Clinical trial NCT02504216
Conditions: Peripheral Artery Disease
Keywords: Rivaroxaban Xarelto Aspirin Acetylic salicylic acid Anticoagulant Peripheral artery disease Peripheral arterial disease Revascularization Acute limb ischemia Amputation Cardiovascular events
Sponsor: Bayer
Start date: 2015-08-18; Completion date: 2020-01-09
Enrollment: 6564 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of study was to test whether rivaroxaban added to standard of care treatment, when compared to placebo, had the potential to reduce the incidence of the clinical events related to the clots and complications of the heart and brain (CV death, MI, or stroke) or the legs (acute limb ischemia or major amputation) in patients who had undergone recent procedure(s) to improve the blood flow of their legs.

Detailed description:

Arms: arm 1: Rivaroxaban 2.5 mg orally twice daily (5 mg cumulative daily dose) arm 2: Rivaroxaban-placebo orally twice daily
Interventions: intervention 1: Rivaroxaban (Xarelto, BAY59-7939) intervention 2: Rivaroxaban-Placebo
Intervention descriptions: intervention 1: 2.5 mg, twice daily, orally, tablet intervention 2: matching placebo, twice daily, orally, tablet

Protocol documents:
Prot_001.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
An international, multicenter, randomized, double-blind, placebo 
controlled phase 3 trial investigating the efficacy and safety of 
rivaroxaban to reduce the risk of major thrombotic vascular events in 
patients with symptomatic peripheral artery disease undergoing 
lower extremity revascularization procedures 
NCT Number: 
NCT02504216 
Document Date: 
21-Mar-2017 
 


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Cover page of the integrated protocol
An international, multicenter, randomized, double-blind, placebo-controlled phase 3 
trial investigating the efficacy and safety of rivaroxaban to reduce the risk of major 
thrombotic vascular events in patients with symptomatic peripheral artery disease 
undergoing lower extremity revascularization procedures
This protocol version is an integration of the following documents / sections:

Original protocol, Version 1.0, dated 23 MAR 2015

Amendment 4 (global amendment described in Section 15.1)
forming integrated protocol Version 2.0, dated 10 FEB 2016

Amendment 5 (global amendment described in Section 15.2)
forming integrated protocol Version 3.0, dated 21 MAR 2017
Amendments not included in the consecutive numbering of amendments are 
local amendments not forming part of this integrated global protocol:

Local Amendment 1, valid for Japan, dated 28 APR 2015

Local Amendment 2, valid for United Kingdom (UK), dated 25 AUG 2015

Local Amendment 3, valid for Czech Republic, dated 15 SEP 2015


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1.
Title page - amended
An international, multicenter, randomized, double-blind, placebo-
controlled phase 3 trial investigating the efficacy and safety of rivaroxaban 
to reduce the risk of major thrombotic vascular events in patients with 
symptomatic peripheral artery disease undergoing lower extremity 
revascularization procedures
Short Title: Vascular Outcomes studY of ASA alonG with rivaroxaban in 
Endovascular or surgical limb Revascularization for peripheral artery disease (PAD)
Acronym: VOYAGER PAD
Test drug:
BAY 59-7939 / Rivaroxaban / Xarelto
Clinical study phase:
3
Date: 21 MAR 2017
Registration:
EudraCT: 2014-005569-58
Version no.:
3.0
Sponsor’s study no.:
BAY 59-7939 / 17454
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, USA1
Sponsor’s study medical 
expert2:
Bayer HealthCare Pharmaceuticals Inc.
100 Bayer Blvd, PO Box 915
Whippany, NJ 07981-0915; United States
Phone No. 
The study will be conducted in compliance with the protocol, ICH-GCP, and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for the guidance of the 
clinical investigation. Reproduction or disclosure of this document - whether in part or in full - to parties not 
associated with the clinical investigation, or its use for any other purpose, without the prior written consent of 
the sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
Rivaroxaban (BAY-59-7939, JNJ-39039039) is being co-developed under a collaboration and license 
agreement between Bayer HealthCare AG (BHC) and Ortho McNeil Pharmaceuticals, Inc. (OMP) dated 01 Oct
2005. As determined by the parties, both BHC and Janssen Pharmaceuticals Inc. (successor in interest to OMP) 
may use affiliated corporate entities to conduct this clinical study. With regard to Janssen Pharmaceuticals Inc., 
such affiliates may include Janssen Research & Development, LLC (formerly Johnson & Johnson 
Pharmaceutical Research & Development LLC), Janssen Scientific Affairs, LLC, and Janssen-Cilag 
International N.V (Corporation). The term "sponsor" or "designee" is used to represent these various legal 
entities that have been identified to perform various clinical study services; the actual sponsor or designee is 
identified on the Contact Information page that accompanies this protocol.
                                                
