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New Text:
Permanent study drug interruption should be recorded on the corresponding follow-up case 
report form, giving the date and primary reason for stopping the study drug.  If one of the 
study treatments needs to be discontinued, other study treatments must be continued. 
Section 6.4.2 Dose modifications and treatment guidance
This section was changed as a result of Modifications 4 and 18. 
Old Text:
This section provides a general guide for investigators on the management of subjects who 
develop intercurrent illnesses or bleeding during the course of the COMPASS trial.  The 
guidance provided in this section does not replace clinical judgment in determining the 
appropriate management strategy for individual subjects. 
New Text:
This section provides a general guide for investigators on the management of subjects who 
develop intercurrent illnesses or bleeding during the course of the COMPASS trial.  The 
guidance provided in this section does not replace clinical judgment nor usual care in 
determining the appropriate management strategy for individual subjects. For specific 
treatment guidance with study pantoprazole/pantoprazole placebo see Section 6.9.4  
Section 6.4.2.1 Guidance for the treatment of subjects who require an invasive 
procedure
This section was changed as a result of Modifications 4 and 18. 
Old Text:
…If study aspirin/aspirin placebo is interrupted, non-study aspirin may be used.  Study 
pantoprazole/pantoprazole placebo should not be interrupted unless subjects develop a need 
for treatment with a PPI.  
New Text:
…If study aspirin/aspirin placebo is interrupted, non-study aspirin may be used.  
Section 6.4.2.2 Guidance for the treatment of subjects who require coronary artery 
bypass graft surgery
This section was changed as a result of Modifications 4 and 18. 
Old Text:
Subjects who are scheduled to be randomized during the first week after CABG surgery will 
not participate in the run-in phase but will sign informed consent and undergo screening 
before the surgery (Section 4.1.1).  The timing of randomization should be no earlier than 4 
days and no more than 7 days after surgery and only once the chest tubes are removed and 
hemostasis is secure.  
…
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In all cases, the goal should be to resume study antithrombotic drugs within 7 days and prior 
to being discharged from hospital.  
Study pantoprazole/pantoprazole placebo should not be interrupted unless subjects develop a 
need for treatment with a PPI.  
New Text:
Subjects who are scheduled to be randomized Day 4-7 after CABG surgery will not 
participate in the run-in phase (Section 4.1.1).  Randomization should only be performed
between Day 4-7 post-CABG and at least 24 hours following the removal of chest tubes and 
at least 12 hours after last administration of any anticoagulant (including DVT prophylaxis).
In all cases, the goal should be to resume study antithrombotic drugs within 14 days and prior 
to being discharged from hospital.  
Section 6.4.2.3 Guidance for the treatment of subjects who develop an acute coronary 
syndrome and those who require percutaneous coronary intervention with stenting
This section was changed as a result of Modifications 4 and 18. 
Old Text:
…Standard anticoagulant therapy can be used without regard to the timing of the most recent 
dose of study rivaroxaban/rivaroxaban placebo because the doses of rivaroxaban being tested 
in the COMPASS trial are lower than the 20 mg dose given for stroke prevention in atrial 
fibrillation and the half-life is short, 5-13 hours.  
Study pantoprazole/pantoprazole placebo should not be interrupted unless subjects have 
developed a need for treatment with a PPI.  
New Text:
…Standard anticoagulant therapy can be used without regard to the timing of the most recent 
dose of study rivaroxaban/rivaroxaban placebo because the doses of rivaroxaban being tested 
in the COMPASS trial are lower than the 15 or 20 mg dose given for stroke prevention in 
atrial fibrillation and the half-life is short, 5-13 hours.  
Section 6.6 Drug logistics and accountability
This section was changed as a result of Modification 4. 
Old Text:
…  The responsible site personnel will confirm the date and time of receipt of study drug and 
will use the study drug only within the framework of this clinical study and in accordance 
with this protocol.  .
New Text:
…The responsible site personnel will confirm the date of receipt of study drug and will use 
the study drug only within the framework of this clinical study and in accordance with this 
protocol.  
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Section 6.9 Prior concomitant therapy
This section was changed as a result of Modification 4. 
Old Text:
As described in Section 5.1.2, Exclusion Criteria, the use of the following agents is not 
permitted at study entry:  systemic treatment with strong CYP 3A4 and P-gp inhibitors(e.g., 
systemic azole antimycotics, such as ketoconazole, and HIV-protease inhibitors, such as 
ritonavir).  Additionally, subjects with a need for dual antiplatelet therapy or oral 
anticoagulant therapy are not eligible for inclusion in COMPASS.
New Text:
As described in Section 5.1.2, Exclusion Criteria, the use of the following agents is not 
permitted at study entry:  systemic treatment with strong inducers of CYP 3A4 (e.g. 
rifampicin) and inhibitors of both CYP 3A4 and P-gp (e.g., systemic azole antimycotics, such 
as ketoconazole, and HIV-protease inhibitors, such as ritonavir).  Additionally, subjects with a 
need for dual antiplatelet therapy or oral anticoagulant therapy are not eligible for inclusion in 
COMPASS.
Section 6.9.1 Combined CYP 3A4 and p-glycoprotein inhibitors
This section was changed as a result of Modifications 18 and 19. 
Old Text:
6.9.1 Combined CYP 3A4 and p-glycoprotein inhibitors
Strong inhibitors of both CYP 3A4 and p-glycoprotein increase plasma concentrations of 
rivaroxaban and are contraindicated in subjects taking rivaroxaban.  These include systemic 
azole antifungal drugs (ketoconazole), macrolide antibiotics (erythromycin, azithromycin, 
clarithromycin) and HIV protease inhibitors.  If any of these treatments are needed, 
randomized study rivaroxaban/rivaroxaban placebo and aspirin/aspirin placebo must be 
temporarily discontinued and open-label aspirin should be begun.  Study 
pantoprazole/pantoprazole placebo should not be interrupted unless subjects develop a need 
for treatment with a PPI.  
New Text:
6.9.1 Combined CYP 3A4 and p-glycoprotein inhibitors and CYP 3A4 inducers
Strong inhibitors of both CYP 3A4 and p-glycoprotein increase plasma concentrations of 
rivaroxaban and are contraindicated in subjects taking rivaroxaban. These include systemic 
azole antifungal drugs (e.g. ketoconazole, itraconazole, posaconazole, etc.), and HIV protease 
inhibitors.  Additionally, strong inducers of CYP 3A4 such as, i.e. rifampicin, rifabutin, 
phenobarbital, phenytoin, and carbamazepine can reduce the plasma concentrations of 
rivaroxaban. If any of these treatments are needed, randomized study rivaroxaban/rivaroxaban 
placebo and aspirin/aspirin placebo must be temporarily discontinued and open-label aspirin 
should be begun. 
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Section 6.9.2 Clopidogrel (or any other non-study antiplatelet treatment)
This section was changed as a result of Modification 4. 
Old Text:
Subjects who develop a need for treatment with non-study antiplatelet therapy, such as aspirin 
plus clopidogrel (e.g., subjects who experience an acute coronary syndrome, those who 
undergo percutaneous coronary intervention with stent insertion) must discontinue study 
rivaroxaban/rivaroxaban placebo.  Study rivaroxaban/rivaroxaban placebo must be restarted 
once dual antiplatelet therapy is stopped (i.e., after completion of an adequate duration of dual 
antiplatelet treatment).  Additional guidance is provided in Section 6.4.2.3.  
New Text:
Subjects who develop a need for treatment with non-study dual antiplatelet therapy, such as 
aspirin plus clopidogrel (e.g., subjects who experience an acute coronary syndrome, those 
who undergo percutaneous coronary intervention with stent insertion) must interrupt study 
treatment of rivaroxaban/rivaroxaban placebo.  Study rivaroxaban/rivaroxaban placebo must 
be restarted once dual antiplatelet therapy is stopped (i.e., after completion of an adequate 
duration of dual antiplatelet treatment).  Additional guidance is provided in Section 6.4.2.3.  
Section 6.9.3 Anticoagulant treatment
This section was changed as a result of Modification 18. 
Old Text:
…In subjects who develop a need for anticoagulant therapy, study aspirin/aspirin placebo may 
also be interrupted, at the discretion of the investigator.  Study pantoprazole/pantoprazole 
placebo should not be interrupted unless subjects have a need for treatment with a PPI.  
New Text:
…In subjects who develop a need for anticoagulant therapy, study aspirin/aspirin placebo may 
also be interrupted, at the discretion of the investigator.  
Section 6.9.4 Proton pump inhibitor treatment
This section was changed as a result of Modifications 4 and 18. 
Old Text:
Subjects who develop a need for treatment with a PPI (e.g., gastroduodenal ulcer) should 
discontinue study pantoprazole/pantoprazole placebo while receiving non-study PPI 
treatment.  Study pantoprazole/pantoprazole placebo must be restarted in all subjects who no 
longer have a need for PPI therapy. 
New Text:
Subjects who develop a continuous need for treatment with a PPI during the study (e.g., 
gastroduodenal ulcer) should discontinue study pantoprazole/pantoprazole placebo while 
receiving non-study PPI treatment.  Study pantoprazole/pantoprazole placebo should be 
restarted in all subjects who no longer have a continuous need for PPI therapy. 
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Section 7.1.1 Tabulated overview
This section was changed as a result of Modification 20. 
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Old Text:
Table 7-1.  Schedule of evaluations
Pre-Screeninga
Screening/Run-in
Randomization
Follow-up
Washout
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15n
Final
Washout
Timing
-4w
0
1 m 3mm 6m 9mm
1y
1.5y
2y
2.5y
3y
3.5y
4y
4.5y
5y
1 m post 
Finalm
Windows
± 5d ± 7d ± 2w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w
± 5d
Informed consent (if required for 
pre-screening)
X
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics
X
Medical history
X
Physical measurementsb
X
X
X
Concomitant medications
X
X
X
X
Pregnancy test if pre-
menopausal
X
Laboratory testsc
Xd
Xe
Blood/DNA collection and 
storage
Xf
Xf
Diet and activity questionnaires
Xo
Xo
X
MoCA, DSS, and SAGE
Xo
Xo
X
X
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Pre-Screeninga
Screening/Run-in
Randomization
Follow-up
Washout
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15n
Final
Washout
Timing
-4w
0
1 m 3mm 6m 9mm
1y
1.5y
2y
2.5y
3y
3.5y
4y
4.5y
5y
1 m post 
Finalm
Windows
± 5d ± 7d ± 2w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w
± 5d
EQ-5Dg
Xo
Xo
X
X
Health Care Costs
X
Driving Status
X
EuroSCORE for subjects 
randomized post CABG surgery
X
CT coronary angiographyh
Xh
MRI braini
X
X
Outcomes
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug dispensed
Xk
Xl
X
X
X
X
X
X
X
X
X
X
Study drug adherence
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations:  w = week; m = month; y = year; d = day; DNA = deoxyribonucleic acid; MoCA = Montreal Cognitive Assessment; DSS = 
Digit Symbol Substitution test; SAGE = Standard Assessment of Global-Activities in the Elderly; EQ-5D = European Quality of Life-5 
Dimensions questionnaire; CT = computed tomography; MRI = magnetic resonance imaging; CABG = coronary artery bypass graft
a.
Pre-screening visit is not mandatory and will be conducted only in some centers and for some subjects. Subjects who will be 
randomized during the first week after CABG surgery do not require pre-screening.
b.
Weight, height, waist and hip circumference, heart rate, ankle-brachial blood pressure index
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c.
Serum creatinine, total cholesterol
d.
If not available within prior 3 months
e.
Repeat serum creatinine in patients being enrolled post CABG surgery
f.
Blood & DNA collection at randomization and blood collection at 1 month for central evaluation will be collected in subjects 
participating in the COMPASS-MIND substudy
g.
Using the European Quality of Life-5 Dimensions questionnaire and to be performed at randomization, year 2 and Final Follow-
up Visit  as well as at the next study clinic visit after each outcome event
h.
CT angiography will be performed at 1 year in all subjects who are randomized during the first week after CABG (except in 
subjects those with specific contraindications)
i.
MRI of the brain will be performed only in COMPASS-MIND substudy subjects, at the time of randomization (or soon thereafter) 
and at the end of the follow-up
j.
Adverse events will be assessed from time of consent to 30 days post last dose of study treatment
k.
Dispense run-in medications. CABG surgery patients will be randomized during the first week after CABG surgery and will not be 
dispensed run-in study drug; however, the Screening/Run-In Visit CRFs are still required to be completed for these subjects.  
l.
Stop run-in medication and begin randomized treatment assignment
m. Telephone visits
n.
Visits will continue every 6 months until the required number of primary efficacy outcomes has been collected
o.
It is optional to administer all or some of the questionnaires (SAGE, DSS, MoCA, EQ-5D, Diet, and Physical Activity) at 
Screening/Run-in instead of at the Randomization Visit 
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New Text:
Pre-Screeninga
Screening/Run-
in
Randomizations
Follow-up
Washout
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15n
Final
Wash
out
Timing
-4w
0
1 m 3mm 6m 9mm
1y
1.5y
2y
2.5y
3y
3.5y
4y
4.5y
5y
1 m post 
Finalm
Windowsq
± 5d ± 7d ± 2w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w
± 5d
Informed consent (if required for 
pre-screening)
X
Informed consent
Xr
Inclusion/exclusion criteria
X
X
X
Demographics
X
Medical history
X
Physical measurementsb
X
X
X
Concomitant medications
X
X
X
X
Pregnancy test if pre-
menopausal
X
Laboratory testsc
Xd
Xe
Blood/DNA collection and
storage
Xf
Xf
Diet and activity questionnaires
Xo
Xo
Xp
X
MoCA, DSS, and SAGE
Xo
Xo
Xp
X
X
EQ-5Dg
Xo
Xo
Xp
X
X
Health Care Costs
X
Driving Status
X
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Pre-Screeninga
Screening/Run-
in
Randomizations
Follow-up
Washout
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15n
Final
Wash
out
Timing
-4w
0
1 m 3mm 6m 9mm
1y
1.5y
2y
2.5y
3y
3.5y
4y
4.5y
5y
1 m post 
Finalm
Windowsq
± 5d ± 7d ± 2w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w
± 5d
EuroSCORE for subjects 
randomized post CABG surgery
X
CT coronary angiographyh
Xh
MRI braini
X
X
Outcomes
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug dispensed
Xk
Xl
X
X
X
X
X
X
X
X
X
X
Study drug adherence
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations:  w = week; m = month; y = year; d = day; DNA = deoxyribonucleic acid; MoCA = Montreal Cognitive Assessment; DSS = 
Digit Symbol Substitution test; SAGE = Standard Assessment of Global-Activities in the Elderly; EQ-5D = European Quality of Life-5 
Dimensions questionnaire; CT = computed tomography; MRI = magnetic resonance imaging; CABG = coronary artery bypass graft
a.
Pre-screening visit is not mandatory and will be conducted only in some centers and for some subjects. Subjects who will be randomized  
Day 4-7 after CABG surgery do not require pre-screening.
b.
Weight, height, waist and hip circumference, heart rate, ankle-brachial blood pressure index
c.
Serum creatinine, total cholesterol
d.
If not available within 1 year prior.
e.
Repeat serum creatinine in patients being enrolled Day 4-7 post CABG surgery For other, non-CABG subjects, the blood results of 
creatinine and total cholesterol  should be available within 3 months of this visit.
f.
Collection of blood & DNA samples for central evaluation in subjects participating in the COMPASS-MIND substudy is optional.  If 
collected, obtain samples at randomization, before starting study drug, and at 1 month, or as close to one month after randomization as 
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possible,. If the first blood sample is not collected before start of study drug, it is not required. Irrespective of whether the first blood 
sample is obtained, collect the second blood sample at 1 month. If either the DNA sample or second blood sample is missed, it should be
collected at the next visit.
g.
Using the European Quality of Life-5 Dimensions questionnaire and to be performed at randomization, year 2 and Final Follow-up Visit  
as well as at the next study clinic visit after each outcome event
h.
CT angiography will be performed at 1 year in all subjects who are randomized Day 4-7 after CABG to evaluate graft patency (except in 
subjects those with specific contraindications). In the event the subject undergoes an invasive coronary angiography at 1 year post 
CABG for any reason, a CT angiogram may not be required.
i.
MRI of the brain will be performed only in COMPASS-MIND substudy subjects, at the time of randomization (or soon thereafter, within 3 
months) and near the end of the follow-up
j.
Adverse events will be assessed from time of consent to 30 days post last dose of study treatment
k.
Stop treatment with non-study aspirin. Dispense run-in medications. CABG surgery patients will be randomized Day 4-7 after CABG 
surgery and will not be dispensed run-in study drug; however, the Screening/Run-In Visit CRFs are still required to be completed for 
these subjects.  
l.
Stop run-in medication and begin randomized treatment assignment
m. Telephone visits
n.
Visits will continue every 6 months until the required number of primary efficacy outcomes has been collected
o.
It is optional to administer all or some of the questionnaires (SAGE, DSS, MoCA, EQ-5D, Diet, and Physical Activity) at Screening/Run-in 
instead of at the Randomization Visit, or as soon as possible thereafter (with the exception of patients randomized Day 4-7 post CABG; 
see “p”).   
p.
For patients randomized Day 4-7 post CABG, questionnaires (SAGE, DSS, MoCA, EQ-5D, Diet, and Physical Activity) should be 
performed at the 1 month visit. 
q.
Clinic visits should be scheduled as close to the specified interval as possible, and preferably within the defined window.  If it is not 
possible for the subject to return within the visit "window," especially due to unforeseen circumstance beyond the control of the subject or 
the study center, then the visit should be scheduled as close to the interval as is convenient for the subject and study center.
r.
CABG subjects can sign the informed consent before or after surgery.
s.
CABG subjects should be randomized between Day 4-7 after the surgery. In the event that a subject is unable to be randomized within 
this time range for medical and logistical reasons, the subject can be randomized, up to Day 14 post-CABG.
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Section 7.1.2.2 Screening and Run-in visit(s)
This section was changed as a result of Modification 21. 
Old Text:
The aim of the screening visit is to confirm eligibility and perform baseline laboratory 
assessments and in most subjects will be performed on the day of the run-in visit as long as 
laboratory tests have been performed within 3 months and a negative pregnancy test result is 
available for premenopausal subjects.  For subjects who are randomized during the first week
after CABG surgery the screening visit will be performed prior to surgery (Section 4.1.1).  
The Screening/Run-in Visit will occur 4 weeks prior to randomization; however, screening 
may be earlier if performed on a separate day.  Screening/run-in activities include:
…

It is optional to administer all or some of the questionnaires (SAGE, DSS, MoCA, EQ-
5D, Diet, and Physical Activity) at Screening/Run-in instead of at the Randomization 
Visit

Collect blood for local laboratory assessment of creatinine and total cholesterol (if not 
performed at pre-screening/screening/run-in, or previous laboratory assessments were 
conducted > 3 months prior)

Collect blood for local laboratory assessment of creatinine and total cholesterol ( 
previous laboratory assessments were conducted > 3 months prior)
…

Obtain medication code for run-in study treatment and dispense run-in study 
medications (not applicable for subjects who are randomized during the first week
after CABG surgery)
New Text:
The aim of the screening visit is to confirm eligibility. Laboratory results of creatinine and 
total cholesterol performed within a year of this visit can be used to assess eligibility. 
Otherwise, obtain relevant laboratory tests.  For subjects who are randomized Day 4-7 after 
CABG surgery, the screening visit may be performed prior to or after surgery (Section 4.1.1).  
Screening/run-in activities include:
…

It is optional to administer all or some of the questionnaires (SAGE, DSS, MoCA, EQ-
5D, Diet, and Physical Activity) at Screening/Run-in instead of at the Randomization 
Visit. (In patients randomized Day 4-7 post CABG, the questionnaires should be 
performed at the 1 month visit).  
…

Obtain medication code for run-in study treatment and dispense run-in study 
medications (not applicable for subjects who are randomized Day 4-7 after CABG 
surgery) 
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A subject can be re-screened/re-run-in, if not previously randomized to study treatment:

Obtain written informed consent, if applicable 

Repeat/complete the rest of the screening/run-in activities, where applicable.
Section 7.1.2.3 Randomization visit (Day 0 ± 5 days)
This section was changed as a result of Modification 21. 
Old Text:
The aim of the randomization visit is to assign blinded study treatment.  Subjects may be 
randomized if they fulfill all study inclusion and exclusion criteria, have at least 80% 
adherence to both run-in study treatments, and remain committed to participate in the trial.  
Randomization activities include: 

Perform run-in drug accountability; assess adherence to run-in drug (not applicable for 
subjects who are randomized during the first week after CABG surgery)

Collect blood (DNA) sample for storage and central evaluation in COMPASS MIND 
substudy subjects
New Text:
The aim of the randomization visit is to assign blinded study treatment.  Subjects may be 
randomized if they fulfill all study inclusion and exclusion criteria, have the blood results of 
the serum creatinine and total cholesterol available within 3 months of this visit, have at least
80% adherence (except for extenuating circumstances) to both run-in study treatments and 
remain committed to participate in the trial and randomization activities including: 

Perform run-in drug accountability; assess adherence to run-in drug (not applicable for 
subjects who are randomized Day 4-7 after CABG surgery)

In patients randomized day 4-7 post CABG perform questionnaires (SAGE, DSS, 
MoCA, EQ-5D, Diet, and Physical Activity) at 1 month visit  

Assess local laboratory results of creatinine and total cholesterol

Collect blood (DNA) sample for storage and central evaluation in COMPASS MIND 
substudy subjects, if applicable

Record outcomes
Section 7.1.2.4.1
Routine follow-up visits (Visits 3, 5, and 7-15+)
This section was changed as a result of Modification 21. 
Old Text:

Perform CT angiography only at Visit 7 (1 year) in all subjects who are randomized 
during the first week after CABG (except in subjects those with specific 
contraindications)
o
Administer diet and activity questionnaires at Visit 9 (2 years)
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New Text:

In patients randomized Day 4-7 post CABG perform questionnaires (SAGE, DSS, 
MoCA, EQ-5D, Diet, and Physical Activity) (1 month).  
…

Perform CT  angiography only at Visit 7 (1 year) in all subjects who are randomized 
during the first week after CABG to evaluate graft patency (except in subjects with 
specific contraindications). In the event the subject undergoes an invasive coronary 
angiography at 1 year post CABG for any reason, a CT angiogram may not be required.
o
Administer diet and activity questionnaires at Visit 9 
Section 7.2.3 Other baseline characteristics
This section was changed as a result of Modification 4. 
Old Text:
Validated health and quality of life questionnaires, SAGE, MoCA, DSS, EQ-5D will be 
administered at randomization, as well as Month 24, and the Final Follow-up Visit to measure 
the effect of randomized treatment on functional outcomes and quality of life, and diet and 
activity questionnaires will also be administered in order to explore the determinants and 
consequences of cognitive decline in patients with CAD and PAD.
New Text:  
Validated health and quality of life questionnaires, SAGE, MoCA, DSS, EQ-5D will be
administered at screening/run-in or randomization, as well as Month 24, and the Final Follow-
up Visit to measure the effect of randomized treatment on functional outcomes and quality of 
life, and diet and activity questionnaires will also be administered in order to explore the 
determinants and consequences of cognitive decline in patients with CAD and PAD.
Section 7.3 Efficacy
This section was changed as a result of Modifications 2, 4 and 22. 
Old Text:
The secondary efficacy outcome is a composite of myocardial infarction, stroke, 
cardiovascular death, venous thromboembolism, and cardiovascular hospitalization.  Mortality 
by any cause is also a secondary efficacy outcome.
Tertiary efficacy outcomes include the evaluation of responses recorded for the SAGE, 
MoCA, DSS, and EQ-5D inventories and the following:  individual components of the 
primary and secondary outcomes, hospitalization, revascularization, amputation, unstable 
angina, worsening angina, new angina, heart failure, resuscitated cardiac arrest, new diagnosis 
of cancer.
MRU data will be incorporated into economic modeling, which will be performed and 
reported separately from this study. 
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The primary outcome for the pantoprazole randomization is a composite of overt bleeding of 
gastroduodenal origin confirmed by endoscopy or radiography, overt upper gastrointestinal 
bleeding of unknown origin, bleeding of presumed occult gastrointestinal origin with 
documented decrease in Hb of 2 g/dL from baseline, symptomatic gastroduodenal ulcer, 
gastrointestinal pain with underlying multiple gastroduodenal erosions, and gastrointestinal 
obstruction or perforation.
A detailed description of outcomes to be analyzed for this study will be provided in the 
separate statistical analysis plan.
New Text:
The secondary efficacy outcome is a composite of myocardial infarction, stroke, 
cardiovascular death, revascularization, venous thromboembolism, and cardiovascular 
hospitalization.  Mortality by any cause is also a secondary efficacy outcome.
Tertiary efficacy outcomes include the evaluation of responses recorded for the SAGE, 
MoCA, DSS, and EQ-5D inventories and the following:  individual components of the 
primary and secondary outcomes, hospitalization, amputation, stent thrombosis, unstable 
angina, worsening angina, new angina, heart failure, resuscitated cardiac arrest, new diagnosis 
of cancer, MRU, coronary artery bypass graft failure.
Hospitalization data will be collected on the CRF to permit the analysis of MRU. These data 
will be analyzed and reported to the sponsor separately and will include:

Total days length of stay

Emergency room visits

Intensive care unit /cardiac care unit days 

Rehabilitation and skilled nursing facilities

Reason for medical resource use, i.e., major adverse cardiovascular event or bleeding
MRU data will be incorporated into economic modeling, which will be performed and 
reported separately from this study. 
The outcome for the pantoprazole randomization is a composite of overt bleeding of 
gastroduodenal origin confirmed by endoscopy or radiography, overt upper gastrointestinal 
bleeding of unknown origin, bleeding of presumed occult gastrointestinal origin with 
documented decrease in Hb of 2 g/dL, symptomatic gastroduodenal ulcer, gastrointestinal 
pain with underlying multiple gastroduodenal erosions, and gastrointestinal obstruction, or 
perforation.
A detailed description of outcomes to be analyzed for this study will be provided in the 
separate statistical analysis plan.
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Section 7.5.1 Definition of (serious) adverse event
This section was changed as a result of Modification 23. 
Old Text:
7.5.1
International Conference of Harmonisation E6 Definition of (serious) adverse 
event
A serious adverse event (SAE) is classified as any untoward medical occurrence that, at any 
dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of 
existing hospitalization, results in persistent or significant disability / incapacity is a 
congenital anomaly / birth defect and/or is another medically important serious event 
representing a significant hazard, which is comparable to the aforementioned criteria. 
New Text:
7.5.1
Definition of (serious) adverse event
A serious adverse event (SAE) is classified as any untoward medical occurrence that, at any 
dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of 
existing hospitalization, results in persistent or significant disability / incapacity is a 
congenital anomaly / birth defect and/or is another medically important serious event 
representing a significant hazard, which is comparable to the aforementioned criteria. A 
surgical procedure or hospitalization that was planned prior to signing of the informed consent 
by any physician treating the subject should not be recorded as an AE. However, the condition 
for which the surgery or hospitalization is required may be an AE.
Section 7.5.2 Casual relationship (new section)
This section was changed as a result of Modification 23. 
New Text:
7.5.2 Causal relationship 
The assessment of the causal relationship between an AE and the administration of study drug 
is a clinical decision based on all available information at the time of the completion of the 
CRF. The causality assessment should be done separately for each study treatment as detailed 
in the CRF. The assessment is based on the question whether there was a “reasonable causal 
relationship” to the study drug in question.
Section 7.5.3 Protocol-specific adverse event definitions
This section was changed as a result of Modifications 2, 22 and 23. 
Old Text:
Rivaroxaban has been extensively studied in Phase 2 and 3 clinical studies involving more 
than 60,000 patients and its overall adverse event profile has been well described.  
Appropriate information concerning adverse events will be systematically collected and 
submitted to regulatory authorities and all data on safety and outcomes will be reviewed 
regularly by an unblinded Data and Safety Monitoring Board.
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For the purposes of this trial, the following events will be captured on the CRF as study 
outcome events only and will be waived from unblinding and will be exempted from the 
expedited reporting but will be included in the final study report. 

Primary Outcomes:
o
Cardiovascular death
o
Myocardial infarction
o
Stroke

Secondary and tertiary outcomes
o
Cardiovascular hospitalization
o
Venous thromboembolism
o
Revascularization
o
Amputation
o
Angina pectoris
o
Heart failure
o
Resuscitated cardiac arrest
o
New diagnosis of cancer 
In addition, events that are expected to occur with high frequency in the population under 
study and for which no safety signal arose from the >60,000 patients already studied in 
clinical trials with rivaroxaban will be captured on the CRF only, will be waived from 
unblinding, and be will be exempted from expedited reporting.  These include:

Planned hospitalizations (e.g., for surgery, respite care) 

Non-cardiovascular SAEs (including unplanned hospitalizations) that are expected to 
occur with high frequency in the population under study (depression, pneumonia, 
trauma, chronic obstructive pulmonary disease, diabetes mellitus)
As bleeding, including fatal bleeding, from all tissues and organs is a known side effect of 
rivaroxaban, bleeding events, including those resulting in hospitalization, will not be reported 
as (S)AEs, but will be captured on the CRF only, and will be reported as outcomes.
Any other non-cardiovascular SAEs must be reported by the investigator to 
 within 24 
hours and will be transmitted to the sponsor via expedited SAE reporting. The sponsor is 
responsible for reporting these events to the health authority. 
In addition, any AEs of particular concern to the investigator may be recorded on the CRF to 
bring them to the attention of the sponsor.
Hospitalization data will be collected on the CRF to permit the analysis of MRU.  These data 
will be analyzed and reported to the sponsor separately and will include:

Total days length of stay
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
Emergency room visits

Intensive care unit /cardiac care unit days 

Rehabilitation and skilled nursing facilities

Reason for medical resource use, i.e., major adverse cardiovascular event or bleeding
7.5.3.1 Adverse events of special safety interest
For ongoing pharmacovigilance, the large COMPASS trial is an opportunity to identify rare 
events in the population that may or may not be drug-related.  The following events have, to 
date, not been observed with increased frequency with rivaroxaban, but are considered AEs of 
special safety interest. These events must be reported to 
 independent of their 
seriousness, but within the same timelines as an SAE (within 24 hours) by reporting them on 
the SAE page of the CRF. Bayer HealthCare Global Pharmacovigilance may decide to 
upgrade the event based on the information received.

A non-cardiovascular AE that recurs when the participant is restarted on study drug 
New Text:
7.5.3.1 Protocol-specific exceptions to SAE reporting 
Rivaroxaban has been extensively studied in Phase 2 and 3 clinical studies involving more 
than 70,000 patients and its overall adverse event profile has been well described.  
Appropriate information concerning adverse events will be systematically collected and 
submitted to regulatory authorities and all data on safety and outcomes will be reviewed 
regularly by an unblinded Data and Safety Monitoring Board.
For the purposes of this trial, the following events will be captured on the CRF as study 
outcome events only and will be waived from unblinding and will be exempted from the 
expedited reporting but will be included in the final study report. 

Primary efficacy outcomes:
o
Cardiovascular death
o
Myocardial infarction
o
Stroke

Secondary and tertiary efficacy outcomes
o
Cardiovascular hospitalization
o
Venous thromboembolism
o
Revascularization
o
Amputation
o
Stent thrombosis
o
Angina pectoris (unstable, worsening or new)
o
Heart failure
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o
Resuscitated cardiac arrest
o
New diagnosis of cancer 

Coronary artery bypass graft failure
o
Primary safety outcomes:
As bleeding, including fatal bleeding, from all tissues and organs is a known side effect of 
rivaroxaban, bleeding events, including those resulting in hospitalization, will not be reported 
as (S)AEs, but will be captured on the CRF only, and will be reported as outcomes.

Expected Events:
In addition, events that are expected to occur with high frequency in the population under 
study and for which no safety signal arose from the more than 70,000 patients already studied 
in clinical trials with rivaroxaban will be captured on the CRF only, will be waived from 
unblinding, and be will be exempted from expedited reporting.  These include:

Planned hospitalizations (e.g., for surgery, respite care) 

Non-cardiovascular SAEs (including unplanned hospitalizations) that are expected to 
occur with high frequency in the population under study (depression, pneumonia, 
trauma, chronic obstructive pulmonary disease, diabetes mellitus)
Section 7.5.3.2 Reporting of (S)AEs 
The following events are to be reported to 
 on the SAE/ESI CRF within 24 hours of the
investigator becoming aware of the event/diagnosis Bayer HealthCare Global 
Pharmacovigilance is responsible for reporting these events to the health authority:

Any non-cardiovascular death of a subject occurring after signing informed consent or 
prior to the end of monitoring for adverse events. (note: fatal bleeding events are 
primary safety outcomes and are exempted)

Any non-cardiovascular SAEs not listed in Section 7.5.3.1

Any non-cardiovascular AE that recurs when the subject is restarted on study drug 
(positive re-challenge).
In addition, any AEs of particular concern to the investigator may be recorded on the CRF to 
bring them to the attention of the sponsor.
7.5.3.3 Adverse events of special safety interest
For ongoing pharmacovigilance, the large COMPASS trial is an opportunity to identify rare 
events in the population that may or may not be drug-related.  The following events have, to 
date, not been observed with increased frequency with rivaroxaban, but are considered AEs of 
special safety interest. These events must be reported to 
 independent of their 
seriousness, but within the same timelines as an SAE (within 24 hours) by reporting them on 
the SAE page of the CRF. Bayer HealthCare Global Pharmacovigilance may decide to 
upgrade the event based on the information received.
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Section 7.5.3.5 Pregnancies
This section was changed as a result of Modification 23. 
Old Text:
For a study subject, the outcome of the pregnancy should be followed up carefully, and any 
abnormal outcome of the mother or the child should be reported.
For the pregnancy of a study subject’s partner, all efforts should be made to obtain similar 
information on course and outcome, subject to the partner’s consent.
New Text:
For a study subject, the outcome of the pregnancy should be followed up carefully, and any 
outcome of the mother or the child should be reported. Abnormal  pregnancy outcomes (eg, 
spontaneous abortion, stillbirth, and congenital anomaly) are considered serious adverse 
events and must be reported using the Serious Adverse Event Form.  For the pregnancy of a 
study subject’s partner, all efforts should be made to obtain similar information on course and 
outcome, subject to the partner’s consent.
Section 7.5.3 Data Monitoring Board (section deleted):
This section was changed as a result of Modification 23. 
Old text:
7.5.3
Data Safety Monitoring Board
A DSMB will monitor the safety data in the study on an ongoing basis.  Serious AEs that are 
outcome events (e.g., stroke, myocardial infarctions), or expected AEs associated with 
anticoagulation therapy (e.g. bleeding), or common events that are part of the natural history 
of the disease (as defined in Section 7.5.2) will be collected on the CRFs and evaluated by the 
DSMB.  These events will not be collected on the SAE page in the CRF for expedited review 
or reporting.  The details of this review will be defined in the DSMB-charter.
Section 7.5.4 Reporting of events to Bayer by 
 and compliance with regulatory 
authorities’ reporting requirements
This section was changed as a result of Modification 23. 
Old Text:
SAEs that require expedited reporting described in Section 7.5.2 (protocol-specific adverse 
event reporting) are to recorded on the appropriate SAE CRF page and are to be forwarded to 
 within 24 hours of the investigator having been made aware of the event.  Upon receipt 
of this form it will be reported to Bayer Global Pharmacovigilance by 
 within 24 hours, 
or 3 calendar days for weekends or public holidays, or next working day whichever is earlier. 
New Text:
Adverse events that require expedited reporting described in Section 7.5.3. 2, 7.5.3.3 and 
7.5.3.5 (protocol-specific adverse event reporting) are to be recorded on the appropriate SAE 
CRF page and are to be forwarded to 
 within 24 hours of the investigator having been 
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made aware of the event. In this trial, exempted outcomes are to be recorded on the 
appropriate outcome CRF page, not the SAE CRF page.  Upon receipt of an SAE CRF page
this form will be reported to Bayer Global Pharmacovigilance by 
 within 24 hours, or 3 
calendar days for weekends or public holidays, or next working day whichever is earlier. 
Section 8.3.2 Secondary efficacy outcomes
This section was changed as a result of Modification 2. 
Old Text:

The composite of outcomes --- myocardial infarction, stroke, cardiovascular death, 
venous thromboembolism, and cardiovascular hospitalization
New Text:

The composite of outcomes --- myocardial infarction, stroke, cardiovascular death, 
revascularization, venous thromboembolism, and cardiovascular hospitalization
Section 8.3.3 Tertiary and other efficacy outcomes
This section was changed as a result of Modification 2. 
Old Text:
Section 8.3.3 Tertiary efficacy outcomes
The tertiary efficacy outcomes are:
…

Revascularization

Amputation 
…

MRU 
New Text:
Section 8.3.3 Tertiary and other efficacy outcomes
The tertiary efficacy outcomes are:
…

Amputation

Stent thrombosis
…

MRU 

Coronary artery bypass graft failure
Section 8.3.5 Outcome for pantoprazole randomization
This section was changed as a result of Modification 4. 
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Old Text:

Bleeding of presumed occult gastrointestinal origin with documented decrease in Hb 
of 2 g/dL from baseline
New Text:

Bleeding of presumed occult gastrointestinal origin with documented decrease in Hb 
of 2 g/dL 
Section 8.3.6 Subgroup variables
This section was changed as a result of Modification 4. 
Old Text:
Homogeneity of treatment effect will be examined for the following subgroup variables:

Coronary artery disease (yes, no)

Peripheral artery disease (yes, no)

CAD and PAD (yes, no)

CAD only, PAD only, CAD and PAD 

CABG at Baseline (yes, no)
New Text:
Homogeneity of treatment effect will be examined for the following subgroup variables:

CAD (yes, no)

PAD (yes, no)

CAD and PAD (yes, no)

CAD only, PAD only, CAD and PAD 

CABG days 4-7 before randomization (yes, no)
Section 8.4.5 Analysis of the outcome for pantoprazole randomization
This section was changed as a result of Modification 4. 
Old Text:
Pantoprazole 40 mg od treatment group and pantoprazole placebo control group will be 
compared. The null hypothesis H0;panto40 stating that “there is no difference between the 
pantoprazole treatment and control groups in the probability of the primary outcome for 
pantoprazole randomization for all time points” will be tested against the alternative 
hypothesis H1;panto40 stating that “there is a difference between the two groups in the 
probability of the primary outcome for at least one time point”.
New Text:
Pantoprazole 40 mg od treatment group and pantoprazole placebo control group will be 
compared. The null hypothesis H0;panto40 stating that “there is no difference between the 
pantoprazole treatment and control groups in the probability of the outcome for pantoprazole 
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randomization for all time points” will be tested against the alternative hypothesis H1;panto40
stating that “there is a difference between the two groups in the probability of the outcome for 
at least one time point”.
Section 8.4.6 Subgroup Analyses
This section was changed as a result of Modification 4. 
Old Text:
Subgroup analyses for the primary efficacy and safety outcomes, and the primary outcome for 
pantoprazole randomization will be performed based on the same analysis sets and data 
scopes as in the main analyses of the study outcomes (Sections 8.4.1, 8.4.2, 8.4.3, 8.4.4 and 
8.4.5). 
New text:
Subgroup analyses for the primary efficacy and safety outcomes, and the outcome for 
pantoprazole randomization will be performed based on the same analysis sets and data 
scopes as in the main analyses of the study outcomes (Sections 8.4.1, 8.4.2, 8.4.3, 8.4.4 and 
8.4.5).
Section 8.6 Determination of sample size
This section was changed as a result of Modification 24. 
Old Text:
In this trial, it is planned to randomize at least 19,500 subjects and to continue the study until 
a minimum of 2,200 subjects experience an event for the primary efficacy outcome.
…
Assumptions for antithrombotic treatment randomization were:

3-arm study with 1:1:1 randomization

In total, a minimum of 19,500 subjects are randomized (at least 6,500 subjects per 
treatment group)

2-sided type I error level of 2.7% for each of the two comparisons to control the 
overall type I error level of 5%

Constant annual event rate in aspirin control group between 4.0% and 4.5%
…
The expected total number of observed events and the estimated power for each of the two 
comparisons are displayed in Table 8-1. 
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Table 8-1.  Events calculations
Assumed annual event 
rate in aspirin control 
group
Expected total study 
duration (years)
Estimated power for one 
comparison
Expected total number 
of events
4.0%
4.5
90.6%
1,923
5.0
93.6%
2,227
4.5%
4.5
93.6%
2,150
5.0
95.9%
2,488
Based on these estimates and the aim to detect a true relative risk reduction of 20% in each of 
the rivaroxaban arms with at least 90% power, it is planned to randomize at least 19,500
subjects and to continue the study until a minimum of 2,200 subjects experience an event for 
the primary efficacy outcome.  In this multi-center study, each center is expected to 
randomize at least 50 subjects.
Assumptions for pantoprazole randomization are: 

Annual event rate for major upper gastrointestinal complications (overt or occult 
bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction or perforation) 
in the range of 1.6% to 2.2%

At least 14,000 subjects included in the study are not proton pump inhibitor users and 
they are randomized to pantoprazole treatment and control groups in 1:1 ratio
…

Under these assumptions, the expected total number of major upper gastrointestinal 
complications is between 300 and 580, depending on the observed event rates and the 
total study duration. The estimated power for the detection of the true relative risk 
reduction of about 50% for major upper gastrointestinal complications for 
pantoprazole 40 mg od vs. pantoprazole placebo is close to 100% for all scenarios 
considered.
Sample size estimation was based on the method by Lakatos implemented in Power Analysis 
and Sample Size (PASS) software, version 11.0.7, and on a Statistical Analysis Software
(SAS) macro provided by J. Shih (1995).  In addition, simulations were performed to confirm 
that the Dunnett step-up testing procedure as described in Section 8.4.1 for the analysis of the 
primary efficacy outcome keeps the overall type I error level of 5%.  SAS calculations and 
simulations were performed using SAS software, version 9.2 (SAS Institute Inc, Cary, NC, 
USA).
New Text:
In this trial, it is planned to randomize at least 21,400 subjects and to continue the study until 
a minimum of 2,200 subjects experience an event for the primary efficacy outcome.
…
Assumptions for antithrombotic treatment randomization were:

3-arm study with 1:1:1 randomization
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
In total, a minimum of 21,400 subjects are randomized (approximately 7,134 subjects 
per treatment group)

2-sided type I error level of 2.7% for each of the two comparisons to control the 
overall type I error level of 5%

Constant annual event rate in aspirin control group between 3.0% and 4.0%
…
The expected total number of observed events and the estimated power for each of the two 
comparisons are displayed in Table 8-1. 
Table 8-1.  Events calculations
Assumed annual event 
rate in aspirin control 
group
Expected total study 
duration (years)
Estimated power for one 
comparison
Expected total number 
of events
3.0%
4.5
5.0
85.1%
89.2%
1,642
1,909
3.5%
4.5
90.2%
1,907
5.0
93.4%
2,215
4.0%
4.5
93.7%
2,171
5.0
96.0%
2,517 
Based on these estimates and the aim to detect a true relative risk reduction of 20% in each of 
the rivaroxaban arms with at least 90% power, it is planned to randomize at least 21,400
subjects and to continue the study until a minimum of 2,200 subjects experience an event for 
the primary efficacy outcome.  In this multi-center study, each center is expected to 
randomize at least 50 subjects.
Assumptions for pantoprazole randomization are: 

Annual event rate for major upper gastrointestinal complications (overt or occult 
bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction or perforation) 
in the range of 1.6% to 2.2%

At least 12,840 subjects included in the study are not proton pump inhibitor users and 
they are randomized to pantoprazole treatment and control groups in 1:1 ratio
…
Under these assumptions, the expected total number of major upper gastrointestinal 
complications is between 450 and 730, depending on the observed event rates and the total 
study duration. The estimated power for the detection of the true relative risk reduction of 
about 50% for major upper gastrointestinal complications for pantoprazole 40 mg od vs. 
pantoprazole placebo is close to 100% for all scenarios considered.
Sample size estimation was based on the method by Lakatos implemented in Power Analysis 
and Sample Size (PASS) software, version 11.0.7, and on a Statistical Analysis System (SAS) 
macro provided by J. Shih (1995).  In addition, simulations were performed to confirm that 
the Dunnett step-up testing procedure as described in Section 8.4.1 for the analysis of the 
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primary efficacy outcome keeps the overall type I error level of 5%.  SAS calculations and 
simulations were performed using SAS software, version 9.2 (SAS Institute Inc, Cary, NC, 
USA).
Section 11.3 Publication policy
This section was changed as a result of Modification 25. 
Old Text:
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. The study results will be reported irrespective of the outcome of the 
study.  The Operations Committee will decide on the authorship of all papers.  The main study 
results will be written by a writing group lead by members of the Operations Committee, and 
may include additional individuals who have made substantial and sustained contributions and 
will be on behalf of the whole study group.
New Text:
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. The study results will be reported irrespective of the outcome of the 
study.  The Operations Committee which will also serve as a Publication Committee, will 
decide on the authorship of all papers.  The main study results will be written by a writing 
group led by members of the Operations Committee, and may include additional individuals 
who have made substantial and sustained contributions and will be on behalf of the whole 
study group.
Section 12 References
This section was changed as a result of Modification 26. 
Old Text:
1. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, de SG et al. Executive 
summary: heart disease and stroke statistics--2010 update: a report from the American 
Heart Association. Circulation 2010 February 23;121(7):948-54.
2. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N et al. Heart disease and 
stroke statistics--2008 update: a report from the American Heart Association Statistics 
Committee and Stroke Statistics Subcommittee. Circulation 2008 January 29;117(4):e25-
146.
New Text:
1. Fact sheet: Cardiovascular diseases (CVDs): World Health Organization; 2013. Available 
from http://www.who.int/mediacentre/factsheets/fs317/en/
2. WHO. The global burden of disease: 2004 update. Geneva: World Health Organization; 
2008b.
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Section 14.1 COMPASS MIND Substudy
This section was changed as a result of Modifications 4 and 27. 
Old Text:
Design: A phase II trial seeking evidence of efficacy in which a convenience sample of 1500 
COMPASS participants over age 65 undergo will be invited to participate – 500 assigned to 
each treatment arm, but balanced for age, prior stroke, and hypertension.  Participants will 
undergo limited brain MRI sequences (Fluid Attenuated Inversion Recovery [FLAIR]), T-1 
and T-2 sequences at entry and near end-study coupled with assessment of function (SAGE), 
and cognition (MoCA, digit symbol substitution).  Recruitment will occur at COMPASS sites 
with access to high-quality (>1.5 Tesla) reasonably-priced MR imaging.  Images will be 
transmitted to the central MR imaging center via discs.  Two-stage central interpretation 
blinded to treatment will be carried-out, with all incident covert infarcts confirmed by a 
second independent interpreter.  The 
 has experience with collection and analysis of 
brain MRIs performed in substudies of several randomized trials:  AVERROES, PURE, 
APOLLO, and (planned) TIPS 3 MIND.
Subjects will have DNA collected at baseline and blood collected at baseline and at the 1 
month visit.  The samples will be processed, and aliquots will be shipped for long-term 
storage in liquid nitrogen at the coordinating center in 
 Canada.  Blood 
samples will be processed and stored in such a way to allow future analysis of these aliquots 
for selected biomarkers, some of which have been observed in other studies to be predictors of 
stroke, and others which have a plausible association with cardiovascular outcomes.  Detailed 
information concerning blood collection, processing, storage, and shipping is provided in the 
Manual of Operations.
Implications:  The COMPASS MRI substudy would be the first randomized trial of an 
anticoagulant to prevent covert brain infarcts in patients with atherosclerotic vascular disease. 
Evidence that rivaroxaban reduces covert stroke better than or in addition to aspirin would 
have an immense potential public health impact.  Within COMPASS trial, the MRI substudy 
offers an opportunity to develop evidence of rivaroxaban efficacy for a separate clinical 
indication applicable to a burgeoning population.
New Text:
Design: A phase II trial seeking evidence of efficacy in which a convenience sample of 1500 
COMPASS participants over age 65 undergo will be invited to participate – 500 assigned to 
each treatment arm, but balanced for age, prior stroke, and hypertension.  Participants will 
undergo limited brain MRI sequences (Fluid Attenuated Inversion Recovery [FLAIR]), T-1, 
T-2, and T-2* GRE sequences at entry and near end-study coupled with assessment of 
function (SAGE), and cognition (MoCA, digit symbol substitution).  Recruitment will occur 
at COMPASS sites with access to high-quality (>1.0 Tesla) reasonably-priced MR imaging.  
Images will be transmitted to the central MR imaging center via discs.  Two-stage central 
interpretation blinded to treatment will be carried-out, with all incident covert infarcts 
confirmed by a second independent interpreter.  The 
 has experience with collection and 
analysis of brain MRIs performed in substudies of several randomized trials:  AVERROES, 
PURE, APOLLO, and (planned) TIPS 3 MIND.
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Subjects will have DNA collected at baseline and blood collected at baseline and at the 1 
month visit. DNA and blood collections are optional (Section 7.1.1, 7.1.2.3 and 7.1.2.4.1).
The samples will be processed, and aliquots will be shipped for long-term storage in liquid 
nitrogen at the coordinating center in 
 Canada.  Blood samples will be 
processed and stored in such a way to allow future analysis of these aliquots for selected 
biomarkers, some of which have been observed in other studies to be predictors of stroke, and 
others which have a plausible association with cardiovascular outcomes.  Detailed information 
concerning blood collection, processing, storage, and ship
ping is provided in the Manual of Operations.
Implications:  The COMPASS MRI substudy is the first randomized trial of an anticoagulant 
to prevent covert brain infarcts in patients with atherosclerotic vascular disease. Evidence that 
rivaroxaban reduces covert stroke better than or in addition to aspirin would have an immense 
potential public health impact.  Within COMPASS trial, the MRI substudy offers an 
opportunity to develop evidence of rivaroxaban efficacy for a separate clinical indication 
applicable to a burgeoning population.
13.2
Amendment 8
13.2.1
Overview changes to the study
Editorial, administrative, and typographical corrections were made that do not affect the 
overall study concept.  These changes are not described in this section. 
The following changes are introduced in Protocol Version 3.0.
Modification 1: Secondary and tertiary efficacy outcomes were revised.  
Rationale:  The secondary outcomes have been modified to include 2 composites of major 
thrombotic events, including new outcome components. These new composites were chosen 
to represent outcomes deemed to be most sensitive to the experimental antithrombotic 
treatment under investigation.
Sections affected:

Synopsis: Study objectives

Section 2  Study objectives

Section 7.3 Efficacy

Section 7.5.3.1 Protocol-specific exceptions to SAE reporting

Section 8.3.2 Secondary efficacy outcomes

Section 8.3.3 Tertiary and other efficacy outcomes
Modification 2: The multiple testing strategy was revised to ensure the control of the 
familywise type I error for both testing of primary and secondary efficacy variables.   
Rationale:  Originally it had been planned to use the step-up Dunnett procedure for the testing 
of the 2 primary outcomes to control the overall type I error level of 5% and to test secondary 
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outcomes at the 5% level without any adjustment for multiplicity.  Triggered by the FDA 
advice letter received in AUG 2014,  this decision was revised to make use of the opportunity
of a potential label claim for secondary outcomes if convincing results will be obtained.  Since 
the Dunnett step-up test is not separable, the former testing strategy was replaced by a mixture 
gatekeeping procedure based on the Hochberg test with a truncation fraction of γ = 0.9, which 
controls the familywise error rate at the pre-assigned level of significance α = 5% in the strong 
sense.
Sections affected:

Section 8.4 Statistical and analytical plans

Section 8.4.1 Analysis of the primary efficacy outcome

Section 8.4.2 Analysis of the secondary efficacy outcomes
Modification 3: Interim analysis revised.   
Rationale:  The statistical analysis plan for the interim analysis was corrected according to the 
advice received by the FDA in the letter received in AUG 2014. The description for the 
analysis in the case where only 1 of the 2 interventional arms is continued after an interim 
analysis was updated. 
Section affected:

8.5 Planned interim analyses
Modification 4: The number of subjects in the trial has been increased.
Rationale:  During the first 2 years after randomization of the first subject, the observed 
cumulated overall annual incidence was at the lower end of the projected range of 3.0% to 
4.0%. This led to the decision to continue enrollment and to thereby roughly maintain the 
study duration in the originally planned range of 4.5 to 5 years.
Sections affected:

Synopsis: Number of subjects

Section 4.1 Design overview

Section 5 Study population

Section 8.6 Determination of sample size
Modification 5:  Emphasis was made that all subjects, including those who experience a 
primary study outcome, need to be followed to the scheduled end of the study.
Rationale:  Some investigators are under the impression that subjects who experience MI or 
stroke no longer need to be followed up because they have already contributed to the study 
outcomes. This is not the case; all outcomes need to be collected until the end of the study. 
Section affected: 

Section 5.2  Discontinuation of subjects from study treatment
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Modification 6: Clarification was added regarding the start of interim study 
rivaroxaban/rivaroxaban placebo and the continued use of study aspirin/placebo.
Rationale:  The protocol appeared to mandate the use of interim study rivaroxaban/
rivaroxaban placebo in subjects who were treated with long-term dual antiplatelet therapy.  
This was never the intent; it is optional for investigators to commence subjects on interim 
study rivaroxaban/rivaroxaban placebo. This change to the protocol clarifies that it is optional.  
Elsewhere in the protocol it is clearly indicated that study aspirin/placebo can be continued in 
subjects who are treated with dual antiplatelet therapy. This clarification has now also been 
included in this section.   
Section affected:

Section 6.4.2.3  Guidance for the treatment of subjects who develop an acute coronary 
syndrome and those who require percutaneous coronary intervention with stenting
Modification 7: Minor clarifications were made.
Rationale:  Minor clarifications were made that do not affect the overall study concept.
Sections affected:

Section 3.1 Study committees

Section 4.3.1  Overall design rationale

Section 6.3  Treatment assignment
Modification 8: The reference to a lack of an antidote for rivaroxaban was removed.
Rationale:  A provision has been made for the future availability of a specific reversal agent 
for rivaroxaban.
Sections affected:

Section 6.4.2.4 Guidance for the treatment of subjects who overdose on study 
rivaroxaban/rivaroxaban placebo

Section 6.4.2.5 Guidance for the treatment of subjects who experience a major bleed
Modification 9: Text regarding post-study therapy was revised.
Rationale:  At the beginning of the study, subjects are transitioned from non-study aspirin to 
experimental study treatment. At the end of the study they should be transitioned back to non-
study aspirin.  Other antithrombotic therapies are not approved as alternatives to aspirin and 
reference to their use at the end of the study is therefore being deleted.
Section affected:

Section 6.8  Post-study therapy
Modification 10:  Text regarding the concomitant use of aspirin/aspirin placebo was revised.
Rationale:  The use of study aspirin/aspirin placebo in subjects who are treated with non-study 
aspirin or dual antiplatelet therapy is optional. As written in the previous version of the 
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protocol, the implication was that this was mandatory but it has been clarified that it is 
optional. Also, study aspirin/aspirin placebo may be continued irrespective of the need for 
other antithrombotic therapies; contrary to what was written in Section 6.9.1, aspirin/aspirin 
placebo does not have to be discontinued.  
Sections affected:

Section 6.9  Prior and concomitant therapy

Section 6.9.1  Combined CYP 3A4 and p-glycoprotein inhibitors and CYP 3A4 
inducers  
Modification 11: Clarification was added regarding the reasons for planned 
hospitalizations/procedures and when they should be considered (S)AEs
Rationale:  This revision reminds investigators that hospitalization planned prior to enrollment 
in the COMPASS trial should not be considered a SAE.  This is not a change to the protocol; 
previously planned hospitalizations were never deemed to be SAEs.
Section affected:

Section 7.5.1  E6 Definition of (serious) adverse event
Modification 12:  Text was updated with revised data/results from newly published studies.
Rationale:  To provide the most recent data.
Sections affected:

Section 1.2.1 Rivaroxaban

Section 1.2.2  Aspirin and anticoagulants

Section 1.3  Benefit-risk assessment

Section 4.3.1 Overall design rationale

Section 7.5.3.1  Protocol-specific exceptions to SAE reporting 

Section 12 Reference list
Modification 13:  Clarification was made when the questionnaires should be completed.
Rationale:  The questionnaires are being used to measure the impact of study treatments on 
function and quality of life. This revision is aimed at ensuring that the questionnaires are also 
completed following major outcomes.  This was inadvertently omitted from previous versions 
of the protocol.
Sections affected:

Section 4.1  Design overview

Section 7.1.1  Tabulated overview

Section 7.2.3  Other baseline characteristics
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Modification 14:  For subjects who are randomized after CABG surgery, clarification was 
made as to when the first dose of study drug will be administered.
Rationale:  The goal is to avoid use of study antithrombotic therapies within 12 hours of 
administration of non-study anticoagulants. The previous version of the protocol indicated 
that subjects should not be randomized until at least 12 hours after administration of any 
anticoagulant. After CABG surgery, subjects commonly receive a morning dose of 
anticoagulant prophylaxis and are then discharged later in the day. By not allowing  
randomization within 12 hours of anticoagulant, these subjects could not be randomized prior 
to discharge. With this revision they can still be randomized before discharge but they will 
still not receive the first dose of study anticoagulant until at least 12 hours after last 
administration of any anticoagulant.
Sections affected:

Section 4.1.1  Subjects randomized after CABG surgery

Section 6.4  Dosage and administration

Section 6.4.2.2 Guidance for the treatment of subjects who require coronary artery 
bypass graft surgery
Modification 15:  Guidance for the management of subjects who develop stroke and who are 
being considered for reperfusion therapy was added.
Rationale:  Investigators have asked for guidance about the management of subjects who 
develop an ischemic stroke and who are being considered for reperfusion therapy.  In response 
to these requests, a section was added to the protocol as the topic was not addressed in the 
previous version.
New section:

Section 6.4.2.6  Guidance for the treatment of subjects who develop a stroke and who 
are being considered for reperfusion therapy 
Modification 16:  An additional subgroup was added to those that will be examined:  “Any 
prior CABG, further subdivided as CABG days 4-7 before randomization and other prior 
CABG”
Rationale: Approximately one-quarter of all subjects enrolled in COMPASS have had a prior 
CABG.  We wish to separately examine outcomes in subjects with prior CABG and those 
who have not had prior CABG, to explore whether the effect of treatment is consistent in 
these subgroups. Similarly, within the CABG population we propose to explore the 
consistency of the treatment effect in those who were randomized early post-CABG and those 
who were randomized later post-CABG.  
Section affected:

Section  8.3.6  Subgroup variables
Modification 17:  Revisions to the description and procedures of the COMPASS-MIND 
substudy were made.  
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Rationale:
a) It had been stated that the substudy would examine the effect of therapies on asymptomatic 
cerebral ischemia and bleeds. The reference to “asymptomatic” cerebral ischemia is 
inaccurate. These episodes of cerebral ischemia are not asymptomatic; rather, the symptoms 
are not attributed to the cerebral ischemia because the event is not recognized. These episodes 
of cerebral ischemia are thus better described as “covert.”  
b) The substudy does not examine the effect of antithrombotic therapies on all bleeding 
events, just microbleeds.  To avoid confusion the reference to bleeding assessment has been 
omitted.
c) As originally designed, the COMPASS MIND substudy was restricted to subjects over the 
age of 65 years because older subjects are more likely to have covert cerebral ischemia than 
those who are younger. The age cut off is, however, purely arbitrary. In order to simplify 
recruitment and increase generalizability of the results the age restriction has been removed.
d) The original timeframe for obtaining an MRI scan was within 3 months of randomization.
This window is being expanded for the following reasons. First, at many sites the COMPASS 
MIND study is not approved until several months after the main study, thereby making some 
subjects already enrolled in the study at participating sites ineligible for the substudy. Second, 
there are sometimes delays in obtaining the MRI scan because of limited access to a scanner, 
and this has prevented some consented subjects from obtaining a scan within 3 months of 
randomization. While it is desirable to perform the scan as early as possible in order to 
maximize the period of exposure to study drug between scans, the opportunity to obtain a later 
scan will help to boost recruitment and this gain will outweigh any possible loss of statistical 
power resulting from a shorter time between the initial and the final scan. The revised 
protocol now indicates that MRI scan should be performed within 3 months or as soon as 
possible thereafter and at the end of the study.  
Sections affected:

Section 2  Study objectives

Section 7.1.2.3  Randomization visit (Day 0 ± 5 days)

Section 14.1  COMPASS MIND substudy
Modification 18:  Text regarding the timing of CT angiograms for COMPASS CABG 
subjects has been added.  Also, in the event that subjects are unable to attend a study visit in 
person, follow-up by telephone is acceptable.
Rationale:  To provide some flexibility.
Sections affected:

Section 4.1.1 Subjects randomized after CABG surgery

Section 7.1.1 Tabulated overview

Section 7.1.2.4.1  Routine follow-up visits (Visits 3, 5, and 7-15+)

Section 9.3  Data processing
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Modification 19:  Text was revised to allow greater flexibility in the event a reduction of dose 
of study treatment is necessary.
Rationale:  To provide more flexibility.
Section affected:

Section 6.4.1  Dose modifications
13.2.2
Changes to protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment and “new text” displays the updated text.
Deletions are crossed out and additions are underlined. Corrections of typing errors or 
editorial changes are not highlighted in this amendment.
Synopsis – Study objectives
This section was changed as a result of Modification 1.
Old Text:
Study objective(s)
Secondary objectives for rivaroxaban randomization

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 
mg od and rivaroxaban 5 mg bid alone reduces the risk of the 
composite of major thrombotic events (myocardial infarction, stroke, 
cardiovascular death, revascularization, and venous 
thromboembolism) and cardiovascular hospitalization compared with 
aspirin 100 mg od in subjects with CAD or PAD
New Text:
Study objectives
Secondary objectives for rivaroxaban randomization

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 
100 mg od and rivaroxaban 5 mg bid alone reduces the risk of the 
composite of major thrombotic events:  (1) coronary heart disease 
death, myocardial infarction, ischemic stroke, acute limb ischemia; 
(2) cardiovascular death, myocardial infarction, ischemic stroke, 
acute limb ischemia compared with aspirin 100 mg od in subjects 
with CAD or PAD
Synopsis – Number of subjects
This section was changed as a result of Modification 4.
Old Text:
Number of subjects
Enrolled = approximately 23,500; randomized = 21,400 in approximately 30
countries worldwide
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Approximately 23,500 subjects will be enrolled; 21,500 will be admitted to the 
run-in period and 2000 subjects will undergo coronary artery bypass graft but 
no run-in.  A non-compliance rate of 10% is anticipated for those subjects in 
the run-in period; thus, approximately  21,400 subjects will be randomized 
(approximately 19,400 subjects who completed run-in and 2000 who 
underwent coronary artery bypass graft without run-in) in approximately 30 
countries worldwide.
New Text:
Number of subjects
Enrolled = approximately 29,940; randomized = approximately 27,400 in 
approximately 33 countries worldwide
Approximately 29,940 subjects will be enrolled; approximately 28,300 will be 
admitted to the run-in period and 2000 subjects will undergo coronary artery 
bypass graft but no run-in.  A non-compliance rate of 10% is anticipated for 
those subjects in the run-in period; thus, approximately  27,400 subjects will 
be randomized (of which approximately 2000 subjects who underwent 
coronary artery bypass graft would be randomized without run-in) in 
approximately 33 countries worldwide.
Section 1.2.1 Rivaroxaban
This section was changed as a result of Modification 12. 
Old Text:
Rivaroxaban has been tested in randomized controlled trials involving more than 70,000
patients and has been used by millions of patients worldwide.  
New Text:
Rivaroxaban has been tested in randomized controlled trials involving more than 80,000
patients and has been used by millions of patients worldwide.  
Section 1.2.2  Aspirin and anticoagulants
This section was changed as a result of Modification 12.
Added Text to end of 5th paragraph:
The PEGASUS trial demonstrated that 33 months of treatment with ticagrelor (90 mg twice-
daily or 60 mg twice-daily) compared with placebo reduced the risk of cardiovascular death, 
myocardial infarction or stroke by 15-16% (ticagrelor 90 mg: 7.85%, ticagrelor 60 mg: 7.77%, 
placebo 9.04%; p=0.008 and p=0.004, respectively) in patients with a history of myocardial 
infarction 1 to 3 years earlier. This came at the cost of a 2-3 fold increase in major bleeding 
(ticagrelor 90 mg: 2.60%, ticagrelor 60 mg: 2.30%, placebo 1.06%; p<0.01 for each dose vs. 
placebo), and there was no reduction in total mortality (ticagrelor 90 mg: 5.15%, ticagrelor 60 
mg: 4.69%, placebo 5.16%; p=0.99 and p=0.14, respectively).
The DAPT trial randomized 9,961 patients with a history of coronary stenting with a drug 
eluting stent who had completed 12 months of dual antiplatelet therapy with a thienopyridine 
and aspirin to receive continuing clopidogrel 75 mg once daily or prasugrel 10 mg once daily 
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or placebo for another 18 months. All patients continued receiving aspirin. Continuing 
treatment with a thienopyridine as compared with placebo reduced the rates of stent 
thrombosis by 71% (0.4% vs. 1.4%, p<0.001) and the composite, death, MI or stroke by 29% 
(4.3% vs. 5.9%, p<0.001) but at the cost of excess moderate or severe bleeding (2.5% vs. 
1.6%, p=0.001) and a borderline significant 36% increase in all-cause death from any cause 
(2.0% vs. 1.5%, p=0.05).
Excess mortality seen with extended dual antiplatelet therapy in the DAPT trial was 
confirmed in a subsequent meta-analysis of 10 randomized trials including 31,666 patients 
who had undergone coronary artery stenting comparing different durations of dual antiplatelet 
therapy. Shorter duration dual antiplatelet therapy was associated with an 18% reduction in 
all-cause mortality (HR 0.82, 95% CI 0.69-0.98; p=0.02), predominantly due lower non-
cardiac mortality (HR 0.67, 0.51-0.89; p=0.006), with similar cardiac mortality (HR 0.93, 
0.73-1.17; p=0.52). Shorter duration dual antiplatelet therapy was also associated with a lower 
risk of major bleeding (HR 0.58, 0.47-0.72; p<0.001), but a higher risk of myocardial 
infarction (HR 1.51, 1.28-1.77; p<0.001) and stent thrombosis (HR 2.04, 1.48-2.80; p<0.001).
Section 1.3  Benefit-risk assessment
This section was changed as a result of Modification 12.
Old Text:
In the ROCKET-AF trial, the 20 mg od dose was associated with an annualized rate of 
International Society on Thrombosis and Haemostasis (ISTH) major and non-major 
gastrointestinal (GI) combined bleeding rate of 2.23/100 patient years. (Sponsor data on file)
New Text:
In the ROCKET-AF trial, the 20 mg od dose was associated with an annualized rate of 
International Society on Thrombosis and Haemostasis (ISTH) major and non-major 
gastrointestinal (GI) combined bleeding rate of 3.2/100 patient years.
Section 2  Study objectives
This section was changed as a result of Modifications 1 and 17. 
Old Text (first secondary objective):

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and 
rivaroxaban 5 mg bid alone reduces the risk of the composite of major thrombotic 
events (myocardial infarction, stroke, cardiovascular death, revascularization, and 
venous thromboembolism) and cardiovascular hospitalization compared with aspirin 
100 mg od in subjects with CAD or PAD
Old Text (Substudy objectives):
The COMPASS-MIND substudy will examine the effect of the antithrombotic therapies being 
tested in COMPASS on asymptomatic cerebral ischemia and bleeds, thereby providing 
additional information about mechanisms of disease and treatment benefits.  
New Text:
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
To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and 
rivaroxaban 5 mg bid alone reduces the risk of the composite of major thrombotic 
events (coronary heart disease death, myocardial infarction, ischemic stroke, acute 
limb ischemia; cardiovascular death, myocardial infarction, ischemic stroke, acute 
limb ischemia) compared with aspirin 100 mg od in subjects with CAD or PAD
The COMPASS-MIND substudy will examine the effect of the antithrombotic therapies being 
tested in COMPASS on covert cerebral ischemia, thereby providing additional information 
about mechanisms of disease and treatment benefits.  
Section 3.1  Study committees
This section was changed as a result of Modification 17.
Old Text:
An Operations Committee will be responsible for ensuring that study execution and 
management of the study are of the highest quality.  This committee will determine its own 
guidelines and approve the criteria and guidelines of the other committees.  The operations 
committee will convene regularly to discuss and report on the ongoing supervision of the 
study.  The committee will consist of the study chair and principal investigators, project 
leader, senior study coordinator, 2-3 sponsor representatives, and 3-4 National Leaders (NL). 
A Steering Committee comprising members of the Operations Committee, university-based 
and sponsor-based scientists with clinical and methodological expertise, and national leaders 
from each country, will be responsible for producing and conducting a scientifically sound 
study design and ensuring accurate reporting of the study.  The steering committee will meet 
periodically to address and resolve scientific and practical issues encountered during the 
study. 
An Events Committee consisting of members with clinical and methodological expertise will 
oversee the process of event verification. The process of event verification is detailed in the 
Manual of Operations. 
New Text:
An Operations Committee will be responsible for ensuring that study execution and 
management of the study are of the highest quality.  This committee is a subcommittee of the 
Steering Committee and will convene regularly to discuss and report on the ongoing 
supervision of the study.  The committee will consist of the study chair and principal 
investigators, project leader, senior study coordinator, 2-3 sponsor representatives, and 3-4 
National Leaders (NL). 
A Steering Committee comprising members of the Operations Committee, university-based 
and sponsor-based scientists with clinical and methodological expertise, and national leaders 
from each country, has overall responsibility for the study. The Steering Committee will be 
responsible for producing and conducting a scientifically sound study design and ensuring 
accurate reporting of the study. The steering committee will meet periodically to address and 
resolve scientific and practical issues encountered during the study. 
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An Events Committee consisting of members with clinical and methodological expertise will 
oversee the process of event adjudication. The process of event adjudication is detailed in the 
Event Adjudication Plan.  
Section 4.1  Design overview
This section was changed as a result of Modifications 4 and 13.
Old Text:
This Phase 3, event-driven (at least 2,200 primary efficacy outcome events), randomized 
controlled trial will have a 3 x 2 partial factorial design and will randomize at least 21,400
subjects who will receive treatment for an expected average duration of 3 to 4 years.
….
Subjects will be seen in the clinic at 1 month and at 6 months after randomization and at 6 
month intervals thereafter in order to collect information on treatment adherence, treatment 
interruption, outcomes, and adverse events (AEs).  Validated questionnaires will be 
administered before or at the time of randomization, or as soon as possible thereafter, and at 
Month 24 to collect data on subject health and quality of life (Standard Assessment of Global-
Activities in the Elderly [SAGE], Montreal Cognitive Assessment [MoCA], DSS [Digital 
Symbol Substitution], European Quality of Life-5 Dimensions [EQ-5D], The Interheart Diet 
Questionnaire, and The International Physical Activity Questionnaire).  All subjects will be 
followed for the duration of the study, irrespective of whether they are receiving study 
treatments or whether an event has occurred. Additional follow-up visits will be conducted by 
telephone at Months 3 and 9.  The Final Follow-up Visit will occur as soon as possible after 
the required pre-specified number of subjects experience a primary efficacy outcome event for 
the antithrombotic randomization (close out is expected to occur over a period of about 2
months).  A final washout period visit (End of Washout Telephone Visit) will be conducted 
by telephone (performed 30 days after the Final Follow-up Visit) to collect information on 
outcomes and protocol specific adverse events.  Adverse events will continue to be collected 
up to 30 days post study drug treatment.  Bayer Global Pharmacovigilance will continue to 
follow the reported AEs until stabilized or resolved.
New Text:
This Phase 3, event-driven (at least 2,200 primary efficacy outcome events), randomized 
controlled trial will have a 3 x 2 partial factorial design and will randomize at least 27,400
subjects who will receive treatment for an expected average duration of 3 to 4 years.
….
Subjects will be seen in the clinic at 1 month and at 6 months after randomization and at 6 
month intervals thereafter in order to collect information on treatment adherence, treatment 
interruption, outcomes, and adverse events (AEs).  Validated questionnaires (Standard 
Assessment of Global-Activities in the Elderly [SAGE], Montreal Cognitive Assessment 
[MoCA], Digital Symbol Substitution [DSS], European Quality of Life-5 Dimensions [EQ-
5D]) will be administered at screening/run-in or randomization, or as soon as possible 
thereafter, as well as at Month 24 and at the Final Follow-Up visit to collect data on subject 
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health and quality of life.  The SAGE, MoCA, DSS, and EQ-5D will also be administered at 
the next study clinic visit after each outcome event.  The Interheart Diet Questionnaire and the 
International Physical Activity Questionnaire will be administered at screening/run-in or 
randomization, or as soon as possible thereafter, and at Month 24.  All subjects will be 
followed for the duration of the study, irrespective of whether they are receiving study 
treatments or whether an event has occurred. Additional follow-up visits will be conducted by 
telephone at Months 3 and 9.  The Final Follow-up Visit will occur as soon as possible after 
the required pre-specified number of subjects experience a primary efficacy outcome event for 
the antithrombotic randomization (close out is expected to occur over a period of about 3
months).  A final washout period visit (End of Washout Telephone Visit) will be conducted 
by telephone (performed 30 days after the Final Follow-up Visit) to collect information on 
outcomes and protocol specific adverse events.  Adverse events will continue to be collected 
up to 30 days post study drug treatment.  Bayer Global Pharmacovigilance will continue to 
follow the reported AEs until stabilized or resolved.
Section 4.1.1  Subjects randomized after CABG surgery
This section was changed as a result of Modifications 14 and 18.
Old Text:
Subjects randomized Day 4-7 after CABG surgery will undergo the same screening, follow-
up, and washout as other COMPASS trial subjects but not run-in. Subjects are to sign 
informed consent before or after the surgery.15  Randomization will occur between Day 4-7 
15 after surgery, at least 24 hours following the removal of chest tubes and at least 12 hours 
after last administration of any anticoagulant (including DVT prophylaxis) (Section 7.1.1 
Tabulated overview).
Subjects randomized Day 4-7 after CABG surgery will undergo computed tomography (CT)  
angiography at 1 year as part of the study protocol to assess graft patency unless they have a 
specific contraindication for CT angiography (e.g., contrast allergy, estimated glomerular 
filtration rate <30 ml/min). In the event the subject undergoes an invasive coronary 
angiography at 1 year post CABG for any reason, a CT angiogram may not be required.
New Text:
Subjects randomized Day 4-7  after CABG surgery will undergo the same screening, follow-
up, and washout as other COMPASS trial subjects but not run-in. Subjects are to sign 
informed consent before or after the surgery.15  Randomization will occur between Day 4-7 
15 after surgery, at least 24 hours following the removal of chest tubes.  The first dose of 
study drug should not be administered until at least 12 hours after last administration of any 
anticoagulant (including DVT prophylaxis) (Section 7.1.1 Tabulated overview).
Subjects randomized Day 4-7 after CABG surgery will undergo computed tomography (CT)  
angiography at 1 year or later as part of the study protocol to assess graft patency unless they 
have a specific contraindication for CT angiography (e.g., contrast allergy, estimated 
glomerular filtration rate <30 ml/min). In the event the subject undergoes an invasive 
coronary angiography at approximately 1 year or later post CABG for any reason, a CT 
angiogram may not be required.
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Section 4.3.1 Overall design rationale
This section was changed as a result of Modifications 7 and 12.
Added Text (5th paragraph) :
…In most cases, the benefit of the experimental treatment has either been of insufficient 
magnitude to warrant a switch in treatment (e.g., clopidogrel, prasugrel) or has been 
accompanied by a substantial excess of bleeding (e.g., vorapaxar, ticagrelor, warfarin).
Old Text (6th paragraph):
The use of aspirin-alone antiplatelet therapy (as provided as a comparator treatment in Arm C)
for atherosclerotic CAD and PAD is well established. As such, most patients will be 
candidates for aspirin monotherapy.  This is in line with current practice guidelines and the 
current prescribing information for secondary prevention.   The dose of aspirin being tested in 
COMPASS is 100 mg/d.  
New Text (6th paragraph):
The use of aspirin-alone antiplatelet therapy for atherosclerotic CAD and PAD is widely 
accepted. As such, most patients will be candidates for aspirin monotherapy.  This is in line 
with current practice guidelines and the current prescribing information for secondary 
prevention.   The dose of aspirin being tested in COMPASS is 100 mg/d.  
Section 5 Study population
This section was changed as a result of Modification 4.
Old Text: 
Approximately 23,500 eligible subjects will be admitted to the run-in period and an additional 
2000 will be enrolled post CABG and without run-in.  Approximately 10% of run-in subjects 
are expected to either be non-compliant with treatment or to decline further interest in 
participating; thus, the study will randomize approximately 21,400 men and women with 
objectively confirmed CAD or PAD from approximately 30 countries worldwide.
New Text: 
Approximately 28,300 eligible subjects will be admitted to the run-in period and an additional 
2000 will be enrolled post CABG and without run-in.  Approximately 10% of run-in subjects 
are expected to either be non-compliant with treatment or to decline further interest in 
participating; thus, the study will randomize approximately 27,400 men and women with 
objectively confirmed CAD or PAD from approximately 33 countries worldwide.
Section 5.2 Discontinuation of subjects from study treatment
This section was changed as a result of Modification 5.
Old Text: 
In all cases, including the subjects with the study outcome, every effort must be made to 
continue to follow the subject at regular study visits.
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New Text: 
In all cases, including the subjects who have had any of the primary study outcome 
events, every effort must be made to continue to follow the subject at regular study 
visits.
Section 6.3  Treatment assignment
This section was changed as a result of Modification 7.
Old Text:
For subjects who successfully complete the run-in period, the investigator or delegate will 
access the 
 randomization and drug management system to confirm eligibility and that 
run-in rivaroxaban placebo bid and aspirin od have been stopped and to obtain the randomized 
treatment allocation. 
New Text:
For subjects who successfully complete the run-in period, the investigator or delegate will 
access the 
 randomization and drug management system to confirm eligibility and 
compliance to run-in rivaroxaban placebo bid and aspirin od and to obtain the randomized 
treatment allocation. 
Section 6.4  Dosage and administration
This section was changed as a result of Modification 14.
Added Text:
….The first doses of study drug should be administered on the day of randomization, or at 
least 12 hours after the last dose of antithrombotic medication if being randomized post-
CABG.   
Section 6.4.1  Dose modifications
This section was changed as a result of Modification 19.
Old Text:
If there is concern that the subject may be intolerant of study treatments or if the subject is 
reluctant to take the full dose of study treatments, a possible approach to restarting study 
medications is to reduce the frequency of dosing to once-daily or alternate-daily.
New Text:
If there is concern that the subject may be intolerant of study treatments or if the subject is 
reluctant to take the full dose of study treatments, a possible approach to restarting study 
medications is to reduce the frequency of dosing (eg, to once-daily or alternate-daily).
Section 6.4.2.2  Guidance for the treatment of subjects who require coronary artery 
bypass graft surgery
This section was changed as a result of Modification 14.
Old Text:
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…Randomization should only be performed between Day 4-7 post-CABG and at least 24 
hours following the removal of chest tubes and at least 12 hours after last administration of 
any anticoagulant (including DVT prophylaxis).
New Text:
…Randomization should only be performed between Day 4-7 post-CABG and at least 24 
hours following the removal of chest tubes. Study drug should not be administered until at 
least 12 hours after last administration of any anticoagulant (including DVT prophylaxis).
Section 6.4.2.3 Guidance for the treatment of subjects who develop an acute coronary 
syndrome and those who require percutaneous coronary intervention with stenting
This section was changed as a result of Modification 6.
Old Text:
Subjects who remain on long term dual antiplatelet therapy should commence “interim study 
rivaroxaban/rivaroxaban placebo” once any non-study anticoagulant therapy is stopped.  
New Text:
Subjects who remain on long term dual antiplatelet therapy may commence “interim study 
rivaroxaban/rivaroxaban placebo” once any non-study anticoagulant therapy is stopped.  
Study aspirin/placebo may be continued.
Section 6.4.2.4 Guidance for the treatment of subjects who overdose on study 
rivaroxaban/rivaroxaban placebo
This section was changed as a result of Modification 8.
Old Text:
A specific antidote for rivaroxaban is not available.  If rivaroxaban overdose is suspected, the 
use of activated charcoal up to 8 hours after overdose to reduce absorption may be considered.  
Due to its low solubility, rivaroxaban absorption plateaus at doses of 50 mg and above, thus 
limiting exposure in the majority of subjects.  Gastrointestinal absorption of rivaroxaban is 
reduced in subjects exposed to high oral doses and thus the anticoagulant effect of an 
overdose of rivaroxaban is expected to be limited. 
New Text:
If rivaroxaban overdose is suspected, the use of activated charcoal up to 8 hours after 
overdose to reduce absorption may be considered.  Due to its low solubility, rivaroxaban 
absorption plateaus at doses of 50 mg and above, thus limiting exposure in the majority of 
subjects.  Gastrointestinal absorption of rivaroxaban is reduced in subjects exposed to high 
oral doses and thus the anticoagulant effect of an overdose of rivaroxaban is expected to be 
limited.  If available, consideration may be given to the use of a specific reversal agent.
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Section 6.4.2.5 Guidance for the treatment of subjects who experience a major bleed
This section was changed as a result of Modification 8.
Old Text:
The management of bleeding in subjects receiving study rivaroxaban/rivaroxaban placebo is 
supportive, as rivaroxaban does not have a specific antidote.  Temporary discontinuation of 
rivaroxaban is expected to be sufficient to control bleeding in most cases because the drug 
half-life is only 5-13 hours.  Local measures should be applied if needed to control bleeding 
(e.g., local pressure, endoscopy and injection of a bleeding vessel, embolization) and 
intravenous fluids and blood transfusion support should be provided as indicated.  In the rare 
case of life-threatening bleeding, the investigator may consider obtaining advice from a 
hematologist.  Animal studies suggest that both prothrombin complex concentrates and 
recombinant factor VIIa partially restore hemostasis following treatment with factor Xa 
inhibitors such as rivaroxaban and a randomized trial involving healthy subjects treated with 
rivaroxaban has demonstrated that prothrombin concentrates reverse prolongation of the 
prothrombin time.(30)  Rivaroxaban cannot be dialyzed as it is highly protein bound.  
New Text:
Temporary discontinuation of rivaroxaban is expected to be sufficient to control bleeding in 
most cases because the drug half-life is only 5-13 hours.  Local measures should be applied if 
needed to control bleeding (e.g., local pressure, endoscopy and injection of a bleeding vessel, 
embolization) and intravenous fluids and blood transfusion support should be provided as 
indicated.  In the rare case of life-threatening bleeding, the investigator may consider 
obtaining advice from a hematologist.  Animal studies suggest that both prothrombin complex 
concentrates and recombinant factor VIIa partially restore hemostasis following treatment 
with factor Xa inhibitors such as rivaroxaban and a randomized trial involving healthy 
subjects treated with rivaroxaban has demonstrated that prothrombin concentrates reverse 
prolongation of the prothrombin time.(30)  Rivaroxaban cannot be dialyzed as it is highly 
protein bound.  If available, consideration may be given to the use of a specific reversal agent.
Section 6.4.2.6 Guidance for the treatment of subjects who develop a stroke and who are 
being considered for reperfusion therapy (Section added)
This section was added as a result of Modification 15.
Added Text:
The decision to use reperfusion therapies (including intravenous, intra-arterial thrombolysis,
or mechanical endovascular approaches) in acute ischemic stroke should follow local practice, 
experience, and guidelines. At present there are limited data to guide treatment in this setting 
in subjects taking rivaroxaban. The following guidance is intended to aid clinical decision 
making in this setting. 
At or around the time of the peak drug levels (we suggest in the first 6 hours after a dose), 
clinicians may choose to unblind and to avoid thrombolysis if the subject is taking 
rivaroxaban. Alternatively, if it is possible to obtain a rivaroxaban anti-Xa level in this time 
period, clinicians may use this information to decide on the appropriateness of starting 
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thrombolysis. Endovascular therapy with clot extraction can proceed whether or not the 
subject is receiving rivaroxaban without the need to unblind.
Section 6.8  Post-study therapy
This section was changed as a result of Modification 9.
Old Text:
At the conclusion of treatment with study medication, the study staff should encourage the 
subject to begin treatment with open-label aspirin or other antithrombotic therapy, as 
indicated.
New Text:
At the conclusion of treatment with study medication, the study staff should encourage the 
subject to resume treatment with open-label aspirin as indicated.
Section 6.9  Prior and concomitant therapy
This section was changed as a result of Modification 10.
Old Text:
As described in Section 5.1.2, Exclusion Criteria, the use of the following agents is not 
permitted at study entry:  systemic treatment with strong inducers of CYP 3A4 (e.g. 
rifampicin) and inhibitors of both CYP 3A4 and P-gp (e.g., systemic azole antimycotics, such 
as ketoconazole, and HIV-protease inhibitors, such as ritonavir).  
…
Study aspirin/aspirin placebo should be continued irrespective of the need for aspirin or dual 
antiplatelet therapy.  
New Text:
As described in Section 5.1.2, Exclusion criteria, the use of the following agents is not 
permitted at study entry:  systemic treatment with strong inducers of CYP 3A4 (e.g. 
rifampicin) and inhibitors of both CYP 3A4 and P-gp (e.g., systemic azole antimycotics, such 
as ketoconazole, and HIV-protease inhibitors, such as ritonavir) (see Section 6.9.1).  
…
Study aspirin/aspirin placebo may be continued irrespective of the need for aspirin or dual 
antiplatelet therapy.  
Section 6.9.1  Combined CYP 3A4 and p-glycoprotein inhibitors and CYP 3A4 inducers
This section was changed as a result of Modification 10.
Old Text:
Strong inhibitors of both CYP 3A4 and p-glycoprotein increase plasma concentrations of 
rivaroxaban and are contraindicated in subjects taking rivaroxaban. These include systemic 
azole antifungal drugs (e.g. ketoconazole, itraconazole, posaconazole, etc.), and HIV protease 
inhibitors.  Additionally,  strong inducers of CYP 3A4 such as i.e. rifampicin, rifabutin, 
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phenobarbital, phenytoin, and carbamazepine can reduce the plasma concentrations of 
rivaroxaban. If any of these treatments are needed, randomized study rivaroxaban/rivaroxaban 
placebo and aspirin/aspirin placebo must be temporarily discontinued and open-label aspirin 
should be begun.
New Text:
Strong inhibitors of both CYP 3A4 and p-glycoprotein increase plasma concentrations of 
rivaroxaban and are contraindicated in subjects taking rivaroxaban. These include systemic 
azole antifungal drugs (e.g. ketoconazole, itraconazole, posaconazole, etc.), and HIV protease 
inhibitors.  Additionally,  strong inducers of CYP 3A4 such as rifampicin, rifabutin, 
phenobarbital, phenytoin, and carbamazepine can reduce the plasma concentrations of 
rivaroxaban. If any of these treatments are needed, randomized study rivaroxaban/rivaroxaban 
placebo must be temporarily discontinued and open-label aspirin should be begun.
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Section 7.1.1 Tabulated overview, Table 7−1
This section was changed as a result of Modifications 13 and 18.
Old Text:
Pre-Screeninga
Screening/
Run-in
Randomizations
Follow-up
Washout
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15n
Final
Wash
out
Timing
-4w
0
1 m 3mm 6m 9mm
1y
1.5y
2y
2.5y
3y
3.5y
4y
4.5y
5y
1 m post 
Finalm
Windows 
± 5d ± 7d ± 2w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w
± 5d
…..
MoCA, DSS, and SAGE
Xo
Xo
Xp
X
X
……
h CT angiography will be performed at 1 year in all subjects who are randomized Day 4-7 after CABG to evaluate graft patency  (except in subjects those with 
specific contraindications). In the event the subject undergoes an invasive coronary angiography at 1 year post CABG for any reason, a CT angiogram may 
not be required.
i MRI of the brain will be performed only in COMPASS-MIND substudy subjects, at the time of randomization (or soon thereafter, within 3 months) and near the 
end of the follow-up
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New Text:
Pre-Screeninga
Screening/
Run-in
Randomizations
Follow-up
Washout
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15n
Final
Wash
out
Timing
-4w
0
1 m 3mm 6m 9mm
1y
1.5y
2y
2.5y
3y
3.5y
4y
4.5y
5y
1 m post 
Finalm
Windows 
± 5d ± 7d ± 2w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w
± 5d
…..
MoCA, DSS, and SAGE t
Xo
Xo
Xp
X
X
……
h.  CT angiography will be performed at 1 year or later in all subjects who are randomized Day 4-7 after CABG to evaluate graft patency  (except in subjects 
those with specific contraindications). In the event the subject undergoes an invasive coronary angiography at 1 year or later post CABG for any reason, a 
CT angiogram may not be required. 
i.   MRI of the brain will be performed only in COMPASS-MIND substudy subjects after randomization and near the end of the follow-up
…
t.  Also to be administered at the next study clinic visit after each outcome event
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Section 7.1.2.3  Randomization visit (Day 0 ± 5 days)
This section was changed as a result of Modification 17.
Added Text:

MRI of the brain will be performed only in COMPASS-MIND substudy subjects after 
randomization
Section 7.1.2.4.1  Routine follow-up visits (Visits 3, 5, and 7-15+)
This section was changed as a result of Modification 18.
Added Text:

Perform CT  angiography only at Visit 7 (1 year or later if not performed at 1 year) in 
all subjects who are randomized during the first week after CABG to evaluate graft 
patency (except in subjects with specific contraindications). In the event the subject 
undergoes an invasive coronary angiography at 1 year or later post CABG for any 
reason, a CT angiogram may not be required.
…
While every effort should be made for the subject to attend those visits that are meant to be in 
person, infrequently it may not be possible to conduct the visit in person in which case the  
visit may occur by telephone instead. 
Section 7.2.3 Other baseline characteristics
This section was changed as a result of Modification 13.
Old Text:
Validated health and quality of life questionnaires, SAGE, MoCA, DSS, EQ-5D will be 
administered at screening/run-in or randomization, as well as Month 24, and the Final Follow-
up Visit to measure the effect of randomized treatment on functional outcomes and quality of 
life, and diet and activity questionnaires will also be administered in order to explore the 
determinants and consequences of cognitive decline in patients with CAD and PAD.  
New Text:
Validated health and quality of life questionnaires (SAGE, MoCA, DSS, and EQ-5D) will be 
administered at screening/run-in or randomization, or as soon as possible thereafter, at Month 
24 and at the Final Follow-up Visit, and at the next study clinic visit after each outcome event 
to measure the effect of randomized treatment on functional outcomes and quality of life.  
Diet and activity questionnaires will also be administered at screening/run-in or 
randomization, or as soon as possible thereafter, and at Month 24 in order to explore the 
determinants and consequences of cognitive decline in patients with CAD and PAD.  
Section 7.3 Efficacy
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This section was changed as a result of Modification 1.
Old Text:
The secondary efficacy outcome is a composite of myocardial infarction, stroke, 
cardiovascular death, revascularization, venous thromboembolism, and cardiovascular 
hospitalization.  Mortality by any cause is also a secondary efficacy outcome.
Tertiary efficacy outcomes include the evaluation of responses recorded for the SAGE, 
MoCA, DSS, and EQ-5D inventories and the following:  individual components of the 
primary and secondary outcomes, hospitalization, amputation, stent thrombosis, unstable 
angina, worsening angina, new angina, heart failure, resuscitated cardiac arrest, new diagnosis 
of cancer, MRU, coronary artery bypass graft failure.
…
A detailed description of outcomes to be analyzed for this study will be provided in the 
separate statistical analysis plan.
New Text:
The secondary efficacy outcomes are: 
a) a composite of coronary heart disease death, myocardial infarction, ischemic stroke or acute 
limb ischemia; and 
b) a composite of cardiovascular death, myocardial infarction, ischemic stroke or acute limb 
ischemia.  
c) mortality by any cause.
Other efficacy outcomes include the evaluation of responses recorded for the SAGE, MoCA, 
DSS, and EQ-5D inventories and the following:  individual components of the primary and 
secondary outcomes, hospitalization,  revascularization, amputation, stent thrombosis, 
unstable angina, worsening angina, new angina, heart failure, resuscitated cardiac arrest, 
venous thromboembolism, new diagnosis of cancer, MRU, coronary artery bypass graft 
failure.
Section 7.5.1 E6 Definition of (serious) adverse event
This section was changed as a result of Modification 11. 
Old Text:
A serious adverse event (SAE) is classified as any untoward medical occurrence that, at any 
dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of 
existing hospitalization, results in persistent or significant disability / incapacity is a 
congenital anomaly / birth defect and/or is another medically important serious event 
representing a significant hazard, which is comparable to the aforementioned criteria. A 
surgical procedure or hospitalization that was planned prior to signing of the informed consent 
by any physician treating the subject should not be recorded as an AE. However, the condition 
for which the surgery or hospitalization is required may be an AE.
New Text:
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Note:  If a subject is hospitalized or has a procedure that was planned or anticipated prior to 
the subject signing the informed consent, the hospitalization/procedure is considered part of 
medical  history or a therapeutic intervention and is not the result of an (S)AE unless the 
severity has worsened or changed unexpectedly. Additionally, a procedure is not an (S)AE, 
but the reason for the procedure may be an (S)AE.
Section 7.5.3.1 Protocol-specific exceptions to SAE reporting
This section was changed as a result of Modifications 1 and 12. 
Old Text:
Rivaroxaban has been extensively studied in Phase 2 and 3 clinical studies involving more 
than 70,000 patients and its overall adverse event profile has been well described. 
…

Secondary and tertiary efficacy outcomes
o
Cardiovascular hospitalization
o
Venous thromboembolism
o
Revascularization
o
Amputation
o
Stent thrombosis
o
Angina pectoris (unstable, worsening or new) 
o
Heart failure
o
Resuscitated cardiac arrest
o
New diagnosis of cancer 
o
Coronary artery bypass graft failure
…
In addition, events that are expected to occur with high frequency in the population under 
study and for which no safety signal arose from more than 70,000 patients already studied in 
clinical trials with rivaroxaban will be captured on the CRF only, will be waived from 
unblinding, and be will be exempted from expedited reporting.  
New Text:
Rivaroxaban has been extensively studied in Phase 2 and 3 clinical studies involving more 
than 80,000 patients and its overall adverse event profile has been well described.  
…

Secondary and tertiary efficacy outcomes
o
Coronary heart disease death
o
Ischemic stroke
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o
Acute limb ischemia
o
Cardiovascular hospitalization
o
Venous thromboembolism
o
Revascularization
o
Amputation
o
Stent thrombosis
o
Angina pectoris (unstable, worsening or new) 
o
Heart failure
o
Resuscitated cardiac arrest
o
New diagnosis of cancer 
o
Coronary artery bypass graft failure
…
In addition, events that are expected to occur with high frequency in the population under 
study and for which no safety signal arose from more than 80,000 patients already studied in 
clinical trials with rivaroxaban will be captured on the CRF only, will be waived from 
unblinding, and be will be exempted from expedited reporting.  
8.3.2 Secondary efficacy outcomes
This section was changed as a result of Modification 1.
Old Text:
The secondary efficacy outcomes are:

The composite of outcomes --- myocardial infarction, stroke, cardiovascular death, 
revascularization, venous thromboembolism, and cardiovascular hospitalization

Mortality (all-cause)
New Text:
The secondary efficacy outcomes are (in the following order):

The composite of outcomes --- coronary heart disease death, myocardial infarction, 
ischemic stroke, acute limb ischemia

The composite of outcomes --- cardiovascular death, myocardial infarction, ischemic 
stroke, acute limb ischemia

Mortality (all-cause)
Section 8.3.3 Tertiary and other efficacy outcomes
This section was changed as a result of Modification 1. 
Old Text:
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The tertiary efficacy outcomes are:

Subject-reported SAGE, MoCA, DSS, and EQ-5D

Individual components of the primary and secondary outcomes

Hospitalization 

Amputation

Stent thrombosis

Unstable angina 

Worsening angina 

New angina 

Heart failure 

Resuscitated cardiac arrest

New diagnosis of cancer

MRU

Coronary artery bypass graft failure
New Text:
The tertiary efficacy outcomes are:

Subject-reported SAGE, MoCA, DSS, and EQ-5D

Individual components of the primary and secondary outcomes

Hospitalization for cardiovascular reasons

Hospitalization

Revascularization

Amputation 

Stent thrombosis

Unstable angina 

Worsening angina 

New angina 

Heart failure 

Venous thromboembolism

Resuscitated cardiac arrest

New diagnosis of cancer

MRU

Coronary artery bypass graft failure
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Section 8.3.6  Subgroup variables
This section was changed as a result of Modification 16.
Added Text:

Any prior CABG (yes, no), further subdivided as CABG days 4-7 before 
randomization and other prior CABG   
Section 8.4 Statistical and analytical plans
This section was changed as a result of Modification 2. 
Added Text:
Testing strategy 
Each of the rivaroxaban-based treatment groups will first be compared to the common aspirin 
control group on the primary efficacy outcome, followed by the same comparisons on the 
three ordered secondary efficacy outcomes. Figure 1 illustrates the hypothesis testing problem 
with ordered hypotheses. The null hypotheses of no effect corresponding to different efficacy 
outcomes will be grouped into four separate families. Standard logical restrictions will be 
imposed, i.e., the null hypotheses will be split into two branches corresponding to the tests for 
rivaroxaban 2.5 mg plus aspirin (hypotheses H1A, H2A, H3A, H4A) and to the tests for 
rivaroxaban 5.0 mg (hypotheses H1B, H2B, H3B, H4B).  A null hypothesis within each branch 
can be tested if and only if the immediately preceding null hypothesis is rejected, e.g., 
hypothesis H2A, is “testable” if and only if hypothesis H1A is rejected. Figure 1, these logical 
restrictions are represented by arrows.
Figure 8-1: Hypothesis testing problem
Multiple hypotheses testing will be performed according to a mixture gatekeeping procedure 
based on the Hochberg test with a truncation fraction of γ = 0.9, which controls the 
familywise error rate at the pre-assigned level of significance α = 5% in the strong sense.  The 
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Hochberg-based gatekeeping procedure based on an extension of the general mixture 
methodology developed in Dmitrienko and Tamhane (2011, 2013) was recently proposed in 
Brechenmacher et al., 2011.  Details for the setting of this study will be described in the SAP.  
Section 8.4.1 Analysis of the primary efficacy outcome
This section was changed as a result of Modification 2. 
Old Text:
The 2 comparisons will be performed using 2 separate stratified log-rank tests.  A step-up 
Dunnett procedure(0,0) analogous to the Hochberg procedure will be used to control the 
overall type I error level of 5%.  The asymptotically normally distributed log-rank test 
statistics will be ordered |t|(1) < |t|(2) and compared to suitably defined critical values in a 
stepwise fashion starting with the smaller test statistic |t|(1). If |t|(1) ≥ c1 = 1.96, i.e. if the larger 
of the two p-values is not greater than the 2-sided 5% type I error level, then both hypotheses 
will be rejected. Otherwise, the null hypothesis corresponding to the smaller test statistic |t|(1)
will be retained and the larger test statistic |t|(2) will be compared to the larger critical value c2
= 2.223, corresponding to a test at the 2-sided 2.63% type I error level.  Proton pump inhibitor
use (3 strata levels: not randomized to a proton pump inhibitor; pantoprazole 40 mg od; 
pantoprazole placebo) will be used as a stratification factor.  Study center will not be used as a 
stratification factor.  There will be no formal comparison between the rivaroxaban 2.5 mg bid 
+ aspirin 100 mg od and rivaroxaban 5 mg bid + aspirin placebo groups.
……
The trial success will be determined based on the totality of evidence for significance, 
magnitude, and direction of treatment effect from the analysis of primary and secondary 
efficacy outcomes.  If the rivaroxaban-based treatment groups and aspirin control group are 
not significantly different in the analysis of the primary efficacy outcome but convincing 
evidence of the superiority of either of the 2 rivaroxaban-based antithrombotic regimens (e.g. 
a reduction of 3 standard deviations) is observed in the analysis of secondary efficacy 
outcomes, then such extreme differences will provide persuasive evidence of superiority of 
rivaroxaban-based antithrombotic therapy over aspirin-based therapy.
New Text:
The 2 comparisons will be performed using 2 separate stratified log-rank tests.  Following the 
mixture gatekeeping procedure as mentioned in Section 8.4, a truncated Hochberg test with 
the pre-specified truncation parameter γ = 0.9 at =0.05 will be used. Further details will be 
described in the SAP.  Proton pump inhibitor use (3 strata levels: not randomized to a proton 
pump inhibitor; pantoprazole 40 mg od; pantoprazole placebo) will be used as a stratification 
factor.  Study center will not be used as a stratification factor.  There will be no formal 
comparison between the rivaroxaban 2.5 mg bid + aspirin 100 mg od and rivaroxaban 5 mg 
bid + aspirin placebo groups.
…
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The trial success will be determined based on the totality of evidence for significance, 
magnitude, and direction of treatment effect from the analysis of primary and secondary 
efficacy outcomes.  
Section 8.4.2 Analysis of the secondary efficacy outcomes
This section was changed as a result of Modification 2. 
Old Text:
Analysis of the secondary efficacy outcomes will be based on the intention-to-treat principle 
(Section 8.2) and will use a similar approach as described in Section 8.4.1. Both comparisons 
of the rivaroxaban-based treatment groups to the common aspirin control group will be 
performed at the 2-sided 5% type I error level.  There will be no adjustment of secondary 
analyses for multiple testing.
New Text:
Analysis of the secondary efficacy outcomes will be based on the intention-to-treat principle 
(Section 8.2) and will use a similar approach as described in Section 8.4.1.  The family-wise 
error rate will be controlled using the truncated and/or regular Hochberg tests as described in 
Section 8.4 and more detailed in the SAP.
Section 8.5 Planned interim analysis
This section was changed as a result of Modification 3.
Old Text:
Given these conservative monitoring boundaries and only 2 interim analyses, the type I error 
level adjustment for the final analysis will be negligible.  If the results are clear with one 
intervention, but not for the second intervention, the DSMB may decide to continue 
evaluation of both or one rivaroxaban treatment arms.  If the study is continued with both 
interventions, then the type I error levels specified in Section 8.4.1 will be used in the final 
analysis; if the decision is made to continue with only one intervention, the final comparison 
will be made at the 5% type I error level. 
The Steering Committee will review overall blinded event rates to ensure that they meet 
protocol projections.  If overall event rates are lower than expected, consideration will be 
given to increasing the sample size or extending the study duration without knowledge of any 
treatment effect.  The trial will aim to enroll about one-third subjects with PAD; this will be 
monitored during the trial and steps may be taken to adjust the proportion during the trial.
New Text:
Given these conservative monitoring boundaries and only 2 interim analyses, the type I error 
level adjustment for the final analysis will be negligible.  If the results are clear with one 
intervention, but not for the second intervention, the DSMB may decide to continue 
evaluation of both or one rivaroxaban treatment arms.  If the study is continued with both 
interventions, then the type I error levels specified in Section 8.4 will be used in the final 
analysis; if the decision is made to continue with only one intervention, the final comparison 
will be made as follows: 
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
If one intervention was stopped early for efficacy, the multiple testing procedure for 
the final analysis will be performed as described in Section 8.4 with the assumption 
that the p-value for the primary efficacy outcome of the arm that was stopped early for 
overwhelming efficacy is smaller than 0.025. For secondary outcomes, the p-values 
will be obtained from log-rank tests based on all available data for the stopped arm 
(data from confirmation analysis 6 months after respective interim look) and the 
complete data from the comparator arm.