1 Updated sponsor information via Protocol Amendment 5 (change no. 1).
2 Updated name and contact details for Sponsor’s medical expert with Protocol Amendment 4 (change no. 1).
PPD
PPD


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


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


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2.
Synopsis - amended
Title
An international, multicenter, randomized, double-blind, placebo-controlled 
phase 3 trial investigating the efficacy and safety of rivaroxaban to reduce the 
risk of major thrombotic vascular events in patients with symptomatic
peripheral artery disease undergoing lower extremity revascularization 
procedures 
Short title /
Acronym
Vascular Outcomes studY of ASA alonG with rivaroxaban in Endovascular 
or surgical limb Revascularization for peripheral artery disease (PAD)
VOYAGER PAD
Secondary IDs
IMPACT No. 17454 / EUDRACT No.: 2014-005569-58
Clinical study phase
Phase 3
Study objective(s)
Primary efficacy objective:
•
to evaluate whether rivaroxaban added to acetylsalicylic acid (ASA) 
is superior to ASA alone in reducing the risk of major thrombotic 
vascular events (defined as myocardial infarction (MI), ischemic 
stroke, cardiovascular (CV) death, acute limb ischemia (ALI), and 
major amputation of a vascular etiology) in symptomatic PAD 
patients undergoing lower extremity revascularization procedure.
Secondary efficacy objectives: 
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of MI, ischemic stroke, coronary heart 
disease mortality, ALI, and major amputation of a vascular etiology;
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of an unplanned index limb 
revascularization for recurrent limb ischemia (subsequent index leg 
revascularizations that were not planned or considered as part of the 
initial treatment plan at the time of randomization);3
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of vascular hospitalizations for a coronary 
or peripheral event (either limb) of a thrombotic nature;
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of MI, ischemic stroke, all-cause mortality, 
ALI, and major amputation of a vascular etiology;
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of MI, all-cause stroke, CV death, ALI,
and major amputation of a vascular etiology;
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of all-cause mortality
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of venous thromboembolic (VTE) events4;
Primary safety objective:
•
to evaluate the overall safety and tolerability of rivaroxaban added to 
ASA compared to ASA alone.
                                                
3 This objective was revised with Protocol Amendment 4 (change no. 8) and Protocol Amendment 5 (change no. 
2).


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Test drugs
Xarelto®
Name of active ingredient
Rivaroxaban
Dose(s)
2.5 mg twice daily (bid)
Route of administration
oral
Duration of treatment
A mean treatment duration of approximately 30 months and a maximum
treatment duration of up to approximately 42 months is estimated. This study 
will be event-driven, thus all patients will be treated (or followed-up in the 
case of permanent discontinuation of study medication) until the required 
primary efficacy outcomes have occurred.
Reference drug(s)
Name of active ingredient
Rivaroxaban-matching placebo
Dose(s)
matching placebo bid
Route of administration
oral
Duration of treatment
Same as for test drug (see above).
Background treatment
All study patients will receive treatment with open label ASA 100 mg orally
once daily (od) during the entire course of the study; additional treatment with 
clopidogrel may be administered for a planned duration of up to 30 days after
the qualifying revascularization procedure (or up to 6 months for complex 
procedures or devices in the investigator’s opinion that require longer use); it 
is strongly recommended that any course of clopidogrel is kept to the 
minimum necessary in accordance with local standard of care and 
international practice guidelines (typically 30 days, or up to 60 days for some 
drug-coated products or devices)( see section 8.1 for further guidance on 
clopidogrel). 5
Indication
Symptomatic PAD
Diagnosis and main criteria for 
inclusion/exclusion6
Main inclusion criteria are:
•
age ≥50,
•
documented moderate to severe symptomatic lower extremity 
atherosclerotic peripheral artery disease as evidenced by ALL of the 
following:
a. clinically, by functional limitations in walking activity, ischemic 
rest pain, or ischemic ulceration,
b. anatomically, by imaging evidence of peripheral artery disease 
distal to the external iliac artery in the index leg within 
12 months prior to or at the time of the qualifying 
revascularization, 
AND
c. hemodynamically in either leg (within 12 months prior to, or at 
the time of, the qualifying revascularization) by:

an ABI ≤ 0.80 or TBI ≤ 0.60 for patients without a prior 
history of limb revascularization,
                                                                                                                                                        
4 The last 2 secondary objectives were revised with Protocol Amendment 4 (change no. 17).
5 This section was modified with Protocol Amendment 5 (change no. 3).
6 Modifications to the inclusion and exclusion criteria were made with Protocol Amendment 4 (change no. 4, 5, 
7, 15, 17 and 20a, b, c)


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OR

an ABI ≤0.85 or TBI ≤ 0.65 for patients with a prior history 
of limb revascularization.
Main exclusion criteria are:
•
patients undergoing revascularization for asymptomatic PAD or mild 
claudication without functional limitation of the index leg,7
•
patients undergoing revascularization of the index leg to treat an 
asymptomatic or minimally symptomatic restenosis of a bypass graft 
or target lesion restenosis,
•
prior revascularization on the index leg within 10 days of the 
qualifying revascularization,
•
Planned dual anti-platelet therapy (DAPT) use for the qualifying 
revascularization procedure of clopidogrel in addition to ASA for >6 
month after the qualifying revascularization procedure; it is strongly 
recommended that any course of clopidogrel is kept to the minimum 
necessary in accordance with local standard of care and international 
practice guidelines (typically 30 days, or up to 60 days  for some 
drug-coated products or devices) and is only allowed for up to 6 
months for complex procedures or devices in the investigator’s 
opinion that require longer use; see section 8.1 for further guidance 
on clopidogrel 8, 9
•
Planned use of any additional antiplatelet agent other than 
clopidogrel and ASA after the qualifying revascularization 
procedure.10
Study design
International, multicenter, randomized, double-blind, placebo-controlled, 
event-driven phase 3 study.
Methodology11
Patients meeting the eligibility criteria will be treated with study ASA and 
randomly allocated by an interactive voice/web response system (IxRS) in a 
ratio of 1:1 to treatment with either rivaroxaban or matching placebo. 
Randomization will be stratified by type of procedure and use of clopidogrel 
(i.e., (i.) surgical vs. (ii.) endovascular with clopidogrel vs. (iii.) endovascular 
without clopidogrel), and treatments will be balanced within a country for 
each stratum by block randomization. Randomization and study treatment 
will commence as soon as possible but no later than 10 days after the 
qualifying revascularization.
The first study visit is a screening visit to be performed within 30 days prior 
to or no more than 10 days after the qualifying revascularization. The second 
study visit is the randomization visit, which should be performed as soon as 
possible (but no later than 10 days) after the qualifying revascularization. The 
first dose of study drug should be taken at the randomization visit. The 
screening and randomization visits can be combined into one visit if all tests 
required for the assessment of all eligibility criteria are available and 
                                                
7 This bullet point was corrected with Protocol Amendment 5 as requested by the Note to File for Protocol
Amendment 4 (change no.  7).
8 Exclusion criterion 7 revised with Protocol Amendment 4 (change no. 17).
9 Exclusion criteria concerning DAPT were modified via Protocol Amendment 5 (change no. 3).
10 Exclusion criterion modified via Protocol Amendment 5 (change no. 7).
11 Text modified with Protocol Amendment 4 (changes no. 2, 3 and 17).