If one intervention was stopped early for futility, the final analysis will be performed 
when at least 1,513* subjects in the 2 remaining arms have experienced an event.
The final analysis will be performed according to the multiple testing strategy as 
described in Section 8.4. P-values for the primary and secondary hypotheses for the 
intervention stopped early will be obtained from the log-rank tests based on all 
available data for the stopped arm and the complete data from the comparator arm. It 
can be assumed that for the stopped intervention the corresponding p-value of the 
primary efficacy outcome will be greater than 0.05. Thus, for the intervention stopped 
early for futility the primary and none of the secondary outcomes can achieve 
statistical significance at the overall type I error level of 5%.  
*The whole study was planned to be stopped when at least 2,200 subjects had experienced a primary outcome 
event. Under the planning assumptions that both alternative hypotheses are true, observed randomization times 
and estimated overall incidence rates based on preliminary data, and projected study duration after sample size 
increase, it is expected that 826 subjects in the control arm and each 687 subjects in the rivaroxaban intervention 
arms will experience a primary outcome event. Dropping one intervention arm early but still expecting that for 
the other comparison the alternative hypothesis holds true, the study needs to be continued until at least 826 + 
687 = 1,513 subjects in the remaining arms have experienced a primary event.
The Steering Committee will review overall blinded event rates to ensure that they meet 
protocol projections.  If overall event rates are lower than expected, consideration will be 
given to increasing the sample size or extending the study duration without knowledge of 
any treatment effect.  The trial will aim to enroll about one-quarter subjects with PAD; 
this will be monitored during the trial and steps may be taken to adjust the proportion 
during the trial.
Section 8.6 Determination of sample size
This section was changed as a result of Modification 4. 
Old Text:
In this trial, it is planned to randomize at least 21,400 subjects and to continue the study until 
a minimum of 2,200 subjects experience an event for the primary efficacy outcome.
The aim is to achieve at least 90% power to detect a 20% relative risk reduction (RRR) for 
each of the 2 rivaroxaban-based treatment groups vs. the common aspirin control group.  The 
total number of events needed is shown in Table 8–1 for different scenarios depending on the 
assumed annual event rate in the aspirin group.  Due to the event-driven study design, the 
number of randomized subjects, length of enrollment and total study duration may vary.  If 
recruitment is going extremely well, a larger number of subjects may be recruited.  All 
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numbers below refer to the minimum number of events to be observed after successful 
completion of the run-in period.  For the total number of subjects to be enrolled in the run-in 
period, at least 10% must be added to the total number below.
Assumptions for antithrombotic treatment randomization were:

3-arm study with 1:1:1 randomization

In total, a minimum of 21,400 subjects are randomized (approximately 7,134 subjects 
per treatment group)

2-sided type I error level of 2.7% for each of the two comparisons to control the 
overall type I error level of 5%

Constant annual event rate in aspirin control group between 3.0% and 4.0%

Effect size: 20% relative risk reduction to be detected for each comparison

Intention-to-treat analysis: all subjects randomized are included in the analysis as 
randomized and the follow-up period for each subject is as long as possible from 
randomization until the date of the Final Follow-up Visit for each subject

Length of recruitment period about 2.5 years 

Early discontinuation of study drug: about 6% and 4% in the 1st and 2nd 6-month 
periods, and 3% in the 6-month periods thereafter
The expected total number of observed events and the estimated power for each of the two 
comparisons are displayed in Table 8−1. 
Table 8-1.  Events calculations
Assumed annual event
rate in aspirin control 
group
Expected total study 
duration (years)
Estimated power for one 
comparison
Expected total number 
of events
3.0%
4.5
85.1%
1,642
5.0
89.2%
1,909
3.5%
4.5
90.2%
1,907
5.0
93.4%
2,215
4.0%
4.5
93.7%
2,171
5.0
96.0%
2,517 
Based on these estimates and the aim to detect a true relative risk reduction of 20% in each of 
the rivaroxaban arms with at least 90% power, it is planned to randomize at least 21,400 
subjects and to continue the study until a minimum of 2,200 subjects experience an event for 
the primary efficacy outcome.  In this multi-center study, each center is expected to 
randomize at least 50 subjects.
Assumptions for pantoprazole randomization are: 

Annual event rate for major upper gastrointestinal complications (overt or occult 
bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction or perforation) 
in the range of 1.6% to 2.2%
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
At least 12,840 subjects included in the study are not proton pump inhibitor users and 
they are randomized to pantoprazole treatment and control groups in 1:1 ratio

2-sided type I error level of 5%

Effect size: 50% relative risk reduction to be detected

Intention-to-treat analysis: all subjects randomized are included in the analysis as 
randomized and the follow-up period for each subject is as long as possible from 
randomization until the date of the Final Follow-up Visit for each subject
Under these assumptions, the expected total number of major upper gastrointestinal 
complications is between 450 and 730, depending on the observed event rates and the total 
study duration. The estimated power for the detection of the true relative risk reduction of 
about 50% for major upper gastrointestinal complications for pantoprazole 40 mg od vs. 
pantoprazole placebo is close to 100% for all scenarios considered.
Sample size estimation was based on the method by Lakatos (40) implemented in Power 
Analysis and Sample Size (PASS) software, version 11.0.7, and on a Statistical Analysis 
System (SAS) macro provided by J. Shih (1995).(41)  In addition, simulations were 
performed to confirm that the Dunnett step-up testing procedure as described in Section 8.4.1
for the analysis of the primary efficacy outcome keeps the overall type I error level of 5%.  
SAS calculations and simulations were performed using SAS software, version 9.2 (SAS 
Institute Inc, Cary, NC, USA).
New Text:
In this trial, it is planned to randomize at least 27,400 subjects and to continue the study until 
a minimum of 2,200 subjects experience an event for the primary efficacy outcome.
The aim is to achieve at least 90% power to detect a 20% relative risk reduction (RRR) for 
each of the 2 rivaroxaban-based treatment groups vs. the common aspirin control group.  The 
total number of events needed is shown in Table 8–1 for different scenarios depending on the 
assumed annual incidence rate for the primary outcome in the aspirin group based on the 
assumptions modified according to Amendment 6 (integrated protocol Version 2.0), dated 
03 JUL 2014.  Due to the event-driven study design, the number of randomized subjects, 
length of enrollment and total study duration may vary.  If recruitment is going extremely 
well, a larger number of subjects may be recruited.  All numbers below refer to the minimum 
number of events to be observed after successful completion of the run-in period.  For the 
total number of subjects to be enrolled in the run-in period, at least 10% must be added to the 
total number below.
Original assumptions for antithrombotic treatment randomization were:

3-arm study with 1:1:1 randomization

In total, a minimum of 21,400 subjects are randomized (approximately 7,134 subjects 
per treatment group) according to a 1:2:3:4:4 pattern within 2.5 years

2-sided type I error level of 2.7% for each of the two comparisons to control the 
overall type I error level of 5%
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
Constant annual incidence rate in aspirin control group between 3.0% and 4.0%

Effect size: 20% relative risk reduction to be detected for each comparison

Intention-to-treat analysis: all subjects randomized are included in the analysis as 
randomized and the follow-up period for each subject is as long as possible from 
randomization until the date of the Final Follow-up Visit for each subject

Length of recruitment period about 2.5 years 

Early discontinuation of study drug: about 6% and 4% in the 1st and 2nd 6-month 
periods, and 3% in the 6-month periods thereafter
The expected total number of observed events and the estimated power for each of the two 
comparisons are displayed in Table 8−1. 
Table 8-1.  Events calculations
Assumed annual 
incidence rate in 
aspirin control group
Expected total study 
duration (years)
Estimated power for one 
comparison
Expected total number 
of events
3.0%
4.5
85.1%
1,642
5.0
89.2%
1,909
3.5%
4.5
90.2%
1,907
5.0
93.4%
2,215
4.0%
4.5
93.7%
2,171
5.0
96.0%
2,517 
Based on these estimates and the aim to detect a true relative risk reduction of 20% in each of 
the rivaroxaban arms with at least 90% power, it was planned to randomize at least 21,400 
subjects and to continue the study until a minimum of 2,200 subjects experience an event for 
the primary efficacy outcome.  In this multi-center study, each center is expected to 
randomize at least 50 subjects.
The originally planned sample size of 21,400 and 5 year study duration was based on an 
annual primary incidence rate in the control group of 3.5% and 90% power to detect a relative 
risk reduction of 20% in each of the rivaroxaban arms. Based on an observed incidence rate of 
2.9% as of JUL 2015, it is now planned to randomize at least 27,400 subjects. This new 
sample size will maintain current study timelines and 90% power to detect a 20% relative risk 
reduction in each of the rivaroxaban arms, based on the following revisions to the original 
assumptions:  

Overall length of recruitment period about 3 to 3.5 years and taking observed 
randomization times up to July 2015 into account

2-sided overall type I error level of 5% using a truncated Hochberg test (γ = 0.9) for 
the testing of the 2 primary hypotheses

Constant overall incidence rate of about 2.9% per year, resulting in a constant 
incidence rate of about 3.3% per year for the aspirin control group assuming a 20% 
relative risk reduction for both hypotheses
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
Censoring due to non-CV death at an event rate of almost 1% per year
Assumptions for pantoprazole randomization are: 

Annual incidence rate for major upper gastrointestinal complications (overt or occult 
bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction or perforation) 
in the range of 1.6% to 2.2%

At least 16,440 subjects included in the study are not proton pump inhibitor users and 
they are randomized to pantoprazole treatment and control groups in 1:1 ratio

2-sided type I error level of 5%

Effect size: 50% relative risk reduction to be detected

Intention-to-treat analysis: all subjects randomized are included in the analysis as 
randomized and the follow-up period for each subject is as long as possible from 
randomization until the date of the Final Follow-up Visit for each subject
Under these assumptions, the expected total number of major upper gastrointestinal 
complications is between 570 and 780, depending on the observed event rates and the total 
study duration. The estimated power for the detection of the true relative risk reduction of 
about 50% for major upper gastrointestinal complications for pantoprazole 40 mg od vs. 
pantoprazole placebo is close to 100% for all scenarios considered.
Sample size estimation was based on the method by Lakatos (40) implemented in Power 
Analysis and Sample Size (PASS) software, version 11.0.7, and on a Statistical Analysis 
System (SAS) macro provided by J. Shih (1995).(41) In addition, simulations were performed 
to confirm that the mixture gatekeeping procedure as described in Section 8.4 for the analysis 
of the primary efficacy outcome keeps the overall type I error level of 5%.  SAS calculations 
and simulations were performed using SAS software, version 9.2 (SAS Institute Inc, Cary, 
NC, USA).
Section 9.3  Data processing
This section was changed as a result of Modification 18.
Added Text:

Visit attendance
Section 12 Reference list
This section was changed as a result of Modification 12. 
Deleted Text:
Dmitrienko A, Tamhane A, Bretz F (editors). Multiple Testing Problems in Pharmaceutical 
Statistics. Chapman and Hall/CRC, 2009.
Dunnett CW and Tamhane AC. A Step-Up Multiple Test Procedure. Journal of the American 
Statistical Association, 1992 87(417):162-170.
Added Text:
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Brechenmacher, T, Xu, J, Dmitrienko, A, Tamhane, AC. A mixture gatekeeping procedure 
based on the Hommel test for clinical trial applications. Journal of Biopharmaceutical 
Statistics, 2011; 21: 748-767.
Dmitrienko, A, Tamhane, AC. Mixtures of multiple testing procedures for gatekeeping 
applications in clinical trials. Statistics in Medicine, 2011; 30: 1473-1488.
Dmitrienko, A, Tamhane, AC. General theory of mixture procedures for gatekeeping. 
Biometrical Journal, 2013; 55: 402-419.
Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al.  Long-term use of 
ticagrelor in patients with prior myocardial infarction.  N Engl J Med 2015; 372:1791-1800. 
Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlio DE, Steg PG, et al.  Twelve of 
30 months of dual antiplatelet therapy after drug-eluting stents.  N Engl J Med 2014; 
371:2155-66. 
Palmerini T, Benedetto U, Bacchi-Reggiani L, Della Riva D, Biondi-Zoccai G, Feres F, et al.  
Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting 
stent implantation: a pairwise and Bayesian network meta-analysis of randomised trial.  
Lancet 2015;385;2371-82. 
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al.  Rivaroxaban versus 
warfarin in nonvalvular atrial fibrillation.  N Engl J Med 2011;Sep 8;365(10):883-91.
Section 14.1 COMPASS MIND Substudy
This section was changed as a result of Modification 17.
Old Text:
Hypotheses:
…
Pre-specified secondary outcomes would consider the effect of rivaroxaban on (1) non-lacunar 
covert brain infarcts; (2) all incident strokes, including clinical strokes (anticipated rate 
1.2%/yr among peripheral arterial disease patients and 0.8%/yr among subjects with CAD), 
and all covert strokes; (3a) functional decline (Standard Assessment of Global-Activities in 
the Elderly [SAGE]) and [3b] cognitive decline (Montreal Cognitive Assessment [MoCA] and 
digit symbol substitution).  Exploratory analyses will examine the predictive value of 
biomarkers (C-reactive protein, nt-proBNP) as independent predictors of covert brain infarcts.
Design: A phase II trial seeking evidence of efficacy in which a convenience sample of 1500 
COMPASS participants over age 65 undergo will be invited to participate – 500 assigned to 
each treatment arm, but balanced for age, prior stroke, and hypertension.  Participants will 
undergo limited brain MRI sequences (Fluid Attenuated Inversion Recovery [FLAIR]), T-1, 
T-2, and T-2* GRE sequences at entry and near end-study coupled with assessment of 
function (SAGE), and cognition (MoCA, digit symbol substitution).  Recruitment will occur 
at COMPASS sites with access to high-quality (>1.0 Tesla) reasonably-priced MR imaging.  
Images will be transmitted to the central MR imaging center via discs.  Two-stage central 
interpretation blinded to treatment will be carried-out, with all incident covert infarcts 
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confirmed by a second independent interpreter.  The 
 has experience with collection and 
analysis of brain MRIs performed in substudies of several randomized trials:  AVERROES, 
PURE, APOLLO, and (planned) TIPS 3 MIND.
Subjects will have DNA collected at baseline and blood collected at baseline and at the 1 
month visit. DNA and blood collections are optional.(Section7.1.1, 7.1.2.3 and 7.1.2.4.1) The 
samples will be processed, and aliquots will be shipped for long-term storage in liquid 
nitrogen at the coordinating center in 
 Canada.  Blood samples will be 
processed and stored in such a way to allow future analysis of these aliquots for selected 
biomarkers, some of which have been observed in other studies to be predictors of stroke, and 
others which have a plausible association with cardiovascular outcomes.  Detailed information 
concerning blood collection, processing, storage, and shipping is provided in the Manual of 
Operations.
New Text:
Hypotheses: 
…
Pre-specified secondary outcomes would consider the effect of rivaroxaban on (1) non-lacunar 
covert brain infarcts; (2) volume of white matter hyperintensities; (3) all incident strokes, 
including clinical strokes (anticipated rate 1.2%/yr among peripheral arterial disease patients 
and 0.8%/yr among subjects with CAD), and all covert strokes; (4a) functional decline 
(Standard Assessment of Global-Activities in the Elderly [SAGE]) and [4b] cognitive decline 
(Montreal Cognitive Assessment [MoCA] and digit symbol substitution).  Exploratory 
analyses will examine the predictive value of biomarkers (C-reactive protein, nt-proBNP) as 
independent predictors of covert brain infarcts.
Design: A phase II trial seeking evidence of efficacy in a convenience sample of 1500 
COMPASS participants with readable baseline MRI scans, 500 assigned to each treatment 
arm, but balanced for age, prior stroke, and hypertension.  Participants will undergo limited 
brain MRI sequences (Fluid Attenuated Inversion Recovery [FLAIR]), T-1, T-2, and T-2* 
GRE sequences after randomization and near end-study coupled with assessment of function 
(SAGE), and cognition (MoCA, digit symbol substitution).  Recruitment will occur at 
COMPASS sites with access to high-quality (>1.0 Tesla) reasonably-priced MR imaging.  
Images will be transmitted to the central MR imaging center via discs.  Two-stage central 
interpretation blinded to treatment will be carried-out, with all incident covert infarcts 
confirmed by a second independent interpreter.  The 
 has experience with collection and 
analysis of brain MRIs performed in substudies of several randomized trials:  AVERROES, 
PURE, APOLLO, and (planned) TIPS 3 MIND.
Some subjects, in participating centers, will have DNA collected at baseline and blood 
collected at baseline and at the 1 month visit. DNA and blood collections are 
optional.(Section7.1.1, 7.1.2.3 and 7.1.2.4.1). The samples will be processed, and aliquots 
will be shipped for long-term storage in liquid nitrogen at the coordinating center in 
 
 Canada.  Blood samples will be processed and stored in such a way to allow future 
analysis of these aliquots for selected biomarkers, some of which have been observed in other 
studies to be predictors of stroke, and others which have a plausible association with 
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cardiovascular outcomes. Detailed information concerning blood collection, processing, 
storage, and shipping is provided in the Manual of Operations.
13.3
Amendment 11
13.3.1
Overview changes to the study
The following changes are made to Protocol Version 3.0. Administrative and editorial 
corrections are made throughout the document. Long-term open-label extension (LTOLE) is 
added and changes are made to COMPASS trial after early termination of rivaroxaban/aspirin 
arms.
Modification 1: Name of the sponsor clinical leader has been updated. LTOLE, MACE and 
PPI are added to List of abbreviations.
Rationale: 
 replaces 
 as the sponsor’s 
 
for the COMPASS trial.
Sections affected:

Title page

Signature of the sponsor’s medically responsible person

List of abbreviations
Modification 2: Adding LTOLE.
Rationale: On February 6, 2017 the COMPASS Data Safety Monitoring Board recommended 
discontinuation of the rivaroxaban/aspirin arms of the COMPASS trial because of a clear 
benefit of one of the two rivaroxaban-containing arms. Final rivaroxaban/aspirin follow-up 
visits were performed during the second quarter of 2017. The protocol was amended to make 
rivaroxaban plus aspirin available to COMPASS trial subjects prior to commercial 
availability.
Sections affected:

Synopsis

Section 1.1 Background

Section 1.2 Study rationale

Section 1.3 Benefit-risk assessment

Section 2 Study objectives

Section 3.1 Study committees

Section 4.1 Design overview

Section 4.2 Primary efficacy and safety variables

Section 4.3 Justification of the design

Section 4.4 Final follow-up visit and end of study
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
Section 5.1 Eligibility

Section 5.2 Discontinuation of subjects from study treatment

Section 6.1 Treatments to be administered

Section 6.3 Treatment assignment

Section 6.4.1 Dose modifications

Section 6.4.2.1 Guidance for the treatment of subjects who require an invasive 
procedure

Section 6.4.2.2 Guidance for the treatment of subjects who require coronary artery 
bypass graft surgery

Section 6.4.2.3 Guidance for the treatment of subjects who develop an acute coronary 
syndrome and those who require percutaneous coronary intervention with stenting

Section 6.4.2.4 Guidance for the treatment of subjects who overdose on study 
rivaroxaban/rivaroxaban placebo

Section 6.4.2.5 Guidance for the treatment of subjects who experience a major bleed

Section 6.4.2.6 Guidance for the treatment of subjects who develop a stroke and who 
are being considered for reperfusion therapy

Section 6.5 Blinding

Section 6.6 Drug logistics and accountability

Section 6.8 Post-study therapy

Section 6.9 Prior and concomitant therapy

Section 6.9.1 Combined CYP 3A4 and p-glycoprotein inhibitors and CYP 3A4 
inducers

Section 6.9.2 Clopidogrel (or any other non-study antiplatelet treatment)

Section 6.9.3 Anticoagulant treatment

Section 7.1 Schedule of procedures

Section 7.1.1 Tabulated overview

Section 7.1.2 Timing of assessment

Section 7.3 Efficacy

Section 7.5 Safety

Section 8.4 Statistical and analytical plans

Section 9.2 Monitoring

Section 10 Premature termination of the study
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
Section 11.2 Subject information and consent
Modification 3: Changes made to COMPASS trial after early termination of 
rivaroxaban/aspirin arms.
Rationale: Due to early termination of rivaroxaban/aspirin arms, a final follow up 
rivaroxaban/aspirin visit and washout visit were introduced while the pantoprazole treatment 
continues. No washout visit for pantoprazole/placebo arms will be needed due to the short 
half-life of pantoprazole.
Sections affected:

Section 4.1 Design overview

Section 7.1 Schedule of procedures

Section 7.1.1 Tabulated overview

Section 7.2.1.5 End of washout telephone visit (30 days post Final Follow-up Visit ± 5 
days)
13.3.2
Changes to protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment and “new text” displays the updated text. 
Deletions are crossed out and additions are underlined. Corrections of typing errors or 
editorial changes are not highlighted in this amendment.
Modification 1: Name of the sponsor clinical leader has been updated. LTOLE, MACE and 
PPI are added to List of abbreviations.
Sponsor Clinical Leader:
Old text:
Global Clinical Development
Bayer HealthCare Pharmaceuticals, Inc.
100 Bayer Boulevard, P.O. Box 915
Whippany, NJ  07981-0915
United States
Tel: 
New text:
 
Bayer U.S. LLC
Development, Pharmaceuticals
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Thrombosis & Hematology Therapeutic Area
11 Waterview Blvd., Location 2095B
Parsippany, New Jersey 07054 USA
Tel: 
Signature of the sponsor’s medically responsible person
Old text:
Name:
New text:
Name:
Modification 2: Adding LTOLE.
Synopsis
Study objectives
Objective for Long-Term Open-Label Extension (LTOLE)
To make rivaroxaban 2.5 mg twice daily (bid) + aspirin 100 mg once daily 
(od) available to COMPASS trial subjects until the rivaroxaban treatment is 
commercially available for this indication or for approximately 3 years from 
regulatory approval of LTOLE in a country, whichever comes first.
Test drugs
      Dose(s)
      Duration of treatment
LTOLE
Rivaroxaban 2.5 mg bid + aspirin 100 mg od
LTOLE: approximately 3 years
Reference drugs
LTOLE: no reference drug
Diagnosis and main criteria for 
inclusion
LTOLE: all subjects randomized to the COMPASS trial willing to consent to 
LTOLE are eligible unless the subjects developed a condition considered by 
the investigator as exclusionary.
Study design
LTOLE: open label uncontrolled study
Methodology
LTOLE: initiation visit and a follow-up period
Type of control
LTOLE: none
Number of subjects
LTOLE: COMPASS trial subjects are potentially eligible.
Primary variable
LTOLE: the same primary safety and efficacy variables will be collected in 
LTOLE.
Plan for statistical analysis
LTOLE: all statistical analyses will be descriptive.
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List of abbreviations
New text:
Lb
LTOLE
Pound
Long-term open-label extension
MACE
Major adverse cardiac event
MD
Medical director/doctor
PPI
Proton pump inhibitor
OR
Odds ratio
Section 1.1 Background
New text:
…… In the (partial factorial) randomization, patients who do not have a continuous need for 
use of a PPI will be randomized to receive pantoprazole 40 mg od or placebo for the 
prevention of major upper gastrointestinal complications, and then randomized to receive 
rivaroxaban in combination with aspirin, rivaroxaban alone, or aspirin alone.
Long-Term Open-Label Extension – amended
On February 6, 2017, the COMPASS Data Safety Monitoring Board (DSMB) recommended 
discontinuation of the rivaroxaban/aspirin arms of the COMPASS trial because of a clear 
benefit of one of the two rivaroxaban-containing arms. The DSMB recommendation was 
made because for rivaroxaban 2.5 mg bid + aspirin 100 mg od, the z-value (test statistic of the 
log-rank test) for efficacy had crossed the critical value for early efficacy as outlined in the 
DSMB charter consistently over a 3-month period, and the z-value for rivaroxaban 5 mg bid 
had reached conventional significance for efficacy. The Steering Committee concurred with 
the recommendation of the DSMB, and the sponsor decided to stop the rivaroxaban/aspirin 
arms of the study based on the recommendation of the DSMB and the Steering Committee. 
The sponsor is making rivaroxaban 2.5 mg bid + aspirin 100 mg od available early for 
COMPASS trial subjects as part of a long-term open-label extension (LTOLE) protocol 
amendment. The dedicated LTOLE sections in this document describe LTOLE activities only; 
activities related to the pantoprazole/placebo arm remain unchanged with the exception of the 
removal of the washout visit. LTOLE activities will be coordinated with those of the ongoing 
pantoprazole/placebo arms of the trial where possible until pantoprazole/placebo part of the 
trial is completed.
Section 1.2 Study rationale
New text:
1.2.4 Long-Term Open-Label Extension
As described in Section 1.1, due to the clinical effect of rivaroxaban 2.5 mg bid + aspirin 
100 mg od over existing standard treatment with aspirin, the sponsor will offer the 
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rivaroxaban 2.5 mg bid + aspirin 100 mg od to trial subjects in a long-term open-label 
extension (LTOLE) until the rivaroxaban treatment is commercially available for this 
indication or for approximately 3 years from regulatory approval of LTOLE in a country, 
whichever comes first. The same efficacy and safety variables as in COMPASS will be 
collected in LTOLE in a descriptive way.
In COMPASS, the combination rivaroxaban 2.5mg bid + aspirin 100mg od compared to 
aspirin 100mg alone:

Reduced the relative risk for the primary composite of stroke, myocardial infarction 
and cardiovascular death by 24% (p<0.0001)

Increased the risk of ISTH modified major bleeding significantly (HR 1.70, 95% CI 
1.40-2.05, p<0.00001)

No significant increase was found in intracranial or fatal bleeds

Reduced the risk for pre-specified net clinical benefit, a composite of outcomes of 
irreversible harm, significantly (HR 0.80, 95% CI 0.70-0.91, p=0.00052)
Rivaroxaban 5.0 mg BID alone compared to 100 mg aspirin alone:

Did not significantly reduce the hazard for the primary outcome (HR 0.90, 95% CI 
0.79-1.03, p=0.11), but increased major bleeding
Findings were consistent across the majority regions and subgroups.
Section 1.3 Benefit-risk assessment
New text:
…...  In the COMPASS trial, the efficacy of pantoprazole will be compared with placebo for 
the prevention of upper gastrointestinal bleeding, ulceration, obstruction or perforation in 
subjects randomized to the combination of rivaroxaban and aspirin, rivaroxaban alone, or 
aspirin alone, using a partial factorial design.
Long-Term Open-Label Extension – amended
Rivaroxaban 2.5mg bid + aspirin 100mg od has demonstrated superior efficacy on reducing 
major adverse cardiac event (MACE) in patients with CAD/PAD as compared to aspirin alone 
and reduced the risk for pre-specified net clinical benefit significantly (refer to Section 1.2.4). 
Therefore, the sponsor aims to make rivaroxaban 2.5 mg bid + aspirin 100 mg od available in 
a long-term open-label extension.
Section 2 Study objectives
New text:
Substudy objectives
The COMPASS-MIND substudy will examine the effect of the antithrombotic therapies being 
tested in COMPASS on covert cerebral ischemia, thereby providing additional information 
about mechanisms of disease and treatment benefits. COMPASS-MIND will be conducted 
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concurrently with the main study in a subset of subjects at selected centers.  A detailed 
description is included in Section 14.1.
Objective for Long-Term Open-Label Extension – amended
The objective of LTOLE is to make rivaroxaban 2.5 mg bid + aspirin 100 mg od available to 
COMPASS trial subjects until the treatment is commercially available or for approximately 3 
years from regulatory approval of LTOLE in a country, whichever comes first. 
Primary, secondary and tertiary efficacy and safety outcomes as described above will be 
collected in the LTOLE.
Section 3.1 Study committees
New text:
…...  The study chair and/or the principal investigators will attend the open portion of the 
meeting to provide reports and respond to questions concerning the study. 
Long-Term Open-Label Extension − amended
Outcome events for LTOLE will be collected in a descriptive way, and no adjudication will be 
performed. 
The DSMB will not monitor the LTOLE and will conclude responsibilities when the 
pantoprazole/placebo treatment is completed.
Section 4.1.1 Design overview
New text:
Subjects randomized Day 4-7 after CABG surgery will undergo computed tomography (CT)  
angiography at 1 year or later as part of the study protocol to assess graft patency unless they 
have a specific contraindication for CT angiography (e.g., contrast allergy, estimated 
glomerular filtration rate <30 ml/min).  In the event the subject undergoes an invasive 
coronary angiography at approximately 1 year or later post CABG for any reason, a CT 
angiogram may not be required.
Long-Term Open-Label Extension − amended
The long-term open-label extension (LTOLE) will provide open-label rivaroxaban 2.5mg bid 
+ aspirin 100mg od to COMPASS subjects until it is commercially available or for 
approximately 3 years from regulatory approval of LTOLE in a country, whichever comes 
first. The implementation of LTOLE is an amendment to the COMPASS trial. 
For inclusion and exclusion criteria, see Section 5.1.3; for treatment related details, see 
Section 6.1.3 (Treatment to be administered), Section 6.6 (Drug logistics and accountability), 
and Section 6.8 (Post-study therapy). 
The LTOLE will involve an initiation visit and a follow-up period. 
Treatment initiation visits can be scheduled as soon as the LTOLE has received regulatory 
and ethics approvals, the site has signed a contract amendment, and the drug is available at the 
site. Before entering LTOLE, informed consent is needed. 
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For detailed procedures and variables, see Section 7.1.1 (Tabulated overview of LTOLE) and 
Section 7.1.2.6 (Timing of assessments in LTOLE).The same efficacy and safety outcomes as 
in the COMPASS trial will be collected in the LTOLE. All statistical analyses will be 
descriptive. 
Section 4.2 Primary efficacy and safety variables
New text:
The primary safety outcome for the rivaroxaban randomization is a composite of: 

fatal bleeding, and/or 

symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with 
compartment syndrome, or bleeding into the surgical site requiring re-operation, 
and/or 

bleeding leading to hospitalization
Long-Term Open-Label Extension − amended
The same primary efficacy and safety outcomes collected in the COMPASS trial will be 
collected during the LTOLE visits.
Section 4.3 Justification of the design
New text:
4.3.2 Design rationale for Long-Term Open-Label Extension
Due to the clinical efficacy of rivaroxaban 2.5mg bid + aspirin 100mg od (see Section 1.2.4), 
participation in the LTOLE will be offered to all subjects who meet the LTOLE 
Inclusion/Exclusion criteria defined in Section 5.1.3.
Section 4.4 Final follow-up visit and end of study
New text:
For each participating European Union (EU) country, the end of the study according to the EU 
Clinical Trial Directive will be reached when the telephone call at the end of the 30 day
washout period for the last subject for all centers in the respective country has occurred.  The 
end of the study as a whole will be reached as soon as the end of the study according to the 
above definition has been reached in all participating countries (EU and non-EU).
Long-Term Open-Label Extension − amended
The final visits of LTOLE will begin, per country, when the duration reaches 3 years from the 
regulatory approval of LTOLE or the rivaroxaban treatment is commercially available for this 
indication in the respective country, whichever comes first. The subject should be called in for 
the final visit within approximately 3 months or at latest the final visit may be conducted at 
the next scheduled visit.
Section 5.1 Eligibility
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New text:
5.1.3 Long-Term Open-Label Extension – amended
All subjects from COMPASS trial will be invited to join LTOLE as long as they continue to 
meet the COMPASS eligibility criteria (refer to sections 5.1.1 and 5.1.2) plus the specific 
ones for LTOLE (refer to sections 5.1.3.1 and 5.1.3.2). All LTOLE subjects must provide 
written informed consent to participate in LTOLE.
5.1.3.1 Inclusion criteria

All subjects randomized to the COMPASS trial willing to consent to LTOLE are 
eligible unless the subjects developed a condition considered by the investigator as 
exclusionary. 

Subjects who have given their written informed consent to participate in the LTOLE 
after having received adequate information prior to any LTOLE specific procedures.
5.1.3.2 Exclusion criteria

Subjects should not be included if, in the judgement of the investigator, they have 
developed a condition which should exclude them from receiving LTOLE study 
medication. For example if the subject has developed atrial fibrillation or had a severe 
allergic rash while in the study, which subsided when drug was stopped and returned 
when drug was reinitiated.
Section 5.2 Discontinuation of subjects from study treatment
New text:
Section 5.2.2 Long-Term Open-Label Extension
In case of permanent discontinuation of LTOLE treatment, the subject should come for a final 
visit within approximately 3 months, but follow the PPI visit schedule if applicable.
Section 6.1 Treatments to be administered
New text:
6.1.3 Treatment in Long-Term Open-Label Extension
The LTOLE treatment will be open-label rivaroxaban 2.5 mg bid + aspirin 100 mg od.
Section 6.3 Treatment assignment
New text:
The 
 randomization and drug management system will assign the subject a unique 
number for each medication that corresponds to one of the treatments listed in Table 4−1.
Long-Term Open-Label Extension − amended
All subjects in the LTOLE will receive the same treatment of rivaroxaban 2.5 mg bid + 
aspirin 100 mg od.
Section 6.4.1 Dose modifications
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New text:
……  For example, if study rivaroxaban/rivaroxaban placebo is interrupted, study 
aspirin/aspirin placebo and study pantoprazole/pantoprazole placebo should be continued.
Long-Term Open-Label Extension − amended
No dose modifications will be conducted in the LTOLE.
Section 6.4.2.1 Guidance for the treatment of subjects who require an invasive 
procedure
New text:
A two-unit single donor platelet transfusion in subjects treated with the combination of aspirin 
and rivaroxaban may restore the capacity to generate thromboxane and thereby overcome the 
antiplatelet effects of aspirin.(29)
Long-Term Open-Label Extension − amended
The same guidance will apply to LTOLE.
Section 6.4.2.2 Guidance for the treatment of subjects who require coronary artery 
bypass graft surgery
New text:
……In all cases, the goal should be to resume study antithrombotic drugs within 14 days and 
prior to being discharged from hospital.  
Long-Term Open-Label Extension − amended
The same guidance will apply to LTOLE. For subjects who are scheduled to undergo CABG, 
LTOLE treatment can be initiated four days after CABG and at least 24 hours after the 
removal of chest tubes. LTOLE treatment should not be administered until at least 12 hours 
after last administration of any anticoagulant (including DVT prophylaxis). 
Section 6.4.2.3 Guidance for the treatment of subjects who develop an acute coronary 
syndrome and those who require percutaneous coronary intervention with stenting
New text:
……When switching back to originally allocated study anticoagulant, interim study 
anticoagulant therapy should be stopped. 
Long-Term Open-Label Extension − amended
Study rivaroxaban should be interrupted in subjects who require anticoagulant or dual 
antiplatelet therapy because of an acute coronary syndrome or need for percutaneous coronary 
intervention with stenting. Standard antiplatelet therapy, including loading doses of aspirin 
and clopidogrel (or prasugrel or ticagrelor) can be administered according to usual practice.  
Study aspirin may be continued. All subjects should resume rivaroxaban 2.5 mg bid + aspirin 
od once non-study dual antiplatelet therapy is stopped and they are not being treated with non-
study anticoagulants.
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Section 6.4.2.4 Guidance for the treatment of subjects who overdose on study 
rivaroxaban/rivaroxaban placebo
New text:
……If available, consideration may be given to the use of a specific reversal agent.
Long-Term Open-Label Extension − amended
The same guidance will apply to LTOLE. 
Section 6.4.2.5 Guidance for the treatment of subjects who experience a major bleed
New text:
……Rivaroxaban cannot be dialyzed as it is highly protein bound. If available, consideration 
may be given to the use of a specific reversal agent.
Long-Term Open-Label Extension − amended
The same guidance will apply to LTOLE.
Section 6.4.2.6 Guidance for the treatment of subjects who develop a stroke and who are 
being considered for reperfusion therapy
New text:
……Endovascular therapy with clot extraction can proceed whether or not the subject is 
receiving rivaroxaban without the need to unblind.
Long-Term Open-Label Extension − amended
The decision to use reperfusion therapies (including intravenous, intra-arterial thrombolysis, 
or mechanical endovascular approaches) in acute ischemic stroke should follow local practice, 
experience, and guidelines. At present there are limited data to guide treatment in this setting 
in subjects taking rivaroxaban. The following guidance is intended to aid clinical decision 
making in this setting. 
At or around the time of the peak drug levels (we suggest in the first 6 hours after a dose), 
clinicians may consider to avoid thrombolysis. If it is possible to obtain a rivaroxaban anti-Xa 
level in this time period, clinicians may use this information to decide on the appropriateness 
of starting thrombolysis. 
Section 6.5 Blinding
New text:
……All subjects should resume study treatments after recovery if it is medically appropriate 
to do so and should be followed until the end of the study.
Long-Term Open-Label Extension – amended
The LTOLE is open label and no blinding procedures are applicable to the LTOLE.
Section 6.6 Drug logistics and accountability
New text:
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Written instructions on medication destruction will be made available to affected parties as 
applicable.
Long-Term Open-Label Extension - amended
Investigator staff will continue to access the 
 randomization and drug management 
system to dispense study medication. LTOLE treatment will be provided in appropriately 
labelled medication kits that identify the treatment. All LTOLE treatment will be stored at the 
site in accordance with GCP and Good Manufacturing Practices (GMP) requirements and the 
instructions given by the clinical supplies department of the sponsor or its affiliates. Receipt, 
distribution, return and destruction (if any) of the study drug must be properly documented 
according to the agreed and specified procedures.
Section 6.8 Post-study therapy
New text:
At the conclusion of treatment with study medication, the study staff should encourage the 
subject to resume treatment with open-label aspirin as indicated.
Long-Term Open-Label Extension − amended
At the conclusion of LTOLE treatment, subject’s will be directed to their usual care physician 
for appropriate treatment.  
Section 6.9 Prior and concomitant therapy
New text:
…...  Study aspirin/aspirin placebo may be continued irrespective of the need for aspirin or 
dual antiplatelet therapy.  
Long-Term Open-Label Extension − amended
During the LTOLE, all subjects should continue to receive any ongoing medications, with the 
exception of the subject’s own aspirin and treatments that are contraindicated in combination 
with rivaroxaban. Subjects may receive all medications that their treating physicians believe 
are necessary. If subjects develop a need for treatments that may interfere with the efficacy or 
safety of LTOLE treatment or for treatments that are taken in place of LTOLE treatment, they 
must temporarily discontinue the relevant study drug (rivaroxaban or aspirin or both) until 
such time that the interacting treatment is discontinued.
Section 6.9.1 Combined CYP 3A4 and p-glycoprotein inhibitors and CYP 3A4 inducers
New text:
…...  If any of these treatments are needed, randomized study rivaroxaban/rivaroxaban 
placebo must be temporarily discontinued and open-label aspirin should be begun.  
Long-Term Open-Label Extension − amended
The same guidance applies to LTOLE. No placebo will be used. 
Section 6.9.2 Clopidogrel (or any other non-study antiplatelet treatment)
New text:
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…… Additional guidance is provided in Section 6.4.2.3.  
Long-Term Open-Label Extension − amended
The same guidance applies to LTOLE. No placebo will be used. 
Section 6.9.3 Anticoagulant treatment
New text:
If therapeutic anticoagulation is required, subjects should start therapeutic anticoagulation 
immediately, irrespective of the timing of the last dose of study rivaroxaban.  
Long-Term Open-Label Extension − amended
Subjects who develop a need for anticoagulant therapy (e.g., thromboprophylaxis in 
subjects undergoing major orthopedic surgery, acute venous thromboembolism, atrial 
fibrillation, mechanical aortic valve replacement) must discontinue LTOLE medication. 
Guidance for converting see below:

Converting from rivaroxaban to oral anti-coagulants
Rivaroxaban affects INR, so INR measurements made during co-administration with oral 
anticoagulant may not be useful for determining the appropriate dose of oral anticoagulant. 
One approach is to discontinue rivaroxaban and begin both a parenteral anticoagulant and oral 
VKA at the time the next dose of rivaroxaban would have been taken.

Converting from rivaroxaban to parenteral anti-coagulants
Discontinue rivaroxaban and give the first dose of parenteral anticoagulant at the time that 
the next rivaroxaban dose would be taken.
Study rivaroxaban can be restarted at the discretion of the investigator in subjects who 
no longer have a need for non-study anticoagulant therapy (e.g., after completion of 
anticoagulant thromboprophylaxis or anticoagulant treatment for venous thromboembolism). 
Guidance for restarting see below:

Converting patients from VKAs to rivaroxaban
When converting patients from VKAs to rivaroxaban, INR values will be falsely elevated 
after the intake of rivaroxaban. The INR is not valid to measure the anticoagulant activity 
of rivaroxaban, and therefore should not be used. 

Converting patients from parenteral anticoagulant to rivaroxaban
For patients currently receiving a parenteral anticoagulant, start rivaroxaban 0 to 2 hours 
before the time of the next scheduled administration of the parenteral drug (e.g. LMWH) or at 
the time of discontinuation of a continuously administered parenteral drug (e.g. intravenous 
unfractionated heparin).
Section 7.1 Schedule of procedures
New text:
Long-Term Open-Label Extension − amended
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A tabulated overview of the procedures conducted during the LTOLE is provided in 
Table 7−3, and the procedures and their timing are described in more detail in Section 7.1.2.6.
7.1.1 Tabulated overview……
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Section 7.1.1 Tabulated overview
New text:
Table 7−3 Schedule of LTOLE Procedures
Visita
1
2
3
4
5
6
Final LTOLE visite
Timingb
0
6m
1y
1.5y
2y
2.5y
3y/
commercial availablef
Windows
± 4w ± 4w ± 4w
± 4w
± 4w
± 4w
Informed consent
X
Inclusion/exclusion criteria
X
Concomitant medications
X
X
Pregnancy test if pre-menopausal
X
Serum creatinine c
X
Outcomes
X
X
X
X
X
X
Adverse events d
X
X
X
X
X
X
Study drug dispensed
X
X
X
X
X
X
Study drug accountability
X
X
X
X
X
X
Study drug adherence
X
X
X
X
X
X
Questionnaires (MoCA, DSS, SAGE, EQ-5D)
X
a.
LTOLE visits may be combined with PPI visits as long as both are ongoing, and the visit window may be adjusted accordingly. 
b. Clinic visits should be scheduled as close to the specified interval as possible, and preferably within the defined window.  If it is not possible for the subject to 
return within the visit "window," especially due to unforeseen circumstance beyond the control of the subject or the study center, then the visit should be 
scheduled as close to the interval as is convenient for the subject and study center. 
c.
If not available in the 1 year prior.
d. Adverse events will be assessed from the start of LTOLE treatment to final visit. 
e. Subject is on LTOLE treatment and will stop it at this visit and will be suggested to start non-study antithrombotic treatment at physician’s discretion. 
f.
If the commercial availability in a country is achieved earlier than 3 years, the subject should be called in for final assessment within approximately 3 months 
or latest at the next scheduled visit; if a participant stops LTOLE treatment, a final visit should be scheduled immediately.
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Section 7.1.2 Timing of assessment
New text:
7.1.2.6 Long-Term Open-Label Extension − amended
The LTOLE protocol amendment requires clinic visits at initiation and every 6 months 
thereafter. For the COMPASS trial subjects continuing in the pantoprazole versus placebo 
randomization, LTOLE visits are recommended to coincide with the ongoing visits for 
pantoprazole comparison. If regulatory and ethics approval is obtained shortly after a 
pantoprazole versus placebo follow-up visit, an additional visit is recommended to evaluate 
eligibility and, if appropriate, initiation of LTOLE treatment.
7.1.2.6.1 Initiation of Long-Term Open-Label Extension − amended
The COMPASS trial subjects will be invited to participate in the LTOLE. Eligibility for 
LTOLE is defined in Section 5.1.3. 
The objective of the LTOLE initiation visit is to evaluate eligibility of COMPASS trial 
subjects for LTOLE. Initiation activities include:

Obtain written informed consent 

Review inclusion and exclusion criteria 

Record concomitant medications

Conduct pregnancy test (serum or urine) for premenopausal subjects

Obtain results of serum creatinine (if not available in within prior 1 year)

Dispense study drug
7.1.2.6.2 Follow-up of Long-Term Open-Label Extension − amended
Subjects will be seen in the clinic every 6 months. Follow-up visit assessments include:

Record outcomes 

Record adverse events

Assess adherence to study drug

Perform study drug accountability (pill count)

Dispense study medication
7.1.2.6.3 Final visit of Long-Term Open-Label Extension − amended
The final visits of LTOLE will begin, per country, when the duration reaches 3 years from the 
regulatory approval of LTOLE or the LTOLE treatment is commercially available in the 
respective country, whichever occurs first. If the commercial availability in a country is 
achieved earlier than 3 years, the subject should be called in for final visit within 
approximately 3 months or at latest the final visit may be conducted at the next scheduled 
visit. The final visit assessments include:
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
Record outcomes

Record adverse events

Assess adherence to study drug

Perform study drug accountability (pill count)

Record concomitant medication

Administer questionnaires (MoCA, DSS, SAGE, EQ-5D)
In the case of permanent discontinuation of LTOLE treatment, the subject will be called in for 
a final visit.
7.2 Population characteristics……
Section 7.3 Efficacy
New text:
The outcome for the pantoprazole randomization is a composite of overt bleeding of 
gastroduodenal origin confirmed by endoscopy or radiography, overt upper gastrointestinal 
bleeding of unknown origin, bleeding of presumed occult gastrointestinal origin with 
documented decrease in Hb of 2 g/dL, symptomatic gastroduodenal ulcer, gastrointestinal 
pain with underlying multiple gastroduodenal erosions, and gastrointestinal obstruction, or
perforation .
Long-Term Open-Label Extension − amended
The same primary, secondary and tertiary efficacy outcomes collected during the COMPASS 
trial will be collected during the LTOLE.
Section 7.5 Safety
New text:
The known side effect profile of rivaroxaban can be found in the Investigator Brochure (IB), 
which is updated on a regular basis.  Any new, relevant information about side effects of 
rivaroxaban will be provided to the subject by the investigator or designate.
Long-Term Open-Label Extension − amended
The safety collection requirements for the COMPASS trial will remain unchanged for the 
LTOLE.
Section 8.4 Statistical and analytical plans
New text:
…… This method for date estimation has been used in many studies and is recommended by 
Dubois and Hebert (2001). 
8.4.8 Long-Term Open-Label Extension – amended
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All primary, secondary, tertiary efficacy outcomes and safety outcomes will be summarized 
using frequency table in a descriptive way. Further details will be included in a separate SAP. 
The same subgroup variables as in the COMPASS trial will apply to LTOLE.
Section 9.2 Monitoring
New text:
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor, auditors, and inspectors direct access to all relevant documents.
Long-Term Open-Label Extension – amended
The same details will apply to LTOLE. Any specific considerations for LTOLE will be 
detailed in the Site Management Coordination Plan.
Section 10 Premature termination of the study
New text:…
If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame as agreed upon by the Steering Committee.
Long-Term Open-Label Extension – amended
The same premature termination reasons will apply to LTOLE with the exception of the 
interim analysis.
Section 11.2 Subject information and consent
New text:
……Any revised written informed consent form and written information must receive the 
IEC/IRB`s approval / favorable opinion in advance of use.
Long-Term Open-Label Extension − amended
Documented informed consent will be required for the LTOLE.
Modification 3: Changes made to COMPASS trial after early termination of 
rivaroxaban/aspirin arms.
Section 4.1 Design overview
New text:
……Bayer Global Pharmacovigilance will continue to follow the reported AEs until stabilized 
or resolved.
Amended after early termination of rivaroxaban/aspirin arms
There will be no washout visit following the completion of the final pantoprazole/placebo 
follow-up visit, due to the short half-life of pantoprazole.
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Section 7.1 Schedule of procedures
New text:
A tabulated overview (Table 7−1) of the procedures conducted in each of these periods is 
provided in Section 7.1.1 and the procedures and their timing are described in more detail in 
Section 7.1.2. 
Early termination of rivaroxaban/aspirin arms of COMPASS − amended
On February 6, 2017, the COMPASS Data Safety Monitoring Board (DSMB) recommended 
discontinuation of the rivaroxaban/aspirin arms of the COMPASS trial. The PPI comparison 
of pantoprazole versus pantoprazole placebo is continuing. 
Another update has been added to the revised schedule of evaluation. Specifically, the 
pantoprazole/placebo washout call previously included in the table was removed as shown in 
Table 7−2. 
Section 7.1.1 Tabulated overview
New text:
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Table 7−2 Schedule of evaluations after DSMB recommendation in Feb 2017
Follow-up
Rivaroxaban/ Aspirin
Pantoprazole/placebo
Pantoprazole/placeboj
Visitj
Final Rivaroxaban/ 
Aspirin Follow-up
Rivaroxaban/ Aspirin 
Washout
Pantoprazole/ Placebo Follow-up
Final Pantoprazole/ 
Placebo Follow-up 
Timing
1 m post Rivaroxaban/ 
Aspirin Finalf
6 m post Rivaroxaban/ Aspirin Final
Follow-up and 6 monthly thereafter
Expected in  2018, 
endpoint dependent
Windowsg
Mar – 15 May 2017 ± 5d
± 4w
± 4w
Complete outstanding re-consents X
Physical measurementsa
X
X
Concomitant medications
X
X
Diet and activity questionnaires
MoCA, DSS, and SAGEh 
X
X
X
EQ-5Db
X
X
CT coronary angiographyc
X if 1yr not done yet
MRI braind
X
Outcomes
X
X
X
X
Adverse eventse
X
X
X
X
Study drug dispensedi
Xi
X
Study drug adherence
X
X
X
Study drug accountability
X
X
X
Abbreviations:  w = week; m = month; y = year; d = day; DNA = deoxyribonucleic acid; MoCA = Montreal Cognitive Assessment; DSS = Digit Symbol 
Substitution test; SAGE = Standard Assessment of Global-Activities in the Elderly; EQ-5D = European Quality of Life-5 Dimensions questionnaire; CT = 
computed tomography; MRI = magnetic resonance imaging; CABG = coronary artery bypass graft
a.
Weight, height, waist and hip circumference, heart rate, ankle-brachial blood pressure index
b.
Using the European Quality of Life-5 Dimensions questionnaire and to be performed at year 2 and Final Follow-up Visit  as well as at the next study clinic 
visit after each outcome event
c.
CT angiography will be performed at 1 year or later in all subjects who are randomized Day 4-7 after CABG to evaluate graft patency  (except in subjects 
those with specific contraindications). In the event the subject undergoes an invasive coronary angiography at 1 year or later post CABG for any reason, a 
CT angiogram may not be required. 
d.
MRI of the brain will be performed only in COMPASS-MIND substudy subjects after randomization and near the end of the follow-up
e.
Adverse events will be assessed from time of consent to last dose of study treatment
f.
Telephone visits
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g.
Clinic visits should be scheduled as close to the specified interval as possible, and preferably within the defined window.  If it is not possible for the subject to 
return within the visit "window," especially due to unforeseen circumstance beyond the control of the subject or the study center, then the visit should be 
scheduled as close to the interval as is convenient for the subject and study center. 
h.
Also to be administered at the next study clinic visit after each outcome event
i.
Applicable only for subjects ongoing with pantoprazole/placebo
j.
For subjects from the PPI part, follow up visits will continue regardless of early stoppage of the rivaroxaban/aspirin treatment arms, and there will be no 
washout visit.
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Section 7.1.2.5 End of washout telephone visit (30 days post Final Follow-up Visit ± 5 
days)
New text:
The washout visit will be conducted by study staff via telephone interview.  Washout visit 
assessments include:

Record outcomes 

Record adverse events (if appropriate, complete the Hospitalization CRF to allow 
collection of MRU data)
Amended after early termination of rivaroxaban/aspirin arms
No washout will be scheduled for PPI treatment groups.
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14.
Appendices
14.1
COMPASS MIND substudy - amended
Magnetic resonance imaging (MRI) substudy evaluating the incidence of clinically silent 
brain infarcts and subclinical brain ischemia  (COMPASS-MIND) 
Background: Clinically-evident strokes are the tip of the iceberg of vascular injury to the 
brain.(42) During the past decade, improvements in, and wider application of, magnetic 
resonance imaging (MRI) make it clear that subclinical (i.e., covert) strokes are more frequent 
than clinically-evident brain infarcts. In population-based cohorts with a mean age of 65 
years, the prevalence of covert strokes is between 15% and 20% (i.e., several times the 
prevalence of symptomatic brain infarcts).  Covert strokes are not benign; they are associated 
with cognitive and functional decline and are harbingers of future clinical strokes. Guidelines 
under development are likely to recommend that patients discovered to have covert strokes be 
treated aggressively regarding secondary prevention.
Figure 14–1: Covert brain infarct (arrow) on MR imaging (T-1 sequence)
Most covert brain infarcts in population-based studies are small subcortical strokes (often 
called lacunar infarcts) (see Figure 14–1) for which hypertension is the dominant risk factor. 
Because of their small size, such strokes are clinically unapparent if they do not involve motor 
or sensory tracts. In subjects with clinical vascular disease that will comprise the COMPASS 
trial cohort, the spectrum and underlying pathogenesis of covert strokes is unknown and may 
well be different from those in population-based studies.
There are no published randomized trials aimed at prevention of covert strokes. The 
AVERROES trial compared the novel oral anticoagulant apixaban with aspirin in atrial 
fibrillation patients deemed unsuitable for warfarin anticoagulation and included 1,185 
patients who underwent brain MR imaging at entry. Covert brain infarcts were seen in 20%. 
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The trial was terminated after only one year of follow-up due to efficacy, and the precipitous 
trial close-out resulted in repeat MR imaging in only 80% of those having an MRI at entry.
The AVERROES MRI substudy (unpublished) was thus underpowered to determine the effect 
of apixaban on prevention of covert brain infarcts in atrial fibrillation patients deemed 
unsuitable for warfarin.
Prior epidemiologic investigations have demonstrated that selected biomarkers are 
significantly associated with the future development of cardiovascular events, including 
clinically evident strokes. Several of these markers (e.g., C-reactive protein) have been 
incorporated into clinical risk prediction models which assist clinicians in determining which 
patients are at low, moderate, or high risk of suffering a stroke. Further, our understanding of 
the mechanism of action of antithrombotic drugs has been increased by studying the effect of 
these therapies on biochemical markers associated with atherothrombosis. The 
COMPASS-MIND substudy provides a unique opportunity to examine biomarker as 
predictive of covert brain infarction and to understand how antiplatelet therapies and 
anticoagulants may modify this process. The main objective of COMPASS-MIND biomarker 
testing is to assess the association between selected biomarkers and the risk of overt and 
especially covert stroke in patients with established CAD and PAD. Markers to be measured 
include inflammatory markers (such as C-reactive protein), markers of neuronal injury (such 
as myelin basic protein, S-100B, neuron-specific enolase) and several miscellaneous markers 
(such as troponin, nt-proBNP) that have been shown to be powerful predictors of stroke in 
patients with atrial fibrillation.  DNA collected in these same patients will enable exploration 
of the genetic determinants of stroke, including etiologic subtypes of stroke (cardioembolic, 
large vessel, small vessel disease) and in particular covert subcortical ischemia that is 
demonstrated on brain MRI and is associated with cognitive decline.
Hypotheses:
1. Treatment with rivaroxaban will reduce the incidence of covert brain infarcts (detected by 
blinded comparison of initial vs. end-study MRIs) compared with aspirin among patients with 
symptomatic atherosclerotic vascular disease involving the coronary and lower limb arteries.
2.  The addition of rivaroxaban to aspirin will reduce the incidence of covert brain infarcts 
(detected by blinded comparison of initial vs. end-study MRIs) compared with aspirin among 
patients with symptomatic atherosclerotic vascular disease involving the coronary and lower 
limb arteries.
Pre-specified secondary outcomes would consider the effect of rivaroxaban on (1) non-lacunar 
covert brain infarcts; (2) volume of white matter hyperintensities; (3) all incident strokes, 
including clinical strokes (anticipated rate 1.2%/yr among peripheral arterial disease patients 
and 0.8%/yr among subjects with CAD159), and all covert strokes; (4a) functional decline
(Standard Assessment of Global-Activities in the Elderly [SAGE]) and [4b] cognitive decline 
(Montreal Cognitive Assessment [MoCA] and digit symbol substitution).160  Exploratory 
                                                
159 Text modified/added as per Amendment 6. (See Section 13.1.2)
160 Sentence revised with Amendment 8.  (See Section 13.2.2)
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analyses will examine the predictive value of biomarkers (C-reactive protein, nt-proBNP) as 
independent predictors of covert brain infarcts.
161Design: A phase II trial seeking evidence of efficacy in a convenience sample of 1500 
COMPASS participants with readable baseline MRI scans, 500 assigned to each treatment 
arm, but balanced for age, prior stroke, and hypertension. Participants will undergo limited 
brain MRI sequences (Fluid Attenuated Inversion Recovery [FLAIR]), T-1, T-2, and T-
2*GRE sequences after randomization and near end-study coupled with assessment of 
function (SAGE), and cognition (MoCA, digit symbol substitution).   Recruitment will occur 
at COMPASS sites with access to high-quality (>1.0 Tesla159) reasonably-priced MR imaging.  
Images will be transmitted to the central MR imaging center via discs.  Two-stage central 
interpretation blinded to treatment will be carried-out, with all incident covert infarcts 
confirmed by a second independent interpreter.  The 
has experience with collection and 
analysis of brain MRIs performed in substudies of several randomized trials:  AVERROES, 
PURE, APOLLO, and (planned) TIPS 3 MIND.
Some subjects, in participating centers, will have DNA collected at baseline and blood 
collected at baseline and at the 1 month visit.162 DNA and blood collections are 
optional.(Section 7.1.1, 7.1.2.3 and 7.1.2.4.1)159. The samples will be processed, and aliquots 
will be shipped for long-term storage in liquid nitrogen at the coordinating center in 
 
 Canada.  Blood samples will be processed and stored in such a way to allow future 
analysis of these aliquots for selected biomarkers, some of which have been observed in other 
studies to be predictors of stroke, and others which have a plausible association with 
cardiovascular outcomes.  Detailed information concerning blood collection, processing, 
storage, and shipping is provided in the Manual of Operations.
Power:  There is insufficient information in the literature to accurately estimate the incidence 
of covert brain infarcts for the COMPASS study cohort, but given a 3%/year incidence in 
population-based cohorts of similar age, 5%/yr in the aspirin arm is a conservative estimate. 
Given a sample size of 1500 participants randomized to 1 of 3 treatment arms (i.e. 500 
patients in each treatment group), there will be approximately 70% power to assess a 
treatment effect of rivaroxaban of 45%.  For the key pre-specified secondary analysis of the 
effect of rivaroxaban on the combined clinical and covert ischemic strokes with estimated 
incidence of 7% per year, the study power would be 0.72 to detect a 40% reduction and 0.85 
to detect a 35% reduction.  About 5% of participants will not undergo the second MRI due to 
acquiring a contraindication (e.g., pacemaker), death or refusal, so the power will be slightly 
less.  These power calculations are based on a conservative estimate of the incidence of covert 
brain infarcts during aspirin therapy in the COMPASS population, and higher rates would 
result in increased statistical power. 
Implications:  The COMPASS MRI substudy is the first randomized trial of an anticoagulant 
to prevent covert brain infarcts in patients with atherosclerotic vascular disease. Evidence that 
rivaroxaban reduces covert stroke better than or in addition to aspirin would have an immense 
                                                
161 Sentences revised with Amendments 6 and 8.  (See Sections 13.1.2 and 13.2.2)
162 Sentence revised with Amendment 8.  (See Section 13.2.2)
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potential public health impact.  Within COMPASS trial, the MRI substudy offers an 
opportunity to develop evidence of rivaroxaban efficacy for a separate clinical indication 
applicable to a burgeoning population.
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SAP_003.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
A randomized controlled trial of rivaroxaban for the prevention 
of major cardiovascular events in patients with coronary or 
peripheral artery disease (COMPASS - Cardiovascular OutcoMes 
for People using Anticoagulation StrategieS) 
NCT Number: 
NCT01776424 
Document Date: 
22-JUL-2021 
 
 


Integrated Statistical Analysis Plan
  
Protocol No.: BAY 59-7939/15786
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Integrated Statistical Analysis Plan
A randomized controlled trial of rivaroxaban for the prevention of major 
cardiovascular events in patients with coronary or peripheral artery disease 
(COMPASS - Cardiovascular OutcoMes for People using Anticoagulation 
StrategieS)
Rivaroxaban for the prevention of major cardiovascular events in CAD or PAD (COMPASS)
Bayer study drug
BAY 59-7939 / Rivaroxaban / Xarelto®
Study purpose:
Comparative combination drug study for new indication
Clinical study phase:
III
Date:
31 March 2017
Study No.:
BAY 59-7939/15786
Version:
4.1
Author:
 (Version 1.0)
 (Version 1.0)
 (Version 2.0, 3.0, 4.1)
 (Version 2.0, 3.0, 4.1)
(Version 3.0, 4.1)
(Version 1.0, 2.0, 3.0, 4.1)
 (Version 4.1)
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 Integrated Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Integrated Statistical Analysis Plan is documented in a separate Signature Document.
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Table of Contents
Integrated Statistical Analysis Plan.........................................................................................1
Abbreviations ............................................................................................................................4
1.
Introduction........................................................................................................................5
2.
Study Objectives.................................................................................................................7
3.
Study Design - Amended ...................................................................................................8
4.
General Statistical Considerations .................................................................................17
4.1
General Principles - Amended........................................................................................17
4.2
Handling of Non-compliance to Study Treatment or Follow up....................................17
4.3
Handling of Missing Data...............................................................................................18
4.4
Interim Analyses and Data Monitoring ..........................................................................19
4.5
Data Rules - Amended....................................................................................................20
4.5.1
Analysis Dates.............................................................................................................20
4.5.2
Data Scopes.................................................................................................................23
4.5.3
Censoring Rules for Time-to-Event Variables............................................................24
5.
Analysis Sets .....................................................................................................................27
5.1
Assignment of analysis sets............................................................................................27
5.1.1
Intention-to-Treat Analysis Set (ITT) - Amended ......................................................27
5.1.2
Safety Analysis Set (SAF) - Amended........................................................................27
6.
Statistical Methodology ...................................................................................................27
6.1
Population characteristics...............................................................................................27
6.1.1
Disposition ..................................................................................................................28
6.1.2
Protocol Deviations.....................................................................................................28
6.1.3
Medical and Surgical History......................................................................................29
6.1.4
Outcomes During Run-in Phase..................................................................................29
6.1.5
Demographics..............................................................................................................29
6.1.6
Other Baseline Characteristics ....................................................................................30
6.1.7
Prior and Concomitant Medication .............................................................................30
6.1.8
Extent of Study Follow-up and Exposure - Amended ................................................30
6.2
Efficacy...........................................................................................................................31
6.2.1
Primary Efficacy .........................................................................................................36
6.2.2
Secondary Efficacy .....................................................................................................42
6.2.3
Tertiary Efficacy .........................................................................................................42
6.2.4
Analysis for Pantoprazole Randomization - Amended...............................................45
6.2.5
Efficacy Subgroup Analysis - Amended.....................................................................49
6.2.6
Analyses of the COMPASS MIND Substudy.............................................................52
6.2.7
Exploratory Analyses ..................................................................................................53
6.3
Pharmacokinetics/pharmacodynamics............................................................................54
6.4
Safety..............................................................................................................................54
6.4.1
Primary Safety.............................................................................................................54
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6.4.2
Other Safety Analyses.................................................................................................55
7.
Sample Size Considerations - Amended ........................................................................57
8.
Document History and Changes in the Planned Statistical Analysis..........................61
8.1
Overview Changes to SAP – Amendment 1 ..................................................................61
8.2
Overview Changes to SAP – Amendment 2 ..................................................................61
8.3
Changes to SAP Text by Amendment 2.........................................................................63
8.4
Overview Changes to SAP – Amendment 3.0 ...............................................................69
8.5
Overview Changes to SAP – Amendment 3.1 ...............................................................69
8.6
Changes to SAP Text by Amendment 3.........................................................................71
9.
References.........................................................................................................................86
10. Appendix...........................................................................................................................88
10.1
Regions ...........................................................................................................................88
10.2
EQ-5D.............................................................................................................................88
10.3
Regular and Truncated Hochberg Tests .........................................................................89
10.4
Sensitivity analyses to address the potential impact of missing data .............................90
10.4.1
Definitions...................................................................................................................90
10.4.2
Descriptive comparison of baseline characteristics and post-randomization events ..92
10.4.3
Sensitivity analysis......................................................................................................93
10.4.4
Parameter estimation...................................................................................................96
10.4.5
Generation of random variables ..................................................................................97
10.4.6
Analysis of imputed data sets......................................................................................97
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Abbreviations
ACE
Angiotensin converting enzyme
AE
Adverse event
ARB
Angiotensin receptor blockers
bid
Twice daily
BNP
Brain natriuretic peptide
CABG
Coronary artery bypass graft
CAD
Coronary artery disease
CHD
Coronary heart disease
CI
Confidence interval
COMPASS
Cardiovascular OutcoMes for People using Anticoagulation StrategieS
CRF
Case report form (either paper or electronic)
CSR
Clinical study report
CT
Computed tomography
DNA
Deoxyribonucleic acid
DSMB
Data Safety Monitoring Board 
DSS
Digit Symbol Substitution
eGFR
estimated glomerular filtration rate
EQ-5D
European Quality of Life-5 Dimensions
ESI
Event of special interest
EuroSCORE
European System for Cardiac Operative Risk Evaluation
Hb
Hemoglobin
ICH
International Conference on Harmonization
IPAQ
International Physical Activity Questionnaire
ISTH
International Society on Thrombosis and Haemostasis
ITT
Intention-to-treat
MAR
Missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MoCA
Montreal Cognitive Assessment
MRI
Magnetic resonance imaging
MRU
Medical resource utilization
NRC
National Research Council
NSAID
Non-steroidal anti-inflammatory drugs
NT-proBNP
N-terminal prohormone of brain natriuretic peptide
od
Once daily
PAD
Peripheral artery disease
PASS
Power Analysis and Sample Size software
PPI
Proton pump inhibitor
PT
Preferred term
RRR
Relative risk reduction
SAE
Serious adverse event
SAF
Safety analysis set
SAGE
Standard Assessment of Global-Activities in the Elderly
SAP
Statistical analysis plan
SAS
Statistical Analysis Software
SOC
System organ class
SSRI
Selective serotonin reuptake inhibitors
TLF
Tables, listings, figures
US FDA
United States Food and Drug Administration
VAS
Visual Analog Scale
VTE
Venous thromboembolism
Xa
Activated coagulation factor X
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1.
Introduction
Coronary artery disease (CAD) is the most common cause of cardiovascular disease.  One-third to 
one-half of middle-aged males and females in high income countries are expected to develop 
manifestations of CAD during their lifetime and the number of patients with chronic CAD is rising 
globally.  Coronary heart disease remains responsible for about one-third of deaths in persons over 
the age of 35 years (WHO, 2008 & 2013). 
Peripheral artery disease (PAD) of the lower extremities, while often undiagnosed, is a powerful risk 
marker of cardiovascular disease (Hirsch et al, 2001). The global prevalence of PAD is less well 
studied than that of CAD but screening studies suggest that approximately 20% of adults older than 
55 years have objective evidence of PAD (Hankey et al, 2006).  The severity of PAD is a major 
determinant of subsequent risk of cardiovascular events and mortality.  
Aspirin, statins, and angiotensin converting enzyme (ACE) inhibitors are effective and widely used 
for the prevention of cardiovascular events in patients with CAD or PAD but the risk of vascular 
events remains high despite these treatments.  A new, safe, and convenient antithrombotic therapy 
that further improves efficacy when it is added to or replaces aspirin could have a major impact in 
reducing the individual, community, and global burden of disability and death due to cardiovascular 
disease.  
Rivaroxaban is an orally active anticoagulant that selectively targets activated coagulation factor X 
(Xa), thereby inhibiting thrombin generation and thrombus formation.  Rivaroxaban has been 
demonstrated in large phase 3 randomized controlled trials to be a highly effective antithrombotic 
treatment for the prevention and treatment of venous thromboembolism, the prevention of stroke and 
systemic embolism in patients with atrial fibrillation, and the prevention of major cardiovascular 
events in patients with recent acute coronary syndrome. The evidence of efficacy of rivaroxaban for 
the prevention of atherothrombotic events on a background of dual antiplatelet therapy in patients 
with recent acute coronary syndrome supports the hypothesis that it may also be effective for 
prevention of atherothrombotic events in patients with established CAD or PAD, receiving usual 
care.1  
The study described in this Statistical Analysis Plan (SAP), Cardiovascular OutcoMes for People 
using Anticoagulation StrategieS (COMPASS), is a randomized double-blind trial utilizing a 3 x 2 
partial factorial design that will evaluate the efficacy and safety of:

rivaroxaban 2.5 mg twice daily (bid) + aspirin 100 mg once daily (od) versus aspirin 100 mg 
daily and 

rivaroxaban 5 mg bid versus aspirin 100 mg od 
for the prevention of myocardial infarction, stroke, and cardiovascular death in patients with 
established CAD or PAD who are receiving standard prevention therapies.  The hypotheses are (a) 
that the combination of rivaroxaban and aspirin compared with aspirin alone will substantially 
reduce the risk of myocardial infarction, stroke, or cardiovascular death and that this benefit will 
readily outweigh any potential2 increase in bleeding and (b) that rivaroxaban compared with aspirin 
                                                
1 Text modified as per integrated CSP, Version 2.0.
2 Text modified as per integrated CSP, Version 2.0.
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will reduce the risk of myocardial infarction, stroke, or cardiovascular death and that this benefit 
will not be accompanied by a clinically relevant increase in major bleeding.  
In the (partial factorial) randomization, patients without a continuous3 need for a proton pump 
inhibitor will be randomized to receive pantoprazole 40 mg od or placebo for the prevention of 
major upper gastrointestinal complications.
An independent Data Safety Monitoring Board (DSMB) will monitor efficacy and safety of the 
studied medications and give recommendations to the steering committee as to whether to continue, 
modify or stop the study.
This SAP contains definitions of analysis sets, key derived variables, and statistical methods for 
analysis of efficacy and safety for the COMPASS study. It provides a technical and detailed 
elaboration of the principal features of the planned analyses, e.g., censoring schemes for time-to-
event variables. Amendments and/or appendices to this SAP may be used to provide more details on 
the coding guidelines, data-handling, and output tables and figures. These SAP-associated 
documents will be finalized ideally 6 months before the planned study end to take into account 
emerging data external to the trial becoming available during conduct of the trial that could 
influence study interpretation. All SAP associated documents will be finalized without knowledge of 
any emerging results by treatment group from the trial.
An amendment of the integrated SAP, Version 3.0, became advisable based on a recommendation 
received from the DSMB to the Study Chair and Co-Principal Investigators, dated February 06, 
2017. The DSMB recommended that treatment arms rivaroxaban 2.5 mg bid + aspirin 100 mg daily, 
rivaroxaban 5.0 mg bid, and aspirin 100 mg daily be stopped as soon as an orderly close-out of this 
portion of the COMPASS study could be carried out. The DSMB made this recommendation 
because they found upon performing the first interim analysis that one of the rivaroxaban arms 
reached the critical value for early efficacy, as outlined in the DSMB charter. Therefore, the Steering 
Committee decided to stop the rivaroxaban/aspirin arms of the study for overwhelming efficacy.
The SAP Amendment v3.1, integrated in SAP, Version 4.1, was written fully blinded to the 
treatment allocation with the intent to fully preserve the statistical analyses that have been outlined 
in the protocol and the previous version of the SAP. It seeks to clarify some aspects pertaining to the 
interim analysis and to reflect the wording and additional close-out visits prompted by the premature 
stop of the anti-thrombotic study treatment arms. In addition, it includes a detailed description of the 
sensitivity analyses planned to explore the potential impact of missing data on the primary analysis.4
This integrated statistical analysis plan for the final analysis of the study is based on the integrated 
clinical study protocols, Version 3.0, and the integrated SAP, Version 3.0, dated 23 January 2017, 
which includes Amendment v2.0. All changes to the SAP, Versions 1.0, 2.0, and 3.0, are described 
in Section 8.
Titles, mock-ups and programming instructions for all statistical output (tables, figures, and listings 
[TLF]) are provided in a separate TLF specifications document.
                                                
3 Text modified as per integrated CSP, Version 2.0.
4 Text modified as per integrated SAP, Version 4.1.
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2.
Study Objectives
Primary objective for rivaroxaban randomization

To determine whether rivaroxaban 2.5 mg bid + aspirin 100 mg od compared with aspirin 
100 mg od reduces the risk of a composite of myocardial infarction, stroke, or cardiovascular 
death in subjects with CAD or PAD

To determine whether rivaroxaban 5 mg bid compared with aspirin 100 mg od reduces the 
risk of a composite of myocardial infarction, stroke, or cardiovascular death in subjects with 
CAD or PAD
Secondary objectives for rivaroxaban randomization

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and rivaroxaban 
5 mg bid alone reduces the risk of the composite of major thrombotic events: coronary heart 
disease death, myocardial infarction, ischemic stroke, and acute limb ischemia, compared 
with aspirin 100 mg od in subjects with CAD or PAD5

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and rivaroxaban 
5 mg bid alone reduces the risk of the composite of major thrombotic events: cardiovascular 
death, myocardial infarction, ischemic stroke, acute limb ischemia, compared with aspirin 
100 mg od in subjects with CAD or PAD6

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and rivaroxaban 5 
mg bid alone reduces the risk of mortality compared with aspirin 100 mg od in subjects with 
CAD or PAD 
Tertiary objective for rivaroxaban randomization

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and rivaroxaban 
5 mg bid alone preserves the ability to perform everyday activities independently in subjects 
with CAD or PAD

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and rivaroxaban 
5 mg bid alone reduces the incidence of hospitalization for any cause compared with aspirin 
100 mg od in subjects with CAD or PAD

To collect medical resource utilization data to be incorporated in economic modeling for 
subjects with CAD or PAD
Objective for pantoprazole randomization

To determine whether pantoprazole 40 mg od compared with placebo reduces the risk of 
upper gastrointestinal bleeding, ulceration, or gastrointestinal obstruction or perforation in 
subjects with CAD or PAD receiving antithrombotic medications
                                                
5 Text modified as per integrated CSP, Version 3.0.
6 Text modified as per integrated CSP, Version 3.0.
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Objectives for (Day 4-7) post-coronary artery bypass graft (CABG) randomization 7

To determine whether each of rivaroxaban 2.5 mg bid + aspirin 100 mg od and rivaroxaban 
5 mg bid alone reduces the risk of bypass graft failure compared with aspirin 100 mg od

To determine the association between post CABG graft failure and risk of a composite of 
myocardial infarction, stroke, or cardiovascular death in subjects with CAD or PAD
Substudy objectives
The COMPASS-MIND substudy will examine the effect of the antithrombotic therapies being tested 
in COMPASS on covert cerebral ischemia, thereby providing additional information about 
mechanisms of disease and treatment benefits.8  COMPASS-MIND will be conducted concurrently 
with the main study in a subset of subjects at selected centers. 
3.
Study Design - Amended9
This Phase 3, event-driven (according to the CSP: at least 2,200 subjects with unrefuted10 primary 
efficacy outcome events), randomized controlled trial will have a 3 x 2 partial factorial design and 
will randomize at least 27,40011 subjects who will receive study treatment for an expected average 
duration of 3 to 4 years.  
The study schedule comprises 4 periods:  

screening, 

run-in, 

follow-up, and 

washout.  
The trial will require clinic visits at screening (in most cases this visit is expected to coincide with 
the run-in visit), run-in, randomization, 1 and 6 months after randomization, and at least every 6 
months thereafter until the end of the study.  Study staff will contact subjects by phone at Month 3, 
Month 9, and at the End of Washout Telephone Visit (30 days post Final Follow-up Visit).  Some 
centers may also perform pre-screening visits.  
An overview of the procedures conducted in each of these periods is provided in Table 3-2.
                                                
7 Text added as per integrated CSP, Version 2.0.
8 Text modified as per integrated CSP, Version 3.0.
9 Text modified as per modification 1 in integrated SAP, Version 4.1.
10 Text added as per modification 1 in integrated SAP, Version 3.0.
11 Text modified as per integrated CSP, Version 3.0.
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Screening
Screening will be performed to determine subject eligibility and will include the review of inclusion 
and exclusion criteria, the collection of medical history, physical measurements, and laboratory 
evaluations.  
Run-in
The run-in period will occur during the 2812 days prior to initiation of randomized study treatment, 
with the exception of subjects who are randomized after CABG surgery, who will not undergo a 
run-in phase.  During run-in, eligible subjects who have signed informed consent and discontinued 
any antithrombotic13 therapy will receive rivaroxaban placebo bid and aspirin 100 mg od.  Study 
pantoprazole or pantoprazole placebo will not be administered during the run-in period. 
Randomization
Subjects who have successfully completed the run-in period (intention is to ensure at least 80% 
adherence to treatment with rivaroxaban placebo bid and aspirin 100 mg od except for extenuating 
circumstances) and14 who remain committed to the study as well as those who are being randomized 
after CABG will be randomized and begin study treatments on Day 1, which will also signal the 
initiation of the follow-up period. Initially, subjects without a continuous15  need for treatment with 
a proton pump inhibitor will be randomized 1:1 to

pantoprazole 40 mg od or 

matching placebo od, 
stratified by center.  
All subjects (including those subjects who entered the study while already receiving a proton pump 
inhibitor) will then be randomized 1:1:1 to anticoagulant therapy stratified by center and by proton 
pump inhibitor use (randomized to pantoprazole, randomized to pantoprazole placebo, and not 
randomized, because subject is already taking a proton pump inhibitor) as shown below:
Group A:  rivaroxaban 2.5 mg bid + aspirin 100 mg od
Group B:  rivaroxaban 5.0 mg bid + aspirin placebo od
Group C:  rivaroxaban placebo bid + aspirin 100 mg od
This leads to combinations of randomized study treatment, as displayed in Table 3-1.   
                                                
12 Text modified as per integrated CSP, Version 2.0.
13 Text modified as per integrated CSP, Version 2.0.
14 Text modified as per integrated CSP, Version 2.0.
15 Text modified as per integrated CSP, Version 2.0.
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Table 3-1.  Randomized study treatments* 
Treatment 
Group
Study Treatment Assignments
A
Rivaroxaban 2.5 mg bid +
Aspirin 100 mg od +
Pantoprazole 40 mg od
Rivaroxaban 2.5 mg bid +
Aspirin 100 mg od +
Pantoprazole placebo od
B
Rivaroxaban 5 mg bid + 
Aspirin placebo od + 
Pantoprazole 40 mg od
Rivaroxaban 5 mg bid + 
Aspirin placebo od +
Pantoprazole placebo od
C
Rivaroxaban placebo + 
Aspirin 100 mg od +
Pantoprazole 40 mg od
Rivaroxaban placebo + 
Aspirin 100 mg od + 
Pantoprazole placebo od
*Subjects who have a continuous need for use of a proton pump inhibitor at baseline will undergo only a single 
randomization (to rivaroxaban 2.5 mg bid + aspirin 100 mg od, rivaroxaban 5 mg bid + aspirin placebo or rivaroxaban 
placebo + aspirin 100 mg od)
All doses will be provided in tablet form for oral administration. Subjects, site personnel, sponsor 
personnel, 
 staff (with few exceptions, see protocol), 
persons performing the assessments, and data analysts (other than the DSMB associated statistician) 
will remain blinded to the identity of the study treatments from the time of randomization until 
database lock.  
Medical history, concomitant medication, adverse events (AEs), as well as study treatment 
adherence during the run-in phase will be assessed.  Validated questionnaires will be administered to 
collect data on subject health and quality of life (Standard Assessment of Global-Activities in the 
Elderly [SAGE], Montreal Cognitive Assessment [MoCA], Digital Symbol Substitution [DSS], 
European Quality of Life-5 Dimensions [EQ-5D], The Interheart Diet Questionnaire, and The 
International Physical Activity Questionnaire [IPAQ]), if this information was not yet obtained at 
the Screening / Run-in Visit.  
Follow-up
Subjects will be seen in the clinic at 1 month and at 6 months after randomization and at 6 month 
intervals thereafter in order to collect information on study treatment adherence, study treatment 
interruption, outcomes, and adverse events (AEs).  Data on the questionnaires will be collected at 
the Month 24 Visit.  The SAGE, MoCA, DSS, and EQ-5D will also be administered at the next 
study clinic visit after each outcome event.16  All subjects will be followed for the duration of the 
study, irrespective of whether they are receiving study treatments or whether an event has occurred. 
Additional follow-up visits will be conducted by telephone at Months 3 and 9.  
Final rivaroxaban/aspirin Follow-up Visit17
The primary analysis will be based on the events that occur after the date and time of randomization 
and up until the global rivaroxaban/aspirin outcomes cut-off date (February 06, 2017, the date of the 
DSMB recommendation to stop the rivaroxaban/aspirin study treatment arms).  At the Final 
rivaroxaban/aspirin Follow-up Visit, subjects will be asked to stop taking all randomized 
                                                
16Text modified as per integrated CSP, Version 3.0. 
17 Text added as per modification 1 in integrated SAP, Version 4.1.
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rivaroxaban and aspirin study treatment, while study treatment with randomized 
pantoprazole/pantoprazole placebo can continue as planned. 
Rivaroxaban/aspirin Washout Telephone Visit18
A rivaroxaban/aspirin Washout Telephone Visit will be conducted by telephone about 30 days after 
the Final rivaroxaban/aspirin Follow-up Visit to collect information on outcomes and protocol 
specific adverse events. 
Note: the rivaroxaban/aspirin Washout Telephone Visit is equivalent to the end of study for those 
subjects who have not been randomized to pantoprazole/placebo.
Final (pantoprazole/placebo) Follow-up Visit and end of study19
The analysis, as pertains to the pantoprazole randomization, will be based on the events that occur 
after the date and time of randomization and up until the Final Follow-up Visit, also referred to as 
“Final pantoprazole/placebo Follow-up Visit”.  Subjects ongoing in the pantoprazole arms will
remain in follow-up until the end of study, irrespective of whether they are still taking study 
treatments or whether they have experienced an outcome.  At the Final Follow-up Visit the 
following information will be obtained from the subject: study treatment adherence, study treatment 
interruption, outcomes and adverse events, physical measurements and concomitant medications, 
and questionnaires (except for the Interheart Diet Questionnaire and the IPAQ).  Subjects will be 
asked to stop taking randomized pantoprazole/placebo study treatment. The Final Follow-up Visit 
(close out is expected to occur over a period of about 3 months)20 and the subsequent 30-day 
washout period will occur nearly simultaneously (as scheduling permits) for all study subjects.  
End of pantoprazole/placebo Washout Telephone Visit21
A pantoprazole/placebo Washout Visit (End of Washout Telephone Visit) will be conducted by 
telephone about 30 days after the Final pantoprazole/placebo Follow-up Visit to collect information 
on outcomes and protocol specific adverse events.  Adverse events will continue to be collected up 
to 30 days post study drug treatment with pantoprazole/placebo.
An overview describing these visits and the data to be included in different type of analyses is given 
in Figure 3-1.
                                                
18 Text added as per modification 1 in integrated SAP, Version 4.1.
19 Text modified as per modification 1 in integrated SAP, Version 4.1.
20 Text modified as per integrated CSP, Version 3.0.
21 Text modified as per modification 1 in integrated SAP, Version 4.1.
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Figure 3-1: Study visits and analyses22
Premature discontinuation
All subjects will be encouraged to remain on study treatments and under observation for the full 
duration of the study.  If a subject stops taking study treatment early, the reason for this permanent 
discontinuation will be recorded in the case report form (CRF).  
It is important to note that discontinuation of study treatment is not the equivalent to withdrawal of 
informed consent.  Additionally, withdrawal of consent does not withdraw permission to collect 
vital status.  In cases where subjects indicate they do not want to “continue”, investigators must 
determine whether this refers to discontinuation of study treatment (the most common expected 
scenario), unwillingness to attend follow-up visits, unwillingness to have telephone contact, 
unwillingness to have any contact with study personnel, or unwillingness to allow contact with a 
third party (e.g., family member, doctor).  In all cases, including the subjects who have had any of 
the primary study outcome events, every effort must be made to continue to follow the subject at 
regular study visits.23 Additionally, survival status and outcome information must be determined for 
all subjects.24
                                                
22 Figure added as per modification 1 in integrated SAP, Version 4.1.
23 Text modified as per integrated CSP, Version 3.0.
24 Text modified as per integrated CSP, Version 2.0.
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Table 3-2.  Schedule of evaluations25
Pre-Screeninga
Screening/
Run-in
Randomizations,26
Follow-up
Washout
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15n
Final 
Rivaroxaban/ 
aspirin
Rivaroxaban/ 
aspirin 
Washout
Final
pantoprazole 
/placebo
Final
Pantoprazole/
placebo 
Washout
Timing
-4w
0
1 m 3mm 6m 9mm
1y
1.5y
2y
2.5y
3y
3.5y
4y
4.5y
5y
30d post
Final 
Rivaroxaban/ 
aspirinm
1 m post 
Final
pantoprazole
/placebom
Windowsq,26
± 5d ± 7d ± 2w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w
± 5d
± 4w
± 5d
Informed consent (if required for 
pre-screening)
X
Informed consent
Xr,26
Inclusion/exclusion criteria
X
X
X26
Demographics
X
Medical history
X
Physical measurementsb
X
X
X
X
Concomitant medications
X
X
X
X
X
Pregnancy test if pre-
menopausal
X
Laboratory testsc
Xd
Xe
                                                
25 Table modified as per integrated CSP, Versions 2.0 and 3.0 and modification 1 in SAP, Version 4.0.
26 Added as per Amendment 6. (See Section 13.1.2)
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Pre-Screeninga
Screening/
Run-in
Randomizations,26
Follow-up
Washout
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15n
Final 
Rivaroxaban/ 
aspirin
Rivaroxaban/ 
aspirin 
Washout
Final
pantoprazole 
/placebo
Final
Pantoprazole/
placebo 
Washout
Timing
-4w
0
1 m 3mm 6m 9mm
1y
1.5y
2y
2.5y
3y
3.5y
4y
4.5y
5y
30d post
Final 
Rivaroxaban/ 
aspirinm
1 m post 
Final
pantoprazole
/placebom
Windowsq,26
± 5d ± 7d ± 2w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w
± 5d
± 4w
± 5d
Blood/DNA collection and 
storage
Xf
Xf
Diet and activity questionnaires
Xo
Xo Xp,27
X
MoCA, DSS, and SAGE t, 28
Xo
Xo Xp,27
X
X
X
EQ-5Dg
Xo
Xo Xp,27
X
X
X
Health Care Costs
X
Driving Status
X
EuroSCORE for subjects 
randomized post CABG surgery
X
CT coronary angiographyh
Xh
X
MRI braini
X
X
X
Outcomes
X27
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug dispensed
Xk
Xl
X
X
X
X
X
X
X
X
X
X
Xu
                                                
27 Added as per Amendment 6. (See Section 13.1.2)
28 Footnote added as per Amendment 8 (See Section 13.3.3)
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Pre-Screeninga
Screening/
Run-in
Randomizations,26
Follow-up
Washout
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15n
Final 
Rivaroxaban/ 
aspirin
Rivaroxaban/ 
aspirin 
Washout
Final
pantoprazole 
/placebo
Final
Pantoprazole/
placebo 
Washout
Timing
-4w
0
1 m 3mm 6m 9mm
1y
1.5y
2y
2.5y
3y
3.5y
4y
4.5y
5y
30d post
Final 
Rivaroxaban/ 
aspirinm
1 m post 
Final
pantoprazole
/placebom
Windowsq,26
± 5d ± 7d ± 2w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w ± 4w
± 5d
± 4w
± 5d
Study drug adherence
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xu
Study drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
Xu
Abbreviations:  w = week; m = month; y = year; d = day; DNA = deoxyribonucleic acid; MoCA = Montreal Cognitive Assessment; DSS = Digit Symbol 
Substitution test; SAGE = Standard Assessment of Global-Activities in the Elderly; EQ-5D = European Quality of Life-5 Dimensions questionnaire; CT = 
computed tomography; MRI = magnetic resonance imaging; CABG = coronary artery bypass graft
a. Pre-screening visit is not mandatory and will be conducted only in some centers and for some subjects. Subjects who will be randomized Day 4-7 after 
CABG surgery do not require pre-screening.
b. Weight, height, waist and hip circumference, heart rate, ankle-brachial blood pressure index
c. Serum creatinine, total cholesterol
d. If not available within 1 year prior. 
e. Repeat serum creatinine in patients being enrolled Day 4-7 post CABG surgery.  For other, non-CABG subjects, the blood results of creatinine and total 
cholesterol should be available within 3 months of this visit. 
f.
Collection of blood & DNA samples for central evaluation in subjects participating in the COMPASS-MIND substudy is optional. If collected, obtain samples at 
randomization, before starting the study drug, and at 1 month, or as close to one month after randomization as possible. If the first blood sample is not 
collected before start of study drug, it is not required. Irrespective of whether the first blood sample is obtained, collect the second blood sample at 1 month. If 
either the DNA sample or second blood sample is missed, it should be collected at the next visit. 
g. Using the European Quality of Life-5 Dimensions questionnaire and to be performed at screening/run-in or randomization (see “o”), year 2 and Final Follow-
up Visit  as well as at the next study clinic visit after each outcome event
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h. CT angiography will be performed at 1 year or later in all subjects who are randomized Day 4-7 after CABG to evaluate graft patency  (except in subjects 
those with specific contraindications). In the event the subject undergoes an invasive coronary angiography at 1 year or later post CABG for any reason, a 
CT angiogram may not be required. 
i.
MRI of the brain will be performed only in COMPASS-MIND substudy subjects after randomization and near the end of the follow-up
j.
Adverse events will be assessed from time of consent to 30 days post last dose of study treatment
k. Stop treatment with non-study aspirin.  Dispense run-in medications. CABG surgery patients will be randomized Day 4-7 after CABG surgery and will not be 
dispensed run-in study drug; however, the Screening/Run-In Visit CRFs are still required to be completed for these subjects.  
l.
Stop run-in medication and begin randomized treatment assignment
m. Telephone visits
n. Visits will continue every 6 months until the required number of primary efficacy outcomes has been collected
o. It is optional to administer all or some of the questionnaires (SAGE, DSS, MoCA, EQ-5D, Diet, and Physical Activity) at Screening/Run-in instead of at the 
Randomization Visit, or as soon as possible thereafter (with the exception of patients randomized Day 4-7 post CABG; see “p”).   
p. For patients randomized Day 4-7 post CABG, questionnaires (SAGE, DSS, MoCA, EQ-5D, Diet, and Physical Activity) should be performed at the 1 month 
visit. 
q. Clinic visits should be scheduled as close to the specified interval as possible, and preferably within the defined window.  If it is not possible for the subject to 
return within the visit "window," especially due to unforeseen circumstance beyond the control of the subject or the study center, then the visit should be 
scheduled as close to the interval as is convenient for the subject and study center. 
r.
CABG subjects can sign the informed consent before or after surgery. 
s. CABG subjects should be randomized between Day 4-7 after the surgery. In the event that a subject is unable to be randomized within this time range for 
medical and logistical reasons, the subject can be randomized, up to Day 14 post-CABG.
t.
Also to be administered at the next study clinic visit after each outcome event.
u. Pantoprazole/pantoprazole placebo study treatment only.
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4.
General Statistical Considerations
4.1
General Principles - Amended
The statistical evaluation will be performed by using the software package SAS release 9.2 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, 
quartiles (inter quartile range), median, and maximum will be calculated for metric data. Frequency 
tables will be generated for categorical data.
Primary outcome events (myocardial infarction, stroke, CV death), selected secondary and tertiary 
outcome events (acute limb ischemia, heart failure, venous thromboembolism, cancer), as well as 
bleeding and GI events will undergo an event adjudication process to evaluate whether events 
reported by investigators meet the pre-specified trial definitions. A reported and adjudicated event is 
designated “unrefuted” if it does meet the specified definition or “refuted” if it does not. Primary 
statistical analyses will be based on unrefuted events. In addition, all reported events will 
summarized. 29
4.2
Handling of Non-compliance to Study Treatment or Follow up30
A subject who signed an informed consent form, and, for any reason (e.g., failure to satisfy the in-
and exclusion criteria) terminates the study without dispensation of run-in study drug and without 
run-in exemption for peri-operative CABG, is regarded as a “screening failure”.
A subject who signed an informed consent form and either received run-in study drug or was 
scheduled for randomization after peri-operative CABG surgery, and, for any reason (e.g., non-
compliance during run-in phase or failure to satisfy the in- and exclusion criteria) terminates the 
study before randomization, is regarded as a “run-in phase failure”.
A randomized subject who permanently stops taking study treatment before their Final 
rivaroxaban/aspirin Follow-up Visit (for rivaroxaban/aspirin) or their Final pantoprazole/placebo 
Follow-up Visit (for pantoprazole/placebo) for any reason is defined as having had a premature 
permanent discontinuation of study treatment (including subjects who were randomized but never 
started taking any study treatment). The reason for permanent discontinuation of study treatments 
will be recorded in the CRF. Subjects who continued on rivaroxaban/aspirin study treatment until 
the global rivaroxaban/aspirin outcomes cut-off date but stopped rivaroxaban/aspirin study treatment 
before their Final rivaroxaban/aspirin Follow-up Visit will still be considered as study 
rivaroxaban/aspirin follow-up completers. 
However, all subjects will be encouraged to remain on their randomized and pertinent (to the portion 
of the study) study treatments and under observation until the end of the study.  Discontinuation of 
study treatment is not the equivalent to withdrawal of informed consent.  In cases where subjects 
indicate they do not want to “continue”, investigators must determine whether this refers to 
discontinuation of study treatment, unwillingness to attend follow-up visits, unwillingness to have 
                                                
29 Text added as per modification 1 in integrated SAP, Version 3.0.
30 Text modified as per modification 1 in integrated SAP, Version 4.1.
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telephone contact, unwillingness to have any contact with study personnel, or unwillingness to allow 
contact with a third party (e.g., family member, doctor).  Every effort will be made to continue to 
follow the subject. Additionally, survival status and outcome information must be determined for all 
subjects at the end of the study.31  The expectation is that only very few subjects will have 
incomplete follow-up (in any form) within this trial.
A subject will be declared to have incomplete follow-up or to be lost to follow-up (i.e., to be 
completely non-compliant to follow-up) if, despite of all possible efforts, all investigators, dedicated 
site staff, the National Leader’s Office and/or 
 Project Office (as applicable and as local 
regulations allow) are not able to contact the subject or to retrieve information about the subject 
from32 a third party (e.g., family member, doctor).  Every possible effort will be made to contact the 
subject or a third party and to determine the endpoint and survival status and reason for 
discontinuation as local law permits.  If it is documented in the database that the subject is alive at 
the global rivaroxaban/aspirin outcomes cut-off date / at the end of the study, the subject will not be 
classified as lost to follow-up, but as alive.
4.3
Handling of Missing Data
All missing or partial data will be presented in the subject data listing as they are recorded on the 
CRF including best estimate dates of site investigators (see below) collected in the clinical database. 
All efforts will be made to collect complete data for all subjects randomized in this study.  Subjects 
will be followed to the study end and will complete all required data collection, regardless of their 
compliance with study medications or visits. 
Missing or incomplete event dates
When an event date is not known, the site investigator will be asked to provide a best estimate as to 
when the event occurred.  Even though the exact date of an event is unknown, the investigator often 
does know some information that would indicate the approximate date, such as the first week of a 
month, in the fall of a year, or the middle of a particular year, or at least the date when the subject 
was last seen or contacted.  This information can be meaningfully incorporated into the estimated 
date recorded, as this is likely to be closer to the true date than any produced by an uninformed 
computer program.  This estimated date should be the middle date within the period that the event is 
known to have occurred.  If the event is known to have occurred in the first week of a month, then 
the date in the middle of that week should be recorded as the estimate.  If it occurred in the fall of a 
year, then the middle date in the fall is the appropriate estimate.  If no information is known then the 
date in the middle of the plausible time period should be given, based on the last contact with the 
subject prior to the event and the date of contact when information about the event was known.  This 
method for date estimation has been used in many studies and is recommended by Dubois and 
Hebert (2001) (6).
If the site investigator does not provide a best estimate as to when the event occurred, the study team 
at 
 will follow the above rules to estimate the event date. If the date/time information is not 
sufficient to determine whether an event occurred prior or after randomization, the event is 
                                                
31 Text modified as per integrated CSP, Version 2.0.
32 Text modified as per SAP amendment 1.0.
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considered as an outcome, to be conservative.  The event start date will be imputed no earlier than 
randomization date.
4.4
Interim Analyses and Data Monitoring
Interim assessments and study monitoring for efficacy and safety will be done by an independent 
DSMB, which will review unblinded event rates. An independent statistician within 
 who is 
not involved with any study conduct, will perform interim data analyses to support the DSMB. The 
description below is largely according to the study protocol. Any further details of the interim 
analyses will be specified in a separate interim statistical analysis plan and/or the DSMB charter.
Two formal interim analyses are planned when 50% (about 1,100) and 75% (about 1,650) of the 
expected number of accumulated primary efficacy outcome events (2,200 subjects with an 
unrefuted33 event) accrue. 
If the interim analyses show clear and consistent benefit in both rivaroxaban treatment groups, the 
DSMB may recommend early study termination.  The Haybittle-Peto rule will be used to guide the 
decision regarding early stopping of some or all of the study treatment groups:  a reduction of 4 
standard deviations in the analysis of the primary efficacy outcome at the first interim analysis (one-
sided p-value < 0.0001) or 3 standard deviations at the second interim analysis (one-sided p-value < 
0.0014).  If the monitoring boundary is crossed at either of the 2 interim analyses, a second look will 
be done after at least an additional 3-6 months34 to confirm the boundary remains crossed and that 
the trend in treatment effect is not temporary.
For a lack of efficacy, a futility approach will be utilized at the time of planned interim analysis. If 
the conditional probability of rejecting the null hypothesis for either primary comparisons, given 
current trends, falls to an unacceptably low level (i.e., <5%), the DSMB may consider 
recommending early termination of the study.
Given these conservative monitoring boundaries and only 2 interim analyses, the type I error level 
adjustment for the final analysis will be negligible.  
If the results are clear with one intervention, but not for the second intervention, the DSMB may 
decide to continue evaluation of both or one rivaroxaban treatment arms. If the study is continued 
with both interventions, then the type I error levels specified in Section 6.2 will be used in the final 
analysis; if the decision is made to continue with only one intervention, the final comparison will be 
made as follows:35

If one intervention was stopped early for efficacy, the multiple testing procedure for the final 
analysis will be performed as described in Section 6.2 with the assumption that the p-value 
for the primary efficacy outcome of the arm that was stopped early for overwhelming 
efficacy is smaller than 0.025. For secondary outcomes, the p-values will be obtained from 
log-rank tests based on all available data for the stopped arm (data from confirmation 
analysis 6 months after respective interim look) and the complete data from the comparator 
arm.
                                                
33 Text added as per modification 1 in integrated SAP, Version 3.0.
34 Text modified as per modification 3 in integrated SAP, Version 3.0.
35 Text modified as per integrated CSP, Version 3.0.
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
If one intervention was stopped early for futility, the final analysis will be performed when at 
least 1,513* subjects in the two remaining arms have experienced an event.
The final analysis will be performed according to the multiple testing strategy as described in 
in Section 6.2.  P-values for the primary and secondary hypotheses for the intervention 
stopped early will be obtained from the log-rank tests based on all available data for the 
stopped arm and the complete data from the comparator arm. It can be assumed that for the 
stopped intervention the corresponding p-value of the primary efficacy outcome will be 
greater than 0.05. Thus, for the intervention stopped early for futility the primary and none of 
the secondary outcomes can achieve statistical significance at the overall type I error level of 
5%.  
*The whole study was planned to be stopped when at least 2,200 subjects had experienced an unrefuted36
primary outcome event. Under the planning assumptions that both alternative hypotheses are true, observed 
randomization times and estimated overall incidence rates based on preliminary data, and projected study 
duration after sample size increase, it is expected that 826 subjects in the control arm and each 687 subjects in 
the rivaroxaban intervention arms will experience a primary outcome event. Dropping one intervention arm 
early but still expecting that for the other comparison the alternative hypothesis holds true, the study needs to be 
continued until at least 826 + 687 = 1,513 subjects in the remaining arms have experienced a primary event.
The steering committee will review overall blinded event rates to ensure that they meet protocol 
projections.  If overall event rates are lower than expected, consideration will be given to increasing 
the sample size or extending the study duration without knowledge of any treatment effect.  The trial 
will aim to enroll about one-quarter subjects with PAD37; this will be monitored during the trial and 
steps may be taken to adjust the proportion during the trial.
The analyses to be performed for the interim analyses include analyses for the primary and 
secondary efficacy outcomes, the primary safety outcome and other safety outcome analyses, and 
adverse events of special interest. In addition, any analyses requested by the DSMB will be 
performed to assess the efficacy and safety of all study treatments.  In addition to these formal 
interim analyses, the DSMB may regularly review unblinded data as outlined in the DSMB charter.
4.5
Data Rules - Amended38
4.5.1
Analysis Dates
A common trial close-out window and a close out (cut-off) date will be chosen by a study committee 
for the COMPASS trial.  All subjects will return to the clinic for a Final Follow-Up Visit within this 
pre-specified acceptable close-out time-window (about 3 months39; period ends with the common 
trial close-out date, see below).  
Based on the DSMB recommendation after the first interim analysis and the early close-out of the 
rivaroxaban/aspirin study treatment portion of the study, some of the previously defined analysis 
dates became less important or dispensable for the rivaroxaban/aspirin randomization, while 
additional dates had to be added. 
                                                
36 Text added as per modification 1 in integrated SAP, Version 3.0.
37 Text modified as per integrated CSP, Version 3.0.
38 Text modified as per modification 1 in integrated SAP, Version 4.1.
39 Text modified as per integrated CSP, Version 3.0.
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
Rivaroxaban/aspirin arms close-out window: 
The pre-specified target calendar date range within which subjects are to return to the clinic 
for a Final rivaroxaban/aspirin Follow-up Visit planned to range from end of February 2017
to 15 May 2017.

Global rivaroxaban/aspirin outcomes cut-off date:
The global rivaroxaban/aspirin outcomes cut-off date is 06 February 2017, i.e., the date when 
the DSMB recommended to stop the study treatment arms rivaroxaban 2.5 mg bid + aspirin 
100 mg daily, rivaroxaban 5.0 mg bid, and aspirin 100 mg daily as soon as an orderly close-
out of this portion of the study could be carried out. Outcome events that occur up until the 
global rivaroxaban/aspirin outcomes cut-off date (inclusive) will be counted in the primary 
analysis, otherwise the subject will be censored at the global rivaroxaban/aspirin outcomes 
cut-off date.

Common trial close-out window: 
The pre-specified acceptable calendar date range within which subjects ongoing in the 
pantoprazole/placebo portion of the study are to return to the clinic for a Final Follow-Up 
Visit (e.g. about 3 months).

Common trial close-out date:
The common trial close out (cut-off) date is the end date of the common trial close-out 
window.  It is the last calendar date acceptable for counting events, prior to the washout 
period.  
If a subject who is unable to attend his/her Final Follow-up Visit within the acceptable 
common trial close-out time-window, has a trial-related contact after the common trial close-
out date, the observation period up until the common trial close-out date (inclusive) will be 
considered in the analysis.
For each subject, the following individual analysis dates will be derived:

Randomization date: 
The date of randomization to antithrombotic treatment of the subject. 

Date of the Final rivaroxaban/aspirin Follow-up Visit:
The date of the Final rivaroxaban/aspirin Follow-up Visit for the individual subject. 
If subjects do not have a Final rivaroxaban/aspirin Follow-up Visit, the date will be missing.

Final (pantoprazole/placebo) Follow-Up Visit date:
The date of the Final (pantoprazole/placebo) Follow-Up Visit for the individual subject. 
Beginning with the announcement of trial close-out, all subjects ongoing in the 
pantoprazole/placebo portion of the study are to return to the clinic for their Final Follow-Up 
Visit within the pre-specified common trial close-out window (see Section 3 for the schedule 
of evaluations at the Follow-Up Visit). If subjects do not have a Final Follow-Up Visit, the 
date will be missing.

Rivaroxaban/aspirin Washout Telephone Visit date:
The date of the rivaroxaban/aspirin Washout Telephone Visit for the individual subject. To 
be performed about 30 days after the Final rivaroxaban/aspirin Follow-up Visit.
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
End of pantoprazole/placebo Washout (Telephone) Visit date:
The date of the End of pantoprazole/placebo Washout Visit for the individual subject.
To be performed about 30 days after the Final pantoprazole/placebo Follow-up Visit.
If subjects do not have an End of pantoprazole/placebo Washout Visit, the date will be 
missing.

Last contact date during rivaroxaban/aspirin portion of the study:
The date of the last documented contact with the subject or a third party up until the 
maximum (later) of the subject’s {date of the Final rivaroxaban/aspirin Follow-up Visit, end 
of rivaroxaban/aspirin Washout date}. For subjects who died after randomization but before 
their scheduled end of rivaroxaban/aspirin Washout date, the date of the last 
rivaroxaban/aspirin related contact is set to the death date.

Date of the last follow-up contact:
The date of the last known documented contact with the subject or a third party (including 
data on subject survival status)
- up until the Final Follow-up Visit date (inclusive), if the subject attends his/her Final 
Follow-up Visit or
- up until the common trial close-out date, if the subject does not attend his/her Final Follow-
up Visit. 
For subjects who die (a) after randomization but before the beginning of the common trial 
close-out window or (b) during the common trial close-out window but before their Final 
Follow-up Visit takes place, the date of the last follow-up contact is set to the death date.
This date is only applicable to analyses for pantoprazole/placebo comparisons at the end of 
the study.

Date of the last trial contact:
The date of the last known documented contact with the subject or a third party (including 
data on subject survival status).

Date of last double-blind dose of antithrombotic study treatment: 
The later date of 
- the last dose of rivaroxaban/rivaroxaban placebo study medication and  
- the last dose of aspirin / aspirin placebo study medication.  
For a subject with premature permanent discontinuation of any study medication, the 
corresponding last dose date(s) will be obtained from the Permanent Discontinuation CRF 
Report. If study medication was continued until the Final rivaroxaban/aspirin Follow-up 
Visit, the date of the last dose of the corresponding study treatment will be the date of the 
Final rivaroxaban/aspirin Follow-up Visit.
If missing or incomplete, the date of last double-blind dose of antithrombotic study treatment 
is set to the latest logically possible date of antithrombotic study medication administration 
on or before the earliest of the subject’s following dates, the date of the last contact for the 
rivaroxaban/aspirin comparison, the date of death, or the end of the rivaroxaban/aspirin arms 
close-out window, and no earlier than the randomization date.  

Date of last double-blind dose of pantoprazole study treatment: 
The date of the last dose of pantoprazole / pantoprazole placebo study medication of a 
subject randomized to pantoprazole.  
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For a subject with premature permanent discontinuation of pantoprazole/pantoprazole 
placebo study medication, the last dose date will be obtained from the Permanent 
Discontinuation CRF Report. If pantoprazole/pantoprazole placebo study medication was 
continued until the Final Follow-up Visit, the date of the last dose of pantoprazole / 
pantoprazole placebo study medication will be the date of the Final Follow-up Visit.
If missing or incomplete, the date of last double-blind dose of pantoprazole study treatment 
is set to the latest logically possible date of pantoprazole study medication administration on 
or before the earliest of the subject’s following dates, the date of last follow-up contact, the 
date of death, or the common trial close-out date, and no earlier than the randomization date. 
4.5.2
Data Scopes
The analysis, as pertains to the rivaroxaban/aspirin randomization, will be based on all data collected 
for a randomized subject until end of the rivaroxaban/aspirin portion of the study, or until the time of 
loss to follow-up with no indication that the subject returned, or complete refusal to provide 
additional information.
The analysis, as pertains to the pantoprazole/placebo randomization, will be based on all data 
collected for a randomized subject until end of study, or until the time of loss to follow-up, or 
complete refusal to provide additional information.40
This section describes the coverage of the event data scopes used for the statistical analyses. 
Analysis sets are described in Section 5.
Data scope for rivaroxaban/aspirin randomization according to intention-to-treat principle
For the rivaroxaban/aspirin comparisons performed after the DSMB recommendation related to the 
results of the first interim analysis, analyses according to the intention-to-treat (ITT) principle will 
be based on the intention-to-treat analysis set (see Section 5.1.1) and will include all outcome events 
that occur after the date and time of randomization and up until the global rivaroxaban/aspirin 
outcomes cut-off date (inclusive) for each subject.  Events occurring after the global 
rivaroxaban/aspirin outcomes cut-off date will not be counted for primary analysis (see also Section 
4.5.1).  Subjects will be kept in the study group to which they were randomized.  This ITT data 
scope will be applied to the analysis of the primary efficacy and safety variables, following the 
intention-to-treat principle. (“ITT” data scope)
Additional data scopes for the rivaroxaban/aspirin randomization
Sensitivity analyses for the primary efficacy outcomes will be based on all outcome events occurring 
after the date and time of randomization and up until the Final rivaroxaban/aspirin Follow-up Visit 
(inclusive) for each subject. (“Rivaroxaban/aspirin Follow-up” data scope)
Data scope for the pantoprazole/placebo randomization according to intention-to-treat 
principle
Analyses according to the intention-to-treat (ITT) principle will be based on the intention-to-treat 
analysis set (see Section 5.1.1) and will include all outcome events that occur after the date and time 
of randomization and up until the Final Follow-up Visit (inclusive) for each subject.  For subjects 
                                                
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who are unable to attend the Final Follow-up Visit within the acceptable common close-out time-
window (range of dates from announcement of trial close-out up to the common trial close-out date), 
events occurring after the common trial close-out date will not be counted (see also Section 4.5.1).  
Subjects will be kept in the study group to which they were randomized and the follow-up period for 
each subject will be as long and complete as possible.  
Additional data scopes for secondary safety analyses for the rivaroxaban/aspirin 
randomization
Additional secondary analyses of safety outcomes will be based on the safety analysis set (see 
Section 5.1.2). Subjects will be kept in the study group to which they were randomized. Additional 
data scopes will be defined to include all outcome events as follows:

All outcome events for each subject occurring after the date and time of randomization and 
up until the global rivaroxaban/aspirin outcomes cut-off date (inclusive) (“ITT” data scope)

All outcome events occurring after the date and time of randomization and up until 2 days 
following permanent discontinuation of double-blind antithrombotic study treatment 
documented in the database (“treatment emergent outcomes” data scope)

All outcome events occurring after the date and time of randomization and up until 30 days 
following permanent discontinuation of double-blind antithrombotic study treatment
documented in the database (“plus 30 days safety” data scope)

All outcome events occurring after the date and time of randomization during the entire 
individual rivaroxaban/aspirin follow-up and wash-out periods documented in the database 
(“Rivaroxaban/aspirin Follow up + Wash out” data scope)
Data scopes for safety analyses for the pantoprazole/placebo randomization
Analyses of safety outcomes for the pantoprazole randomization will be based on the safety analysis 
set related to the pantoprazole randomization. Subjects will be kept in the study group to which they 
were randomized. The outcome events will include:

All outcome events observed from randomization until 2 days following permanent 
discontinuation of the pantoprazole study drug (“treatment emergent outcomes” analysis)

All outcome events observed from randomization during the entire follow-up and wash-out 
periods up until the end of the trial
Corresponding censoring rules are described in Section 4.5.3.
4.5.3
Censoring Rules for Time-to-Event Variables
For any time-to-event variable in this study, the following censoring rules will be applied: 
Censoring rules for analyses related to the rivaroxaban/aspirin randomization according to 
the intention-to-treat principle

For analyses according to the intention-to-treat principle which are related to the 
rivaroxaban/aspirin randomization and performed after the DSMB recommendation, 
randomized subjects without documentation of an evaluable event will be censored at 
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o
the minimum (earliest) of the global rivaroxaban/aspirin outcomes cut-off date and 
the subject’s last contact date during the rivaroxaban/aspirin portion of the study.
This censoring rule will be applied to all analyses according to the intention-to-treat 
principle. In the rare event that for a subject only survival status information can be retrieved 
at the end of the study rivaroxaban/aspirin portion of the trial but no information on other 
outcomes, the last study rivaroxaban/aspirin follow-up contact where survival status 
information was obtained will still be used to determine the censoring date for the subject 
and if there were no known events up to then the subject will be considered as event-free. 
Censoring rules for analyses related to the pantoprazole/placebo randomization according to 
the intention-to-treat principle

For analyses according to the intention-to-treat principle, randomized subjects without 
documentation of an outcome41 event will be censored at 
o
the subject’s Final Follow-Up Visit if the subject attends the Final Follow-Up Visit 
before the common trial close-out date.
o
the subject’s date of last follow-up contact up to the common trial close-out date 
(inclusive) if (a) the subject does not attend his/her Final Follow-Up Visit before the 
common trial close-out date and (b) the subject’s date of last trial contact is not after 
the common trial close-out date. 
o
the common trial close-out date if (a) the subject does not attend his/her Final 
Follow-Up Visit before the common trial close-out date and(b) the subject’s date of 
last trial contact is after the common trial close-out date.
This censoring rule will be applied to all analyses related to the pantoprazole/placebo
randomization performed after common trial close-out according to the intention-to-treat 
principle. In the rare event that for a subject only survival status information can be retrieved 
at the end of the study but no information on other outcomes, the last follow-up / trial contact 
where survival status information was obtained will still be used to determine the censoring 
date for the subject and if there were no known events up to then the subject will be 
considered as event-free. 
Censoring rules for secondary safety analyses related to the rivaroxaban/aspirin 
randomization

For secondary safety analyses based on the safety analysis set and the ITT data scope, all 
randomized subjects with at least one dose of either randomized study medication and 
without documentation of an outcome42 event within the ITT data scope will be censored as 
stated above for study rivaroxaban/aspirin analyses according to the ITT principle.

For “treatment-emergent” secondary safety analyses, all randomized subjects with at least 
one dose of study medication and without documentation of an outcome43 event within the 
                                                
41 Text modified as per modification 1 in integrated SAP, Version 3.0.
42 Text modified as per modification 1 in integrated SAP, Version 3.0.
43 Text modified as per modification 1 in integrated SAP, Version 3.0.
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“treatment-emergent” data scope will be censored at the date of last double-blind dose of 
antithrombotic study treatment + 2 days.  
Note that if a subject stops treatment at the Final rivaroxaban/aspirin Follow-up Visit and 
experiences an event up to 2 days thereafter, the event will be counted in this analysis but not 
in the primary analysis using the ITT data scope.

For secondary safety analyses based on the safety analysis set and the “plus 30 days safety” 
data scope, all randomized subjects with at least one dose of study medication and without 
documentation of an outcome44 event within the “plus 30 days safety” data scope will be 
censored at the date of last double-blind dose of antithrombotic study treatment + 30 days.  
Note that if a subject stops treatment at the Final rivaroxaban/aspirin Follow-up Visit and 
experiences an event up to 30 days thereafter, the event will be counted in this analysis but 
not in the primary analysis using the ITT data scope.

For secondary safety analyses based on the safety analysis set and the “Study 
rivaroxaban/aspirin Follow up + Wash out” data scope, all randomized subjects with at least 
one dose of study medication and without documentation of an outcome45 event will be 
censored at the subject’s last contact date during the rivaroxaban/aspirin portion of the study.
Censoring rules for secondary safety analyses related to the pantoprazole/placebo
randomization

For “treatment-emergent” safety analyses, all randomized subjects with at least one dose of 
pantoprazole/placebo study medication and without documentation of an outcome46 event 
within the “treatment-emergent” data scope will be censored at the date of last dose of 
pantoprazole study treatment + 2 days.