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randomization and dosing can be performed within close proximity. 
Subsequent on-site study visits will be completed at 1, 3, 6, and 12 months 
(Visits 1-4) after randomization, and then every 6 months after Visit 4 until 
end of treatment (EOT visit).
Due to the event-driven study design, no firm treatment duration can be 
stipulated for an individual patient. However, the mean treatment duration is 
estimated to be approximately 30 months and the maximum treatment period 
for an individual patient to be approximately 42 months. The EOT visit will 
be performed as soon as possible after the announcement of study end or
upon individual premature termination of the study. All efforts must be 
taken to engage patients to continue to be followed until the end of the 
trial preferably by regular site visits, or at least by phone contacts.
Finally, a post-study treatment follow-up visit will be performed by phone in 
all patients one month after the EOT visit.
Patients will be assessed at each study visit for the occurrence of study 
efficacy outcome events, bleeding events, and adverse events (AEs). The time 
period for reporting of all these events will begin with informed consent and 
will end with the post-study treatment follow-up visit.
Patients who experience a study efficacy outcome event or bleeding event 
while enrolled in the trial should continue study treatment, if medically 
justifiable. All patients who have discontinued study drug treatment 
prematurely will be followed according to the regular visit schedule, and 
ascertainment of all events including, but not limited to study efficacy 
outcome events, bleeding events, and vital status (alive or deceased) must be 
assessed in these patients until the end of the study via clinic visits or 
telephone contacts, as outlined in the protocol. Patients who withdraw consent 
will continue to be monitored for vital status and study efficacy outcome 
events as allowable per country regulations.
Type of control
Matching placebo
Trial Committees
An Executive Committee (EC) will contribute to the protocol development, 
analysis plans, and publications and oversee the conduct of the trial.
An International Steering Committee (ISC) will provide scientific input and 
oversight of countries and sites.
The study efficacy outcome and bleeding events will be adjudicated by an 
Independent Central Adjudication Committee (ICAC). 
Safety data will be continuously assessed by an Independent Data Monitoring 
Committee (IDMC). 
Number of subjects
Approximately 6,500 patients (i.e., 3,250 per treatment group) will be 
enrolled in order to attain 1,015 patients that experience a positively-
adjudicated primary efficacy outcome event. The number of patients enrolled 
may be adjusted based on a blinded review of the observed overall event rate 
of confirmed and projected primary outcome events during the study.


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Primary and secondary 
variable(s)
The primary efficacy outcome variable will be a composite endpoint 
consisting of the time from randomization to the first occurrence of any of the 
following major thrombotic vascular events: MI, ischemic stroke, CV death, 
ALI, and major amputation due to a vascular etiology.
The secondary efficacy variables of the study will be:
•
time from randomization to the first occurrence of MI, ischemic stroke, 
coronary heart disease mortality, ALI, and major amputation of a 
vascular etiology;
•
time from randomization to the first occurrence of an unplanned index 
limb revascularization for recurrent limb ischemia (subsequent index leg 
revascularizations that were not planned or considered as part of the 
initial treatment plan at the time of randomization);12
•
time from randomization to the first occurrence of hospitalization for a 
coronary or peripheral cause (either lower limb) of a thrombotic nature;
•
time from randomization to the first occurrence of MI, ischemic stroke, 
all-cause mortality, ALI, and major amputation of a vascular etiology;
•
time from randomization to the first occurrence of MI, all-cause stroke, 
CV death, ALI, and major amputation of a vascular etiology;
•
time from randomization to the first occurrence of all-cause mortality.
•
time from randomization to the first occurrence of venous 
thromboembolic (VTE) events;
The primary safety outcome will be major bleeding events according to the 
Thrombolysis in Myocardial Infarction (TIMI) classification.
Plan for statistical analysis
The primary efficacy analyses will be based on the intent-to-treat (ITT) 
population using adjudicated results. The rivaroxaban plus study ASA group 
will be compared to the placebo plus study ASA group using a stratified log 
rank test. Kaplan-Meier curves for the cumulative incidence risk and 
cumulative incidence functions will be provided to evaluate the timing of 
event occurrence. Relative risk reduction will be estimated with the stratified 
Cox proportional hazards model.
Secondary efficacy outcomes will be analyzed using similar methods as for 
the primary efficacy analysis. Testing will be performed in an hierarchical 
order.
The analysis of the primary safety outcome will be similar to those described 
for the primary efficacy outcome.
There will be one formal interim analysis to assess efficacy and allow for 
stoppage if overwhelming superiority is detected (p<0.001), which will occur 
when approximately 67% of the planned primary efficacy outcomes have 
accrued.
                                                
12 Text modified with Protocol Amendment 4 (change no. 8) and Protocol Amendment 5 (see change no 2).


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Anticipated total study duration 
and study duration per patient
Total study duration: 
~42 months
Enrollment period: 
~18 months
Treatment duration for last patient randomized: 
~24 months
Mean treatment duration per patient: 
~30 months
Maximum treatment duration per patient:
~42 months
The study will be event-driven and these timelines may vary depending on the 
enrollment rate and event rate in the study.


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Table of contents
Cover page of the integrated protocol.................................................................................... 1
1.
Title page - amended......................................................................................................... 2
Signature of the Sponsor’s medically responsible person .................................................... 3
Signature of the principal investigator for the study............................................................ 4
2.
Synopsis - amended........................................................................................................... 5
Table of contents..................................................................................................................... 11
Table of tables......................................................................................................................... 15
Table of figures....................................................................................................................... 15
List of abbreviations - amended............................................................................................ 16
Definitions of medical terms - amended............................................................................... 19
3.
Introduction..................................................................................................................... 20
3.1
Background - amended .................................................................................................. 20
3.2
Drug management of PAD ............................................................................................ 21
3.3
Rationale of the study .................................................................................................... 23
3.4
Benefit/risk assessment.................................................................................................. 24
4.
Study objectives - amended............................................................................................ 25
5.
Study design - amended.................................................................................................. 26
6.
Study population ............................................................................................................. 28
6.1
Inclusion criteria - amended........................................................................................... 28
6.2
Exclusion criteria - amended ......................................................................................... 29
6.3
Discontinuation of study medication by subjects and withdrawal criteria .................... 31
6.3.1
Discontinuation and withdrawal - amended............................................................... 31
6.3.2
Replacement ............................................................................................................... 32
6.4
Subject identification ..................................................................................................... 33
7.
Treatments....................................................................................................................... 33
7.1
Treatments to be administered - amended ..................................................................... 33
7.2
Identity of study treatment............................................................................................. 33
7.3
Treatment assignment - amended .................................................................................. 34
7.4
Dosage and administration - amended........................................................................... 34
7.4.1
Dose modifications..................................................................................................... 35
7.4.2
Guidance for the treatment of subjects who require an invasive procedure............... 35
7.4.3
Guidance for the treatment of subjects who require coronary artery bypass graft 
(CABG) surgery – amended....................................................................................... 36
7.4.4
Guidance for the treatment of subjects who develop an acute coronary 
syndrome and those who require percutaneous coronary intervention with 
stenting - amended...................................................................................................... 36
7.4.5
Guidance for the treatment of subjects who overdose on study medication .............. 36


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7.4.6
Guidance for the treatment of subjects who experience a major bleed...................... 36
7.4.7
Guidance for the treatment of subjects who have impaired  renal function............... 37
7.5
Blinding ......................................................................................................................... 37
7.6
Drug logistics and accountability................................................................................... 37
7.7
Treatment compliance.................................................................................................... 38
8.
Non-study therapy........................................................................................................... 38
8.1
Prior and concomitant therapy - amended ..................................................................... 38
8.2
Post-study therapy.......................................................................................................... 42
8.3
Background non-antithrombotic therapy....................................................................... 42
9.
Procedures and variables ............................................................................................... 42
9.1
Tabular schedule of evaluations - amended................................................................... 42
9.2
Visit description............................................................................................................. 46
9.2.1
Timing of assessments................................................................................................ 46
9.2.1.1
Screening Visit (ScV): 30 days before, or up to 10 days after qualifying 
revascularization procedure - amended................................................................... 46
9.2.1.2
Randomization visit (RxV): 0-10 days after the qualifying revascularization 
procedure - amended ............................................................................................... 47
9.2.1.3
Treatment phase: Regular study visits from Visit 1 onwards - amended................ 48
9.2.1.4
End of treatment (EOT) visit - amended................................................................. 49
9.2.1.5
Post-study treatment follow-up visit (PS-FU): one month post-EOT 
(± 1 week)................................................................................................................ 50
9.3
Population characteristics .............................................................................................. 50
9.3.1
Demographics............................................................................................................. 50
9.3.2
Medical history........................................................................................................... 51
9.3.3
Definition of qualifying revascularization procedure - amended............................... 51
9.4
Efficacy.......................................................................................................................... 52
9.4.1
Assessments and procedures at occurrence of primary efficacy events -
amended...................................................................................................................... 52
9.4.2
Definition of study efficacy outcome events.............................................................. 53
9.4.3
Efficacy variables ....................................................................................................... 53
9.4.3.1
Primary efficacy variable ........................................................................................ 53
9.4.3.2
Secondary efficacy variables - amended................................................................. 53
9.4.3.3
Other efficacy variables - amended......................................................................... 54
9.5
Pharmacokinetics / pharmacodynamics......................................................................... 54
9.6
Safety ............................................................................................................................. 54
9.6.1
Adverse events............................................................................................................ 54
9.6.1.1
Definitions............................................................................................................... 55
9.6.1.2
Classifications for adverse event assessment.......................................................... 56
9.6.1.3
Targeted safety data collection................................................................................ 58
9.6.1.4
Expected adverse events.......................................................................................... 61
9.6.2
Pregnancies................................................................................................................. 61
9.6.3
Further safety – amended ........................................................................................... 61
9.7
Other procedures and variables...................................................................................... 61
9.7.1
European Quality of Life-5 Dimensions Questionnaire - amended ........................... 61
9.7.2
Walking Impairment Questionnaire - amended.......................................................... 62