For safety analyses based on the safety analysis set and the “Follow up + Wash out” data 
scope, all randomized subjects with at least one dose of pantoprazole/placebo study 
medication and without documentation of an outcome47 event will be censored at the date of 
last trial contact.
                                                
44 Text modified as per modification 1 in integrated SAP, Version 3.0.
45 Text modified as per modification 1 in integrated SAP, Version 3.0.
46 Text modified as per modification 1 in integrated SAP, Version 3.0.
47 Text modified as per modification 1 in integrated SAP, Version 3.0.
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5.
Analysis Sets
5.1
Assignment of analysis sets
All subjects who have been randomized in the COMPASS study are valid for assignment to analysis 
sets.
5.1.1
Intention-to-Treat Analysis Set (ITT) - Amended
The intention-to-treat analysis set, also termed full analysis set in the International Conference on 
Harmonization (ICH) E9 guideline, will include all unique48 randomized subjects. 
If a subject is unintentionally randomized twice in the study, the subject will be included in the 
statistical analysis with the ID from the site where the initial randomization took place. Data from 
the randomization at the second site will be documented and reported49.
5.1.2
Safety Analysis Set (SAF) - Amended50
The safety analysis set for secondary analyses related to the rivaroxaban/aspirin randomization will 
include all unique randomized subjects who received at least one dose of rivaroxaban/aspirin study 
medication. 
The safety analysis set for secondary analyses related to the pantoprazole randomization will include 
all unique randomized subjects who received at least one dose of randomized pantoprazole/placebo
medication. 
6.
Statistical Methodology
All data will be listed and all variables will be summarized by means of descriptive statistics 
according to their type.
Summaries by randomized antithrombotic study treatment group using appropriate descriptive 
statistics will be provided for all study variables including demographic and baseline characteristics.  
No imputation will be applied, unless specified otherwise in the SAP.  Descriptive statistics such as 
mean, standard deviation, median, quartiles (inter quartile range), minimum, and maximum will be 
used to summarize continuous variables.  Counts and percentages will be used to summarize 
categorical variables.  Life tables and Kaplan-Meier estimates will be used to summarize time-to-
event variables.  Graphical data displays may also be used to summarize the data.  Confidence 
intervals will be provided at a 2-sided level of 95% unless otherwise stated.
6.1
Population characteristics
Note that all summaries related to the pantoprazole randomization described in this section of the 
SAP will only be provided at the end of the pantoprazole portion of the study. 
                                                
48 Text added as per modification 4 in integrated SAP, Version 3.0.
49 Text added as per modification 4 in integrated SAP, Version 3.0.
50 Text modified as per modification 1 in integrated SAP, Version 4.1.
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6.1.1
Disposition
The following will be tabulated overall and/or by antithrombotic treatment group:

Study sample sizes by region and country

Study sample sizes by country and site

Subject disposition

Number of subjects and primary reasons for screening failures 

Number of subjects and primary reasons for run-in phase failures 

Number of subjects eligible for pantoprazole randomization

Number of subjects and primary reasons for premature permanent discontinuation of study 
medication (for each type of randomized study medication, as applicable regarding the 
portion of the study)

Number of subjects and primary reasons for premature permanent discontinuation of study 
follow up
The number of subjects randomized after CABG surgery will be displayed. 
Incidences for permanent discontinuation of the double-blinded antithrombotic study drug(s) and of 
the follow-up period will be provided by randomized antithrombotic study treatment groups, based 
on the case report form data.  In addition, incidences for permanent discontinuation of the double-
blinded pantoprazole study drug and of the follow-up period will be provided by pantoprazole 
treatment groups, including the group of subjects not considered eligible for pantoprazole 
randomization, based on the case report form data.  
Kaplan-Meier estimates will be used to present

time to the date of last double-blind dose of antithrombotic study treatment (calculated as 
days from randomization),

time to the date of last double-blind dose of pantoprazole study treatment (after completion 
of pantoprazole/placebo portion of the study), and 

time to the date of last follow-up contact,  
all calculated as days from randomization, by randomized (antithrombotic or pantoprazole) study 
treatment group.   
Other details regarding visit adherence (e.g., visit completed in person, by telephone, through third 
party) and completion as well as study drug adherence collected via CRFs will be summarized using 
frequency tables by visit and randomized antithrombotic study treatment group.
6.1.2
Protocol Deviations
No per protocol analysis set will be defined in this study.  The number of subjects with major 
protocol deviations according to the CRF will be summarized by randomized antithrombotic study 
treatment group. The types of deviations will be described in the Data Management Plan.
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6.1.3
Medical and Surgical History
Medical history data will be evaluated by frequency tables, showing the number of subjects with 
medical history findings (i.e., listed conditions of previous diagnoses, diseases, or surgeries based on 
the CRF) that started before signing of the informed consent and that are considered relevant to the 
study.
For subjects randomized after CABG surgery, all characteristics of the CABG surgery collected on 
the corresponding randomization CRF page will be summarized. 
6.1.4
Outcomes During Run-in Phase
The number of subjects with events since enrollment but before randomization (as reported on the 
Randomization CRF page) will be summarized by event type.
6.1.5
Demographics
Demographic data (obtained at the Screening Visit) will be evaluated descriptively for the ITT 
population as well as for the population for secondary safety analyses, by randomized 
antithrombotic study treatment groups, by proton pump inhibitor (PPI) study treatment groups, and 
overall.
Descriptive statistics (such as mean, standard deviation, median, quartiles (inter quartile range), 
minimum and maximum) will be provided for continuous variables such as 

Age [years] 

Height [cm]

Weight [kg] 

Waist and hip circumference [cm]

Body mass index [kg/m²]
Counts and (appropriate) percentages will be provided for categorical variables such as

Gender

Ethnic group and ethnicity/race

Tobacco use
The number of subjects taking a proton pump inhibitor at baseline will be summarized by 
medication name. 
For subjects randomized after CABG surgery, the pre-operative standard additive EuroSCORE 
(European System for Cardiac Operative Risk Evaluation) model will be applied. The EuroSCORE 
is a scoring system for the prediction of operative mortality for subjects undergoing cardiac surgery, 
where higher scores suggest a higher risk. The total score obtained will be summarized by 
descriptive statistics and frequency tables using the categories based on EuroSCORE classification 
(0-2, 3-4, 5+). 
Furthermore, frequency tables will be used to summarize adherence prediction data obtained at the 
Screening / Run-in Visit.
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Data on health care costs and driving status will be listed in the Appendix of the Clinical Study 
Report.
6.1.6
Other Baseline Characteristics
The number of subjects falling in the categories of the list of subgroup variables, see subsection 
6.2.5, will be summarized by means of frequency tables, by both randomized antithrombotic and 
pantoprazole study treatment groups and overall. 51
In addition, the number and proportion of subjects who

prematurely discontinued randomized study treatment (by medication type)

have been declared as lost to follow-up 
will be summarized by the baseline characteristics listed above and study medication.
6.1.7
Prior and Concomitant Medication
Frequency tables will be used to summarize the number of subjects with

prior relevant antiplatelet agents and anticoagulant reported by the subject at the 
Screening/Run-in Visit

type of proton pump inhibitor reported by the subject at the Screening/Run-in Visit

relevant concomitant medications at randomization (non-study medications taken regularly 
for at least 1 month at the time of the randomization visit): non-study proton pump inhibitor, 
ACE inhibitor/ Angiotensin receptor blocker (ARB), alpha blocker or other vasodilator, 
diuretic, lipid lowering agent, calcium channel blocker, beta blocker, Non-steroidal anti-
inflammatory drugs (NSAIDs), hypoglycemic agent, selective serotonin reuptake inhibitors 
(SSRIs).

non-study antithrombotic therapy (antiplatelet agents and anticoagulant) reported at the 
scheduled follow-up visits

relevant concomitant medications recorded at a Follow-Up Visit 2 years after randomization

relevant concomitant medications recorded at the Final rivaroxaban/aspirin Follow-Up Visit 
and the Final Follow-Up Visit.
Non-study medications reported on any of the event reports (e.g., angina, heart failure, AEs) will be 
displayed separately. 
6.1.8
Extent of Study Follow-up and Exposure - Amended52
The total duration of study follow-up for a subject in the rivaroxaban/aspirin portion of the study and 
overall will be calculated as follows:

Total duration of <rivaroxaban/aspirin, study> follow-up = 
Date of last <rivaroxaban/aspirin, study> follow-up contact  –  Randomization date + 1.
                                                
51 Text modified as per modification 5 in integrated SAP, Version 3.0.
52 Text modified as per modification 1 in integrated SAP, Version 4.1.
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Total duration of antithrombotic study treatment will be calculated as follows:

Total duration of antithrombotic study treatment (including days on/off study drug) = 
Date of last double-blind dose of antithrombotic study treatment –  
Randomization date + 1  
For the different types of study medication, total treatment duration will be calculated as:

Total duration of study treatment <type> (including days on/off study drug) = 
Date of last dose of study treatment <type> – Randomization date + 1, 
where <type> is replaced by rivaroxaban(/rivaroxaban placebo), aspirin(/aspirin placebo), 
and pantoprazole(/pantoprazole placebo).
Descriptive statistics for total duration of study follow-up and study treatment will be provided by 
treatment group.  
Because the number of days off study drug cannot be reliably determined from the CRF data, no 
study duration excluding study drug interruptions or compliance will be calculated.  However, the 
number and length of study drug interruptions and/or study drug dose reductions as far as 
documented on any CRF page will be summarized by means of descriptive statistics by randomized 
study treatments. 
Frequency tables will be used to summarize compliance to study drug since last visit (i.e., at least 
80% of pills taken) by visit and randomized study treatments.
6.2
Efficacy
Unless otherwise specified, all statistical tests will be interpreted at a 2-sided type I error level of 
= 0.05 and all confidence intervals at a 2-sided level of 95%.  Due to the conservative boundaries 
according to Haybittle – Peto used for interim analyses, no adjustment will be performed for the 
final primary efficacy analysis. 
Primarily, for time-to-event analyses the censoring mechanism will be assumed to be non-
informative due to an anticipated low non-cardiovascular death rate and almost complete follow-up 
for outcomes within this trial (according to expectations). Subjects will be handled as right-censored 
in primary time-to-event analyses. For the unexpected case that sensitivity analyses are needed, 
please refer to Section 6.2.7.
The trial success will be determined based on the totality of evidence for significance, magnitude, 
and direction of treatment effect from the analysis of primary and secondary efficacy outcomes. 53
The recommendation by the independent DSMB to stop the rivaroxaban/aspirin arms early due to 
overwhelming efficacy after the first interim analysis was guided by a modified Haybittle-Peto rule, 
expecting “a reduction of at least 4 standard deviations in the analysis of the primary efficacy 
outcome”. The 2-sided type I error level corresponding to this decision rule can be calculated via 
* = Φ(-4) + 1 – Φ(4) = 0.0000633, where Φ denotes the cumulative distribution function of the 
standard normal distribution.  Considering the two comparisons, one for each rivaroxaban-treatment 
                                                
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arm, being made according to this rule, the type I error level applied at the first interim analysis is 
about 1 = 2* = 0.0001267. 54
Testing strategy55
Each of the rivaroxaban-based treatment groups will first be compared to the common aspirin 
control group on the primary efficacy outcome, followed by the same comparisons on the three 
ordered secondary efficacy outcomes.  Figure 6-1 illustrates the hypothesis testing problem with 
ordered hypotheses. The null hypotheses of no effect corresponding to different efficacy outcomes 
will be grouped into four separate families. Standard logical restrictions will be imposed, i.e., the 
null hypotheses will be split into two branches corresponding to the tests for rivaroxaban 2.5 mg
plus aspirin (hypotheses H1A, H2A, H3A, H4A) and to the tests for rivaroxaban 5.0 mg (hypotheses 
H1B, H2B, H3B, H4B).  A null hypothesis within each branch can be tested if and only if the 
immediately preceding null hypothesis is rejected, e.g., hypothesis H2A, is “testable” if and only if 
hypothesis H1A is rejected. In Figure 6-1, these logical restrictions are represented by arrows.
Figure 6-1: Hypothesis testing problem
Multiple hypotheses testing will be performed according to a mixture gatekeeping procedure based 
on the Hochberg test with a truncation fraction of γ = 0.9, which controls the familywise error rate at 
the pre-assigned level of significance α = 5% in the strong sense.  The Hochberg-based gatekeeping 
procedure based on an extension of the general mixture methodology developed in Dmitrienko and 
Tamhane (2011, 2013) (3, 4) was recently proposed in Brechenmacher et al., 2011 (1).  It has found 
multiple applications in Phase III clinical trials.  For example, it was successfully applied to 
construct powerful gatekeeping procedures in lurasidone Phase III clinical trials (Meltzer et al., 2011
[16]; Brechenmacher et al., 2011 [1]).  
The Hochberg-based gatekeeping procedure provides strong Type I error rate control across the four 
families of null hypotheses. Key features of the Hochberg-based gatekeeping procedure include:
                                                
54 Text modified as per modification 2 in integrated SAP, Version 4.1.
55 Text added as per integrated CSP, Version 3.0.
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
The gatekeeping procedure accounts for the logical restrictions defined above.  

The gatekeeping procedure utilizes powerful Hochberg-type tests for testing the hypotheses 
within each family:
o
Families 1 to 3: Truncated Hochberg test.
o
Family 4: Regular Hochberg test.
Formal definitions of the regular and truncated Hochberg tests are given in Appendix 10.3.  

The gatekeeping procedure uses the truncated Hochberg test in Families 1 to 3 because the 
families serve as gatekeepers for the next family in the sequence.  The regular Hochberg test 
is applied in Family 4 since this is the last family in the testing sequence.  Thanks to the 
truncated Hochberg test, the gatekeeping procedure can pass a gatekeeper even if only one 
test is significant in this gatekeeper (for example, proceed to Family 2 if only one of the two 
rivaroxaban regimen is significantly different from aspirin control in Family 1).  The 
truncated Hochberg tests in Families 1 to 3 are defined using a pre-specified truncation 
parameter γ, here γ = 0.9. 
It is important to point out that the regular and truncated Hochberg tests control the local Type I 
error rate within each family of hypotheses.  The test statistics within each family follow a bivariate 
normal distribution with a positive correlation and thus the positive dependence condition (MTP2 
condition), which guarantees local familywise error rate control, is met (Sarkar and Chang, 1997
[18]; Sarkar, 1998 [19]).  Further, the Hochberg-based gatekeeping procedure does not make any 
assumptions about the correlations across the four families of hypotheses. 
In the following, a simple stepwise algorithm of the Hochberg-based gatekeeping procedure for the 
COMPASS study based on a truncation fraction of γ = 0.9 is described in detail. A truncation 
fraction γ close to 1 has been chosen to ensure a high probability of success for the primary 
hypotheses, considering that potentially only a small fraction of is carried forward to the next 
family of hypotheses. 
Step 1 (Family 1): 
The two dose-placebo comparisons in Family 1 (Hypotheses H1A and H1B) will be performed using a 
truncated Hochberg test with the pre-specified truncation parameter γ = 0.9 at =0.05. Consider the 
null hypotheses H1A and H1B and their associated raw p-values p1A and p1B.
(a)
If max(p1A, p1B) ≤α (1+γ)/2 = 0.0475,
then 
reject both hypotheses H1A and H1B and continue with Step 2a.
(b)
If max(p1A, p1B) > α (1+γ)/2 = 0.0475 and 
  
    min(p1A, p1B) ≤α/2 = 0.025,
then
accept Hik, for all i = 1,2,3,4 where k ϵ {A,B} corresponds to 
the hypothesis yielding the larger of the two p-values and 
reject H1j, where j ϵ {A,B} corresponds to the hypothesis yielding 
the smaller of the two p-values and continue with Step 2b.
(c)
If max(p1A, p1B) > α (1+γ)/2 = 0.0475 and 
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    min(p1A, p1B) > α/2 = 0.025,
then
accept Hik, for all i = 1,2,3,4 and all k = A,B and stop. 
Step 2 (Family 2):
The overall significance level used in Family 2 is determined by the number of significant tests in 
Step 1. If both null hypotheses H1A and H1B are rejected in Step 1, continue with Step 2a. If only one 
null hypothesis is rejected in Step 1, the corresponding null hypothesis will be tested according to 
Step 2b.
Step 2a: 
The two dose-placebo comparisons in Family 2 (Hypotheses H2A and H2B) will be performed using a 
truncated Hochberg test with the pre-specified truncation parameter at the full =0.05. Consider 
the null hypotheses H2A and H2B and their associated raw p-values p2A and p2B.
(a)
If max(p2A, p2B) ≤α (1+γ)/2 = 0.0475,
then 
reject both hypotheses H2A and H2B and continue with Step 3a.
(b)
If max(p2A, p2B) > α (1+γ)/2 = 0.0475 and 
   
    min(p2A, p2B) ≤α/2 = 0.025,
then
accept Hik, for all i =2,3,4, where k ϵ {A,B} corresponds to 
the hypothesis yielding the larger of the two p-values and 
reject H2j, where j ϵ {A,B} corresponds to the hypothesis yielding
the smaller of the two p-values and continue with Step 3b.
(c)
If max(p2A, p2B) > α (1+γ)/2 = 0.0475 and 
   
    min(p2A, p2B) > α/2 = 0.025,
then
accept Hik, for all i = 2,3,4 and all k = A,B and stop. 
Step 2b: Consider the null hypothesis H2j, where j ϵ {A,B} corresponds to null hypothesis H1j
rejected in step 1, and its associated raw p-value p2j. Null hypothesis H2j will be tested using the 
univariate test at (1- γ)/2.
(a)
If p2j ≤(1- γ)/2= 0.0025,
then 
reject H2j and continue with Step 3b.
(b)
If p2j > (1- γ)/2= 0.0025,
then
accept Hij, for all i = 2,3,4 and stop.
Step 3 (Family 3):
The overall significance level used in Family 3 is determined by the number of significant tests in 
Steps 1 and 2. If all null hypotheses are rejected in Steps 1 and 2, continue with Step 3a. 
If both null hypotheses are rejected in Step 1 and one null hypothesis is rejected in Step 2 or if one 
null hypothesis is rejected in Step 1 and one null hypothesis is rejected in Step 2, continue with Step 
3b.
Step 3a: The two dose-placebo comparisons in Family 3 (Hypotheses H3A and H3B) will be 
performed using a truncated Hochberg test with the pre-specified truncation parameter at the full 
=0.05. Consider the null hypotheses H3A and H3B and their associated raw p-values p3A and p3B.
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(a)
If max(p3A, p3B) ≤α (1+γ)/2 = 0.0475,
then 
reject both hypotheses H3A and H3B and continue with Step 4a.
(b)
If max(p3A, p3B) > α (1+γ)/2 = 0.0475 and 
    min(p3A, p3B) ≤α/2 = 0.025,
then
accept Hik, for all i = 3,4 where k ϵ {A,B} corresponds to 
the hypothesis yielding the larger of the two p-values and 
reject H3j, where j ϵ {A,B} corresponds to the hypothesis yielding
the smaller of the two p-values and continue with Step 4b.
(c)
If max(p3A, p3B) > α (1+γ)/2 = 0.0475 and 
    min(p3A, p3B) > α/2 = 0.025,
then
accept Hik, for all i = 3,4 and all k = A,B and stop.
Step 3b: Consider the null hypothesis H3j, where j ϵ {A,B} corresponds to null hypothesis H2j
rejected in step 2, and its associated raw p-value p3j. Null hypothesis H3j will be tested using the 
univariate test at (1- γ)/2.
(a)
If p3j ≤(1- γ)/2= 0.0025,
then 
reject H3j and continue with Step 4b.
(b)
If p3j > (1- γ)/2= 0.0025,
then
accept Hij, for all i = 3,4 and stop.
Step 4 (Family 4):
The overall significance level used in Family 4 is determined by the number of significant tests in 
Steps 1, 2, and 3. If all null hypotheses are rejected in Steps 1 to 3, continue with Step 4a. If both 
null hypotheses are rejected in Step 1 and 2 and one null hypothesis is rejected in Step 3 or if both 
null hypotheses are rejected in Step 1 and one null hypothesis is rejected in Steps 2 and 3 or if one 
null hypothesis is rejected in Steps 1 to 3, continue with Step 4b.
Step 4a: The two dose-placebo comparisons in Family 4 (Hypotheses H4A and H4B) will be 
performed using a regular Hochberg test at the full =0.05. Consider the null hypotheses H4A and 
H4B and their associated raw p-values p4A and p4B.
(a)
If max(p4A, p4B) ≤α = 0.05,
then 
reject both hypotheses H4A and H4B.
(b)
If max(p4A, p4B) > α = 0.05 and 
    min(p4A, p4B) ≤α/2 = 0.025,
then
accept H4k, where k ϵ {A,B} corresponds to 
the hypothesis yielding the larger of the two p-values and 
reject H4j, where j ϵ {A,B} corresponds to the hypothesis yielding
the smaller of the two p-values.
(c)
If max(p4A, p4B) > α = 0.05 and
    min(p4A, p4B) > α/2 = 0.025,
then
accept H4k, for all k = A,B. 
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Step 4b: Consider the null hypothesis H4j, where j ϵ {A,B} corresponds to null hypothesis H3j
rejected in step 3,  and its associated raw p-value p4j. Null hypothesis H4j will be tested using the 
univariate test at (1- γ)/2.
(a)
If p4j ≤(1- γ)/2= 0.0025,
then 
reject H4j.
(b)
If p4j > (1- γ)/2= 0.0025,
then
accept H4j.
6.2.1
Primary Efficacy
6.2.1.1
Primary Efficacy Variable
The primary efficacy variable is the time (in days) from randomization to the first occurrence of the 
following primary efficacy outcome events:

Myocardial infarction 

Stroke 

Cardiovascular death 
All unrefuted56 primary efficacy outcome events within the data scope according to intention-to-treat 
principle (see Section 4.5.2) will be considered for the derivation of the primary efficacy variable.

For those subjects with documentation of an unrefuted57 primary efficacy outcome event 
occurring
after the date and time of randomization and up until the minimum (earliest) of the 
global rivaroxaban/aspirin outcomes cut-off date and the subject’s last contact date 
during the rivaroxaban/aspirin portion of the study58
time (in days) from randomization to the first occurrence of the primary efficacy outcome 
will be derived as: 
o
the date of the subject’s first primary efficacy outcome event 
–  the randomization date + 1. 
This will constitute an uncensored observation.

For those subjects without documentation of an unrefuted59 primary efficacy outcome event 
within the data scope according to intention-to-treat principle, 
time (in days) from randomization to the first occurrence of the primary efficacy outcome 
will be derived as:
                                                
56 Text modified as per modification 1 in integrated SAP, Version 3.0.
57 Text modified as per modification 1 in integrated SAP, Version 3.0.
58 Text modified as per modification 1 in integrated SAP, Version 4.1.
59 Text modified as per modification 1 in integrated SAP, Version 3.0.
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o
the minimum (earliest) of {the global rivaroxaban/aspirin outcomes cut-off date, the 
subject’s last contact date during the rivaroxaban/aspirin portion of the study}  –  the 
randomization date +1.60
This will constitute a right-censored observation.
6.2.1.2
Primary Efficacy Analysis
Analysis of the primary efficacy outcome will be based on the intention-to-treat principle.  Two 
comparisons will be performed to compare each of the rivaroxaban-based treatment groups to the 
common aspirin-control group to evaluate:

Superiority of rivaroxaban 2.5 mg bid + aspirin 100 mg od over 
rivaroxaban placebo + aspirin 100 mg od (control)

Superiority of rivaroxaban 5 mg bid + aspirin placebo over 
rivaroxaban placebo + aspirin 100 mg od (control).
The primary null hypothesis H0;riva2.5: 
“There is no difference between 
the rivaroxaban 2.5 mg bid + aspirin 100 mg od treatment group and 
the rivaroxaban placebo + aspirin 100 mg od (control)
in the probability of the primary efficacy outcome 
for all time points t 0 relative to randomization.”
will be tested against the alternative hypotheses H1;riva2.5: 
“There is a difference between 
the rivaroxaban 2.5 mg bid + aspirin 100 mg od treatment group and 
the rivaroxaban placebo + aspirin 100 mg od (control)
in the probability of the primary efficacy outcome 
for at least one time point t 0 relative to randomization.”
The corresponding primary null hypothesis H0;riva5 will be tested comparing rivaroxaban 5 mg bid + 
aspirin placebo treatment with rivaroxaban placebo + aspirin 100 mg od (control). Statistical testing 
will be performed by a comparison of the “survival functions” S(t), i.e., the probability that “time 
from randomization to the first occurrence of the following primary efficacy outcomes” is > t, for a 
time t relative to randomization.  
The 2 comparisons will be performed using two separate stratified log-rank tests. Proton pump 
inhibitor use (3 strata levels: not randomized to a proton pump inhibitor; pantoprazole 40 mg od; 
pantoprazole placebo) will be used as a stratification factor in the statistical analysis.  Study center 
will not be used as a stratification factor in the statistical analysis.  
Following the mixture gatekeeping procedure as mentioned in Section 6.2, a truncated Hochberg test 
with the pre-specified truncation parameter γ = 0.9 at =0.05 will be used.
There will be no formal comparison between the rivaroxaban 2.5 mg bid + aspirin 100 mg od and 
rivaroxaban 5 mg bid + aspirin placebo groups.
                                                
60 Text modified as per modification 1 in integrated SAP, Version 4.1.
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Kaplan-Meier estimates of cumulative risk functions and Nelson-Aalen estimates of the cumulative 
hazard functions will be provided to evaluate the timing of event occurrence in the 3 antithrombotic 
study groups and the consistency of the respective treatment effects for all time points (the two 
survival curves in each comparison do not cross). 
To derive the log-rank Z test statistic and the variance V of the log-rank statistics, SAS program 
code corresponding to the following will be used: 
PROC LIFETEST DATA = <dataset> ALPHA=0.05 METHOD=KM NELSON;
  STRATA stratumn / GROUP=trtgrpn TEST=(LOGRANK);61
  TIME ttevalue * ttecnsr(0);
RUN;
/*
where
dataset  = name of sub-dataset including all ITT subjects randomized to 
           respective rivaroxaban treatment group and control group
trtgrpn  = variable coding randomized antithrombotic treatment group
           (0 = control group, 1 = rivaroxaban 2.5 mg + aspirin 100 mg)
ttevalue = time to first occurrence of primary efficacy outcome event
ttecnsr  = censoring index (0 = right-censored, 1 = event)
stratumn = variable for PPI stratification factor (three levels)
*/
Hazard ratio, relative risk reduction (RRR; RRR = 100 × [1 – hazard ratio]%), and corresponding 2-
sided 95% confidence intervals will be estimated based on two separate stratified Cox proportional 
hazards models. Censoring will be assumed independent of the randomized group assignment.  
For the analysis of the primary outcome in this study, the hazard function h(t) is the chance that an 
individual experiences an event of the primary efficacy outcome in the next instant in time, given 
that the individual has not had such an event up to time t. For example, for the comparison of 
rivaroxaban 2.5 mg bid + aspirin 100 mg od with rivaroxaban placebo + aspirin 100 mg od (control), 
the corresponding stratified Cox proportional hazards model can be described by the following 
equation:
hk(t,xi) = h0k(t) exp(β xi),
where 
hk(.)
hazard function for primary efficacy outcome for stratum k, k = 1,2,3 
(k represents PPI stratification factor), as a function of time and subject’s covariates
h0k(.)
unspecified underlying baseline hazard function for primary efficacy outcome per stratum 
k; hazard of an individual with xi = 0
t
time (in days) relative to the randomization date
                                                
61 Text modified as per modification 3 in integrated SAP, Version 4.1.
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xi
antithrombotic treatment group of subject i
(0 corresponds to “rivaroxaban placebo + aspirin 100 mg od (control)” and
1 corresponds to “rivaroxaban 2.5 mg bid + aspirin 100 mg od”)
β
unknown parameter (to be estimated); hazard ratio = exp(β)
SAS program code corresponding to the following will be used:
PROC PHREG DATA = <dataset>;
  MODEL ttevalue * ttecnsr(0) = trtgrpn / RL TIES=EFRON ALPHA=0.05;
  STRATA stratumn;
RUN;
/*
where
dataset  = name of sub-dataset including all ITT subjects randomized to 
           respective rivaroxaban treatment group and control group
trtgrpn  = variable coding randomized antithrombotic treatment group
           (0 = control group, 1 = rivaroxaban 2.5 mg + aspirin 100 mg)
ttevalue = time to first occurrence of primary efficacy outcome event
ttecnsr  = censoring index (0 = right-censored, 1 = event)
stratumn = variable for PPI stratification factor (three levels)
*/
Additional procedure options controlling the output may be added to the program codes.
Sensitivity analyses62
Sensitivity analyses will be performed to include all primary efficacy outcome events up until the 
minimum (earliest) of the Final rivaroxaban/aspirin Follow-up Visit date and the subject’s last 
contact date during the rivaroxaban/aspirin portion of the study.
In addition, the number of primary efficacy outcome events occurring after the Final 
rivaroxaban/aspirin Follow-up Visit until the rivaroxaban/aspirin Washout Telephone Visit, included 
in the clean database for the rivaroxaban/aspirin comparisons, will be summarized by 
rivaroxaban/aspirin study treatment group.
The plausibility of the proportional hazards assumption will be assessed by visually examining both 
the plot of the log of the negative log of Kaplan-Meier estimates of the survival function versus the 
log time for evidence of non-parallelism and the smoothed plot of the scaled Schoenfeld residuals to 
directly visualize the log hazard ratio (Grambsch and Therneau, 1994 [8]), for each stratum 
separately, and by including a time-treatment interaction term in the Cox model (time log 
transformed).  The SAS code is adapted as follows:
                                                
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PROC PHREG DATA = <dataset>;
  MODEL ttevalue * ttecnsr(0) = trtgrpn trtltime / RL TIES=EFRON ALPHA=0.05;
  STRATA stratumn;
  trtltime = trtgrpn*log(ttevalue);
RUN;
The significance of the interaction will be tested at the 5% type I error level. If the interaction is 
significant and there is strong evidence of non-proportionality from the plots, time-dependent hazard 
ratios will be estimated with the model that includes the interaction term.  
Analysis of the joint effect and/or interaction of study treatments63
In addition, an analysis of the joint effect and/or interaction between rivaroxaban-based anti-
thrombotic therapy and proton pump inhibitor use on the primary efficacy outcome will be 
performed for those subjects randomized to both antithrombotic and pantoprazole study medication.  
Joint effect and interaction between the antithrombotic and pantoprazole study groups on the 
primary efficacy outcome will be explored based on the intention-to-treat principle.  The analysis 
will use two separate Cox proportional hazards models, one for the comparison of rivaroxaban 
2.5 mg bid + aspirin 100 mg od vs. rivaroxaban placebo + aspirin 100 mg od, and one for the 
comparison of rivaroxaban 5 mg bid+ aspirin placebo vs. rivaroxaban placebo + aspirin 100 mg od.  
The Cox proportional hazards model (e.g., for the comparison of rivaroxaban 2.5 mg bid + aspirin 
100 mg od vs. rivaroxaban placebo + aspirin 100 mg od) can be described by the following 
equation:
h(t,x1i,x2i,x3i) = h0 (t) exp(β1 x1i + β2 x2i + β12 x1i x2i),
where 
h(.)
hazard function for primary efficacy outcome as a function of time and subject’s 
covariates
h0(.)
unspecified underlying baseline hazard function for primary efficacy outcome
t
time (in days) relative to the randomization date
x1i
antithrombotic treatment group of subject i
(0 corresponds to “rivaroxaban placebo + aspirin 100 mg od (control)” and
1 corresponds to “rivaroxaban 2.5 mg bid + aspirin 100 mg od”)
x2i
indicator variable for “pantoprazole 40 mg od treatment group”,
i.e., x2i = 1 if subject i was randomized to pantoprazole 40 mg treatment, 
x2i = 0 if subject i was randomized to pantoprazole placebo
β1, β2, β12  unknown parameters (to be estimated)
SAS program code corresponding to the following will be used:
                                                
63 Text added as per modification 7 in integrated SAP, Version 3.0.
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PROC PHREG DATA = <dataset>;
  MODEL ttevalue * ttecnsr(0) = trtgrpn ppigrpn trtgrpn*ppigrpn 
                               / RL TIES=EFRON ALPHA=0.05;
RUN;
/*
where
dataset  = name of sub-dataset including all ITT subjects randomized to 
           respective rivaroxaban treatment group and control group
trtgrpn  = variable coding randomized antithrombotic treatment group
           (0 = control group, 1 = rivaroxaban 2.5 mg + aspirin 100 mg)
ppigrpn = indicator variable: ppi1grpn = 1, if subject randomized to 
           pantoprazole 40 mg treatment, else ppi1grpn = 0, 
           if subject randomized to pantoprazole placebo
ttevalue = time to first occurrence of primary efficacy outcome event
ttecnsr  = censoring index (0 = right-censored, 1 = event)
*/
If the interaction term for the two randomized treatments is significant at the 5% type I error level, 
then an interaction ratio will be calculated (McAlister et al., 2003 [15]) to describe the clinical 
significance of any synergy and sub-additivity of the two treatment effects on the primary efficacy 
outcome. For the comparison of rivaroxaban 2.5 mg bid + aspirin 100 mg od vs. rivaroxaban 
placebo + aspirin 100 mg od this means that the following two ratios are determined, where the 
cumulative event rate is determined including all events considered in the primary analysis.

Ratio A: 
Cumulative event rate for the primary efficacy outcome for subjects randomized to both 
rivaroxaban 2.5 mg bid + aspirin 100 mg od and pantoprazole 40 mg od divided by 
cumulative event rate for the primary efficacy outcome for subjects randomized to both 
rivaroxaban placebo + aspirin 100 mg od and pantoprazole 40 mg od

Ratio B: 
Cumulative event rate for the primary efficacy outcome for subjects randomized to both 
rivaroxaban 2.5 mg bid + aspirin 100 mg od and pantoprazole placebo divided by cumulative 
event rate for the primary efficacy outcome for subjects randomized to both rivaroxaban 
placebo + aspirin 100 mg od and pantoprazole placebo.
The ratio of ratio A and ratio B gives an estimate of the interaction ratio. Given the large sample size 
of this trial, a very small interaction may be detected that lacks clinical significance. An interaction 
ratio estimate of ≤ 0.8 (antagonism or sub-additivity) or  ≥ 1.25 (synergy) will be considered 
“clinically significant”.  
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6.2.2
Secondary Efficacy
6.2.2.1
Secondary Efficacy Variables
Secondary efficacy variables are the time (in days) from randomization to the first occurrence of the 
following secondary efficacy outcomes64 – in the order as specified below:
1. The composite of outcomes --- coronary heart disease death, myocardial infarction, ischemic 
stroke, acute limb ischemia
2. The composite of outcomes --- cardiovascular death, myocardial infarction, ischemic stroke, 
acute limb ischemia
3. Mortality (all-cause)
The time-to-event variables will be derived similar to the derivation described in Section 6.2.1.1 for 
the primary efficacy variable.
In addition, a net clinical benefit time-to-event variable will be defined which is a composite of the

primary efficacy outcome

primary safety outcome, excluding bleedings leading to hospitalization  and bleedings into 
surgical site associated with re-operation.65
6.2.2.2
Secondary Efficacy Analysis
Analysis of the secondary efficacy outcomes will be based on the intention-to-treat principle and 
will essentially use the same statistical methods, as described in Section 6.2.1.2. Both comparisons 
of the rivaroxaban-based treatment groups to the common aspirin-control group will be performed 
using the truncated and/or regular Hochberg tests as described in in Section 6.2 to control the 
family-wise error rate of 5%.66
6.2.3
Tertiary Efficacy
6.2.3.1
Tertiary Efficacy Variables
Tertiary efficacy variables are 

the time (in days) from randomization to the first occurrence of the following tertiary 
efficacy outcomes67:
o
Individual components of the primary and secondary outcomes, i.e., 
myocardial infarction, stroke, ischemic stroke, cardiovascular death, coronary heart 
disease death, acute limb ischemia, and all-cause mortality
o
Hospitalization for cardiovascular reasons
o
Hospitalization
                                                
64 Text modified as per integrated CSP, Version 3.0.
65 Text added as per modification 7 of the SAP, Version 4.0.
66 Text modified as per integrated CSP, Version 3.0.
67 Text modified as per integrated CSPs, Versions 2.0 and 3.0.
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o
Venous thromboembolism
o
Revascularization 
o
Amputation 
o
Stent thrombosis
o
Unstable angina 
o
Worsening angina 
o
New angina 
o
Heart failure 
o
Resuscitated cardiac arrest
o
New diagnosis (/recurrence) of cancer
o
Coronary artery bypass graft failure

Subject-reported SAGE, MoCA, DSS, and EQ-5D

Medical resource utilization (MRU) 
The time-to-event variables will be derived similar to the derivation described in Section 6.2.1.1 for 
the primary efficacy variable.
SAGE
The SAGE questionnaire comprises 15 items, each describing an activity for which the respondent 
has to indicate how much difficulty the subject has encountered in performing this activity in the 
past month. Regarding scoring for an item, 0 points are assigned if the participants endorse the 
“None/never performed” response, 1 point to the “Mild” response, 2 points to the “Moderate” 
response, and 3 points to the “Severe” response.  One additional point will be assigned when in 
response to question 11, 12, and 15 the respondent declares the need for help from another person or 
a tool to walk, jump the stairs or to bath. The total score will range from 0, describing a very 
independent participant over a broad spectrum of activities, to 48, describing a very dependent 
subject.
MoCA
The Montreal Cognitive Assessment (MoCA) test assesses several cognitive domains: attention and 
concentration, executive functions, memory, language, visuoconstructional skills, conceptual 
thinking, calculations, and orientation. For each task correctly completed, one point is assigned.  All 
subscores are summed up and adjusted for individuals with ≤ 12 years education to derive a total 
score ranging between 0 (for a totally cognitive impaired subject) and a maximum of 30 points 
(cognitively healthy participant).
DSS
The DSS test is a neuropsychological test sensitive to brain damage, dementia, age and depression.  
It consists of nine digit-symbol pairs followed by a list of digits. Under each digit the subject should 
write down the corresponding symbol as fast as possible. The number of correct symbols within the 
allowed time (120 sec) is measured.
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EQ-5D
EQ-5D is a standardized measure of health status developed by the EuroQol Group in order to 
provide a simple, generic measure of health for clinical and economic appraisal. Assessments will be 
done using both a descriptive system and the subject’s self-rated health on a visual analogue scale 
where the endpoints are labeled ‘Best imaginable health state’ and ‘Worst imaginable health state’.
The descriptive system comprises five dimensions (mobility, self-care, usual activity, 
pain/discomfort, anxiety/depression). The subject is asked to indicate his/her current health state by 
ticking the most appropriate of three statements about each of the dimensions. Each statement has an 
increasing degree of severity (no problems / some problems / extreme problems) thus defining 243 
health states.
Data from the EuroQoL questionnaire will be analyzed as available, no imputation of missing values 
will be performed. In case a subject ticks more than one level as responses for the same item, the 
item is set to missing.
The following variables are of interest:

EQ-5D single dimensions 

EQ-5D index score, combining the recordings for each of the five EQ-5D dimensions into 
one single score (see Appendix 10.2)

EQ-5D Visual Analogue Scale (VAS) values
6.2.3.2
Tertiary Efficacy Analysis
Analysis of the tertiary efficacy outcomes will be based on the intention-to-treat principle. The 
analysis of the time-to-event variables will be based on a similar approach as described in Section
6.2.1.2, including stratified log-rank tests, stratified Cox models, and Kaplan-Meier estimates.  Both 
comparisons of the rivaroxaban-based treatment groups to the common aspirin-control group will be 
performed at the 2-sided 5% type I error level.  There will be no adjustment of these analyses for 
multiple testing.
Subject reported data from the EQ-5D questionnaire will be summarized by means of descriptive 
statistics and frequency tables by antithrombotic treatment group and overall and by visit. All data 
will be listed in the Appendix of the Clinical Study Report. In depth analyses of the SAGE, MoCA, 
and DSS questionnaire data will be displayed in a separate report/after completion of the 
pantoprazole/placebo portion of the study. Additional analyses of the EQ-5D will be used for 
economic modeling. These analyses will be described in a separate SAP.
The analysis of MRU data will be described in a separate SAP. MRU data will be incorporated into 
economic modeling, which will be performed and reported separately from this study in a stand-
alone report.  The data will be listed in Appendix of the Clinical Study Report.
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6.2.4
Analysis for Pantoprazole Randomization - Amended68
All analyses related to the pantoprazole randomization described in this section of the SAP will only 
be performed at the end of the pantoprazole portion of the study. The CSR related to the 
rivaroxaban/aspirin randomization will only use the pantoprazole/placebo randomization data for 
stratified testing and interaction analyses of efficacy / safety outcomes in relation to the 
rivaroxaban/aspirin randomization.
6.2.4.1
Variables for Pantoprazole Randomization - Amended69
The main variable for the pantoprazole randomization is the time (in days) from randomization to 
the first occurrence of the following outcomes: 

Overt bleeding of gastroduodenal origin confirmed by endoscopy or radiography 

Overt upper gastrointestinal bleeding of unknown origin 

Bleeding of presumed occult gastrointestinal origin with documented decrease in Hb of 
2 g/dL70

Symptomatic gastroduodenal ulcer 

Gastrointestinal pain with underlying multiple gastroduodenal erosions, obstruction or 
perforation 
The time-to-event variable will be derived in a similar manner as originally described for the 
primary efficacy variable.

For those subjects with documentation of an unrefuted pantoprazole outcome event 
occurring
(a) after the date and time of randomization and up until the Final Follow-up Visit, or
(b) after the date and time of randomization and up until the common trial close-out 
date, if the subject was not available for a Final Follow-up Visit up to the common 
trial close-out date 
time (in days) from randomization to the first occurrence of the unrefuted pantoprazole
outcome will be derived as: 
o
the date of the subject’s first unrefuted pantoprazole outcome event – the 
randomization date + 1. 
This will constitute an uncensored observation.

For those subjects without documentation of an unrefuted pantoprazole outcome event 
within the data scope according to intention-to-treat principle, 
time (in days) from randomization to the first occurrence of a pantoprazole outcome will be 
derived as:
                                                
68 Text modified as per modification 1 in integrated SAP, Version 4.1.
69 Text modified as per modification 6 in integrated SAP, Version 3.0.
70 Text modified as per integrated CSP, Version 2.0.
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o
the subject’s Final Follow-Up Visit date  –  the randomization date +1,
if the subject was available for the Final Follow-Up Visit before the common trial 
close-out date.
o
the subject’s date of last follow-up contact up to the common trial close-out date  –  
the randomization date +1, if 
(a) the subject did not attend his/her Final Follow-Up Visit before the common trial 
close-out date and 
(b) the subject’s date of last trial contact is not after the common trial close-out date. 
o
the common trial close-out date  –  the randomization date +1, if 
(a) the subject did not attend his/her Final Follow-Up Visit before the common trial 
close-out date and
(b) the subject’s date of last trial contact is after the common trial close-out date.
This will constitute a right-censored observation.
Other outcomes of interest for the pantoprazole randomization are:

pneumonia, enteric infections, and bone fractures as well as new diagnosis of gastric atrophy, 
chronic kidney disease, diabetes, chronic obstructive lung disease, and dementia since 
randomization. 
6.2.4.2
Statistical Analysis for Pantoprazole Randomization
The statistical analysis of the outcome for pantoprazole randomization will be based on the 
intention-to-treat principle and will include all subjects randomized to receive pantoprazole 40 mg 
od or pantoprazole placebo. The randomized pantoprazole 40 mg od study treatment group and 
randomized pantoprazole placebo-control group will be compared. 
The null hypothesis H0;panto40 stating that
“there is no difference between the pantoprazole treatment and control groups 
in the probability of the outcome for pantoprazole randomization for all time points” will be 
tested against the alternative hypothesis H1;panto40 stating that 
“there is a difference between the two groups in the probability of the outcome 
for at least one time point”.
The comparison will be performed using a log-rank test stratified by antithrombotic study treatment 
(three strata levels: rivaroxaban 2.5 mg bid + aspirin 100 mg od; rivaroxaban 5 mg bid + aspirin 
placebo; rivaroxaban placebo + aspirin 100 mg od), conducted at the 2-sided 5% type I error level. 
There will be no interim analyses for the pantoprazole randomization.
Kaplan-Meier estimates of cumulative risk functions and Nelson-Aalen estimates of the cumulative 
hazard functions will be provided to evaluate the timing of event occurrence in the two proton pump 
inhibitor study groups and the consistency of the treatment effect for all time points (the two 
survival curves do not cross).
Hazard ratios, relative risk reduction, and corresponding 2-sided 95% confidence intervals will be 
estimated based on a Cox proportional hazards model stratified by antithrombotic therapy study 
group.  Censoring will be assumed independent of the treatment group assignment. Similar 
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strategies to those outlined in Section 6.2.1.2 will be used for assessing the plausibility of the 
proportional hazards assumption.
For the analysis of the outcome for the pantoprazole randomization in this study, the hazard function 
h(t) is the chance that an individual experiences an event of the outcome of the pantoprazole 
randomization in the next instant in time, given that the individual has not had such an event up to 
time t. For example, for the comparison of pantoprazole 40 mg od to pantoprazole placebo (control), 
the corresponding stratified Cox proportional hazards model can be described by the following 
equation:
hk(t,xi) = h0k(t) exp(β xi),
where 
hk(.)
hazard function for primary efficacy outcome for stratum k, k = 1,2,3 
(k represents randomized antithrombotic study treatment stratification factor), 
as a function of time and subject’s covariates
h0k(.)
unspecified underlying baseline hazard function for primary efficacy outcome per stratum 
k; hazard of an individual with xi = 0
t
time (in days) relative to the randomization date
xi
PPI treatment group of subject i
(0 corresponds to “pantoprazole placebo (control)” and
1 corresponds to “pantoprazole 40 mg od”)
β
unknown parameter (to be estimated); hazard ratio = exp(β)
SAS program code corresponding to the following will be used:
PROC PHREG DATA = <dataset>;
  MODEL ttevalue * ttecnsr(0) = ppi1grpn / RL TIES=EFRON ALPHA=0.05;
  STRATA stratumn;
RUN;
/*
where
dataset  = name of sub-dataset including all ITT subjects randomized to 
           pantoprazole 40 mg or pantoprazole placebo study treatment
ppi1grpn  = variable coding randomized pantoprazole treatment group
           (0 = pantoprazole placebo, 1 = pantoprazole 40 mg treatment)
ttevalue = time to first occurrence of pantoprazole outcome event
ttecnsr  = censoring index (0 = right-censored, 1 = event)
stratumn = variable for randomized antithrombotic study treatment 
           stratification factor (three levels)
*/
Additional procedure options controlling the output may be added to the program codes.
In addition, joint effect and interaction between the antithrombotic and pantoprazole study groups on 
the pantoprazole outcome will be explored based on the intention-to-treat principle in subjects 
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randomized to receive pantoprazole 40 mg od or pantoprazole placebo.  The analysis will use two 
separate Cox proportional hazards models, one for the comparison of rivaroxaban 2.5 mg bid + 
aspirin 100 mg od vs. rivaroxaban placebo + aspirin 100 mg od, and one for the comparison of 
rivaroxaban 5 mg bid+ aspirin placebo vs. rivaroxaban placebo + aspirin 100 mg od.  The models 
will include:

a covariate for the effect of the considered rivaroxaban-based treatment group vs. the 
aspirin-control group,

a covariate for the effect of pantoprazole 40 mg od treatment group vs. pantoprazole 
placebo-control group,

an interaction term of these two factors.
Therefore, the Cox proportional hazards model (e.g., for the comparison of rivaroxaban 2.5 mg bid + 
aspirin 100 mg od vs. rivaroxaban placebo + aspirin 100 mg od) can be described by the following 
equation:
h(t,x1i,x2i) = h0 (t) exp(β1 x1i + β2 x2i + β12 x1i x2i),
where 
h(.)
hazard function for pantoprazole outcome as a function of time and subject’s 
covariates
h0(.)
unspecified underlying baseline hazard function for pantoprazole outcome
t
time (in days) relative to the randomization date
x1i
antithrombotic treatment group of subject i
(0 corresponds to “rivaroxaban placebo + aspirin 100 mg od (control)” and
1 corresponds to “rivaroxaban 2.5 mg bid + aspirin 100 mg od”)
x2i
pantoprazole group of subject i
(0 corresponds to “pantoprazole placebo-control group” and
1 corresponds to “pantoprazole 40 mg od treatment group”)
β1, β2, β12  unknown parameters (to be estimated)
SAS program code corresponding to the following will be used:
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PROC PHREG DATA = <dataset>;
  MODEL ttevalue * ttecnsr(0) = trtgrpn ppi1grpn trtgrpn*ppi1grpn /
                                RL TIES=EFRON ALPHA=0.05;
RUN;
/*
where
dataset  = name of sub-dataset including all ITT subjects randomized to 
           respective rivaroxaban treatment group and control group
trtgrpn  = variable coding randomized antithrombotic treatment group
           (0 = control group, 1 = rivaroxaban 2.5 mg + aspirin 100 mg)
ppi1grpn = variable coding randomized pantoprazole treatment group
           (0 = pantoprazole placebo, 1 = pantoprazole 40 mg treatment)
ttevalue = time to first occurrence of pantoprazole outcome event
ttecnsr  = censoring index (0 = right-censored, 1 = event)
*/
If the interaction term is significant at the 5% type I error level, then an interaction ratio will be 
calculated (McAlister et al., 2003 [15]) to describe the clinical significance of any synergy and sub-
additivity of the two treatment effects on the pantoprazole outcome (see Section 6.2.1.2).  
Additional exploratory analyses will include, e.g., a comparison of subjects who used proton pump 
inhibitor at baseline (and therefore were not randomized to receive pantoprazole 40 mg od or 
pantoprazole placebo) with subjects randomized to pantoprazole placebo group with regard to the 
pantoprazole outcome.
Further details characterizing gastrointestinal bleeding events collected on the Gastrointestinal CRF 
Report will be summarized by means of descriptive statistics and frequency tables.
6.2.5
Efficacy Subgroup Analysis - Amended71
Subgroup analyses 

for the primary efficacy outcome comparing 
o
rivaroxaban 2.5 mg + aspirin with rivaroxaban placebo + aspirin 100 mg
o
rivaroxaban 5 mg + aspirin placebo with rivaroxaban placebo + aspirin 100 mg

and for the outcome for pantoprazole randomization comparing
o
pantoprazole 40 mg with pantoprazole placebo
will be performed based on the same analysis sets and data scopes as in the main analyses of the 
study outcomes. The subgroup analyses for the rivaroxaban/aspirin comparisons will be performed 
after the end of the study rivaroxaban/aspirin portion of the trial, while subgroup analyses for the 
pantoprazole comparison will be performed after the end of the pantoprazole portion of the trial. 72
                                                
71 Text modified as per modification 5 in integrated SAP, Version 3.0.
72 Text modified as per modification 1 in integrated SAP, Version 4.1.
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Homogeneity of treatment effect (i.e., the effect of antithrombotic study treatment on the primary 
efficacy outcome and effect of pantoprazole study treatment on the pantoprazole outcome) will be 
examined for the following subgroup variables, where important subgroups are distinguished from 
“other” subgroups that are examined to assess the consistency of a treatment effect:
Important subgroups

Coronary artery disease (yes, no)

Peripheral artery disease (yes, no)

CAD and PAD (yes, no)

CAD only, PAD only, CAD and PAD 

History of prior asymptomatic carotid artery stenosis >= 50%/revascularization (yes, no)

History of polyvascular disease with number of vascular beds affected 
[CAD, PAD, cerebrovascular disease, i.e., prior stroke or asymptomatic carotid artery 
stenosis >= 50%/revascularization] (1, 2, or 3 vascular beds affected)

Prior CABG surgery 
o
Any prior CABG surgery (yes, no)
o
Study baseline CABG surgery [planned within 4-7 days before randomization] (yes, 
no)
o
Prior CABG surgery (no prior CABG surgery, study baseline CABG surgery, other 
history of prior CABG73 surgery)

CAPRIE-like population with medical history of any of the following prior events:
MI, (ischemic) stroke, or PAD (yes, no)

History of prior MI (yes, no)

History of both prior MI and polyvascular disease or multivessel CAD (yes, no)
Other subgroups

Region
o
North America, Western Europe and AUS/ISR/ZAF, Eastern Europe, Asia Pacific, 
and South America, see Appendix 10.1
o
US, non-US

Sex (male, female)

Age 
o
Categories 1: <55, 55 to <65, 65 to 75, >75 years
o
Categories 2: < 65, ≥ 65 to < 75, ≥ 75 years

Race (White or Caucasian, Black or African American, Asian, other)

Body weight at baseline (≤ 60 kg, > 60 kg)

Baseline renal function 
o
estimated glomerular filtration rate (eGFR) categories 1: <60, ≥60 mL/min
                                                
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o
eGFR categories 2: < 15, 15 to < 30, 30 to < 60, ≥ 60 mL/min
o
eGFR categories 3: < 30, 30 to 50, >50 to 80 ml/min, >80 ml/min

Smoking status 
o
Tobacco use at baseline (yes, no)
o
History of tobacco use (yes, no)

Baseline proton pump inhibitor use (yes, no)

Baseline lipid lowering agent use (yes, no)

Baseline diabetes (yes, no)

History of a prior heart failure (yes, no)

History of peptic ulcer (yes, no)

History of (non-lacunar ischemic) stroke (yes, no)

History of peripheral artery bypass surgery or peripheral percutaneous transluminal 
angioplasty (yes, no)

History of limb or foot amputation for arterial vascular disease (yes, no)

History of hypertension (yes, no)

History of prior coronary PTCA/Atherectomy/PCI (yes, no)

History of prior MI and age < 65 years (yes, no)

History of prior MI and reduced renal function, i.e., eGFR <60 mL/min (yes, no)
Additional subgroup analyses, if identified, will be specified before unblinding of treatment 
assignment. The pre-specified categories may be collapsed if the number of events is too small for 
some subgroups.  In addition to analyses of the subgroups listed above, analyses for the Asian 
populations, especially Chinese and Japanese subjects, will be performed as required and presented 
in separate reports.
Homogeneity of study treatment effect in subgroups, both in magnitude and direction, will be 
assessed by adding a covariate for the subgroup variable and the corresponding treatment-subgroup 
interaction to the respective stratified Cox proportional hazards model used in the main analysis.  
Cox proportional hazards regression model (not stratified) will be used for the subgroup variable 
referring to baseline proton pump inhibitor use (yes, no).
As the number of subgroup analyses may be large, the probability of observing at least one 
statistically significant but spurious interaction is high despite the lack of a biological or 
pharmacological basis for expecting an interaction.  Thus any significant interactions in the analysis 
of primary outcomes will be interpreted as “flags” to prompt further investigation.
No interactions with any of the subgroup variables are expected.  If,

for important subgroups: the interaction term is significant at the 5% type I error level in the 
analysis of the primary efficacy outcome,

for other subgroups: the interaction term is significant at the 1% type I error level in the 
analysis of the primary efficacy outcome and there is a biologically coherent explanation for 
the finding,
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secondary and tertiary efficacy outcomes will be investigated to evaluate the plausibility of such an 
effect. Furthermore, in the analysis of all outcomes, if the interaction term is significant at the 5% 
type I error level, the likelihood ratio test proposed by Gail and Simon (1985) [7] will be performed 
to test the hypothesis that there is no crossover or qualitative interaction at the 1% type I error level 
(H0: The direction of treatment effect is the same for all levels of a subgroup variable vs. H1: The 
direction of treatment effect is different for at least one level of a subgroup variable).  As was shown 
by Li et al (2007) [12], the probability of observing the treatment effect in the opposite direction to 
the true overall treatment effect for at least one subgroup level is not negligible. The contributing 
factors may be small subgroup sizes, imbalance of randomized groups within the subgroups, and 
small true overall treatment effect. 
Following the test of interaction, hazard ratios (and relative risk reduction) with 2-sided 95% 
confidence intervals for the treatment effect will be estimated separately within each level of a 
subgroup variable using the stratified Cox proportional hazards models that were used in the main 
analyses of study outcomes.  
In the subgroup of subjects randomized 4-7 days (according to protocol plan) after CABG surgery, 
further subgroup analyses as outlined above will be performed to investigate the consistency of the 
antithrombotic treatment effect across EuroSCORE categories (0-2, 3-4, 5+) on the primary efficacy 
outcome. 
6.2.6
Analyses of the COMPASS MIND Substudy
Subclinical (i.e., covert) strokes are more frequent than clinically evident brain infarcts, with a 
prevalence of covert strokes of 15% to 20% in population-based cohorts with a mean age of 65 
years.
The COMPASS MIND substudy is a magnetic resonance imaging (MRI) substudy evaluating the 
incidence of clinically silent brain infarcts and subclinical brain ischemia and the effect of the 
antithrombotic therapies being tested in COMPASS on covert cerebral ischemia, thereby providing 
additional information about mechanisms of disease and treatment benefits.  
A total of 1,500 COMPASS participants will be invited to participate (500 subjects per treatment 
group, balanced for age, prior stroke, and hypertension).  Participants will undergo limited brain 
MRI sequences at entry and near study end.  Two-stage central interpretation blinded to treatment 
will be carried out, with all incident covert infarcts confirmed by a second independent interpreter.  
Subjects will have DNA collected at baseline and blood collected at baseline and at the 1 month 
visit.  
Data related to the COMPASS MIND substudy will be reported separately.74
6.2.6.1
Variables of the COMPASS MIND Substudy
Outcomes of the COMPASS MIND substudy are:

Covert brain infarcts 
(detected by blinded comparison of initial vs. end-study MRIs)
                                                
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
Non-lacunar covert brain infarcts 

All incident strokes, including clinical strokes and all covert strokes
Furthermore, functional decline (based on SAGE), cognitive decline (based on MoCA and DSS), 
and biomarkers (C-reactive protein, NT-proBNP) will be assessed.
6.2.6.2
Statistical Analysis of the COMPASS MIND Substudy
The incidence of the COMPASS MIND substudy outcomes will be determined for each 
antithrombotic study treatment group.  Two comparisons will be performed to compare 

rivaroxaban 2.5 mg bid + aspirin 100 mg od treatment with
rivaroxaban placebo + aspirin 100 mg od (control), and

rivaroxaban 5 mg bid + aspirin placebo treatment with
rivaroxaban placebo + aspirin 100 mg od (control)
within the subpopulation included in the COMPASS MIND substudy.  
Functional and cognitive decline as well as the predictive value of biomarkers as independent 
predictors of covert brain infarcts will be explored by means of descriptive statistics.  Details of 
additional analyses will be described in a separate document; results will be reported separately.
6.2.7
Exploratory Analyses
In the unexpected event that the number of subjects who need to be declared as lost to follow-up is 
unexpectedly high and evidence suggests that the assumption of non-informative censoring cannot 
be adopted, additional sensitivity analyses might be performed in order to evaluate the robustness of 
the primary analysis. Where a subject is completely non-compliant with study follow up, the 
likelihood that this participant has experienced a study outcome will be derived and this information 
incorporated, as appropriate, in the analyses (Little et al., 2012 [13]). With SAP amendment v3.0, 
integrated in SAP, Version 4.0, sensitivity analyses to address the potential impact of missing data 
on the results of the primary analysis are described in Appendix 10.4.75
The types of myocardial infarction and further details obtained on the myocardial infarction (MI) 
CRF Reports will be summarized at the event level by randomized antithrombotic study treatment 
group for subjects who experienced MI events during the study. The efficacy outcomes will also be 
evaluated by MI types according to the universal definition, see derivation document for details.76
Symptoms, recovery status (Rankin scale), and further details obtained on the Stroke CRF Reports 
will be summarized at the event level by randomized antithrombotic treatment group for subjects 
who experienced ‘stroke’ events during the study.
Further characteristics related to heart failure obtained on the Heart Failure CRF Reports will be 
summarized at the event level by randomized antithrombotic treatment group for subjects who 
experienced ‘heart failure’ events during the study.
                                                
75 Text added as per modification 4 in integrated SAP, Version 4.1.
76 Text added as per modification 8 in integrated SAP, Version 3.0.
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Further characteristics related to venous thromboembolisms obtained on the VTE CRF Reports will 
be summarized at the event level by randomized antithrombotic treatment group for subjects who 
experienced ‘venous thromboembolisms’ events during the study.
Further characteristics related to new diagnoses (/recurrence) of cancer obtained on the Cancer CRF 
Reports will be summarized at the event level by randomized antithrombotic treatment group for 
subjects who experienced ‘new diagnoses of cancer’ events during the study.
If applicable, information on subjects with multiple outcome events will be displayed as appropriate.  
Further tables summarizing study data will be specified in the TLF document.
Efficacy events occurring after the discontinuation of antithrombotic study treatment will be 
summarized for the subjects who have at least 1 day follow-up post last dose of antithrombotic study 
medication by treatment group and summarized by means of frequency tables.  Specifically, events 
occurring within 30 days of permanent discontinuation of antithrombotic study medication will be 
the focus for the assessment of potential rebound effects. 
Data collected with the International Physical Activity Questionnaire (IPAQ) and the Diet 
Questionnaire will be listed in the Appendix of the Clinical Study Report. Further analyses will be 
reported in a separate report.
6.3
Pharmacokinetics/pharmacodynamics
Not applicable.
6.4
Safety
6.4.1
Primary Safety
6.4.1.1
Primary Safety Variable
The primary safety variable is the time (in days) from randomization to the first occurrence of the 
following primary safety outcome:
modified International Society on Thrombosis and Haemostasis (ISTH) major bleeding, defined 
as:

fatal bleeding, and/or 
symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, 
respiratory, liver, pancreas, adrenal gland or kidney, retroperitoneal, intraarticular or 
pericardial, or intramuscular with compartment syndrome, or bleeding into the surgical site 
requiring reoperation, and/or

bleeding leading to hospitalization 
The primary safety time-to-event variable will be derived in a manner similar to that described in 
Section 6.2.1.1 for the primary efficacy variable.
In addition to the analysis and censoring scheme according to the intention-to-treat principle, 
secondary safety analyses will be performed using time-to-event variables with censoring according 
to the censoring schemes for secondary safety analyses as described in Section 4.5.3.
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6.4.1.2
Primary Safety Analysis
The principal analysis of the primary safety outcome will be based on the intention-to-treat 
principle. The analysis will follow similar methodology as the analysis of the primary efficacy 
outcome described in Section 6.2.1.2.
In addition, the primary safety outcome will be analyzed based on the safety analysis set and the 
secondary safety data scopes and corresponding censoring rules defined in Sections 4.5.2 and 4.5.3.  
The number of subjects with multiple primary safety outcomes will be summarized, and further 
analyzed if applicable. Further details characterizing the bleeding events collected on the Bleeding 
CRF Report will be summarized by means of descriptive statistics and frequency tables.
6.4.1.3
Safety Subgroup Analyses
Subgroup analyses for the primary safety outcomes will be performed based on ITT analysis set and 
scope and based on the safety analysis set and treatment-emergent data scope similar to the 
methodology outlined in Section 6.2.5.
6.4.2
Other Safety Analyses
For the purposes of this trial, the following events will be captured on the CRF as study outcome 
events and will be reported as primary, secondary, or tertiary outcomes or as outcome of the 
pantoprazole randomization (see Section 6.2): 
cardiovascular death, myocardial infarction, stroke, major bleeding, cardiovascular 
hospitalization, venous thromboembolism, revascularization, amputation, angina, heart 
failure, resuscitated cardiac arrest, new diagnosis (/recurrence) of cancer, gastrointestinal 
bleeding, ulcer, perforation, or obstruction, and other expected non-cardiovascular causes of 
hospitalization and death.
6.4.2.1
Adverse Events
A Serious Adverse Event / Event of Special Interest (SAE/ESI) CRF Report is to be completed 
when a subject has an event that is (a) not an exempted study outcome and serious, or (b) an event of 
special interest. In addition, any AEs of particular concern to the investigator may be recorded on 
the CRF. While AEs that are not serious but that lead to permanent discontinuation of study 
medication will be captured in the CRF, non-serious AEs that do not lead to discontinuation of study 
medication will not be collected.
Additional hospitalization data will be collected on the CRF to permit the analysis of MRU data, 
which will be reported separately in another stand-alone report.
Analyses of reported adverse events will be performed based on 

the ITT analysis set using the “ITT” data scope

the safety analysis set and the “treatment emergent outcomes” data scope77
as outlined in Section 4.5.2.
                                                
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In case of uncertainty (e.g., missing or incomplete dates), adverse events will be classified as 
“treatment emergent” and be included in the ITT scope following the worst case approach. In 
addition, those AEs occurring during the run-in phase and those AEs occurring after discontinuation 
of anti-thrombotic study treatment will be summarized, respectively.78
The original terms used by investigators to report AEs via the CRFs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA).  All reported serious adverse events, adverse 
events leading to discontinuation of study drug, and adverse events of special interest with onset at 
the date of or after randomization will be summarized by means of AE tables. 
For each AE and serious adverse event (SAE), the number and percentage of subjects who 
experienced at least 1 occurrence of the given event will be tabulated according to the affected 
primary system organ class (SOC) and preferred term (PT) by randomized antithrombotic study 
treatment group. A total column will be included in all safety summaries.  After study close-out for 
the pantoprazole/placebo portion of the study, similar tables will display the same information by 
PPI study treatment group, see also analyses described in Section 5.  
Frequency tables, showing an overall summary of number of subjects with AEs and SAEs, will be 
given, and will include the following information.

if AE (/ SAE) occurred with causal relationship to study drug separately for each study 
medication, i.e., rivaroxaban/rivaroxaban placebo, aspirin/aspirin placebo, and 
pantoprazole/pantoprazole placebo,

maximum intensity for any AE / any study-drug related AE,

AE related deaths,

discontinuation of study treatment use due to AE (as well as due to SAE).
A similar table showing overall summary information of AEs during run-in will be given. 
In addition, frequency tables will summarize the number of subjects with 

any event occurring within 30 days before permanent study drug discontinuation

any event occurring more than 2 days after permanent study drug discontinuation
for antithrombotic study medication.
6.4.2.2
Death
Deaths will be summarized by cardiovascular cause and non-cardiovascular cause and sub-
categories as specified in the Death CRF Report. 
6.4.2.3
Pregnancies
Any pregnancy occurring in a study subject (or in partners of study subjects) during the subject’s 
participation in this study will be displayed.
                                                
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6.4.2.4
Vital Signs
Systolic and diastolic blood pressure (in mm Hg) for both left and right arm as well as left and right 
ankle and heart rate, and other physical measurements (weight, height, hip circumference, and waist 
circumference) obtained at screening/run-in, at the 2 Year Visit, the Final rivaroxaban/aspirin 
Follow-up Visit and at the Final Follow-up Visit will be displayed by means of descriptive statistics. 
6.4.2.5
Clinical Laboratory Tests
Descriptive statistics (mean, standard deviation, median, minimum and maximum) will be provided 
for each laboratory parameter as follows:

Serum creatinine and estimated glomerular filtration rate (eGFR) at Screening/Run-in Visit

Serum creatinine and eGFR at randomization (planned 4-7 days after CABG)

Total cholesterol at Screening/Run-in Visit

Cardiac markers for MI events

Brain natriuretic peptide (BNP)and NT-proBNP for heart failure events, if available
Results from laboratory samples for the COMPASS-MIND substudy will be summarized separately 
for the subgroup of subjects participating in the substudy by antithrombotic study treatment.  
7.
Sample Size Considerations - Amended79
In this trial, it was originally planned to randomize at least 19,500 subjects and to continue the study 
until a minimum of 2,200 subjects experience an event for the primary efficacy outcome with the 
objective to achieve at least 90% power to detect a 20% RRR for each of the 2 rivaroxaban-based 
treatment groups vs. the common aspirin-control group.  The total number of events needed under 
the original assumptions made in the protocol, version 1.1, dated 28 November 2012, is shown in 
Table 7-1 for different scenarios depending on the assumed annual incidence rate in the aspirin 
group.  Due to the event-driven study design, the number of randomized subjects, length of 
enrollment and total study duration may vary.  It was specified in the protocol that a larger number 
of subjects may be recruited, if recruitment is going well.  All numbers below (in Table 7-1 and the 
conclusion) refer to the minimum number of events to be observed after successful completion of 
the run-in period.  For the total number of subjects to be enrolled in the run-in period, at least 10% 
must be added to the total number below.
Original assumptions for antithrombotic treatment randomization were:

3-group study with 1:1:1 randomization

In total, a minimum of 19,500 subjects will be randomized (at least 6,500 subjects per 
treatment group) according to a 1:2:3:4:4 pattern within 2.5 years

2-sided type I error level of 2.7% for each of the two comparisons to control the overall type 
I error level of 5%
                                                
79 Text in this section revised based on changes in the integrated CSPs, Versions 2.0 and 3.0.
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
Constant annual incidence rate in aspirin-control group between 4.0% and 4.5%

Effect size: 20% relative risk reduction to be detected for each comparison

Intention-to-treat analysis: all subjects randomized are included in the analysis as 
randomized and the follow-up period for each subject is as long as possible from 
randomization until the date of the Final Follow-up Visit for each subject

Length of recruitment period is about 2.5 years 

Early discontinuation of study drug: about 6% and 4% in the 1st and 2nd 6-month periods, 
respectively, and 3% in the 6-month periods thereafter
The expected total number of observed events and the estimated power for each of the two 
comparisons are displayed in Table 7-1. 
Table 7-1.  Events calculations – CSP Version 1.1
Assumed annual 
incidence rate in 
aspirin-control 
group
Expected total study 
duration (years)
Estimated power for 
one comparison
Expected total number of 
events
4.0%
4.5
90.6%
1,923
5.0
93.6%
2,227
4.5%
4.5
93.6%
2,150
5.0
95.9%
2,488
Based on these estimates and the aim to detect a true relative risk reduction of 20% in each of the 
rivaroxaban treatment groups, with at least 90% power, it was planned to randomize at least 19,500 
subjects and to continue the study until a minimum of 2,200 subjects experience an unrefuted80
event for the primary efficacy outcome.  In this multi-center study, each center is expected to 
randomize at least 50 subjects.
As explained in the integrated CSP, Version 2.0, the sample size was increased by protocol 
Amendment 6. Based on emerging data from the ORIGIN trial  and the TRA2P-TIMI 50 
(vorapaxar) secondary prevention trial, a realistic incidence rate was found to be 3.5-4.0% rather 
than 4.0-4.5%.  Keeping all other assumptions as in the original CSP, Version 1.1, but assuming 

that, in total, a minimum of 21,400 subjects are randomized (approximately 7,134 subjects 
per treatment group) and

a constant annual incidence rate in the aspirin control group between 3.0% and 4.0%,
the expected total number of observed events and the estimated power for each of the two 
comparisons are displayed in Table 7-2. 
                                                
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Table 7-2.  Events calculations – Integrated CSP, Version 2.0 
Assumed annual 
incidence rate in aspirin 
control group
Expected total study 
duration (years)
Estimated power for one 
comparison
Expected total number of 
events
3.0%
4.5
85.1%
1,642
5.0
89.2%
1,909
3.5%
4.5
90.2%
1,907
5.0
93.4%
2,215
4.0%
4.5
93.7%
2,171
5.0
96.0%
2,517 
Based on these estimates, it was then planned to randomize at least 21,400 subjects and to continue 
the study until a minimum of 2,200 subjects experience an unrefuted81 event for the primary efficacy 
outcome.  
However, during the first 2 years after randomization of the first patient, it was found that the actual 
randomization was slower than expected and that the observed cumulated overall annual incidence 
was at the lower end of the projected range of 3.0 to 4.0%. This led to the decision to continue 
enrollment and to thereby roughly maintain the study duration in the originally planned range of 4.5 
to 5 years. Simulations were performed to justify the implied sample size increase, based on the 
following revised assumptions, which are partially taken from the blinded data observed within the 
first 2 years of the trial:

In total, a minimum of 27,400 subjects are randomized (approximately 9,134 subjects per 
treatment group)

Overall length of recruitment period about 3 to 3.5 years, where randomization times are
o
taken as observed for the first ~18,000 subjects
o
assumed to be approximately uniform over about 10 months with some seasonal 
variation for the remaining ~9,400 subjects 

2-sided overall type I error level of 5% using a truncated Hochberg test (γ = 0.9) for the 
testing of the two primary hypotheses

Constant overall incidence rate of about 2.9% per year (95% CI: 2.56 – 3.22%), resulting in a 
constant incidence rate of about 3.3% (95% CI: 2.95 – 3.71%) per year for the aspirin control 
group assuming a 20% relative risk reduction for both hypotheses

Early discontinuation of study drug: about 6% and 4.5% in the 1st and 2nd 6-month periods, 
and 3% in the 6-month periods thereafter

Censoring due to non-CV death at an event rate of almost 1% per year

The study is continued until a minimum of 2,200 subjects experience an event for the 
primary efficacy outcome
The simulation results under these assumptions, based on 3,000 repetitions, are displayed in Table 
7-3.
                                                
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Table 7-3.  Estimated power and time to 2,200 subjects with primary outcome
Assumed annual 
incidence rate in aspirin 
control group
Projected time from first 
patient randomized to 2,200 
subjects experienced primary 
outcome event
Estimated power for at 
least one significant 
primary comparison
Estimated power for 
both comparisons 
significant
2.95%
5 years, 7-8 months
98.17%
92.13%
3.32%
4 years, 9-10 months
98.27%
92.97%
3.71%
4 years, 6 months
98.40%
93.63%
Based on these simulation results, the sample size was increased by CSP Amendment 8. It is 
planned to randomize at least 27,400 subjects and to continue the study until a minimum of 2,200 
subjects experience an unrefuted82 event for the primary efficacy outcome.
Assumptions for pantoprazole randomization are: 

Annual incidence rate for major upper gastrointestinal complications (overt or occult 
bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction or perforation) in the 
range of 1.6% to 2.2%

At least 16,440 (as per integrated CSP, Version 2.0) subjects included in the study are not 
proton pump inhibitor users and they are randomized to pantoprazole treatment and control 
groups in a 1:1 ratio

2-sided type I error level of 5%

Effect size: 50% relative risk reduction to be detected

Intention-to-treat analysis: all subjects randomized are included in the analysis as 
randomized and the follow-up period for each subject is as long as possible from 
randomization until the date of the individual subject’s Final Follow-up Visit 
Under these assumptions, the expected total number of major upper gastrointestinal complications is 
between 570 and 780, depending on the observed incidence rates and the total study duration. The 
estimated power for the detection of the true relative risk reduction of about 50% for major upper 
gastrointestinal complications for pantoprazole 40 mg od vs. pantoprazole placebo is close to 100% 
for all scenarios considered.
Sample size estimation was based on the method by Lakatos (Lakatos, 1988 [11]) implemented in 
Power Analysis and Sample Size (PASS) software, version 11.0.7, and on a Statistical Analysis 
Software (SAS) macro provided by Shih (1995) (20).  In addition, simulations were performed to (1) 
confirm that the Dunnett step-up testing procedure (Dunnett and Tamhane, 1992 [2]) as originally 
planned for the analysis of the primary efficacy outcome as well as (2) the mixture gatekeeping 
procedure as described in Section 6.2 for the analysis of the primary efficacy outcome keeps the 
overall type I error level of 5%.  SAS calculations and simulations were performed using SAS 
software, version 9.2 (SAS Institute Inc, Cary, NC, USA).
                                                
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8.
Document History and Changes in the Planned Statistical Analysis

SAP, version 1.0, dated January 10, 2013 (without attachments) approved on 
January 10, 2013: 
o
approved core SAP document for submission to US FDA.
8.1
Overview Changes to SAP – Amendment 1
The SAP, Version 1.0, dated 10 January 2013, was amended with the changes resulting from global 
CSP amendments. An integrated statistical analysis plan was prepared.

Integrated statistical analysis plan, version 2.0, dated August 19, 2015 (without attachments):
o
This document was revised to reflect the CSP modifications, additions, and deletions 
resulting from 
- global amendment 6, forming integrated CSP Version 2.0, 
  dated 03 July 2014, and
- global amendment 8, forming integrated CSP Version 3.0, 
  dated 19 August 2015. 
o
SAP modifications resulting from the integrated CSP Version 2.0 are primarily
- administrative, editorial, typographical, and consistency-related corrections,
- minor clarifications for the secondary and  tertiary efficacy outcomes,
- sample size increase based on emerging data external to the COMPASS trial,
- addition of CABG specific objectives,
- clarifications in the discontinuations of subjects from study treatment, and
- timing and tabulated overview.
The SAP, version 1.0, was not immediately amended after approval of the integrated 
CSP, version 2.0, since an FDA Advice Letter, dated 29 August 2014, had triggered 
further discussions affecting statistical topics.
o
SAP modifications resulting from the integrated CSP Version 3.0 are primarily
- a change in secondary and tertiary efficacy outcomes,
- a change in testing strategy to control familywise type I error rate 
  for testing of primary and secondary hypotheses, 
- sample size increase to maintain study timelines as originally planned 
  given lower incidence in the primary efficacy outcome and 
  slower randomization than originally expected, and
- a revision of the description of the interim analysis.
8.2
Overview Changes to SAP – Amendment 2
Editorial, administrative, and typographical corrections were made that do not affect the overall 
integrated SAP.  These changes are not described in this section. 
The following changes are introduced in SAP Version 3.0.
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Modification 1: Introduction of the terminology “unrefuted event”.  
Rationale:  CSP and SAP were not yet referring to the harmonized terminology resulting from the 
event adjudication plan, version 3.0. According to the event adjudication plan, a reported and 
adjudicated event is designated “unrefuted” if it does meet the specified definition or “refuted” if it 
does not. The wording “verified” event from the original SAP has been revised to reflect the 
harmonized terminology.
Sections affected:

Section 3: Study Design

Section 4.1: General Principles

Section 4.4: Interim Analyses and Data Monitoring

Section 4.5.1: Analysis Dates

Section 4.5.3: Censoring Rules for Time-to-Event Variables

Section 6.2.1.1: Primary Efficacy Variable

Section 7: Sample Size Considerations – Amended 
Modification 2: Clarification of data scope.  
Rationale:  Clarification that all data collected for a randomized subject until end of study, or until 
the time of loss to follow-up, or complete refusal to provide additional information will be used for 
the statistical analysis.
Sections affected:

Section 4.5.2: Data Scopes 
Modification 3: Time window for second look in interim analysis.  
Rationale:  The time window for the second look after crossing the monitoring boundary in the 
interim analysis was not consistent with the DSMB Charter, which states 3 months. Therefore, the 
time window in the SAP was made a little more flexible to allow for 3-6 months instead of 4-6 
months.
Sections affected:

Section4.4: Interim Analyses and Data Monitoring
Modification 4: ITT analysis set and unique randomized subjects.  
Rationale: After completion of the randomization phase for the study, it has been detected that few 
subjects have unintentionally been randomized twice in the study, some at a different site from the 
first. Therefore, the definition of the ITT analysis set was amended by adding that only unique 
subjects will be considered. In the analysis, these subjects will be considered with the treatment to 
which they have randomly been assigned at the initial site. Data from the randomization at the 
second site will be documented and reported.
Sections affected:
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
Section 5.1.1: Intention-to-Treat Analysis Set (ITT) 
Modification 5: Subgroup variables.  
Rationale: Additional subgroups and clarifications for existing subgroups variables have been added. 
Furthermore, important subgroups have been distinguished from other subgroups that are examined 
to assess the consistency of a treatment effect.
Sections affected:

Section 6.1.6: Other Baseline Characteristics 

Section 6.2.5: Efficacy Subgroup Analysis
Modification 6: Pantoprazole outcomes.  
Rationale: Observational studies have associated pantoprazole use with a range of adverse 
outcomes.  Therefore, it is now of interest to explore the effect of pantoprazole compared with 
placebo on these outcomes in the COMPASS study.
Sections affected:

Section 6.2.4.1: Variables for Pantoprazole Randomization 
Modification 7: Analysis of the joint effect and/or interaction of study treatments.  
Rationale: A subheader for the section describing the additional analysis of the joint effect and/or 
interaction between rivaroxaban-based anti-thrombotic therapy and proton pump inhibitor use on the 
primary efficacy outcome was added to better structure the section and emphasize this type of 
analysis.
Sections affected:

Section 6.2.1.2: Primary Efficacy Analysis
Modification 8: MI type criteria according to universal definition of myocardial infarction.  
Rationale: As far as possible based on the collected data, type of MI will also be determined based 
on the MI type criteria according to the universal definition of myocardial infarction. Details will 
described in the derivation document. The efficacy outcomes will then be evaluated by MI types 
according to the universal definition.
Sections affected:

Section 6.2.7: Exploratory Analysis 
8.3
Changes to SAP Text by Amendment 2

Changes as a result of Modification 1 in Sections 3, 4.4, 4.5.1, 4.5.3, 6.2.1.1, and 7.
Old Text (1):
[…] a verified event […]  
New Text (1):
[…] an outcome event […]  
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Old Text (2):
[…] a verified event […]  
New Text (2):
[…] an unrefuted event […]  
Old Text (3):
[…] an event […]  
New Text (3):
[…] an unrefuted event […]  

Changes as a result of Modification 1 in Section 4.1. 
Added Text:
Primary outcome events (myocardial infarction, stroke, CV death), selected secondary and 
tertiary outcome events (acute limb ischemia, heart failure, venous thromboembolism, 
cancer), as well as bleeding and GI events will undergo an event adjudication process to 
evaluate whether events reported by investigators meet the pre-specified trial definitions. A 
reported and adjudicated event is designated “unrefuted” if it does meet the specified 
definition or “refuted” if it does not. Primary statistical analyses will be based on unrefuted 
events. In addition, all reported events will summarized.

Changes as a result of Modification 2 in Section 4.5.2. 
Added Text:
The analysis will be based on all data collected for a randomized subject until end of study, 
or until the time of loss to follow-up, or complete refusal to provide additional information.

Changes as a result of Modification 3 in Section 4.4. 
Old Text:
If the monitoring boundary is crossed at either of the 2 interim analyses, a second look will 
be done after at least an additional 4-6 months to confirm the boundary remains crossed and 
that the trend in treatment effect is not temporary.
New Text:
If the monitoring boundary is crossed at either of the 2 interim analyses, a second look will 
be done after at least an additional 3-6 months to confirm the boundary remains crossed and 
that the trend in treatment effect is not temporary.

Changes as a result of Modification 4 in Section 5.1.1.
New Text:
The intention-to-treat analysis set, also termed full analysis set in the International 
Conference on Harmonization (ICH) E9 guideline, will include all unique randomized 
subjects. 
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If a subject is unintentionally randomized twice in the study, the subject will be included in 
the statistical analysis with the ID from the site where the initial randomization took place.  
Data from the randomization at the second site will be documented and reported.

Changes as a result of Modification 5 in Section 6.1.6. 
Old Text:
The number of subjects falling in the categories of the following list of (subgroup) variables 
will be summarized by means of frequency tables, by both randomized antithrombotic and 
pantoprazole study treatment groups and overall.

Coronary artery disease (yes, no)

Peripheral artery disease (yes, no)

CAD and PAD (yes, no)

CAD only, PAD only, CAD and PAD 

CABG surgery (planned within 4-7 days) before randomization (yes, no)

Region (North America, Western Europe, Eastern Europe, Asia Pacific and other, and 
South America; see Appendix 10.1)

History of a prior heart failure (yes, no)

History of non-lacunar ischemic stroke ≥1 months ago (yes, no)

Age (<55, 55 - <65, 65 - 75, >75 years)

Baseline renal function (estimated glomerular filtration rate <60, ≥60 mL/min)

Baseline diabetes (yes, no)

Smoking status at baseline (smoker, nonsmoker)

Baseline proton pump inhibitor use (yes, no)

Peptic ulcer history at baseline (yes, no)
New Text:
The number of subjects falling in the categories of the list of subgroup variables, see 
subsection 6.2.5, will be summarized by means of frequency tables, by both randomized 
antithrombotic and pantoprazole study treatment groups and overall.

Changes as a result of Modification 5 in Section 6.2.5. 
Old Text:
Homogeneity of treatment effect (i.e., the effect of antithrombotic study treatment on the 
primary efficacy outcome and effect of pantoprazole study treatment on the pantoprazole 
outcome) will be examined for the following subgroup variables:

Coronary artery disease (yes, no)

Peripheral artery disease (yes, no)

CAD and PAD (yes, no)

CAD only, PAD only, CAD and PAD 
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
CABG surgery (planned within 4-7 days) before randomization (yes, no)

Any prior CABG (yes, no), further subdivided as CABG days 4-7 before 
randomization and other prior CABG 

Region (North America, Western Europe, Eastern Europe, Asia Pacific and other, and 
South America)

History of a prior heart failure (yes, no)

History of non-lacunar ischemic stroke ≥1 months ago (yes, no)

Sex (male, female)

Age (<55, 55 - <65, 65 - 75, >75 years)

Race (White or Caucasian, Black or African American, Asian, other)

Baseline renal function (estimated glomerular filtration rate <60, ≥60 mL/min)

Baseline diabetes (yes, no)

Smoking status at baseline (smoker, nonsmoker)

Baseline proton pump inhibitor use (yes, no)

Peptic ulcer history at baseline (yes, no)
Additional subgroup analyses, if identified, will be specified before unblinding of treatment 
assignment. […].
No interactions with any of the subgroup variables are expected.  If the interaction term is 
significant at the 5% type I error level in the analysis of the primary efficacy outcome, 
secondary and tertiary efficacy outcomes will be investigated to evaluate the plausibility of 
such an effect.  […]  
New Text:
Homogeneity of treatment effect (i.e., the effect of antithrombotic study treatment on the 
primary efficacy outcome and effect of pantoprazole study treatment on the pantoprazole 
outcome) will be examined for the following subgroup variables, where important subgroups 
are distinguished from “other” subgroups that are examined to assess the consistency of a 
treatment effect:
Important subgroups

Coronary artery disease (yes, no)

Peripheral artery disease (yes, no)

CAD and PAD (yes, no)

CAD only, PAD only, CAD and PAD 

History of prior asymptomatic carotid artery stenosis >= 50%/revascularization (yes, 
no)

History of polyvascular disease with number of vascular beds affected 
[CAD, PAD, cerebrovascular disease, i.e., prior stroke or asymptomatic carotid artery 
stenosis >= 50%/revascularization] (1, 2, or 3 vascular beds affected)

Prior CABG surgery 
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o
Any prior CABG surgery (yes, no)
o
Study baseline CABG surgery [planned within 4-7 days before 
randomization] (yes, no)
o
Prior CABG surgery (no prior CABG surgery, study baseline CABG surgery, 
other history of prior CABG surgery)

CAPRIE-like population with medical history of any of the following prior events:
MI, (ischemic) stroke, or PAD (yes, no)

History of prior MI (yes, no)

History of both prior MI and polyvascular disease or multivessel CAD (yes, no)
Other subgroups

Region
o
North America, Western Europe, Eastern Europe, Asia Pacific and other, and 
South America, see Appendix 10.1
o
US, non-US

Sex (male, female)

Age 
o
Categories 1: <55, 55 to <65, 65 to 75, >75 years
o
Categories 2: < 65, ≥ 65 to < 75, ≥ 75 years

Race (White or Caucasian, Black or African American, Asian, other)

Body weight at baseline (≤ 60 kg, > 60 kg)

Baseline renal function 
o
estimated glomerular filtration rate (eGFR) categories 1: <60, ≥60 mL/min
o
eGFR categories 2: < 15, 15 to < 30, 30 to < 60, ≥ 60 mL/min
o
eGFR categories 3: < 30, 30 to 50, >50 to 80 ml/min, >80 ml/min

Smoking status 
o
Tobacco use at baseline (yes, no)
o
History of tobacco use (yes, no)

Baseline proton pump inhibitor use (yes, no)

Baseline lipid lowering agent use (yes, no)

Baseline diabetes (yes, no)

History of a prior heart failure (yes, no)

History of peptic ulcer (yes, no)

History of (non-lacunar ischemic) stroke (yes, no)

History of peripheral artery bypass surgery or peripheral percutaneous transluminal 
angioplasty (yes, no)

History of limb or foot amputation for arterial vascular disease (yes, no)

History of hypertension (yes, no)
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
History of prior coronary PTCA/Atherectomy/PCI (yes, no)

History of prior MI and age < 65 years (yes, no)

History of prior MI and reduced renal function, i.e., eGFR <60 mL/min (yes, no)
Additional subgroup analyses, if identified, will be specified before unblinding of treatment 
assignment.  […]. 
No interactions with any of the subgroup variables are expected.  If,

for important subgroups: the interaction term is significant at the 5% type I error level 
in the analysis of the primary efficacy outcome,

for other subgroups: the interaction term is significant at the 1% type I error level in 
the analysis of the primary efficacy outcome and there is a biologically coherent 
explanation for the finding,
secondary and tertiary efficacy outcomes will be investigated to evaluate the 
plausibility of such an effect. […]  

Changes as a result of Modification 6 in Section 6.2.4.1. 
Old Text:
Variable for Pantoprazole Randomization
The variable for the pantoprazole randomization is the time (in days) from randomization to 
the first occurrence of the following outcomes: 

Overt bleeding of gastroduodenal origin confirmed by endoscopy or radiography 

Overt upper gastrointestinal bleeding of unknown origin 

Bleeding of presumed occult gastrointestinal origin with documented decrease in Hb 
of 2 g/dL 

Symptomatic gastroduodenal ulcer 

Gastrointestinal pain with underlying multiple gastroduodenal erosions, obstruction 
or perforation 
The time-to-event variable will be derived in a similar manner as described in Section 6.2.1.1
for the primary efficacy variable.
New Text:
Variables for Pantoprazole Randomization – Amended
The main variable for the pantoprazole randomization is the time (in days) from 
randomization to the first occurrence of the following outcomes: 

Overt bleeding of gastroduodenal origin confirmed by endoscopy or radiography 

Overt upper gastrointestinal bleeding of unknown origin 

Bleeding of presumed occult gastrointestinal origin with documented decrease in Hb 
of 2 g/dL 

Symptomatic gastroduodenal ulcer 
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
Gastrointestinal pain with underlying multiple gastroduodenal erosions, obstruction 
or perforation 
The time-to-event variable will be derived in a similar manner as described in Section 6.2.1.1
for the primary efficacy variable.
Other outcomes of interest for the pantoprazole randomization are:

pneumonia, enteric infections, and bone fractures as well as new diagnosis of gastric 
atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, and 
dementia since randomization. 

Changes as a result of Modification 7 in Section 6.2.1.2. 
Added Text:
Analysis of the joint effect and/or interaction of study treatments

Changes as a result of Modification 8 in Section 6.2.7. 
Added Text:
The efficacy outcomes will also be evaluated by MI types according to the universal 
definition, see derivation document for details.
8.4
Overview Changes to SAP – Amendment 3.0
The SAP Version 4.0 (including SAP amendment v3.0) was written after the first interim analysis 
with the intent to fully preserve the statistical analyses that have been outlined in the protocol and 
the previous version of the SAP but to clarify some aspects pertaining to the interim analysis and to 
reflect the wording and additional close-out visits prompted by the premature stop of the anti-
thrombotic study treatment arms. 
Version 4.0 of the SAP was contentwise finalized on 17 March 2017.  During the approval process, 
an open question was raised and the approval process was put on hold on 21 March 2017.  As not all 
approvers, including the principal investigator, had signed off Version 4.0, this version is not 
considered to be in effect or approved.  The withdrawn document is retained without changes 
together with a memo and the available signature forms. A revised version 4.1 of the integrated SAP 
was prepared instead.
8.5
Overview Changes to SAP – Amendment 3.1
Editorial, administrative, and typographical corrections were made that do not affect the overall 
integrated SAP.  These changes are not described in this section. 
The following changes are introduced in SAP, Version 4.1.
Modification 1: Early close-out of the rivaroxaban/aspirin portion of the trial.  
Rationale:  Some aspects pertained to the interim analysis, wording, and design amendments 
prompted by the premature stop of the anti-thrombotic study treatment arms are clarified. These 
changes include the description of additional study visits, dates, data scopes and rules due to the 
early close-out of the rivaroxaban/aspirin portion of the trial. In addition, it is described that the 
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analyses pertained to the pantoprazole/placebo randomization will be deferred to a later date at the 
end of the study.
Sections affected:

Section 3: Study Design

Section 4.2: Handling of Non-Compliance to Study Treatment or Follow-up

Section 4.5: Data Rules

Section 5.1.2: Safety Analysis Set

Section 6.1.1: Disposition

Section 6.1.7: Prior and Concomitant Medication

Section 6.1.8: Extent of Study Follow-up and Exposure

Section 6.2.1.1: Primary Efficacy Variable

Section 6.2.1.2: Primary Efficacy Analysis

Section 6.2.3.2: Tertiary Efficacy Analysis

Section 0: Analysis for Pantoprazole Randomization

Section 6.2.4.1: Variables for Pantoprazole Randomization

Section 6.2.5: Efficacy Subgroup Analysis

Section 6.2.6: Analyses of the COMPASS MIND Substudy
Modification 2: Type I error at first interim analysis.  
Rationale:  Details regarding the type I error at the first interim analysis or testing of secondary 
hypotheses after premature stopping for efficacy according to the modified Haybittle-Peto boundary 
had not been specified in the SAP. A clarification of the type I error at the first interim analysis has 
been added.
Sections affected:

Section 6.2: Efficacy
Modification 3: SAS code – stratified log-rank test.  
Rationale:  The SAS code provided for carrying out the stratified log-rank test has been updated to
reflect the FDA preferred implementation, with the difference being how tied event times are 
handled.
Sections affected:

Section 6.2.1.2: Primary Efficacy Analysis
Modification 4: Clarification of data scopes and timing of AE data summaries.  
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Rationale:  Safety analyses for variables related to bleedings will be performed on all safety data 
scopes defined. The data scopes for summaries of AE data have been adapted to the study design 
and the two portions of the study after the interim analyses.
Sections affected:

Section 6.4.2.1: Adverse Events
Modification 5: Sensitivity analyses to address potential impact of missing data on primary 
analysis.  
Rationale:  As already described in Section 6.2.7 of the SAP, Version 1.0, it was planned to perform
additional sensitivity analyses in order to evaluate the robustness of the primary analysis. A detailed 
description of the planned sensitivity analyses has been added in Appendix 10.4.
Sections affected:

Section 6.2.7: Exploratory Analyses

Section 10.4: Sensitivity analyses to address the potential impact of missing data
Modification 6: Regions.  
Rationale:  The allocation of countries to regions has been revised.
Sections affected:

Section 10.1: Regions
Modification 7: Net clinical benefit.  
Rationale:  A net clinical benefit variable has been added to the SAP.
Sections affected:

Section 6.2.2.1: Secondary Efficacy Variables
8.6
Changes to SAP Text by Amendment 3

Changes as a result of Modification 1 in Section 3:
Old Text:
[…]
Final Follow-up Visit and end of study
The primary analysis will be based on the events that occur after the date and time of 
randomization and up until the Final Follow-up Visit.  The date of the Final Follow-up Visit
cannot be pre-determined as this study is event-driven, but the visits will be scheduled when at 
least 2,200 subjects have experienced an unrefuted event (after adjudication) for the primary 
efficacy outcome for the rivaroxaban randomization.  These events are expected to accumulate 
over approximately 4-5 study years after randomization of the first subject.  All subjects will 
remain in follow-up until this minimum number of primary outcome events has been reached, 
irrespective of whether they are still taking study treatments or whether they have experienced 
an outcome.  […]  
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End of Washout Visit
A final Washout Visit (End of Washout Telephone Visit) […]
New Text:
Final rivaroxaban/aspirin Follow-up Visit
The primary analysis will be based on the events that occur after the date and time of 
randomization and up until the global rivaroxaban/aspirin outcomes cut-off date (February 06, 
2017, the date of the DSMB recommendation to stop the rivaroxaban/aspirin study treatment 
arms).  At the Final rivaroxaban/aspirin Follow-up Visit, subjects will be asked to stop taking all 
randomized rivaroxaban and aspirin study treatment, while study treatment with randomized 
pantoprazole/pantoprazole placebo can continue as planned.
Rivaroxaban/aspirin Washout Telephone Visit
A rivaroxaban/aspirin Washout Telephone Visit will be conducted by telephone about 30 days 
after the Final rivaroxaban/aspirin Follow-up Visit to collect information on outcomes and 
protocol specific adverse events. 
Note: the rivaroxaban/aspirin Washout Telephone Visit is equivalent to the end of study for 
those subjects who have not been randomized to pantoprazole/placebo.
Final (pantoprazole/placebo) Follow-up Visit and end of study
The analysis, as pertains to the pantoprazole randomization, will be based on the events that 
occur after the date and time of randomization and up until the Final Follow-up Visit, also 
referred to as “Final pantoprazole/placebo Follow-up Visit”. Subjects ongoing in the 
pantoprazole arms will remain in follow-up until the end of study, irrespective of whether they 
are still taking study treatments or whether they have experienced an outcome.  At the Final 
Follow-up Visit the following information will be obtained from the subject: study treatment 
adherence, study treatment interruption, outcomes and adverse events, physical measurements 
and concomitant medications, and questionnaires (except for the Interheart Diet Questionnaire 
and the IPAQ).  Subjects will be asked to stop taking randomized pantoprazole study treatment. 
The Final Follow-up Visit (close out is expected to occur over a period of about 3 months) and 
the subsequent 30-day washout period will occur nearly simultaneously (as scheduling permits) 
for all study subjects.  
End of pantoprazole/placebo Washout Telephone Visit
A pantoprazole/placebo Washout Visit (End of Washout Telephone Visit) will be conducted by 
telephone about 30 days after the Final pantoprazole/placebo Follow-up Visit to collect 
information on outcomes and protocol specific adverse events.  Adverse events will continue to 
be collected up to 30 days post study drug treatment with pantoprazole/placebo.
An overview describing these visits and the data to be included in different type of analyses is 
given in Figure 3-1.
Newly added: Figure 3-1: Study visits and analyses
Editorial changes in Table 3-2.  Schedule of evaluations
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
Changes as a result of Modification 1 in Section 4.2:
Old Text:
A randomized subject who permanently stops taking study treatment before their Final Follow-
up Visit for any reason is defined as having had a premature permanent discontinuation of study 
treatment (including subjects who were randomized but never started taking any study 
treatment). The reason for permanent discontinuation of study treatments will be recorded in the 
CRF. 
However, all subjects will be encouraged to remain study treatments and under observation the 
full duration of the study.  
New Text:
A randomized subject who permanently stops taking study treatment before their Final 
rivaroxaban/aspirin Follow-up Visit (for rivaroxaban/aspirin) or their Final pantoprazole/placebo
Follow-up Visit (for pantoprazole/placebo) for any reason is defined as having had a premature 
permanent discontinuation of study treatment (including subjects who were randomized but 
never started taking any study treatment). The reason for permanent discontinuation of study 
treatments will be recorded in the CRF. Subjects who continued on rivaroxaban/aspirin study 
treatment until the global rivaroxaban/aspirin outcomes cut-off date but stopped 
rivaroxaban/aspirin study treatment before their Final rivaroxaban/aspirin Follow-up Visit will 
still be considered as study rivaroxaban/aspirin follow-up completers.
However, all subjects will be encouraged to remain on their randomized and pertinent (to the 
portion of the study) study treatments and under observation until the end of the study.  […]
If it is documented in the database that the subject is alive at the global rivaroxaban/aspirin 
outcomes cut-off date / at the end of the study, the subject will not be classified as lost to follow-
up, but as alive.

Changes as a result of Modification 1 in Section 4.5:
Old Text:
4.5.1
Analysis Dates
A common trial close-out window and a close out (cut-off) date will be chosen by a study 
committee for the COMPASS trial.  They will be announced and all sites will be notified before 
unblinding.  The announcement of the common trial close out window will be timed to ensure at 
least 2,200 subjects will have experienced an unrefuted event for the primary efficacy outcome 
for the rivaroxaban randomization within this trial. All subjects will return to the clinic for a 
Final Follow-Up Visit within this pre-specified acceptable close-out time-window (about 3 
months; period ends with the common trial close-out date, see below).  […]

Common trial close-out date:
The common trial close out (cut-off) date is the end date of the common trial close-out 
window.  It is the last calendar date acceptable for counting events within the primary 
analysis, prior to the washout period.  
If a subject who is unable to attend his/her Final Follow-up Visit within the acceptable 
common trial close-out time-window, has a trial-related contact after the common trial 
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close-out date, the observation period up until the common trial close-out date (inclusive) 
will be considered in the primary analysis. , i.e., events that occur up until the common 
trial close-out date (inclusive) will be counted in the primary analysis, otherwise the 
subject will be censored at the common trial close-out date.
For each subject, the following individual analysis dates will be derived: […]

Final Follow-Up Visit date:
The date of the Final Follow-Up Visit for the individual subject. 
Beginning with the announcement of trial close-out, all subjects are to return to the clinic 
for their Final Follow-Up Visit within the pre-specified common trial close-out window 
(see Section 3 for the schedule of evaluations at the Follow-Up Visit). If subjects do not 
have a Final Follow-Up Visit, the date will be missing.  For subjects who have a Final 
Follow-up Visit, events that occur after the date and time of randomization and up until 
the Final Follow-up Visit (inclusive) will be considered in the primary analysis.  […]

Date of last double-blind dose of antithrombotic study treatment: 
[…] If missing or incomplete, the date of last double-blind dose of antithrombotic study 
treatment is set to the latest logically possible date of antithrombotic study medication 
administration on or before the earliest of the subject’s following dates, the date of, the 
date of death, or the common trial close-out date, and no earlier than the randomization 
date.  
4.5.2
Data Scopes
[…] Data scope according to intention-to-treat principle
Analyses according to the intention-to-treat (ITT) principle will be based on the intention-to-
treat analysis set (see Section 5.1.1) and will include all outcome events that occur after the date 
and time of randomization and up until the Final Follow-up Visit (inclusive) for each subject.  
For subjects who are unable to attend the Final Follow-up Visit within the acceptable common 
close-out time-window (range of dates from announcement of trial close-out up to the common 
trial close-out date), events occurring after the common trial close-out date will not be counted 
for primary analysis (see also Section 4.5.1).  Subjects will be kept in the study group to which 
they were randomized and the follow-up period for each subject will be as long and complete as 
possible.  This ITT data scope will be applied to the primary analysis of the primary efficacy and 
safety variables, following the intention-to-treat principle.
Additional data scopes for secondary safety analyses 
[…]

All outcome events for each subject occurring after the date and time of randomization 
and up until the global rivaroxaban/aspirin outcomes cut-off date (inclusive) Final 
Follow-up Visit, or the common trial close-out date if subjects are unable to attend the 
Final Follow-Up Visit within the acceptable common close-out time-window, 
documented in the database (“ITT” data scope) […]
New Text:
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4.5.1
Analysis Dates
A common trial close-out window and a close out (cut-off) date will be chosen by a study 
committee for the COMPASS trial.  All subjects will return to the clinic for a Final Follow-Up 
Visit within this pre-specified acceptable close-out time-window (about 3 months; period ends 
with the common trial close-out date, see below).  
Based on the DSMB recommendation after the first interim analysis and the early close-out of 
the rivaroxaban/aspirin study treatment portion of the study, some of the previously defined 
analysis dates became less important or dispensable for the rivaroxaban/aspirin randomization, 
while additional dates had to be added. 

Rivaroxaban/aspirin arms close-out window: 
The pre-specified target calendar date range within which subjects are to return to the 
clinic for a Final rivaroxaban/aspirin Follow-up Visit planned to range from end of 
February 2017 to 15 May 2017.

Global rivaroxaban/aspirin outcomes cut-off date:
The global rivaroxaban/aspirin outcomes cut-off date is 06 February 2017, i.e., the date 
when the DSMB recommended to stop the study treatment arms rivaroxaban 2.5 mg bid 
+ aspirin 100 mg daily, rivaroxaban 5.0 mg bid, and aspirin 100 mg daily as soon as an 
orderly close-out of this portion of the study could be carried out.  Outcome events that 
occur up until the global rivaroxaban/aspirin outcomes cut-off date (inclusive) will be 
counted in the primary analysis, otherwise the subject will be censored at the global 
rivaroxaban/aspirin outcomes cut-off date.

Common trial close-out window: 
The pre-specified acceptable calendar date range within which subjects ongoing in the 
pantoprazole/placebo portion of the study are to return to the clinic for a Final Follow-Up 
Visit (e.g. about 3 months). […]
For each subject, the following individual analysis dates will be derived:

Randomization date: 
The date of randomization to antithrombotic treatment of the subject. 

Date of the Final rivaroxaban/aspirin Follow-up Visit:
The date of the Final rivaroxaban/aspirin Follow-up Visit for the individual subject. 
If subjects do not have a Final rivaroxaban/aspirin Follow-up Visit, the date will be 
missing.

Final (pantoprazole/placebo) Follow-Up Visit date:
The date of the Final (pantoprazole/placebo) Follow-Up Visit for the individual subject. 
Beginning with the announcement of trial close-out, all subjects ongoing in the 
pantoprazole/placebo portion of the study are to return to the clinic for their Final 
Follow-Up Visit within the pre-specified common trial close-out window (see Section 3
for the schedule of evaluations at the Follow-Up Visit). If subjects do not have a Final 
Follow-Up Visit, the date will be missing.  
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
Rivaroxaban/aspirin Washout Telephone Visit date:
The date of the rivaroxaban/aspirin Washout Telephone Visit for the individual subject. 
To be performed about 30 days after the Final rivaroxaban/aspirin Follow-up Visit.

End of pantoprazole/placebo Washout Visit date:
The date of the End of pantoprazole/placebo Washout Visit for the individual subject.
To be performed about 30 days after the Final pantoprazole/placebo Follow-up Visit.
If subjects do not have an End of pantoprazole/placebo Washout Visit, the date will be
missing.

Last contact date during rivaroxaban/aspirin portion of the study:
The date of the last documented contact with the subject or a third party up until the 
maximum (later) of the subject’s {date of the Final rivaroxaban/aspirin Follow-up Visit, 
end of rivaroxaban/aspirin Washout date}. For subjects who died after randomization but 
before their scheduled end of rivaroxaban/aspirin Washout date, the date of the last 
rivaroxaban/aspirin related contact is set to the death date.

Date of the last follow-up contact:
The date of the last known documented contact with the subject or a third party 
(including data on subject survival status)
- up until the Final Follow-up Visit date (inclusive), if the subject attends his/her Final 
Follow-up Visit or
- up until the common trial close-out date, if the subject does not attend his/her Final 
Follow-up Visit. 
For subjects who die (a) after randomization but before the beginning of the common 
trial close-out window or (b) during the common trial close-out window but before their 
Final Follow-up Visit takes place, the date of the last follow-up contact is set to the death 
date.
This date is only applicable to analyses for pantoprazole/placebo comparisons at the end 
of the study. […]

Date of last double-blind dose of antithrombotic study treatment: 
The later date of 
- the last dose of rivaroxaban/rivaroxaban placebo study medication and  
- the last dose of aspirin / aspirin placebo study medication.  
For a subject with premature permanent discontinuation of any study medication, the 
corresponding last dose date(s) will be obtained from the Permanent Discontinuation 
CRF Report. If study medication was continued until the Final rivaroxaban/aspirin
Follow-up Visit, the date of the last dose of the corresponding study treatment will be the 
date of the Final rivaroxaban/aspirin Follow-up Visit.
If missing or incomplete, the date of last double-blind dose of antithrombotic study 
treatment is set to the latest logically possible date of antithrombotic study medication 
administration on or before the earliest of the subject’s following dates, the date of the 
last contact for the rivaroxaban/aspirin comparison, the date of death, or the end of the 
rivaroxaban/aspirin arms close-out window, and no earlier than the randomization date.  
[…]
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4.5.2
Data Scopes
The analysis, as pertains to the rivaroxaban/aspirin randomization, will be based on all data 
collected for a randomized subject until end of the rivaroxaban/aspirin portion of the study, or 
until the time of loss to follow-up with no indication that the subject returned, or complete 
refusal to provide additional information.
The analysis, as pertains to the pantoprazole/placebo randomization, will be based on all data 
collected for a randomized subject until end of study, or until the time of loss to follow-up, or 
complete refusal to provide additional information.
This section describes the coverage of the event data scopes used for the statistical analyses. 
Analysis sets are described in Section 5.
Data scope for rivaroxaban/aspirin randomization according to intention-to-treat principle
For the rivaroxaban/aspirin comparisons performed after the DSMB recommendation related to 
the results of the first interim analysis, analyses according to the intention-to-treat (ITT) 
principle will be based on the intention-to-treat analysis set (see Section 5.1.1) and will include 
all outcome events that occur after the date and time of randomization and up until the global 
rivaroxaban/aspirin outcomes cut-off date (inclusive) for each subject.  Events occurring after 
the global rivaroxaban/aspirin outcomes cut-off date will not be counted for primary analysis 
(see also Section 4.5.1).  Subjects will be kept in the study group to which they were 
randomized.  This ITT data scope will be applied to the analysis of the primary efficacy and 
safety variables, following the intention-to-treat principle. (“ITT” data scope)
Additional data scopes for the rivaroxaban/aspirin randomization
Sensitivity analyses for the primary efficacy outcomes will be based on all outcome events 
occurring after the date and time of randomization and up until the Final rivaroxaban/aspirin 
Follow-up Visit (inclusive) for each subject. (“Rivaroxaban/aspirin Follow-up” data scope)
Data scope for the pantoprazole/placebo randomization according to intention-to-treat 
principle
[…]
Additional data scopes for secondary safety analyses for the rivaroxaban/aspirin 
randomization
Additional secondary analyses of safety outcomes will be based on the safety analysis set (see 
Section 5.1.2). Subjects will be kept in the study group to which they were randomized. 
Additional data scopes will be defined to include all outcome events as follows:

All outcome events for each subject occurring after the date and time of randomization 
and up until the global rivaroxaban/aspirin outcomes cut-off date (inclusive) (“ITT” data 
scope)

[…]

All outcome events occurring after the date and time of randomization during the entire 
individual rivaroxaban/aspirin follow-up and wash-out periods documented in the 
database (“Rivaroxaban/aspirin Follow up + Wash out” data scope)
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Data scopes for safety analyses for the pantoprazole/placebo randomization
Analyses of safety outcomes for the pantoprazole randomization will be based on the safety 
analysis set related to the pantoprazole randomization. Subjects will be kept in the study group to 
which they were randomized. The outcome events will include:

All outcome events observed from randomization until 2 days following permanent 
discontinuation of the pantoprazole study drug (“treatment emergent outcomes” analysis)

All outcome events observed from randomization during the entire follow-up and wash-
out periods up until the end of the trial
Corresponding censoring rules are described in Section 4.5.3.
4.5.3
Censoring Rules for Time-to-Event Variables
For any time-to-event variable in this study, the following censoring rules will be applied: 
Censoring rules for analyses related to the rivaroxaban/aspirin randomization according to 
the intention-to-treat principle

For analyses according to the intention-to-treat principle which are related to the 
rivaroxaban/aspirin randomization and performed after the DSMB recommendation, 
randomized subjects without documentation of an evaluable event will be censored at 
o
the minimum (earliest) of the global rivaroxaban/aspirin outcomes cut-off date 
and the subject’s last contact date during the rivaroxaban/aspirin portion of the 
study.
This censoring rule will be applied to all analyses according to the intention-to-treat 
principle. In the rare event that for a subject only survival status information can be 
retrieved at the end of the study rivaroxaban/aspirin portion of the trial but no 
information on other outcomes, the last study rivaroxaban/aspirin follow-up contact 
where survival status information was obtained will still be used to determine the 
censoring date for the subject and if there were no known events up to then the subject 
will be considered as event-free. 
Censoring rules for analyses related to the pantoprazole/placebo randomization according 
to the intention-to-treat principle
[…]
This censoring rule will be applied to all analyses related to the pantoprazole/placebo 
randomization performed after common trial close-out according to the intention-to-treat 
principle. […]. 
Censoring rules for secondary safety analyses related to the rivaroxaban/aspirin 
randomization

For secondary safety analyses based on the safety analysis set and the ITT data scope, all 
randomized subjects with at least one dose of either randomized study medication and 
without documentation of an outcome event within the ITT data scope will be censored 
as stated above for study rivaroxaban/aspirin analyses according to the ITT principle.
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
[…]  
Note that if a subject stops treatment at the Final rivaroxaban/aspirin Follow-up Visit and 
experiences an event up to 2 days thereafter, the event will be counted in this analysis but 
not in the primary analysis using the ITT data scope.