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9.7.3
Health resource use - amended................................................................................... 62
9.7.4
PAD Symptom Status - amended............................................................................... 62
9.8
Appropriateness of procedures / measurements ............................................................ 62
10. Statistical methods and determination of sample size ................................................. 62
10.1
General considerations................................................................................................... 62
10.2
Analysis sets .................................................................................................................. 63
10.3
Variables and planned statistical analyses..................................................................... 63
10.3.1
Variables..................................................................................................................... 63
10.3.2
Planned subgroups...................................................................................................... 63
10.3.3
Statistical and analytical plans.................................................................................... 63
10.3.3.1
Analysis of the primary efficacy variable ............................................................... 63
10.3.3.2
Analysis of the secondary and other efficacy variables .......................................... 64
10.3.3.3
Analysis of safety outcomes and regular adverse events ........................................ 64
10.3.3.4
Analysis of subgroups ............................................................................................. 64
10.3.3.5
Handling of missing data......................................................................................... 65
10.4
Determination of sample size......................................................................................... 65
10.5
Planned interim analyses ............................................................................................... 66
11. Data handling and quality assurance............................................................................ 66
11.1
Data recording................................................................................................................ 66
11.2
Monitoring ..................................................................................................................... 67
11.3
Data processing.............................................................................................................. 67
11.4
Audit and inspection ...................................................................................................... 68
11.5
Archiving ....................................................................................................................... 68
12. Premature termination of the study.............................................................................. 68
13. Ethical and legal aspects................................................................................................. 69
13.1
Investigator(s) and other study personnel...................................................................... 69
13.1.1
Investigators ............................................................................................................... 69
13.1.2
Study personnel .......................................................................................................... 69
13.1.3
External data evaluation bodies.................................................................................. 69
13.2
Funding and financial disclosure ................................................................................... 70
13.3
Ethical and legal conduct of the study........................................................................... 70
13.4
Subject information and consent.................................................................................... 71
13.5
Publication policy and use of data ................................................................................. 72
13.6
Compensation for health damage of subjects / insurance.............................................. 73
13.7
Confidentiality ............................................................................................................... 73
14. Reference list - amended................................................................................................. 74
15. Protocol amendments...................................................................................................... 78
15.1
Amendment 4................................................................................................................. 78
15.1.1
Overview of changes to the study............................................................................... 78
15.1.2
Changes to the protocol text....................................................................................... 87
15.1.2.1
Title page................................................................................................................. 87
15.1.2.2
Section 2.  Synopsis, Study objective(s) ................................................................. 87
15.1.2.3
Section 2.  Synopsis, Background treatment........................................................... 88