[…]
Note that if a subject stops treatment at the Final rivaroxaban/aspirin Follow-up Visit and 
experiences an event up to 30 days thereafter, the event will be counted in this analysis 
but not in the primary analysis.

For secondary safety analyses based on the safety analysis set and the “Study 
rivaroxaban/aspirin Follow up + Wash out” data scope, all randomized subjects with at 
least one dose of study medication and without documentation of an outcome event will 
be censored at the subject’s last contact date during the rivaroxaban/aspirin portion of the 
study.
Censoring rules for secondary safety analyses related to the pantoprazole/placebo 
randomization

For “treatment-emergent” safety analyses, all randomized subjects with at least one dose 
of pantoprazole/placebo study medication and without documentation of an outcome 
event within the “treatment-emergent” data scope will be censored at the date of last dose 
of pantoprazole study treatment + 2 days.

For safety analyses based on the safety analysis set and the “Follow up + Wash out” data 
scope, all randomized subjects with at least one dose of pantoprazole/placebo study 
medication and without documentation of an outcome event will be censored at the date 
of last trial contact.

Changes as a result of Modification 1 in Section 5.1.2:
Old Text:
The safety analysis set for secondary analyses will include all randomized subjects who received 
at least one dose of either randomized study medication. 
New Text:
The safety analysis set for secondary analyses related to the rivaroxaban/aspirin randomization
will include all unique randomized subjects who received at least one dose of 
rivaroxaban/aspirin study medication. 
The safety analysis set for secondary analyses related to the pantoprazole randomization will 
include all unique randomized subjects who received at least one dose of randomized 
pantoprazole/placebo medication. 

Changes as a result of Modification 1 in Sections 6.1, 6.1.1 and 6.1.8:
New Text:
Note that all summaries related to the pantoprazole randomization described in this section of the 
SAP will only be provided at the end of the pantoprazole portion of the study. 
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[…]
The following will be tabulated overall and/or by antithrombotic treatment group:
[…]

Number of subjects and primary reasons for premature permanent discontinuation of 
study medication (for each type of randomized study medication, as applicable regarding 
the portion of the study)
[…] 
Kaplan-Meier estimates will be used to present […]

time to the date of last double-blind dose of pantoprazole study treatment (after 
completion of pantoprazole/placebo portion of the study) […] 
[…]

relevant concomitant medications recorded at the Final rivaroxaban/aspirin Follow-Up 
Visit and the Final Follow-Up Visit. 
[…]
The total duration of study follow-up for a subject in the rivaroxaban/aspirin portion of the study 
and overall will be calculated as follows:

Total duration of <rivaroxaban/aspirin, study> follow-up =  Date of last 
<rivaroxaban/aspirin, study> follow-up contact  –  Randomization date + 1.

Changes as a result of Modification 1 in Section 6.2.1.1:
Old Text:
All unrefuted primary efficacy outcome events within the data scope according to intention-to-
treat principle (see Section 4.5.2) will be considered for the derivation of the primary efficacy 
variable.

For those subjects with documentation of an unrefuted primary efficacy outcome event 
occurring
(a) after the date and time of randomization and up until the Final Follow-up Visit, or
(b) after the date and time of randomization and up until the common trial close-out date, 
if the subject was not available for a Final Follow-up Visit up to the common trial close-
out date 
time (in days) from randomization to the first occurrence of the primary efficacy outcome will 
be derived as: 
o
the date of the subject’s first primary efficacy outcome event 
–  the randomization date + 1. 
This will constitute an uncensored observation.

For those subjects without documentation of an unrefuted primary efficacy outcome event 
within the data scope according to intention-to-treat principle, 
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time (in days) from randomization to the first occurrence of the primary efficacy outcome 
will be derived as:
o
the subject’s Final Follow-Up Visit date  –  the randomization date +1,
if the subject was available for the Final Follow-Up Visit before the common trial close-
out date.
o
the subject’s date of last follow-up contact up to the common trial close-out date  –  the 
randomization date +1, if 
(a) the subject did not attend his/her Final Follow-Up Visit before the common trial 
close-out date and 
(b) the subject’s date of last trial contact is not after the common trial close-out date. 
o
the common trial close-out date  –  the randomization date +1, if 
(a) the subject did not attend his/her Final Follow-Up Visit before the common trial 
close-out date and
(b) the subject’s date of last trial contact is after the common trial close-out date.
New Text:
All unrefuted primary efficacy outcome events within the data scope according to intention-to-
treat principle (see Section 4.5.2) will be considered for the derivation of the primary efficacy 
variable.

For those subjects with documentation of an unrefuted primary efficacy outcome event 
occurring
after the date and time of randomization and up until the minimum (earliest) of the global 
rivaroxaban/aspirin outcomes cut-off date and the subject’s last contact date during the 
rivaroxaban/aspirin portion of the study
time (in days) from randomization to the first occurrence of the primary efficacy outcome will 
be derived as: 
o
the date of the subject’s first primary efficacy outcome event 
–  the randomization date + 1. 
This will constitute an uncensored observation.

For those subjects without documentation of an unrefuted primary efficacy outcome event 
within the data scope according to intention-to-treat principle, 
time (in days) from randomization to the first occurrence of the primary efficacy outcome 
will be derived as:
o
the minimum (earliest) of {the global rivaroxaban/aspirin outcomes cut-off date, the 
subject’s last contact date during the rivaroxaban/aspirin portion of the study}  –  the 
randomization date +1.

Changes as a result of Modification 1 in Section 6.2.1.2:
New Text:
Sensitivity analyses
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Sensitivity analyses will be performed to include all primary efficacy outcome events up until 
the minimum (earliest) of the Final rivaroxaban/aspirin Follow-up Visit date and the subject’s 
last contact date during the rivaroxaban/aspirin portion of the study.
In addition, the number of primary efficacy outcome events occurring after the Final 
rivaroxaban/aspirin Follow-up Visit until the rivaroxaban/aspirin Washout Telephone Visit, 
included in the clean database for the rivaroxaban/aspirin comparisons, will be summarized by 
rivaroxaban/aspirin study treatment group.

Changes as a result of Modification 1 in Section 6.2.3.2:
Old Text:
Subject reported data from the SAGE, MoCA, DSS, and EQ-5D questionnaire will be 
summarized by means of descriptive statistics and frequency tables by antithrombotic treatment 
group and overall and by visit. All data will be listed in the Appendix of the Clinical Study 
Report. In depth analyses of questionnaire data will be displayed in a separate report. 
New Text:
Subject reported data from the EQ-5D questionnaire will be summarized by means of descriptive 
statistics and frequency tables by antithrombotic treatment group and overall and by visit. All 
data will be listed in the Appendix of the Clinical Study Report. In depth analyses of the SAGE, 
MoCA, and DSS questionnaire data will be displayed in a separate report/after completion of the 
pantoprazole/placebo portion of the study. 

Changes as a result of Modification 1 in Section 6.2.4:
New Text:
All analyses related to the pantoprazole randomization described in this section of the SAP will 
only be performed at the end of the pantoprazole portion of the study. The CSR related to the 
rivaroxaban/aspirin randomization will only use the pantoprazole/placebo randomization data for 
stratified testing and interaction analyses of efficacy / safety outcomes in relation to the 
rivaroxaban/aspirin randomization.

Changes as a result of Modification 1 in Section 6.2.4.1:
Old Text:
The time-to-event variable will be derived in a similar manner as described in Section 6.2.1.1 for 
the primary efficacy variable.
New Text:
The time-to-event variable will be derived in a similar manner as originally described for the 
primary efficacy variable.

For those subjects with documentation of an unrefuted pantoprazole outcome event 
occurring
(a) after the date and time of randomization and up until the Final Follow-up 
Visit, or
(b) after the date and time of randomization and up until the common trial close-
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out date, if the subject was not available for a Final Follow-up Visit up to the 
common trial close-out date 
time (in days) from randomization to the first occurrence of the unrefuted pantoprazole 
outcome will be derived as: 
o
the date of the subject’s first unrefuted pantoprazole outcome event – the 
randomization date + 1. 
This will constitute an uncensored observation.

For those subjects without documentation of an unrefuted pantoprazole outcome event 
within the data scope according to intention-to-treat principle, 
time (in days) from randomization to the first occurrence of a pantoprazole outcome will 
be derived as:
o
the subject’s Final Follow-Up Visit date  –  the randomization date +1,
if the subject was available for the Final Follow-Up Visit before the common trial 
close-out date.
o
the subject’s date of last follow-up contact up to the common trial close-out date  
–  the randomization date +1, if 
(a) the subject did not attend his/her Final Follow-Up Visit before the common 
trial close-out date and 
(b) the subject’s date of last trial contact is not after the common trial close-out 
date. 
o
the common trial close-out date  –  the randomization date +1, if 
(a) the subject did not attend his/her Final Follow-Up Visit before the common 
trial close-out date and
(b) the subject’s date of last trial contact is after the common trial close-out date.
This will constitute a right-censored observation.

Changes as a result of Modification 1 in Section 6.2.5:
New Text:
The subgroup analyses for the rivaroxaban/aspirin comparisons will be performed after the end 
of the study rivaroxaban/aspirin portion of the trial, while subgroup analyses for the 
pantoprazole comparison will be performed after the end of the pantoprazole portion of the trial.

Changes as a result of Modification 1 in Section 6.2.5:
New Text:
Data related to the COMPASS MIND substudy will be reported separately.

Changes as a result of Modification 2 in Section 6.2:
New Text:
The recommendation by the independent DSMB to stop the rivaroxaban/aspirin arms early due 
to overwhelming efficacy after the first interim analysis was guided by a modified Haybittle-
Peto rule, expecting “a reduction of at least 4 standard deviations in the analysis of the primary 
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efficacy outcome”. The 2-sided type I error level corresponding to this decision rule can be 
calculated via * = Φ(-4) + 1 – Φ(4) = 0.0000633, where Φ denotes the cumulative distribution 
function of the standard normal distribution.  Considering the two comparisons, one for each 
rivaroxaban-treatment arm, being made according to this rule, the type I error level applied at the 
first interim analysis is about 1 = 2* = 0.0001267. 

Changes as a result of Modification 3 in Section 6.2.1.2:
Old Text:
PROC LIFETEST DATA = <dataset> ALPHA=0.05 METHOD=KM NELSON;
  STRATA stratumn;
  TEST trtgrpn;
  TIME ttevalue * ttecnsr(0);
RUN;
New Text:
PROC LIFETEST DATA = <dataset> ALPHA=0.05 METHOD=KM NELSON;
  STRATA stratumn / GROUP=trtgrpn TEST=(LOGRANK);
  TIME ttevalue * ttecnsr(0);
RUN;

Changes as a result of Modification 4 in Sections 6.4.1.3 and 6.4.2.1:
Old Text:
Subgroup analyses for the primary safety outcomes will be performed based on the same 
analysis sets and data scopes as in the main analyses of the study similar to the methodology 
outlined in Section 6.2.5.
[…]
Analyses of reported adverse events will be performed based on the safety analysis set and all 
secondary safety analysis data scopes.  […]
In addition, frequency tables will summarize the number of subjects with 

any event occurring within 30 days before permanent study drug discontinuation

any event occurring more than 2 days after permanent study drug discontinuation
for both antithrombotic study medication and pantoprazole study medication.
New Text:
Subgroup analyses for the primary safety outcomes will be performed based on ITT analysis set 
and scope and based on the safety analysis set and treatment-emergent data scope similar to the 
methodology outlined in Section 6.2.5.
[…]
Analyses of reported adverse events will be performed based on 

the ITT analysis set using the “ITT” data scope

the safety analysis set and the “treatment emergent outcomes” data scope
as outlined in Section 4.5.2.
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In case of uncertainty (e.g., missing or incomplete dates), adverse events will be classified as 
“treatment emergent” and be included in the ITT scope following the worst case approach.  In 
addition, those AEs occurring during the run-in phase and those AEs occurring after 
discontinuation of anti-thrombotic study treatment will be summarized, respectively.
[…] A total column will be included in all safety summaries.  After study close-out for the 
pantoprazole/placebo portion of the study, similar tables will display the same information by 
PPI study treatment group, see also analyses described in Section 5.   

Changes as a result of Modification 5 in Sections 6.2.7 and 9:
New Text
With SAP amendment v3.0, integrated in SAP, Version 4.0, sensitivity analyses to address the 
potential impact of missing data on the results of the primary analysis are described in Appendix 
10.4.
[…]
Little, R J, Wang, J, Sun, X, Tian, H, Suh, E-H, Lee, M, Sarich T, Oppenheimer, L, Plotnikov, 
A, Wittes, J, Cook-Bruns, N, Burton, P, Gibson, C M and Mohanty, S. The treatment of 
missing data in a large cardiovascular clinical outcomes study. Clinical Trials, 2016; 13(3): 
344–351.
National Research Council Panel on Handling Missing Data in Clinical Trials. The prevention 
and treatment of missing data in clinical trials. Washington, DC: National Academy Press, 
2012.
Zhao, Y, Herring, A H, Zhou, H, Ali, M W, Koch, G G.A Multiple imputation method for 
sensitivity analyses of time-to-event data with possibly informative censoring. J Biopharm 
Stat. 2014 ; 24(2): 229–253.

Changes as a result of Modification 6 in Section 10.1:
Old Text:
Table 10-1.  Classification of countries to regions
Region 
Countries
North America 
Canada, USA
Western Europe 
Belgium, Denmark, Finland, France, Germany, Ireland, Italy, Netherlands, Sweden, 
Switzerland, United Kingdom
Eastern Europe 
Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, Ukraine
Asia Pacific and other
China, Japan, Malaysia, Philippines, South Korea, Israel, South Africa, Australia
South America
Argentina, Brazil, Chile, Colombia, Ecuador
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New Text:
Table 10-1.  Classification of countries to regions
Region 
Countries
North America 
Canada, USA
Western Europe (and 
AUS/ISR/ZAF)
Australia, Belgium, Denmark, Finland, France, Germany, Ireland, Israel, Italy, 
Netherlands, South Africa, Sweden, Switzerland, United Kingdom
Eastern Europe 
Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, Ukraine
Asia Pacific 
China, Japan, Malaysia, Philippines, South Korea
South America
Argentina, Brazil, Chile, Colombia, Ecuador

Changes as a result of Modification 7 in Section 6.2.2.1:
New Text:
In addition, a net clinical benefit time-to-event variable will be defined which is a composite of 
the

primary efficacy outcome

primary safety outcome, excluding bleedings leading to hospitalization  and bleedings 
into surgical site associated with re-operation.
9.
References
1. Brechenmacher, T, Xu, J, Dmitrienko, A, Tamhane, AC. A mixture gatekeeping procedure 
based on the Hommel test for clinical trial applications. Journal of Biopharmaceutical 
Statistics, 2011; 21: 748-767.
2. Dunnett CW and Tamhane AC. A Step-Up Multiple Test Procedure. Journal of the American 
Statistical Association, 1992; 87(417):162-170.
3. Dmitrienko, A, Tamhane, AC. Mixtures of multiple testing procedures for gatekeeping 
applications in clinical trials. Statistics in Medicine, 2011; 30: 1473-1488.
4. Dmitrienko, A, Tamhane, AC. General theory of mixture procedures for gatekeeping. 
Biometrical Journal, 2013; 55: 402-419.
5. Dmitrienko A, Tamhane AC, Bretz F (editors). Multiple Testing Problems in Pharmaceutical 
Statistics. Chapman and Hall/CRC, 2009.
6. Dubois MF, Hébert R. Imputation of missing dates of death or institutionalization for time-
to-event analyses in the Canadian Study of Health and Aging. Int Psychogeriatr., 2001;13 
Supp 1:91-7. 
7. Gail M., Simon R. Testing for qualitative interactions between treatment effects and patient 
subsets. Biometrics,1985; 41:361-372.
8. Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted 
residuals. Biometrika, 1994; 81(3):515-526.
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9. Hankey GJ, Norman PE, Eikelboom JW. Medical treatment of peripheral arterial disease. 
JAMA 2006 February 1;295(5):547-53.
10. Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW et al. 
Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001 
September 19;286(11):1317-24.
11. Lakatos, E. Sample sizes based on the log-rank statistic in complex clinical trials. 
Biometrics, 1988; 44:229-241.
12. Li Z., Chuang-Stein C, Hoseyni C. The probability of observing negative subgroup results 
when the treatment effect is positive and homogeneous across all subgroups. Drug 
Information Journal, 2007; 41:47-56.
13. Little RJ, D'Agostino R, Cohen ML, et al. The prevention and treatment of missing data in 
clinical trials. N Engl J Med, 2012; 367:1355-1360.
14. Little, R J, Wang, J, Sun, X, Tian, H, Suh, E-H, Lee, M, Sarich T, Oppenheimer, L, 
Plotnikov, A, Wittes, J, Cook-Bruns, N, Burton, P, Gibson, C M and Mohanty, S. The 
treatment of missing data in a large cardiovascular clinical outcomes study. Clinical Trials, 
2016; 13(3): 344–351.
15. McAlister FA, Straus SE, Sackett DL, Altman DG. Analysis and reporting of factorial trials: 
a systematic review. JAMA, 2003; 289(19):2545-53.
16. Meltzer, HY et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, 
placebo- and olanzapine-controlled study. American Journal of Psychiatry, 2011; 168, 957-
967.
17. National Research Council Panel on Handling Missing Data in Clinical Trials. The 
prevention and treatment of missing data in clinical trials. Washington, DC: National 
Academy Press, 2012.
18. Sarkar, S, Chang, C K. Simes’ method for multiple hypothesis testing with positively 
dependent test statistics. Journal of the American Statistical Association, 1997; 92, 1601-
1608.
19. Sarkar, SK. Some probability inequalities for censored MTP2 random variables: A proof of 
the Simes conjecture. Annals of Statistics, 1998; 26, 494-504. 
20. Shih, J. Sample size calculation for complex clinical trials with survival. Controlled Clinical 
Trials, 1995; 16:395-407.
21. WHO. The global burden of disease: 2004 update. Geneva: World Health Organization; 
2008.
22. WHO. Fact sheet: Cardiovascular diseases (CVDs): World Health Organization; 2013. 
Available from http://www.who.int/mediacentre/factsheets/fs317/en
23. Zhao, Y, Herring, A H, Zhou, H, Ali, M W, Koch, G G.A Multiple imputation method for 
sensitivity analyses of time-to-event data with possibly informative censoring. J Biopharm 
Stat. 2014 ; 24(2): 229–253.
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10.
Appendix
10.1
Regions83
For subgroup analyses according to region, countries will be assigned to regions as shown in Table 
10-1. below. If additional countries participate in the trial, their assignment to a region will be 
described in an amendment to the SAP before unblinding.
Table 10-1.  Classification of countries to regions
Region 
Countries
North America 
Canada, USA
Western Europe (and 
AUS/ISR/ZAF)
Australia, Belgium, Denmark, Finland, France, Germany, Ireland, Israel, Italy, 
Netherlands, South Africa, Sweden, Switzerland, United Kingdom
Eastern Europe 
Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, Ukraine
Asia Pacific
China, Japan, Malaysia, Philippines, South Korea
South America
Argentina, Brazil, Chile, Colombia, Ecuador
10.2
EQ-5D
The EuroQol – a standardized instrument for use as a measure of health outcome -
http://www.euroqol.org/.
Based on large population surveys, an algorithm has been developed to combine the recordings for 
each of these five EQ-5D dimensions into one single health state. The algorithm for the derivation of 
the EQ-5D health state (ranging from +1 to –0.59) using the UK value set (weights) is given below 
together with a worked example.
Step 1: Take the value 1.0  (equivalent to full health ‘11111’).
Step 2: Subtract 0.081 if the state is different from ‘11111’.
Step 3: Subtract for each dimension the appropriate value for Level 2 or Level 3 
as given in the table below  (no subtraction for Level 1).
EuroQoL Dimension
Level 2
Level 3
Mobility
0.069
0.314
Self-care
0.104
0.214
Usual activity
0.036
0.094
Pain / discomfort
0.123
0.386
Anxiety / depression
0.071
0.236
                                                
83 Tables modified based on list of participating countries as of August 2015 and modification 6 of SAP, Version 4.0.
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Step 4: Subtract 0.269 if any dimension has a record of Level 3.
Example: The EQ-5D index score value for the state ‘11223’ is given by
Step 1
Step 2
Step 3
Step 4
EQ-5D index 
score
1.0
minus 0.081
minus 0.036
minus 0.269
→
0.255
minus 0.123
minus 0.236
10.3
Regular and Truncated Hochberg Tests
Consider a general problem of testing m null hypotheses denoted by H1,…,Hm. Let p1,…,pm denote 
the associated raw p-values. Further, let p(1)<…<p(m) denote the ordered p-values and H(1),…,H(m)
denote the hypotheses corresponding to the ordered p-values. Finally, let α denote the overall Type I 
error rate.  
The regular Hochberg procedure is based on the following testing algorithm:

Step 1: If p(m) > α, accept H(m) and go to Step 2, 
otherwise reject all null hypotheses and stop.

Step i = 2,…,m-1: If p(m-i+1) >  α/i, accept H(m-i+1) and go to Step i+1, 
otherwise reject all remaining null hypotheses and stop.

Step m: If p(1) >  α/m, accept H(1), 
otherwise reject H(1).
The truncated Hochberg procedure is defined as a convex combination of the Bonferroni procedure 
and regular Hochberg procedure based on a pre-specified truncation parameter 
0 ≤ γ < 1 (Dmitrienko, Tamhane and Wiens, 2008 [5]).  
The truncated Hochberg procedure is based on the following testing algorithm:

Step 1: If p(m) > (γ +(1-γ)/m) α, accept H(m) and go to Step 2, 
otherwise reject all null hypotheses and stop.

Step i = 2,…,m-1: If p(m-i+1) > (γ /i+(1- γ)/m) α, accept H(m-i+1) and go to Step i+1, 
otherwise reject all remaining null hypotheses and stop.

Step m: If p(1) >  α/m, accept H(1), 
otherwise reject H(1).
With γ = 0, the truncated Hochberg procedure simplifies to the Bonferroni procedure and, with γ = 
1, the truncated Hochberg procedure simplifies to the regular Hochberg procedure.
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10.4
Sensitivity analyses to address the potential impact of missing data84
For the purpose of the sensitivity analyses described in this Appendix, missing data as related to the 
primary analysis is unobserved follow-up time up until the global rivaroxaban/aspirin outcomes cut-
off date. Unobserved follow-up time may occur due to subjects who are non-compliant with study 
follow-up, for example due to loss of follow-up or premature complete withdrawal of informed 
consent.  Subjects censored administratively at the “global rivaroxaban/aspirin outcomes cut-off 
date” or censored at time of non-CV death are not contributing missing follow-up time.  
In the primary analysis, missing data due to rivaroxaban/aspirin follow-up non-completion before 
experiencing an unrefuted primary efficacy outcome event is addressed by assuming that such 
censoring is noninformative/ignorable in a sense like the (missing at random) MAR assumption.
That is to say the assumption of its independence from the possibly unobserved time-to-event 
applies: the possibly unknown true time to the event for a subject is the same regardless of whether 
or not it is actually observed (or whether censoring occurs or not prior to it) (Zhao, 2014). 
Subjects who prematurely discontinue rivaroxaban/aspirin follow-up (rivaroxaban/aspirin follow-up 
non-completers) may differ systematically from subjects who complete rivaroxaban/aspirin follow-
up, thus introducing the possibility of non-ignorable censoring. 
Non-ignorable censoring is differential if it leads to bias in the comparison of treatment groups, that 
is, if the differences in the hazard due to nonignorable censoring in the treatment groups do not 
“cancel out.” (Little et al., 2016). 
The sensitivity analyses described in this Appendix to the SAP address the potential impact of 
missing data on the primary efficacy outcome and follow the elements described by Little et. al. 
(2016), involving two steps: 
1. A descriptive comparison of key baseline characteristics and post-randomization events 
preceding the end of rivaroxaban/aspirin follow-up to assess whether subjects with missing 
data differ systematically from subjects who complete the rivaroxaban/aspirin follow-up.
2. A pattern mixture model using multiple imputation techniques to investigate the potential 
impact of missing data on the primary efficacy analysis if non-ignorable censoring is 
assumed to be differential. 
In addition, the extent of missing data will be described by the fraction of subjects with unobserved 
rivaroxaban/aspirin follow-up time and the fraction of unobserved rivaroxaban/aspirin follow-up 
subject-years.
All analyses of the potential impact of missing data will be performed in the ITT analysis set.
10.4.1
Definitions
In the context of missing data sensitivity analyses for the primary efficacy analysis we define, using 
the terms described in Table 10-2,
                                                
84 Text added as per modification 5 in integrated SAP, Version 4.1.
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
a subject with unobserved rivaroxaban/aspirin follow-up time,
as a rivaroxaban/aspirin follow-up non-completer for whom no unrefuted primary efficacy 
outcome event was documented and who is alive at the time of censoring,

a subject’s observed rivaroxaban/aspirin follow-up time,
as the time used in the primary efficacy outcome analysis (time under risk),

a subject’s unobserved rivaroxaban/aspirin follow-up time, 
as the time from censoring to the global rivaroxaban/aspirin outcomes cut-off date for 
subjects with unobserved rivaroxaban/aspirin follow-up time and zero for subjects with no 
unobserved rivaroxaban/aspirin follow-up time.
With regard to the extent of “missing data”, we define 

the fraction of subjects with unobserved rivaroxaban/aspirin follow-up time, 
as the number of subjects with unobserved rivaroxaban/aspirin follow-up time divided by the 
number of subjects in the ITT population 

the fraction of missing rivaroxaban/aspirin follow-up subject-years,
as the sum of the subjects’ unobserved rivaroxaban/aspirin follow-up time divided by the 
sum of the subjects’ observed and unobserved rivaroxaban/aspirin follow-up time
These definitions rely on the division of the ITT study population into rivaroxaban/aspirin follow-up 
completers and rivaroxaban/aspirin follow-up non-completers, see Table 10-2.
Table 10-2. Definition of sensitivity analysis subject characteristics
Subgroups
Definition
Rivaroxaban/aspirin 
follow-up non-completer
Subjects alive for whom 

the last contact date during rivaroxaban/aspirin portion of the study is before the 
global rivaroxaban/aspirin outcomes cut-off date.
Rivaroxaban/aspirin 
follow-up completer
Subjects for whom

the last contact date during rivaroxaban/aspirin portion of the study is at or after the 
global rivaroxaban/aspirin outcomes cut-off date

subject died
Rivaroxaban/aspirin
study treatment non-
completer
Subjects 

who are rivaroxaban/aspirin follow-up non-completers and/or

whose date of last rivaroxaban/rivaroxaban placebo or date of last aspirin/aspirin 
placebo study treatment is before the global rivaroxaban/aspirin outcomes cut-off 
date or before the subject’s death date (whatever comes first)
Rivaroxaban/aspirin
study treatment 
completer
Subjects 

who are rivaroxaban/aspirin follow-up completers and

whose date of last rivaroxaban/rivaroxaban placebo and date of last aspirin/aspirin 
placebo study treatment is at or after the global rivaroxaban/aspirin outcomes cut-
off date or identical to the death date
Note: the follow-up definitions from Table 10-2 do not depend on 

premature discontinuation of study medication, 
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
the experience of an unrefuted primary efficacy outcome (rivaroxaban/aspirin follow-up non-
completers may have experienced an unrefuted primary efficacy outcome event before 
premature discontinuation of their rivaroxaban/aspirin follow-up.  However, only 
rivaroxaban/aspirin follow-up non-completers for whom no unrefuted primary efficacy 
outcome event is documented might impact the primary analysis due to missing outcome 
information.) and/or 

the reasons for being a rivaroxaban/aspirin follow-up non-completer, for example “complete 
withdrawal of informed consent”, “lost to follow-up”, or “other”.
Subjects who died are considered rivaroxaban/aspirin follow-up completers and having no missing 
outcome information, because subjects who experienced a terminal event cannot be followed-up.
10.4.2
Descriptive comparison of baseline characteristics and post-randomization 
events
Subjects who prematurely discontinue rivaroxaban/aspirin follow-up (rivaroxaban/aspirin follow-up 
non-completers) may differ systematically from subjects who complete rivaroxaban/aspirin follow-
up. This concern is particularly important if these differences depend on and are different for the 
study treatment groups. 
Therefore descriptive comparisons of key baseline characteristics and post-randomization events 
preceding end of the rivaroxaban/aspirin follow-up will be conducted. The comparison can provide 
indirect evidence that the degree of differential nonignorable censoring might be limited.  
The analyses will be done for the following subgroups:
-
rivaroxaban/aspirin follow-up completers who completed study treatment with rivaroxaban
and aspirin
-
rivaroxaban/aspirin follow-up completers who prematurely discontinued study treatment
with rivaroxaban or aspirin
-
rivaroxaban/aspirin follow-up non-completers.
For each subgroup the proportion of subjects with certain baseline characteristics and selected post-
randomization events (or means) will be presented by treatment group. 
To provide indirect evidence for ignorable censoring, those descriptive comparison will also be 
conducted for the groups of 
-
rivaroxaban/aspirin follow-up non-completers for which no unrefuted primary efficacy 
outcome event was documented 
-
rivaroxaban/aspirin follow-up completers and non-completers for which an unrefuted 
primary efficacy outcome event was documented.
In Section 10.4.3, a sensitivity analysis to investigate the potential impact of missing data on the 
primary efficacy analysis is described. To provide indirect evidence that the selection of the study 
cohort of subjects from whom information about the unobserved event process is borrowed is 
reasonable, the descriptive comparison will also include the group of
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-
subjects who prematurely discontinued any anti-thrombotic study treatment and who are not 
in the group mentioned above: rivaroxaban/aspirin follow-up non-completers for which no 
unrefuted primary efficacy outcome event was documented.
Baseline characteristics considered in these analyses are 

Coronary artery disease 

Peripheral artery disease 

CABG surgery (planned within 4-7 days) before randomization

History of any prior CABG

Region (North America, Western Europe and AUS/ISR/ZAF, Eastern Europe, Asia Pacific, 
and South America)

History of a prior heart failure 

History of (non-lacunar ischemic) stroke 

History of prior MI 

History of prior asymptomatic carotid artery stenosis >= 50%/ revascularization

Age (<65, 65 years or older)

Baseline renal function: estimated glomerular filtration rate (eGFR) (<60 mL/min, 
>=60mL/min)

Baseline diabetes 

Smoking at baseline
Selected post-randomization events are 

occurrence of an unrefuted major bleeding event

occurrence of at least one serious adverse event/event of special interest (SAE/ESI) 

hospitalization

premature discontinuation of blinded rivaroxaban treatment 

premature discontinuation of blinded aspirin treatment.
For the occurrence of major bleedings and SAEs/ESI only events occurring (start date) during the 90 
days preceding the unrefuted primary efficacy outcome event or the censoring date relevant for 
primary analysis will be considered. For subjects observed for less than 90 days after randomization, 
only the time after randomization will be considered.
10.4.3
Sensitivity analysis
To investigate the potential impact of missing data on the primary efficacy analysis if nonignorable 
censoring is differential, a sensitivity analysis similar to sensitivity analyses based on pattern-
mixture models described by the NRC (NRC 2012) will be employed. 
Primary efficacy outcome events in subjects with missing rivaroxaban/aspirin follow-up data will be 
generated in a three-step process by 
(1) defining a cohort (pattern) of subjects from whom information about the unobserved event 
process is borrowed and estimation of individual hazards from an imputation model
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(2) simulation of primary outcome events using individualized hazard estimates at the censoring 
date to create multiple data sets with imputed data; fitting of the primary analysis model to 
the imputed data sets; combining the analysis results to generate statistical inference
(3) assessment of the robustness by repetition of step 2 after inflation of the individual hazard 
estimates in the rivaroxaban treatment groups and determination of the “tipping point”.
The subdivision of the ITT set as described in the following steps is illustrated by Figure 10-1.
Figure 10-1 Subdivision of ITT set for estimation of individual hazards for imputation
Step 1:
According to the study protocol all subjects are to be followed until the end of the 
rivaroxaban/aspirin follow-up / end of the study and data on the primary efficacy outcomes are 
collected irrespective of whether or not a subject is on or off anti-thrombotic treatment. The cohort 
of subjects who prematurely discontinue any anti-thrombotic study treatment (i.e. either study 
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rivaroxaban bid and/or study aspirin treatment) will be used for imputation of unobserved follow-up 
time. 
More specifically, for subjects who prematurely discontinued any anti-thrombotic study treatment, a 
Weibull85 survival model will be fitted to estimate the individual hazard of a primary outcome event 
at the last contact date of the rivaroxaban/aspirin portion of the trial. The model will be adjusted for 
treatment groups (rivaroxaban 2.5 mg bid + aspirin 100 mg od, rivaroxaban 5 mg bid + aspirin 
placebo od, rivaroxaban placebo + aspirin 100 mg od), stratification factor (not randomized to a 
proton pump inhibitor; pantoprazole 40 mg od; pantoprazole placebo) and the following baseline 
covariates:

CAD and PAD, CAD only, PAD only 

Age (<65, 65 years or older)

Region (North America, Western Europe, Eastern Europe, Asia Pacific and other, and South 
America)

History of a prior heart failure 

History of prior stroke 

History of prior MI 
The imputation model will also include a covariate indicating the occurrence of a major bleeding 
event (post-randomization event), if the bleeding occurred (start date) during the 90 days preceding 
the unrefuted primary efficacy outcome event or the censoring date relevant for primary analysis:
If the individual hazard for a subject cannot be estimated from the above model due to missing 
covariates the hazard estimate from a crude model – adjusted for treatment groups and stratification
factor only – will be used for this subject (see Section 10.4.4). 
Step 2:
For subjects with missing rivaroxaban/aspirin follow-up time who did not experience an unrefuted 
primary outcome event and were alive at censoring, random variables reflecting a subject’s 
individualized hazard (from step 1) will be simulated using the conditional time to event distribution 
after the last available rivaroxaban/aspirin follow-up (see Section 10.4.5). If this randomly generated 
variable has a value less than the elapsed time between the last available rivaroxaban/aspirin follow-
up date (exclusive) and the “global rivaroxaban/aspirin outcomes cut-off date” (inclusive), the 
subject will be treated as having an primary efficacy event occurring at the date of last available 
rivaroxaban/aspirin follow-up plus the value from the random variable. Otherwise, the subject is re-
adjusted to be censored at the “global rivaroxaban/aspirin outcomes cut-off date”. Events and time at 
risk is imputed assuming that no death due to non-CV causes occurs.
Imputed events and event-free time at risk will be added to the observed events and times under risk 
in the study and the primary efficacy analysis will be repeated: The Cox proportional-hazards 
models from primary efficacy analysis will be fitted to the imputed data sets. This imputation and 
                                                
85 Experience shows that exponential distribution adequately models the survival time. In case of 
deviating data this approach can easily be extended to Weibull distribution by estimating the scale 
parameter .
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analysis of primary outcome events will be repeated 1,000 times. Inferences for combined 
parameters will be done using multiple imputation rules that reflect imputation uncertainty (see 
Section 10.4.6).
Step 3:
To assess the robustness of the analyses for deviations from ignorable censoring the last step will be 
repeated after inflating the hazards for rivaroxaban/aspirin follow-up non-completers in the 
rivaroxaban groups. The hazards in the control group will not be inflated, that is, for these subjects, 
rivaroxaban/aspirin follow-up non-completion will be treated as ignorable. Thereafter, the multiple 
imputation described above will be repeated with the inflated hazards. 
The inflation factor be increased stepwise to determine the factor F, for which the upper limit of the 
95%-CI for the HR for rivaroxaban 2.5 mg bid + aspirin 100 mg od relative to rivaroxaban placebo 
+ aspirin 100 mg od crosses 1 – the “tipping-point” – and the factor G, for which the upper limit of 
the 95%-CI for the HR for rivaroxaban 5 mg bid + aspirin placebo od relative to rivaroxaban 
placebo + aspirin 100 mg od crosses 1. 
The following inflation factors will be considered: 10% to 200% increased by 10% steps, 200% to 
500% increased by 50% steps and 500% to 1000% increased by 100% steps. 
The sensitivity analysis described in this section will be repeated using a Weibull survival model 
fitted to all randomized subjects and adjusted for treatment groups, stratification factor and the 
baseline covariates described above.
10.4.4
Parameter estimation
For subjects who prematurely discontinued any anti-thrombotic study treatment, a Weibull survival 
model will be fitted to estimate the hazard of a primary outcome event at the last contact date in the 
rivaroxaban/aspirin portion of the trial:
PROC LIFEREG DATA = <dataset> OUTEST=<dataset1>;
    MODEL ttevalue*ttecnsr(1) = trtgrpn stratum <covariates> / 
                                DISTRIBUTION = weibull INTERCEPT=8 INITIAL=0.2;
    OUTPUT OUT=<dataset2> CDF=cdf XBETA=xbeta;
RUN;
/*
where
dataset  = name of sub-dataset including all ITT subjects who prematurely 
discontinued any anti-thrombotic study treatment 
dataset1 = SAS data set containing the parameter estimates
dataset2 = SAS data set containing statistics (CDF and x’β) calculated after 
fitting the model
ttevalue = time to first occurrence of primary efficacy outcome event
ttecnsr  = censoring index (1 = right-censored, 0 = event)
trtgrpn  = variable coding randomized antithrombotic treatment group
           (0 = control group, 1 = rivaroxaban 2.5 mg + aspirin 100 mg)
stratumn = variable for PPI stratification factor (three levels)
*/
The SAS LIFEREG procedure will be used to model the natural logarithm w = log (t) of the 
survival time. The survival function used by SAS has the form 
() = exp −exp 

 ,
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where μ is the location parameter and σ the scale parameter.
Re-parameterization by λ = exp(μ) and β = 1/σ results in the survival function S with 
() =  (!) = exp (−
"
#
$
).
The estimated hazard at the last contact date in the rivaroxaban/aspirin portion of the trial will be 
obtained from the fitted Weibull model, adjusted for treatment and baseline covariates for each 
subject.
10.4.5
Generation of random variables
Let the survival time T be Weibull distributed, with survival function S .
The conditional distribution function of T after the censoring date CD (given that no event was 
observed before) is given for s ≥0 by 
+(,) ∶= .(/ ≤, + 23|/ > 23) = 1 −.(/ > , + 23|/ > 23) = 1 −.(/ > , + 23)
.(/ > 23)
= 1 − (, + 23)
 (23)
.
With scale parameter λ and shape parameter β from the underlying Weibull distribution we have
+(,) = 1 −
exp 6−, + 23
7

$
8
exp 6−23
7 
$
8
,
hence
+ (,) = 7 6:23
7 ;
$
−log(1 −,)8
 /$
−23. 
If s is generated as a random variable with uniform distribution between 0 and 1, a random variable 
with distribution function G can be generated using the inverse transformation technique from 
7>(23/7)$ −log(1 −?@AB(′DAEFG?HI))J
 /$ −23.
10.4.6
Analysis of imputed data sets
SAS program code corresponding to the following will be used to get a dataset with hazard ratio 
estimates from the 1,000 datasets with imputed primary outcome events: 
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ODS LISTING CLOSE;
PROC PHREG DATA = <dataset>;
  MODEL ttevalue * ttecnsr(1) = trtgrpn / RL TIES=EFRON ALPHA=0.05;
  STRATA stratumn;
  ODS OUTPUT PARAMETERESTIMATES=phregparms;
  BY _imputation_;
RUN;
ODS LISTING;
/*
where
dataset  = name of sub-dataset including all ITT subjects randomized to 
           respective rivaroxaban treatment group and control group
trtgrpn  = variable coding randomized antithrombotic treatment group
           (0 = control group, 1 = rivaroxaban 2.5 mg + aspirin 100 mg)
ttevalue = time to first occurrence of primary efficacy outcome event
ttecnsr  = censoring index (1 = right-censored, 0 = event)
stratumn = variable for PPI stratification factor (three levels)
_imputation_ = variable for the imputation
*/
Finally, the results from the 1000 complete datasets will be combined to produce inferential results 
using the following program code:
PROC MIANALYZE PARMS=phregparms;
  MODELEFFECTS trtgrpn;
RUN;
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A randomized controlled trial of rivaroxaban for the prevention of major 
cardiovascular events in patients with coronary or peripheral artery 
disease (COMPASS - Cardiovascular OutcoMes for People using 
Anticoagulation StrategieS)
Rivaroxaban for the prevention of major cardiovascular events in CAD or PAD 
(COMPASS)
Bayer study drug
BAY 59-7939 / Rivaroxaban / Xarelto®
Study purpose:
Comparative combination drug study for new indication SAP 
documenting analyses for PPI close-out
Clinical study 
phase:
III
Date:
09 Mai 2018
Study No.:
BAY 59-7939/15786
Version:
1.0
Authors:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
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Table of Contents
Abbreviations............................................................................................................................ 3
1.
Introduction ....................................................................................................................... 3
2.
Study Objectives................................................................................................................ 4
3.
Study Design ...................................................................................................................... 4
4.
General Statistical Considerations .................................................................................. 5
4.1
Analysis Sets.................................................................................................................... 5
4.2
Data scopes and censoring rules ...................................................................................... 6
4.2.1
ITT data scope for CDB2 ............................................................................................. 6
4.2.2
Rivaroxaban/aspirin follow-up data scope ................................................................... 7
4.2.3
Pantoprazole treatment emergent data scope................................................................ 7
5.
Statistical Methodology..................................................................................................... 7
5.1
Population characteristics ................................................................................................ 7
5.1.1
Sample sizes.................................................................................................................. 7
5.1.2
Subject disposition – Overview/Details at visits .......................................................... 8
5.1.3
Visit and study drug adherence..................................................................................... 8
5.1.4
Protocol Deviations ...................................................................................................... 9
5.1.5
Medical History ............................................................................................................ 9
5.1.6
Demographics............................................................................................................... 9
5.1.7
Prior and Concomitant Medication............................................................................... 9
5.2
Efficacy.......................................................................................................................... 10
5.2.1
Efficacy Variables for the Pantoprazole Randomization............................................ 10
5.2.2
Efficacy Outcomes for the Antithrombotic Randomization by Pantoprazole 
Treatment Groups ....................................................................................................... 11
5.2.3
Statistical Analysis for the Pantoprazole Randomization........................................... 11
5.2.4
Further Statistical Analysis for the Pantoprazole Randomization.............................. 16
5.2.5
Subgroup Analyses..................................................................................................... 16
5.2.6
Potential Modification of Rivaroxaban Treatment Effect by Pantoprazole ............... 17
5.2.7
Analysis of Efficacy Outcomes for Antithrombotic Randomization by 
Pantoprazole Treatment Groups ................................................................................. 18
5.3
Pharmacokinetics/Pharmacodynamics........................................................................... 19
5.4
Safety ............................................................................................................................. 19
5.4.1
Safety Outcome Events for the Antithrombotic Randomization................................ 19
5.4.2
Events of Special Interest for the Pantoprazole Randomization ................................ 19
5.4.3
Adverse Events........................................................................................................... 20
5.4.4
Death........................................................................................................................... 20
5.4.5
Pregnancies................................................................................................................. 20
5.4.6
Vital Signs .................................................................................................................. 20
5.4.7
Clinical Laboratory Tests ........................................................................................... 20
5.5
Analysis of COMPASS MIND Study............................................................................ 21
6.
Definitions ........................................................................................................................ 21
7.
Document History and Changes in the Planned Statistical Analysis ......................... 22
8.
References ........................................................................................................................ 22


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Abbreviations
AE
Adverse event
ALI
Acute Limb Ischemia
AUS/ISR/ZAF
Australia/Israel/South Africa
bid
Twice daily
CAD
Coronary artery disease
CDB 
Clean database
CHD
Coronary heart disease
CI
Confidence interval
CLI
Chronic Limb Ischemia
COMPASS
Cardiovascular OutcoMes for People using Anticoagulation StrategieS
COMPASS LTOLE
COMPASS Long-term Open-Label Extension
CRF
Case report form (either paper or electronic)
CSR
Clinical study report
CV
Cardiovascular
DSMB
Data Safety Monitoring Board 
eGFR
estimated glomerular filtration rate
GI
Gastrointestinal
Hb
Hemoglobin
ICH
International Conference on Harmonization
ISTH
International Society on Thrombosis and Haemostasis
ITT
Intention-to-treat
MI
Myocardial infarction
NSAID
Non-steroidal anti-inflammatory drugs
od
Once daily
PAD
Peripheral artery disease
PPI
Proton pump inhibitor
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical Analysis Software
1.
Introduction
On February 06, 2017 the Data Safety Monitoring Board (DSMB) for the COMPASS study 
recommended that the antithrombotic study treatment arms rivaroxaban 2.5 mg bid/aspirin 
100 mg od, rivaroxaban 5 mg bid, and aspirin 100 mg od be stopped as soon as an orderly 
close-out of this portion of the COMPASS trial could be carried out based on results of the 
first formal interim analysis. The DSMB made no recommendations regarding early 
termination of the pantoprazole treatment arms of the study. The Steering Committee decided 
that the pantoprazole study treatment arms will continue.
The database (Clean Database 1, CDB1) underlying the CSR and the publications is based on 
a cut-off date of July 22, 2017 and, at Bayer, the release date of the first clinical database on 
August 04, 2017. The results for the antithrombotic randomization have been analyzed and 
reported in the clinical study report (CSR, PH-39342) of the COMPASS study and multiple 
scientific publications. The statistical analyses comprise records up to the subjects’ 
rivaroxaban/aspirin washout visits since these data are considered relevant to the 
antithrombotic study treatment arms. 
The close-out of the pantoprazole treatment arms will lead to a second database release (Clean 
Database 2, CDB2).  The primary purpose of the analyses described in this SAP is the 
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evaluation of outcomes with respect to the pantoprazole randomization.  All outcomes with 
respect to the antithrombotic randomization have been evaluated extensively at CDB1.  In 
addition, it will be explored whether PPI treatment interferes with the effects of rivaroxaban.
Hence, this SAP is to be read in conjunction with the study protocol and the SAP, version 4.1, 
of the COMPASS study. The SAP describes the planned statistical analyses after CDB2 in the 
COMPASS study, focusing on analyses with respect to the pantoprazole/placebo
randomization. 
2.
Study Objectives
The main objective for the pantoprazole randomization is

To determine whether pantoprazole 40 mg od compared with placebo reduces the risk 
of upper gastrointestinal bleeding, ulceration, or gastrointestinal obstruction or 
perforation in subjects with CAD or PAD receiving antithrombotic medications.
Other objectives for the pantoprazole randomization are:

To determine the effect of pantoprazole 40 mg od compared with placebo on the risk 
of pneumonia, clostridium difficile (C. diff) and other enteric infections, bone 
fractures, and new diagnosis since randomization of gastric atrophy, chronic kidney 
disease, diabetes, chronic obstructive lung disease and dementia in subjects with CAD 
or PAD. 

To determine whether treatment with pantoprazole 40 mg od potentially modifies the 
effects of antithrombotic treatment on major cardiovascular outcomes or bleeding 
events. I.e. whether pantoprazole interacts with the treatment effects of rivaroxaban 
2.5 mg bid/aspirin 100 mg od vs. aspirin 100 mg od in its impact on outcomes.

To determine whether treatment with pantoprazole 40 mg od has an effect on 
premature discontinuation of antithrombotic study treatment. 
For further details on study objectives, please refer to integrated SAP, version 4.1.
3.
Study Design
For the general study design, please refer to integrated SAP, version 4.1.
Following the decision of early termination of the antithrombotic treatment arms, all subjects 
were to stop randomized antithrombotic study treatment with the Final rivaroxaban/aspirin 
Follow-up Visit (in mid 2017). 

Subjects randomized to pantoprazole or pantoprazole placebo were to continue study 
follow-up as per study protocol up until their Final pantoprazole/placebo Follow-Up 
Visit (planned for mid 2018).

Subjects not randomized to pantoprazole or pantoprazole placebo were followed-up 
until their Rivaroxaban/aspirin Washout Visit, i.e. the end of the rivaroxaban/aspirin 
portion of the trial.  
All subjects from COMPASS trial are to be invited to join the COMPASS Long-term Open-
Label Extension (COMPASS LTOLE) as long as they continue to meet the COMPASS 
eligibility criteria plus specific criteria for LTOLE as described in the integrated study 


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protocol, version 4.0. Initiation visits for the LTOLE study started early 2018 and occur 
dependent on the approval of the integrated study protocol in the respective country.
Continued antithrombotic therapy between the Final rivaroxaban/aspirin Follow-up Visit and 
the LTOLE initiation visit was at the discretion of the investigator.
4.
General Statistical Considerations
Please also refer to integrated SAP, version 4.1.
4.1
Analysis Sets
The following analysis sets will be used for the analysis of the data from CDB2.

Intention-to-treat Analysis Set (ITT): 
The intention-to-treat analysis set, also termed full analysis set in the International 
Conference on Harmonization (ICH) E9 guideline, includes all subjects randomized to 
antithrombotic study treatment. The ITT set comprises both subjects randomized to 
pantoprazole/placebo and subjects not randomized to pantoprazole/placebo.

Pantoprazole ITT Analysis Set (pantoprazole ITT): 
The pantoprazole ITT analysis set comprises all subjects that have been randomized to 
pantoprazole 40mg or pantoprazole placebo.

Pantoprazole Safety Analysis Set (pantoprazole SAF): 
The safety analysis set for secondary analyses related to the pantoprazole randomization 
(pantoprazole safety analysis set) will include all subjects randomized to 
pantoprazole/placebo who received at least one dose of randomized pantoprazole/placebo 
medication.
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medication if the date of permanent discontinuation of pantoprazole/placebo study 
treatment is later than the randomization date.
4.2
Data scopes and censoring rules
As per study design, in CDB2 the mean follow-up time of subjects not randomized to 
pantoprazole or pantoprazole placebo is expected to be significantly shorter than the mean 
follow-up time of those subjects randomized to pantoprazole/placebo.  To reflect this 
difference, subjects randomized to pantoprazole/placebo and the subjects not randomized to 
pantoprazole/placebo will be displayed separately to avoid confusion, where applicable. 
In general, subjects not randomized to pantoprazole/placebo will only be analyzed up until 
their Final Rivaroxaban/Aspirin Follow-up Visit.  I.e., with respect to the pantoprazole 
randomization analyses will only consider outcomes up until the Final Rivaroxaban/Aspirin 
Follow-up Visit for those subjects. Analyses of outcomes with respect to antithrombotic 
randomization will not be repeated for these subjects, because the analysis has been reported 
in the CSR (PH-39342) / publications of the COMPASS study.
The following data scopes will be applied in the analyses:
1. ITT data scope for CDB2
2. Rivaroxaban/aspirin follow-up data scope 
3. Pantoprazole treatment emergent data scope
4.2.1
ITT data scope for CDB2
The ITT data scope for CDB2 is the primary data scope for analyses of CDB2 data.
For the ITT data scope for CDB2, only outcome events at or after the date of randomization 
up until Last Follow-up Date (see Section 6 for definition) will be considered for analysis. 
For those subjects with documentation of an outcome event within the ITT data scope for 
CDB2, time (in days) from randomization to the first occurrence of the event will be derived 
as: 
o
the date of the subject’s first event – the randomization date + 1. 
This will constitute an uncensored observation.


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For those subjects without documentation of an outcome event within the ITT data scope for 
CDB2, time (in days) from randomization to the censoring date will be derived as:
o
the subject’s Last Follow-up Date  – the randomization date + 1.
This will constitute a right-censored observation.
4.2.2
Rivaroxaban/aspirin follow-up data scope
The rivaroxaban/aspirin follow-up data scope includes all outcome events from randomization 
up until the Final rivaroxaban/aspirin Follow-up Visit, for details please refer to the integrated 
SAP, version 4.1.
4.2.3
Pantoprazole treatment emergent data scope
The pantoprazole treatment emergent data scope includes outcome events from randomization 
up until two days after permanent discontinuation of pantoprazole study treatment.
It will be used for secondary safety analyses in the pantoprazole safety analysis set. All 
subjects randomized to pantoprazole/placebo with at least one dose of pantoprazole/placebo 
study medication and without documentation of an outcome event within the pantoprazole 
treatment-emergent data scope will be censored at the date of last dose of pantoprazole study 
treatment + 2 days.
5.
Statistical Methodology
All data will be listed and all variables will be summarized by means of descriptive statistics 
according to their type.
Summaries by randomized study treatment pantoprazole and pantoprazole placebo using 
appropriate descriptive statistics will be provided overall and/or by antithrombotic treatment 
group for all study variables including demographic and baseline characteristics. The group 
not randomized to pantoprazole/placebo due to continuous need for a PPI will be presented 
separately. No imputation will be applied. Descriptive statistics such as mean, standard
deviation, median, quartiles, minimum, and maximum will be used to summarize continuous 
variables. Counts and percentages will be used to summarize categorical variables. Life tables 
and Kaplan-Meier estimates will be used to summarize time-to-event variables. Graphical 
data displays may also be used to summarize the data. Confidence intervals will be provided 
at a 2-sided level of 95% unless otherwise stated.
5.1
Population characteristics
The structure of the tables describing population characteristics will closely follow the tables 
provided for CDB1 but comparing randomized pantoprazole treatment with placebo instead of 
comparing antithrombotic treatment arms.
5.1.1
Sample sizes 
Study sample sizes (PPI related analysis sets) will be tabulated overall and by PPI and 
antithrombotic treatment arms as follows: 
• Study sample sizes by region and country 
• Study sample sizes by country and site 


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5.1.2
Subject disposition – Overview/Details at visits
Subject disposition will be presented with primary focus on the PPI related part of the study.
5.1.3
Visit and study drug adherence
The following will be tabulated overall and by PPI treatment arm:

Number of subjects and reasons for premature permanent discontinuation of study 
pantoprazole medication 

Number of subjects and reasons for premature permanent discontinuation of study 
rivaroxaban/aspirin medication 

Number of subjects and reasons for premature permanent discontinuation of study 
follow up, i.e. consent withdrawn or lost to follow-up.
For CSR purposes, incidences for permanent discontinuation of the double-blinded 
pantoprazole study drug and of the follow-up period will be provided by randomized 
pantoprazole study treatment groups, based on the case report form data. In addition, 
incidences for permanent discontinuation of the double-blinded pantoprazole study drug and 
of the follow-up period will be provided by PPI treatment groups.  
Kaplan-Meier estimates will be used to present

time to the date of last dose of pantoprazole study treatment (calculated as days from 
randomization), and,

time to last follow-up date
all calculated as days from randomization, by randomized pantoprazole treatment group.
Other details regarding visit adherence (e.g., visit completed in person, by telephone, through 
third party) and completion as well as study drug adherence collected via CRFs will be 
summarized using frequency tables by visit and randomized pantoprazole treatment group.
Potential pantoprazole effect on premature discontinuation of antithrombotic treatment
A time-to-event variable “Time to premature discontinuation of rivaroxaban/aspirin study 
treatment” will be defined as follows:
For those subjects with documentation of premature discontinuation of either 
rivaroxaban/placebo or aspirin/placebo treatment before the common outcomes cut-off date 
used in CDB1, February 06, 2017, time (in days) from randomization to the occurrence of the 
event will be derived as: 
o
the date of permanent treatment discontinuation – the randomization date + 1. 
This will constitute an uncensored observation.
For those subjects without documentation of premature discontinuation of either 
rivaroxaban/placebo or aspirin/placebo treatment before the common outcomes cut-off date 
used in CDB1, February 06, 2017, time (in days) from randomization to the censoring date 
will be derived as:
o
common outcomes cut-off date  –  the randomization date + 1.
This will constitute a right-censored observation.


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A potential effect of pantoprazole treatment on premature discontinuation of antithrombotic 
treatment will be analyzed in the pantoprazole ITT analysis set using a log-rank test and a Cox 
proportional hazards model. 
In the unlikely event that the risk to prematurely discontinue antithrombotic treatment is 
significantly reduced in the pantoprazole treatment group, further analyses will be performed 
to explore this finding. This exploration may include a time-dependent Cox model 
investigating the effect of premature discontinuation of antithrombotic treatment on major 
cardiovascular outcomes.
5.1.4
Protocol Deviations
No per protocol analysis set will be defined in this study. The number of subjects with major 
protocol deviations according to the CRF will be summarized by randomized pantoprazole
and antithrombotic treatment groups, and overall. The types of deviations are described in the 
Data Management Plan.
5.1.5
Medical History
Medical history will be evaluated by frequency tables in the ITT analysis set (and, for CSR 
purposes, the pantoprazole safety set) by pantoprazole treatment groups, showing the number 
of subjects with medical history findings (i.e., listed conditions of previous diagnoses, 
diseases, or surgeries based on the CRF).
5.1.6
Demographics
Demographic data will be evaluated descriptively for the ITT analysis set (and, for CSR 
purposes, the pantoprazole safety set) by PPI and antithrombotic study treatment groups, and 
overall.
Descriptive statistics (such as mean, standard deviation, median, quartiles, minimum and 
maximum) will be provided for continuous variables such as 

Age [years] 

Height [cm]

Weight [kg] 

Waist and hip circumference [cm]

Body mass index [kg/m²]
Counts and (appropriate) percentages will be provided for categorical variables such as

Gender

Ethnic group and ethnicity/race

Tobacco use
5.1.7
Prior and Concomitant Medication
Frequency tables by pantoprazole treatment group and overall, will be used to summarize the 
number of subjects with


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
prior relevant antiplatelet agents and anticoagulant reported by the subject at the 
Screening/Run-in Visit

relevant concomitant medications at randomization (non-study medications taken 
regularly for at least 1 month at the time of the randomization visit), for CDB2 defined 
as: non-study proton pump inhibitor and Non-steroidal anti-inflammatory drugs 
(NSAIDs).

non-study antithrombotic therapy (antiplatelet agents and anticoagulant) reported at 
the scheduled follow-up visits

relevant concomitant medications recorded at a Follow-Up Visit 2 years after 
randomization

relevant concomitant medications recorded at the Final Follow-Up Visit(s).
5.2
Efficacy
In general, due to the early discontinuation of antithrombotic treatment arms, subjects 
randomized to pantoprazole 40 mg or placebo on the one hand and subjects not randomized to 
pantoprazole/placebo but randomized to antithrombotic treatment only on the other hand, are 
suspected to differ in time under observation systematically. The following analyses attempt
to take this bias into account.
5.2.1
Efficacy Variables for the Pantoprazole Randomization
The main efficacy variable for the pantoprazole randomization is the time (in days) from 
randomization to the first occurrence of an unrefuted GI outcome event, which is the 
composite of the following outcomes: 

Overt bleeding of gastroduodenal origin confirmed by endoscopy or radiography 

Overt upper gastrointestinal bleeding of unknown origin 

Bleeding of presumed occult upper gastrointestinal tract origin with documented 
decrease in Hb of 2 g/dL 

Symptomatic gastroduodenal ulcer 

Gastrointestinal pain with underlying multiple gastroduodenal erosions

Upper GI obstruction/perforation.
Details by individual components will also be presented.
Further outcomes of interest for the pantoprazole randomization, which will also be evaluated 
as time-to-event variables, are:

GI bleeding, defined as the composite of the first three components above:
o
Overt bleeding of gastroduodenal origin confirmed by endoscopy or 
radiography 
o
Overt upper gastrointestinal bleeding of unknown origin 


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o
Bleeding of presumed occult upper gastrointestinal tract origin with 
documented decrease in Hb of 2 g/dL 
5.2.2
Efficacy Outcomes for the Antithrombotic Randomization by 
Pantoprazole Treatment Groups
Other efficacy outcomes of interest are the unrefuted occurrences of outcomes which had been 
defined in the clinical study protocol for the objectives of the antithrombotic randomization, 
i.e.:

MI, stroke, or CV death
o
MI 
o
Stroke 
o
CV death (and its cause)

MI, ischemic stroke, ALI, CHD death
o
Ischemic Stroke
o
ALI 
o
CHD death

MI, ischemic stroke, ALI, CV death

All-cause mortality
o
Non-CV death (and its cause)

Major adverse limb event
o
ALI
o
Chronic limb ischemia

New diagnosis of cancer (including subtypes)

Recurrence of cancer

Hospitalization
o
Hospitalization for CV reasons
Other outcomes of interest for the antithrombotic randomization related to cognition and 
function will be reported separately.
5.2.3
Statistical Analysis for the Pantoprazole Randomization
The following analyses are to be conducted for the efficacy variables of the pantoprazole 
randomization as defined in section 5.2.1 separately for the ITT data scope for CDB2

in the pantoprazole ITT analysis set and 

in the subjects not randomized to pantoprazole/placebo.
Descriptive statistics for pantoprazole outcomes


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For outcomes relevant for the pantoprazole/placebo randomization, the number of subjects 
with event, crude incidences and incidence rates will be depicted in the following manner:
Subjects randomized to pantoprazole 40 mg or placebo on the one hand and subjects not 
randomized to pantoprazole/placebo on the other hand are suspected to differ in time under 
observation systematically. Hence, those two groups will be displayed in separate tables to 
avoid potential confusion arising from erroneously comparing these groups, see the following 
example:
The following tables will be repeated for the antithrombotic treatment arms <xxx>:

Overall and,

for CSR purposes only, by antithrombotic treatment arm
o
Randomized to Rivaroxaban 2.5 mg bid, Aspirin 100 mg od
o
Randomized to Rivaroxaban 5 mg
o
Randomized to Aspirin 100 mg od
Table: Number of subjects with <event> in ITT data scope for CDB2 (pantoprazole ITT
analysis set)
Antithrombotic treatment arm: <xxx>
Pantoprazole 40 mg od
N=xxx (100%)
      N (%)      N/100 p-yrs (95% CI)
Pantoprazole placebo od 
N=xxx (100%)
      N (%)      N/100 p-yrs (95% CI)
Total
N= xxx (100%)
      N (%)      N/100 p-yrs (95% CI)
<event>
xx  (    x.x%)  x.xx  (x.xx;x.xx)
xx  (    x.x%)  x.xx  (x.xx;x.xx)
xx  (    x.x%)  x.xx  (x.xx;x.xx)
-
Only events that occurred during ITT data scope for CDB2 are taken into account.
Table: Number of subjects with <event> in ITT data scope for CDB2 (ITT 
analysis set)
Antithrombotic treatment arm: <xxx>
Not randomized to pantoprazole/placebo
N=xxx (100%)
      N (%)      N/100 p-yrs (95% CI)
<event>
xx  (    x.x%)  x.xx  (x.xx;x.xx)
-
Only events that occurred during ITT data scope for CDB2 are taken into account.
Inferential statistics for pantoprazole outcomes
The statistical analysis of the outcome for the pantoprazole randomization will be based on 
the intention-to-treat principle and will include all subjects randomized to receive 
pantoprazole 40 mg od or pantoprazole placebo.
The null hypothesis H0;panto40 stating that
“there is no difference between the pantoprazole treatment and control group 
in the probability of the outcome for all time points” 
will be tested against the alternative hypothesis H1;panto40 stating that 
“there is a difference between the two groups in the probability of the outcome 
for at least one time point”.
Stratified log-rank test and Kaplan-Meier estimates


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Statistical testing will be performed by a comparison of the “survival functions” S(t), i.e., the 
probability that “time from randomization to the first occurrence of the outcome” is > t, for a 
time t relative to randomization. The comparison will be performed using a log-rank test 
stratified by antithrombotic study treatment (three strata levels: rivaroxaban 2.5 mg bid + 
aspirin 100 mg od; rivaroxaban 5 mg bid + aspirin placebo; rivaroxaban placebo + aspirin 
100 mg od), conducted at the 2-sided 5% type I error level. 
Kaplan-Meier estimates of cumulative risk functions and Nelson-Aalen estimates of the 
cumulative hazard functions will be provided to evaluate the timing of event occurrence in the 
two proton pump inhibitor study groups and the consistency of the treatment effect for all 
time points (the two survival curves do not cross).
To derive the log-rank Z test statistic and the variance V of the log-rank statistics, SAS 
program code corresponding to the following will be used: 
PROC LIFETEST DATA = <dataset> ALPHA = 0.05 METHOD = KM NELSON; 
STRATA stratumn / GROUP = ppi1grpn TEST = (LOGRANK);
TIME ttevalue * ttecnsr(1); 
RUN; 
/* 
where 
dataset  = name of sub-dataset including all ITT subjects randomized to pantoprazole 
     treatment groups: pantoprazole 40 mg/pantoprazole placebo
ppi1grpn = variable coding randomized pantoprazole treatment group (0 = pantoprazole 
     placebo, 1 = pantoprazole 40 mg) 
ttevalue = time to first occurrence of pantoprazole outcome event 
ttecnsr  = censoring index (1 = right-censored, 0 = event) 
stratumn = variable for antithrombotic stratification factor (three levels) 
*/ 
Cox proportional hazards model
Hazard ratios and corresponding 2-sided 95% confidence intervals will be estimated based on 
a Cox proportional hazards model stratified by antithrombotic therapy study group. Censoring 
will be assumed independent of the treatment group assignment. 
For the analysis of the outcome for the pantoprazole randomization in this study, the hazard 
function h(t) is the chance that an individual experiences an event of the outcome of the 
pantoprazole randomization in the next instant in time, given that the individual has not had 
such an event up to time t. For example, for the comparison of pantoprazole 40 mg od to 
pantoprazole placebo (control), the corresponding stratified Cox proportional hazards model 
can be described by the following equation:
hk(t,xi) = h0k(t) exp(β xi),
where 
hk(.)
hazard function for primary efficacy outcome for stratum k, k = 1,2,3 
(k represents randomized antithrombotic study treatment stratification factor), 
as a function of time and subject’s covariates
h0k(.)
unspecified underlying baseline hazard function for primary efficacy outcome per 
stratum k; hazard of an individual with xi = 0


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t
time (in days) relative to the randomization date
xi
PPI treatment group of subject i
(0 corresponds to “pantoprazole placebo (control)” and
1 corresponds to “pantoprazole 40 mg od”)
β
unknown parameter (to be estimated); hazard ratio = exp(β)
SAS program code corresponding to the following will be used:
PROC PHREG DATA = <dataset>;
  MODEL ttevalue * ttecnsr(1) = ppi1grpn / RL TIES=EFRON ALPHA=0.05;
  STRATA stratumn;
RUN;
/*
where
dataset  = name of sub-dataset including all ITT subjects randomized to 
           pantoprazole 40 mg or pantoprazole placebo study treatment
ppi1grpn  = variable coding randomized pantoprazole treatment group
           (0 = pantoprazole placebo, 1 = pantoprazole 40 mg treatment)
ttevalue = time to first occurrence of pantoprazole outcome event
ttecnsr  = censoring index (1 = right-censored, 0 = event)
stratumn = variable for randomized antithrombotic study treatment 
           stratification factor (three levels)
*/
Additional procedure options controlling the output may be added to the program codes.
Plausibility of proportional hazards assumption
The plausibility of the proportional hazards assumption will be assessed by visually examining 
both the plot of the log of the negative log of Kaplan-Meier estimates of the survival function 
versus the log time for evidence of non-parallelism and the smoothed plot of the scaled 
Schoenfeld residuals to directly visualize the log hazard ratio (Grambsch and Therneau, 1994), for 
each stratum separately, and by including a time-treatment interaction term in the Cox model 
(time log transformed). The significance of the interaction will be tested at the 5% type I error 
level. If the interaction is significant and there is strong evidence of non-proportionality from the 
plots, time-dependent hazard ratios will be estimated with the model that includes the interaction 
term.
Interaction between pantoprazole and antithrombotic treatment groups
The randomized antithrombotic treatment was to be stopped with the Final 
rivaroxaban/aspirin Follow-up Visit. Hence, the analysis of joint effects and interaction 
between antithrombotic and pantoprazole treatments on the pantoprazole outcome as 
described below will be based on the rivaroxaban/aspirin follow-up data scope, including 
events from randomization up until Final rivaroxaban/aspirin Follow-up Visit.
The joint effect and interaction between the antithrombotic and pantoprazole study groups on 
the pantoprazole outcome will be explored based on the intention-to-treat principle in subjects 
randomized to receive pantoprazole 40 mg od or pantoprazole placebo. The analysis will use 
two separate Cox proportional hazards models, one for the comparison of rivaroxaban 2.5 mg 
bid + aspirin 100 mg od vs. rivaroxaban placebo + aspirin 100 mg od, and one for the 


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comparison of rivaroxaban 5 mg bid+ aspirin placebo vs. rivaroxaban placebo + aspirin 
100 mg od.  The models will include:

a covariate for the effect of the considered rivaroxaban-based treatment group vs. the 
aspirin-control group,

a covariate for the effect of pantoprazole 40 mg od treatment group vs. pantoprazole 
placebo-control group,

an interaction term of these two factors.
Therefore, the Cox proportional hazards model (e.g., for the comparison of rivaroxaban 
2.5 mg bid + aspirin 100 mg od vs. rivaroxaban placebo + aspirin 100 mg od) can be 
described by the following equation:
h(t,x1i,x2i) = h0 (t) exp(β1 x1i + β2 x2i + β12 x1i x2i),
where 
h(.)
hazard function for pantoprazole outcome as a function of time and subject’s 
covariates
h0(.)
unspecified underlying baseline hazard function for pantoprazole outcome
t
time (in days) relative to the randomization date
x1i
antithrombotic treatment group of subject i
(0 corresponds to “rivaroxaban placebo + aspirin 100 mg od (control)” and
1 corresponds to “rivaroxaban 2.5 mg bid + aspirin 100 mg od”)
x2i
pantoprazole group of subject i
(0 corresponds to “pantoprazole placebo-control group” and
1 corresponds to “pantoprazole 40 mg od treatment group”)
β1, β2, β12  unknown parameters (to be estimated)
SAS program code corresponding to the following will be used:
PROC PHREG DATA = <dataset>;
  MODEL ttevalue * ttecnsr(0) = trtgrpn ppi1grpn trtgrpn*ppi1grpn /
                                RL TIES=EFRON ALPHA=0.05;
RUN;
/*
where
dataset  = name of sub-dataset including all ITT subjects randomized to 
           respective rivaroxaban treatment group and control group
trtgrpn  = variable coding randomized antithrombotic treatment group
           (0 = control group, 1 = rivaroxaban 2.5 mg + aspirin 100 mg)
ppi1grpn = variable coding randomized pantoprazole treatment group
           (0 = pantoprazole placebo, 1 = pantoprazole 40 mg treatment)
ttevalue = time to first occurrence of pantoprazole outcome event
ttecnsr  = censoring index (0 = right-censored, 1 = event)
*/


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Additional analyses
Additional exploratory analyses will include, e.g., a comparison of subjects of the ITT 
analysis set who were not randomized to receive pantoprazole 40 mg od or pantoprazole 
placebo with subjects randomized to pantoprazole placebo with regard to the pantoprazole 
outcome during the Rivaroxaban/aspirin follow-up data scope.
5.2.4
Further Statistical Analysis for the Pantoprazole Randomization
Furthermore, the following additional statistical analyses will be provided: 

For the components of the unrefuted GI outcome, descriptive statistics and Kaplan-
Meier estimates will be provided and the components will be analyzed using the 
stratified log-rank test and the Cox proportional hazards model as described above in 
the pantoprazole ITT analysis set for the ITT data scope for CDB2.

For the unrefuted GI outcome and it components, descriptive statistics will be 
provided and an analysis using the stratified log-rank test and the Cox proportional 
hazards model as described above will be repeated in the pantoprazole safety set for
the pantoprazole treatment emergent data scope.
5.2.5
Subgroup Analyses
Subgroup analyses for comparison of pantoprazole 40 mg and pantoprazole placebo will be 
performed based on the pantoprazole ITT analysis set for the ITT data scope for CBD2.
Homogeneity of treatment effect (i.e., the effect of pantoprazole study treatment on the 
pantoprazole outcome) will be examined for the following subgroup variables, where 
important subgroups are distinguished from “other” subgroups that are examined to assess the 
consistency of a treatment effect:
Important subgroups

Antithrombotic treatment group (rivaroxaban 2.5mg, rivaroxaban 5mg, aspirin 100mg)

Coronary artery disease (yes, no)

Peripheral artery disease (yes, no)
Other subgroups

Region
o
North America, Western Europe and AUS/ISR/ZAF, Eastern Europe, Asia 
Pacific, and South America, see SAP, version 4.1, Appendix 10.1
o
US, non-US

Sex (male, female)

Age 
o
Categories 1: <55, 55 to <65, 65 to 75, >75 years
o
Categories 2: < 65, ≥ 65 to < 75, ≥ 75 years

Race (White or Caucasian, Black or African American, Asian, other)

Body weight at baseline (≤ 60 kg, > 60 kg)

Baseline renal function 
o
estimated glomerular filtration rate (eGFR) categories 1: <60, ≥60 mL/min


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o
eGFR categories 2: < 15, 15 to < 30, 30 to < 60, ≥ 60 mL/min
o
eGFR categories 3: < 30, 30 to 50, >50 to 80 ml/min, >80 ml/min

Smoking status 
o
Tobacco use at baseline (yes, no)
o
History of tobacco use (yes, no)

Baseline diabetes (yes, no)

History of peptic ulcer (yes, no)

History of Helicobacter pylori (yes, no, unknown)

Baseline NSAID use (yes, no)
Additional subgroup analyses, if identified, can be specified. The pre-specified categories may 
be collapsed if the number of events is too small for some subgroups.  In addition to analyses 
of the subgroups listed above, analyses for the Asian populations, especially Chinese and 
Japanese subjects, will be performed as required and presented in separate reports.
Homogeneity of study treatment effect in subgroups, both in magnitude and direction, will be 
assessed by adding a covariate for the subgroup variable and the corresponding treatment-
subgroup interaction to the respective stratified Cox proportional hazards model used in the 
main analysis.  
As the number of subgroup analyses may be large, the probability of observing at least one 
statistically significant but spurious interaction is high despite the lack of a biological or 
pharmacological basis for expecting an interaction.  Thus any significant interactions in the 
analysis of primary outcomes will be interpreted as “flags” to prompt further investigation. 
No interactions with any of the subgroup variables are expected. Furthermore, in the analysis 
of all outcomes, if the interaction term is significant at the 5% type I error level, the likelihood 
ratio test proposed by Gail and Simon (1985) will be performed to test the hypothesis that 
there is no crossover or qualitative interaction at the 1% type I error level (H0: The direction 
of treatment effect is the same for all levels of a subgroup variable vs. H1: The direction of 
treatment effect is different for at least one level of a subgroup variable). As was shown by Li
et al (2007), the probability of observing the treatment effect in the opposite direction to the 
true overall treatment effect for at least one subgroup level is not negligible. The contributing 
factors may be small subgroup sizes, imbalance of randomized groups within the subgroups, 
and small true overall treatment effect. 
Following the test of interaction, hazard ratios with 2-sided 95% confidence intervals for the 
treatment effect will be estimated separately within each level of a subgroup variable using 
the stratified Cox proportional hazards models that were used in the main analyses of study 
outcomes.  
5.2.6
Potential Modification of Rivaroxaban Treatment Effect by 
Pantoprazole
The results of the Cox proportional hazards model including the effects of antithrombotic 
treatment, pantoprazole treatment, and the interaction of those have been reported for selected 
outcomes based on CDB1 to exclude an interaction effect between antithrombotic and 
pantoprazole treatment.


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To further investigate if pantoprazole treatment has the potential to modify the rivaroxaban 
treatment effect on the following unrefuted outcomes

Primary efficacy outcome 

Composite of MI, ischemic stroke, and CV death

Secondary efficacy outcome 

Modified ISTH major bleeding

Modified ISTH major bleeding in gastrointestinal tract

GI bleeding (composite of the first three components of the GI outcome referring to 
upper GI bleeding),
these outcomes will be evaluated for the ITT analysis set by antithrombotic treatment groups
in the rivaroxaban/aspirin follow-up data scope by depicting

the number of subjects with event, crude incidences, incidence rates and Kaplan-
Meier estimates in 
o
the ITT analysis set
o
the pantoprazole treatment groups

pantoprazole 40mg od

pantoprazole placebo od

not randomized to pantoprazole/placebo

the assessment of homogeneity of rivaroxaban treatment effect by the pantoprazole 
treatment groups (including subgroup-interaction p-value)

forest plots for the above.
5.2.7
Analysis of Efficacy Outcomes for Antithrombotic Randomization by 
Pantoprazole Treatment Groups
Subjects not randomized to pantoprazole/placebo were not followed up from the termination 
of the antithrombotic portion of the COMPASS study until the initiation of COMPASS 
LTOLE. Only subjects of the pantoprazole ITT analysis set were to be followed up until the 
Final pantoprazole/placebo Follow-up Visit, mainly to evaluate pantoprazole related 
outcomes.
Efficacy outcomes defined to analyze the objectives of the antithrombotic randomization in 
ITT data scope for CDB2 (i.e., up until the Final pantoprazole/placebo Follow-up Visit) will 
be reported by means of frequency tables only based on the pantoprazole ITT analysis set, by 
pantoprazole treatment groups, as suggested in the following example.
Table: Number of subjects with primary efficacy event and its components in ITT data 
scope for CDB2 (pantoprazole ITT analysis set)
Pantoprazole 40 mg od
N=xxxx (100%)
Pantoprazole placebo od 
N=xxxx (100%)
Total
N= xxxx (100%)
MI, stroke, or CV death
xxx  (  xx.x%)
xxx  (  xx.x%)
xxx  (  xx.x%)


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MI
xxx  (  xx.x%)
xxx  (  xx.x%)
xxx  (  xx.x%)
Stroke
xxx  (  xx.x%)
xxx  (  xx.x%)
xxx  (  xx.x%)
CV death
xxx  (  xx.x%)
xxx  (  xx.x%)
xxx  (  xx.x%)
Footnotes:
-
Only events that occurred in ITT data scope for CDB2 are taken into account.
-
The events presented were efficacy events with respect to antithrombotic randomization. Antithrombotic study medication 
was to be stopped with Final Rivaroxaban/Aspirin Follow-up Visit. Hence, the randomized antithrombotic study 
medication was not to be taken for about one year during pantoprazole/placebo follow-up.
5.3
Pharmacokinetics/Pharmacodynamics
Not applicable.
5.4
Safety
5.4.1
Safety Outcome Events for the Antithrombotic Randomization
Safety outcomes defined to analyze the objectives of the antithrombotic randomization in ITT 
data scope for CDB2 will be reported by means of frequency tables only based on the 
pantoprazole ITT analysis set, by pantoprazole treatment groups, as described in Section 
5.2.7.  These tables will be provided similarly to but separate from summaries of AE data. 
The following safety events and their composites will be tabularized:

Modified ISTH major bleeding
o
Fatal
o
Critical organ bleeding (non-fatal)
o
Requiring re-operation (non-fatal and non- critical organ)
o
Hospitalization  (non-fatal, non-critical organ, not leading to re-operation)
o
Hospitalization where admission date < discharge date
o
Hospitalization where admission date = discharge date
o
Gastrointestinal
o
Gastrointestinal (excl. oral cavity and esophagus)
o
Intracranial

Minor bleeding

Modified ISTH major bleeding by bleeding site
5.4.2
Events of Special Interest for the Pantoprazole Randomization
Other (adverse) events of special interest with respect to the pantoprazole/placebo 
randomization are

Pneumonia

Clostridium difficile infection

Other enteric infections 

Fracture

Gastric atrophy


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
Chronic kidney disease

Diabetes

Chronic obstructive lung disease

Dementia. 
The number and crude incidence of subjects with such events since informed consent (as the 
CRF suggests) will be summarized. The binary response variables will be evaluated with 
logistic regression as suggested by the following SAS code:
PROC LOGISTIC DATA = <dataset>;
CLASS trtgrpn stratumn;
MODEL outcome (event=’1’) = trtgrpn / CLODDS= WALD CLPARM= WALD ;
STRATA stratumn;
RUN;
/*
where
dataset = name of sub-dataset including Pantoprazole ITT subjects (those
subjects randomized to pantoprazole/placebo)
trtgrpn = variable coding randomized pantoprazole treatment group
(0 = Pantoprazole placebo, 1 = Pantoprazole)
outcome = event indicator (0 = no event, 1 = event)
stratumn = variable for antithrombotic stratification factor (three levels)
*/
5.4.3
Adverse Events
Summaries of reported adverse events will be provided based on 

the pantoprazole ITT analysis set using the ITT data scope for CDB2 and,

for CSR purpose only, the pantoprazole safety analysis set and the pantoprazole 
treatment emergent data scope
as outlined in Section 4.2. The remaining principles of adverse event analyses will be applied
as specified in the SAP, version 4.1.
5.4.4
Death
Please refer to Section 5.4.1.
5.4.5
Pregnancies
Please refer to SAP, version 4.1.
5.4.6
Vital Signs
Please refer to SAP, version 4.1.
5.4.7
Clinical Laboratory Tests
Please refer to SAP, version 4.1.


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5.5
Analysis of COMPASS MIND Study
Will be reported separately.
6.
Definitions
Pantoprazole ITT 
analysis set
The pantoprazole ITT analysis set comprises all subjects that have 
been randomized to pantoprazole 40mg or pantoprazole placebo.
Final 
pantoprazole/placeb
o Follow-up Visit
Final visit at the end of the pantoprazole/placebo follow-up of the
COMPASS trial
Pantoprazole/placeb
o Washout Visit
For subjects who participate in COMPASS in countries that have 
not yet approved the protocol amendment no. 11 forming integrated 
protocol version 4.0, an End of Washout Telephone Visit (Washout 
Visit) is envisaged 30 days post Final pantoprazole/placebo Follow-
up Visit.
Last 
rivaroxaban/aspirin 
Follow-up Date
If consent was not withdrawn:
Last rivaroxaban/aspirin Follow-up Date  
= first of 

date of death (if applicable)

date of completed Final rivaroxaban/aspirin Follow-
up visit (if applicable) 

max (dates of visits completed, event dates).
If consent was withdrawn:
Last rivaroxaban/aspirin Follow-up Date
= first of 

max (date of death, date of withdrawal, date of 
confirmed alive)

date of completed Final rivaroxaban/aspirin Follow-
up visit (if applicable).
Last 
pantoprazole/placeb
o Follow-up Date
If consent was not withdrawn:
Last pantoprazole/placebo Follow-up Date  
= first of 

date of death (if applicable)

date of completed Final pantoprazole/placebo 
Follow-up visit (if applicable) 


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
max (dates of visits completed, event dates).
If consent was withdrawn:
Last pantoprazole/placebo Follow-up Date
= first of 

max (date of death, date of withdrawal, date of 
confirmed alive)

date of completed Final pantoprazole/placebo 
Follow-up visit (if applicable).
Last Follow-up 
Date
If subject is in pantoprazole ITT set:
Last Follow-up Date = Last pantoprazole/placebo Follow-up Date
  
If subject is not randomized to pantoprazole/placebo:
Last Follow-up Date = Last rivaroxaban/aspirin Follow-up Date
7.
Document History and Changes in the Planned Statistical Analysis
8.
References
CSR, Clinical Study Report of the COMPASS study, PH-39342, October 16, 2017.
Gail M., Simon R. Testing for qualitative interactions between treatment effects and patient 
subsets. Biometrics,1985; 41:361-372.
Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted 
residuals. Biometrika, 1994; 81(3):515-526.
Li Z., Chuang-Stein C, Hoseyni C. The probability of observing negative subgroup results 
when the treatment effect is positive and homogeneous across all subgroups. Drug 
Information Journal, 2007; 41:47-56.
SAP, version 4.1. Integrated Statistical Analysis Plan for the COMPASS study, March 31, 
2017.


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A randomized controlled trial of rivaroxaban for the prevention of major 
cardiovascular events in patients with coronary or peripheral artery 
disease (COMPASS - Cardiovascular OutcoMes for People using 
Anticoagulation StrategieS)
Rivaroxaban for the prevention of major cardiovascular events in CAD or PAD 
(COMPASS)
Bayer study drug
BAY 59-7939 / Rivaroxaban / Xarelto®
Study purpose:
Summary of the long term open label extension part of COMPASS
Clinical study 
phase:
III
Date:
21 JUL 2021
Study No.:
BAY 59-7939/15786
Version:
2.0
Authors:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


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Table of Contents
Abbreviations............................................................................................................................ 3
1.
Introduction ....................................................................................................................... 4
2.
Study Objectives................................................................................................................ 4
3.
Study Design ...................................................................................................................... 5
4.
General Statistical Considerations .................................................................................. 6
4.1
Analysis Sets.................................................................................................................... 6
4.2
Data scopes and censoring rules ...................................................................................... 7
5.
Statistical Methodology..................................................................................................... 7
5.1
Population characteristics ................................................................................................ 7
5.1.1
Sample sizes.................................................................................................................. 7
5.1.2
Subject disposition – Overview/Details at visits .......................................................... 8
5.1.3
Visit and study drug adherence..................................................................................... 8
5.1.4
Protocol Deviations ...................................................................................................... 8
5.1.5
Medical History ............................................................................................................ 8
5.1.6
Demographics............................................................................................................... 9
5.1.7
Prior and Concomitant Medication............................................................................... 9
5.2
Efficacy............................................................................................................................ 9
5.2.1
Efficacy Variables for LTOLE ..................................................................................... 9
5.2.2
Efficacy analysis for LTOLE...................................................................................... 11
5.2.3
Subgroup Analyses ..................................................................................................... 11
5.3
Pharmacokinetics/Pharmacodynamics........................................................................... 11
5.4
Safety ............................................................................................................................. 11
5.4.1
Safety Outcome Events for the Antithrombotic Randomization................................ 11
5.4.2
Other Events of interest .............................................................................................. 12
5.4.3
Adverse Events........................................................................................................... 12
5.4.4
Death........................................................................................................................... 12
5.4.5
COVID-19 related analyses........................................................................................ 13
5.4.6
Pregnancies................................................................................................................. 13
5.4.7
Vital Signs .................................................................................................................. 13
5.4.8
Clinical Laboratory Tests ........................................................................................... 13
6.
Definitions ........................................................................................................................ 13
6.1
Arrangement of LTOLE and non-LTOLE events.......................................................... 14
7.
Document History and Changes in the Planned Statistical Analysis ......................... 15
8.
References ........................................................................................................................ 15


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Abbreviations
AE
Adverse event
AUS/ISR/ZAF
Australia/Israel/South Africa
bid
Twice daily
CAD
Coronary artery disease
CDB 
Clean database
CHD
Coronary heart disease
CI
Confidence interval
CLI
Chronic Limb Ischemia
COMPASS
Cardiovascular OutcoMes for People using Anticoagulation StrategieS
COMPASS LTOLE
COMPASS Long-term Open-Label Extension
CRF
Case report form (either paper or electronic)
CSR
Clinical study report
CV
Cardiovascular
DSMB
Data Safety Monitoring Board 
eGFR
estimated glomerular filtration rate
GI
Gastrointestinal
Hb
Hemoglobin
ICH
International Conference on Harmonization
ISTH
International Society on Thrombosis and Haemostasis
ITT
Intention-to-treat
LTOLE
Long-Term Open-Label Extension ( = COMPASS LTOLE)
MI
Myocardial infarction
od
Once daily
PAD
Peripheral artery disease
PPI
Proton pump inhibitor
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical Analysis Software
PPD


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1.
Introduction
The COMPASS study is a randomized double-blind trial utilizing a 3 x 2 partial factorial 
design evaluating the efficacy and safety of:

rivaroxaban 2.5 mg twice daily (bid) + aspirin 100 mg once daily (od) versus aspirin 
100 mg od and

rivaroxaban 5 mg bid versus aspirin 100 mg od
for the prevention of myocardial infarction, stroke, and cardiovascular death in patients with 
established CAD or PAD who are receiving standard prevention therapies. Details about the 
study, as well as the already specified and conducted analyses are described in the integrated 
clinical study protocol, Version 4.0, dated 12 September 2017, the integrated SAP, Version 
4.1, dated 31 March 2017 and the SAP for PPI-specific analyses, Version 1.0, dated 09 May 
2018.
On February 06, 2017 the Data Safety Monitoring Board (DSMB) for the COMPASS study 
recommended that the antithrombotic study treatment arms rivaroxaban 2.5 mg bid/aspirin 
100 mg od, rivaroxaban 5 mg bid, and aspirin 100 mg od be stopped as soon as an orderly 
close-out of this portion of the COMPASS trial could be carried out based on results of the 
first formal interim analysis. The DSMB made no recommendations regarding early 
termination of the pantoprazole treatment arms of the study. The Steering Committee decided 
that the pantoprazole study treatment arms would continue.
The database (Clean Database 1, CDB1) underlying the CSR and the main publications is 
based on a cut-off date of July 22, 2017 and, at Bayer, the release date of the first clinical 
database on August 04, 2017. The results for the antithrombotic randomization have been 
analyzed and reported in the clinical study report (CSR, PH-39342) of the COMPASS study 
and multiple scientific publications. The corresponding statistical analyses comprise 
information up to the subjects’ rivaroxaban/aspirin washout visits since these data are 
considered relevant to the antithrombotic study treatment arms.
Based on a further data cut-off on August 31, 2018 a second Clean Database (CDB2) has been 
released on September 21, 2018 underlying the CSR addendum (PH-40183) and summarizing 
the results focusing on the pantoprazole randomization.
After the early stop of the antithrombotic study treatment in the COMPASS study, the 
sponsor made rivaroxaban 2.5 mg bis + aspirin 100 mg od available early for COMPASS trial 
subjects as part of a Long-Term Open-Label Extension (COMPASS LTOLE; short: LTOLE).
Subjects who participated in the COMPASS study were invited to join LTOLE, and eligible 
subjects who agreed to participate were treated with the combination of rivaroxaban 2.5 mg 
bid/aspirin 100 mg od.
The primary purpose of the analyses described in this SAP is the evaluation of relevant 
outcomes in COMPASS that occurred during the LTOLE part of the study.
Hence, this SAP is to be read in conjunction with the study protocol and the SAPs mentioned 
above. The COMPASS study will be concluded with the completion of LTOLE.
2.
Study Objectives
Objective for Long-Term Open-Label Extension


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
The objective of LTOLE is to make rivaroxaban 2.5 mg bid + aspirin 100 mg od 
available to COMPASS trial subjects until the treatment is commercially available or 
for approximately 3 years from regulatory approval of LTOLE in a country, whichever 
comes first.
3.
Study Design
For the general study design, please refer to integrated SAP, version 4.1.
LTOLE will provide open-label rivaroxaban 2.5 mg bid plus aspirin 100 mg od to COMPASS 
subjects until it is commercially available or for approximately 3 years from regulatory 
approval of LTOLE in a country, which ever comes first. 
Not all sites who participated in COMPASS also participated in LTOLE. For subjects 
participating in COMPASS, the follow-up before LTOLE depends on the treatment group: 
follow-up for the antithrombotic portion ended in 2017 (release data of first clean database 04 
AUG 2017), and follow up of pantoprazole/placebo randomization ended in 2018 (relase date 
of second clean data base 21 SEP 2018). First Patient First Visit for COMPASS LTOLE was
achieved on 09 JAN 2018. Hence, patients who had not been randomized to 
pantoprazole/placebo have not been followed up during the time from close-out of the 
antithrombotic portion of the trial until they entered LTOLE. On the other hand, subjects 
randomized to pantoprazole/placebo may have had their final pantoprazole/placebo follow-up 
visit with or after LTOLE initiation visit. Hence, these subjects have been followed-up 
continuously.
LTOLE will involve an initiation visit and a follow-up period with follow-up visits every 6 
months. The follow-up will be concluded with a final follow-up visit at the end of the study.


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4.
General Statistical Considerations
Please also refer to integrated SAP, version 4.1.
During LTOLE, no outcome events are planned to undergo an event adjudication process as 
was done during the initial part of the study and all events will be analyzed as reported by the 
investigators. Please refer to Section 6.1 for the arrangement of events during LTOLE and 
before LTOLE iniation.
4.1
Analysis Sets
The following analysis sets will be used for the analysis of the data after full close-out of the 
COMPASS trial after LTOLE.

Intention-to-treat Analysis Set (ITT): 
The intention-to-treat analysis set, also termed full analysis set in the International 
Conference on Harmonization (ICH) E9 guideline, includes all subjects randomized to 
antithrombotic study treatment for the initial study part. The ITT set comprises both 
subjects randomized to pantoprazole/placebo and subjects not randomized to 
pantoprazole/placebo.
Randomization
Randomized to Pantoprazole/Placebo: N = 17598
Pantoprazole 40 mg od: N = 8791
Pantoprazole placebo od: N = 8807
Not randomized to Pantoprazole/Placebo: N = 9797
Eligible for LTOLE
N = XXX
Not eligible 
- country not participating
- XXX
- tbd
Entered LTOLE
N = XXX
Completed LTOLE
N = XXX
Death 
Alive
Randomized to antithrombotic treatment: N = 27395
Rivaroxaban 2.5 mg bid/Aspirin 100 mg od: N = 9152
Rivaroxaban 5 mg bid: N= 9117
Asxpirin 100 mg od: N = 9126
Follow-Up


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
Long-Term Open-Label Extension ITT Analysis Set (LTOLE ITT): 
The LTOLE ITT analysis set comprises all subjects who completed LTOLE initiaton 
visit (LTOLE initiation visit date entered).

Long-Term Open-Label Extension Safety Analysis Set (LTOLE SAF): 
The LTOLE Safety analysis set will include all subjects who completed LTOLE 
initiaton visit and who received at least one dose of LTOLE medication.
A subject is considered to have taken at least one dose of LTOLE study medication if 
date of permanent discontinuation of LTOLE study medication is later than the date of 
the completed LTOLE initiation visit.
4.2
Data scopes and censoring rules
The following data scopes will be considered:
-
LTOLE follow-up
o
From date of LTOLE initiation visit to last LTOLE follow-up date
-
LTOLE treatment emergent
o
From LTOLE initiation visit until last date of drug intake of LTOLE study 
medication + 2 days
-
COMPASS follow-up
o
From randomization until last Follow-up date as defined in section 6.
5.
Statistical Methodology
All data will be listed and all variables will be summarized by means of descriptive s tatistics 
according to their type.
Descriptive statistics such as mean, standard deviation, median, quartiles, minimum, and 
maximum will be used to summarize continuous variables. Counts and percentages will be 
used to summarize categorical variables. Event rates, life tables and Kaplan-Meier estimates 
will be used to summarize time-to-event variables. Graphical data displays may also be used 
to summarize the data. Confidence intervals calculated similar to the main part of the study
will be provided at a 2-sided level of 95% unless otherwise stated.
5.1
Population characteristics
The structure of the tables describing population characteristics will closely follow the tables 
provided for CDB1 but no statistical testing will be used to compare randomized treatment 
arms. Population characteristics will be displayed for the total of all subjects in LTOLE.
Baseline characteristics have not been collected for LTOLE initiation but at baseline of the 
COMPASS study. Hence, the data presented will represent the status at baseline of the 
COMPASS study, which may have been several years before LTOLE initiation.
5.1.1
Sample sizes
Study sample sizes will be tabulated overall for subjects in LTOLE as follows:
• Study sample sizes by region and country


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• Study sample sizes by country and site
5.1.2
Subject disposition – Overview/Details at visits
Subject disposition will be presented with focus on the LTOLE related part of the study.
An overview of reasons not participating in COMPASS  subjects approached to 
participateeparticipate in LTOLE will be given.
An overview of subjects entering LTOLE by randomized antithrombotic and pantoprazole 
treatment groups will be given. To help understand about the LTOLE entry, Kaplan-Meier 
estimates for the time from Final Rivaroxaban/Aspirin Follow-Up visit to LTOLE initiation 
visit will be provided.
A subject is considered as a LTOLE completer if the subject entered LTOLE and completed 
the LTOLE final vist or died.
A table presenting all subjects who changed study site will be presented including all cases of 
change of site during the study.
5.1.3
Visit and study drug adherence
The following will be tabulated :

Number of subjects and reasons for premature permanent discontinuation of LTOLE
study medication during LTOLE part

Number of subjects and reasons for premature permanent discontinuation of LTOLE 
study follow up, i.e. consent withdrawn or lost to follow-up.
Kaplan-Meier estimates will be used to present

time to the date of last dose of antithrombotic study treatment (calculated as days from 
LTOLE initiation visit), and,

time to last follow-up date
all calculated as date of event – date of LTOLE initiation visit + 1.
Other details regarding visit adherence (e.g., visit completed in person, by telephone, through 
third party) and completion as well as study drug adherence collected via CRFs will be 
summarized using frequency tables by visit overall subjects in LTOLE.
In addition, after the final close-out of the study, a bulk batch listing including information of 
all bulk batches of the study will be provided.
5.1.4
Protocol Deviations
No per protocol analysis set will be defined. The number of subjects with major protocol 
deviations during LTOLE according to the CRF will be summarized overall. The types of 
deviations are described in the Data Management Plan.
5.1.5
Medical History
Medical history (recorded at initial randomization visit of the COMPASS study) will be 
evaluated by frequency tables for subjects in the LTOLE ITT analysis set and the LTOLE
Safety analysis set, showing the number of subjects with medical history findings (i.e., listed 
conditions of previous diagnoses, diseases, or surgeries based on the CRF).


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5.1.6
Demographics
Demographic data (with baseline defined as baseline of COMPASS study) will be evaluated 
descriptively for the LTOLE ITT analysis set and the LTOLE Safety analysis set for subjects 
on LTOLE rivaroxaban/aspirin.
Descriptive statistics (such as mean, standard deviation, median, quartiles, minimum and 
maximum) will be provided for continuous variables such as

Age [years] 

Height [cm]

Weight [kg] 

Waist and hip circumference [cm]

Body mass index [kg/m²]
Counts and (appropriate) percentages will be provided for categorical variables such as

Gender

Ethnic group and ethnicity/race

Tobacco use
5.1.7
Prior and Concomitant Medication
Frequency tables will be used to summarize the number of subjects with

relevant antiplatelet agents and anticoagulant between Final Rivaroxaban/Aspirin 
Follow up visit and LTOLE initiation reported by the subject at the LTOLE initiation
visit

relevant concomitant medications at LTOLE initiation (non-study medications taken 
regularly for at least 1 month at the time of the LTOLE initiaion visit) and at final 
LTOLE follow up visit: non-study proton pump inhibitor, ACE inhibitor/ Angiotensin 
receptor blocker (ARB), alpha blocker or other vasodilator, diuretic, lipid lowering 
agent, calcium channel blocker, beta blocker, Non-steroidal anti-inflammatory drugs 
(NSAIDs), hypoglycemic agent, selective serotonin reuptake inhibitors (SSRIs).
5.2
Efficacy
LTOLE is designed as an open label single arm extension of the COMPASS study. No 
statistical testings are planned to compare treatment effects and efficacy results will be 
summarized descriptively with number of subjects with event, crude incidences, and incidence 
rates, where applicable.
5.2.1
Efficacy Variables for LTOLE
The outcome events from the following list will be analysed. For the arrangement of events in 
LTOLE and not in LTOLE, refer to section 6.1.

The primary efficacy outcome (composite of myocardial infarction, stroke and 
cardiovascular death)


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
Myocardial infarction 

Stroke 

Cardiovascular death

Mortality (all-cause)

Non-cardiovascular death

Hospitalization

Hospitalization for cardiovascular reasons
The following reasons for admission will count as cardiovascular reasons:

Myocardial infarction

Stroke

Angina

Heart Failure

Venous thromboembolism

Revascularization

Amputation

Resuscitated cardiac arrest

Severe limp ischemia

Transient ischemuc attack

Stable agina pectoris

Cardiac arrhythmia

Syncope

Systemic artrial embolism

Ischemic stroke

Hemorrhagic stroke

Uncertain stroke

Severe limb ischemia

Venous thromboembolism

Pulmonary embolism

Deep vein thrombosis

Revascularization 

Vascular Amputation 

Angina (unstable, new or worsening)

Heart failure 


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
Resuscitated cardiac arrest

New cancer

Recurrence of cancer

GI event

Overt bleeding of gastroduodenal origin

Overt upper GI bleeding of unknown origin

Bleeding of presumed occult GI origin

Symptomatic gastroduodenal ulcer

Upper GI Perforation

Upper GI Obstruction 

Gastrointestinal Pain
5.2.2
Efficacy analysis for LTOLE
For the efficacy variables defined in section 5.2.1 in the LTOLE ITT analysis set in the 
LTOLE ITT data scope the number of subjects with event, crude incidences and incidence 
rates will be presented.
For all subjects of the ITT set in the COMPASS follow-up data scope, number of subjects 
with event and crude incidences will be presented. No incidence rates are planned to be 
presented in this data scope.
5.2.3
Subgroup Analyses
The efficacy analyses will be repeated for the following subgroups:

Coronary artery disease (yes, no)

Peripheral artery disease (yes, no)

CAD and PAD (yes, no)

CAD only, PAD only, CAD and PAD
5.3
Pharmacokinetics/Pharmacodynamics
Not applicable.
5.4
Safety
5.4.1
Safety Outcome Events for the Antithrombotic Randomization
Safety outcomes of the antithrombotic randomization will be reported with number and 
percentage of subjects for the LTOLE ITT analysis set as well as the LTOLE Safety analysis 
set. Incidence in events per 100-patient years will be presented.
For the LTOLE ITT analysis set

during LTOLE follow-up


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
and time from randomization up until LTOLE final follow-up. For this data scope no 
incidence rates will be presented.
For the LTOLE Safety analysis set, all events from LTOLE initiation up until last LTOLE 
study drug intake plus 2 days will be presented.
The following safety events will be tabularized:

Modified ISTH major bleeding
o
Fatal
o
Critical organ bleeding (non-fatal)
o
Requiring re-operation (non-fatal and non- critical organ)
o
Hospitalization  (non-fatal, non-critical organ, not leading to re-operation)
o
Gastrointestinal
o
Gastrointestinal (excl. oral cavity and esophagus)
o
Intracranial

Minor bleeding
The bleeding classification will be assesed via an algorithm. The classification by the 
algorithm will be used as “adjudicated bleedings” and will be mainly used for safety analyses. 
In addition the bleedings as reported by inverstigators will be shown.
5.4.2
Other Events of interest
Other events of interest are:

Pneumonia

Clostridium difficile infection

Other enteric infections 

Fracture

Gastric atrophy

Chronic kidney disease

Diabetes

Chronic obstructive lung disease

Dementia
For these events the crude incidence of subjects in the LTOLE ITT analysis set having an 
event during LTOLE will be presented.
5.4.3
Adverse Events
Summaries of reported adverse events will be provided based on the LTOLE Safety analysis 
set using the LTOLE treatment emergent data scope as outlined in Section 4.2. The remaining 
principles of adverse event analyses will be applied as specified in the SAP, version 4.1.
5.4.4
Death
Deaths will be summarized by cardiovascular cause and non-cardiovascular cause


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
from randomization to last trial contact (in ITT set)

from LTOLE initiation to last trial contact (in LTOLE ITT set).
For these data scopes the number of subjects with an event, the crude incidences and the 
incidence rates will be presented.
5.4.5
COVID-19 related analyses
Subjects affected by the COVID-19 pandemic will be listed with the affected visits, the visit 
adherence and drug dispenstation method.
5.4.6
Pregnancies
Please refer to SAP, version 4.1.
5.4.7
Vital Signs
Not applicable.
5.4.8
Clinical Laboratory Tests
Descriptive statistics (mean, standard deviation median, minimum and maximum) will be 
provided for the laboratory parameters serum creatinine and estimated glomerular filtration 
rate (eGFR) at the LTOLE initiation visit.
6.
Definitions
Final LTOLE
Follow-up Visit
Final visit at the end of the LTOLE follow-up of the COMPASS 
trial
Last LTOLE 
Follow-up Date
If consent was not withdrawn:
Last LTOLE Follow-up Date  
= first of
o
date of death (if applicable)
o
maximum date of completed Final LTOLE
Follow-up visit and last study drug intake, if 
Final LTOLE Follow-up Visit is completed
o
max (dates of visits completed during 
LTOLE, event dates during LTOLE).
If consent was withdrawn:
Last LTOLE Follow-up Date
= first of

max (date of death, date of withdrawal, date of 
confirmed alive)
o
maximum date of completed Final LTOLE
Follow-up visit (if applicable) and last study 
drug intake


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
Last 
rivaroxaban/aspirin
Follow-up Date
As defined for CDB1
Last 
pantoprazole/placeb
o Follow-up Date
As defined for CDB2
Last Follow-up 
Date
If subject is in LTOLE ITT set:
Last Follow-up Date = Last LTOLE Follow-up Date
Else If subject is in pantoprazole ITT set:
Last Follow-up Date = Last pantoprazole/placebo Follow-up Date
Else If subject is not randomized to pantoprazole/placebo:
Last Follow-up Date = Last rivaroxaban/aspirin Follow-up Date
6.1
Arrangement of LTOLE and non-LTOLE events
In the LTOLE part of the study there is no adjudication of efficacy events, contrary to the 
antithrombotic as well the pantoprazole/placebo part of the study. For an arrangement for the 
whole study the following definitions hold:

For event types not adjudicated at any time of the study: count all events as 
reported

For events adjudicated at any time of the study:
o
Unrefuted events are all events confirmed in an adjudication plus the 
events that did not undergo adjudication
o
Investigator reported events are all events reported by the investigators 
regardless of any result of the adjudication process.
For the LTOLE part of the study the event CRF pages were simplified. The event “Bleeding 
leading to hospitalization” was not queried on the CRF page in the LTOLE event form. Thus 
all hospitalization with primary reason for admission “bleeding” will be counted for these 
events.
In the LTOLE event CRF the reasons for hospitalization are simplified and especially the 
other diagnoses is not divided into CV and non-CV reasons. Thus the event “Hospitalization 
for CV reasons” for the whole study is the combination of Hospitalizations for CV reasons as 
defined for CDB1 and CDB2 for the antithrombotic and pantoprazole/placebo part of the 
study and the events with reasons defined in section 5.2.1 as “cardiovascular reasons” for 
events during the LTOLE part of the study.


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The event “Severe Limb Ischemia” was reported differently in the main part of the study and 
the LTOLE part. However, for the data scopes from randomization onwards the events of the 
antithrombotic and pantoprazole/placebo part will be combined with the events collected in 
LTOLE.
7.
Document History and Changes in the Planned Statistical Analysis
Version 2 implements analyses with respect to COVID-19 pandemic, updated definition of 
Last LTOLE Follow-up date due to reported number of patients that reported to take study 
drug after final LTOLE visit and minor changes for the analyses of prior and concomitant
medication.
8.
References
CSR, Clinical Study Report of the COMPASS study, PH-39342, October 16, 2017.
SAP, version 4.1. Integrated Statistical Analysis Plan for the COMPASS study, March 31, 
2017.
SAP; version 1.0. Integrated Statistical Analysis Plan for the COMPASS study for the PPI 
close-out, May 9, 2018.