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15.1.2.4
Section 2.  Synopsis, Diagnosis and main criteria for inclusion/exclusion............. 88
15.1.2.5
Section 2. Synopsis, Methodology......................................................................... 90
15.1.2.6
Section 2.  Synopsis, Primary and secondary variable(s) ....................................... 91
15.1.2.7
Definition of medical terms..................................................................................... 91
15.1.2.8
Section 3.4.  Benefit/risk assessment ...................................................................... 92
15.1.2.9
Section 4.  Study objectives .................................................................................... 93
15.1.2.10 Section 5.  Study design.......................................................................................... 93
15.1.2.11 Section 6.1.  Inclusion criteria................................................................................. 95
15.1.2.12 Section 6.2  Exclusion criteria................................................................................. 97
15.1.2.13 Section 6.3.1 Discontinuation and withdrawal........................................................ 98
15.1.2.14 Section 7.1.  Treatments to be administered ........................................................... 99
15.1.2.15 Section 7.4.  Dosage and administration................................................................. 99
15.1.2.16 Section 7.4.1  Dosage modifications....................................................................... 99
15.1.2.17 Section 7.4.4.  Guidance for the treatment of subjects who develop an acute 
coronary syndrome and those who require percutaneous coronary 
intervention with stenting...................................................................................... 100
15.1.2.18 Section 8.1. Prior and concomitant therapy .......................................................... 101
15.1.2.19 Section 9.1.  Tabular schedule of evaluations....................................................... 103
15.1.2.20 Section 9.2.1.1.  Screening Visit (ScV)................................................................. 110
15.1.2.21 Section 9.2.1.2.  Randomization visit (RxV) 0-10 days after the qualifying 
revascularization procedure - amended................................................................. 112
15.1.2.22 Section 9.2.1.3.  Treatment phase:  Regular study visits from Visit 1 onwards ... 114
15.1.2.23 Section 9.2.1.4.  End of treatment (EOT) visit...................................................... 115
15.1.2.24 Section 9.3.3.  Definition of qualifying revascularization procedure ................... 116
15.1.2.25 Section 9.4.1  Assessments and procedures at occurrences of primary efficacy 
events..................................................................................................................... 118
15.1.2.26 Section 9.4.2  Definition of study outcome events ............................................... 118
15.1.2.27 Section 9.4.3.2.  Secondary efficacy variables...................................................... 120
15.1.2.28 Section 9.4.3.3.  Other efficacy variables ............................................................. 120
15.1.2.29 Section 9.6.1.2.6.  Intensity (section added) ......................................................... 121
15.1.2.30 Section 9.6.1.3.1.  Assessment of bleeding events................................................ 121
15.1.2.31 Section 9.6.1.3.2.  Assessment and documentation of adverse events.................. 121
15.1.2.32 Section 9.6.3 Further safety................................................................................... 122
15.1.2.33 Section 9.7.1 European Quality of Life-5 Dimensions Questionnaire.................. 122
15.1.2.34 Section 9.7.2 Walking Impairment Questionnaire................................................ 123
15.1.2.35 Section 9.7.3 Health resource use ......................................................................... 123
15.1.2.36 Section 9.7.4.  PAD Symptom Status (section added).......................................... 123
15.1.2.37 Section 10.4.  Determination of sample size......................................................... 124
15.1.2.38 Section 11.1.  Data recording................................................................................ 124
15.1.2.39 Section 13.2.  Funding and financial disclosure.................................................... 125
15.1.2.40 Section 14.  Reference list..................................................................................... 126
15.1.2.41 Section 16 Appendices.......................................................................................... 126
15.2
Amendment 5............................................................................................................... 127
15.2.1
Overview of changes to the study............................................................................. 127
15.2.1.1
Change 1: Change of sponsorship information..................................................... 127


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15.2.1.2
Change 2: Further specification of secondary objective concerning risk of 
index limb revascularization ................................................................................. 127
15.2.1.3
Change 3: Changes to exclusion criteria concerning DAPT................................. 127
15.2.1.4
Change 4: Amendment of definitions for Endovascular procedure and 
Surgical procedure................................................................................................. 128
15.2.1.5
Change 5: Addition of requirement that ABI/TBI assessments done after 
consenting must be performed per ABI/TBI Site Manual .................................... 128
15.2.1.6
Change 6: Addition of possible requirement for submission of source 
documents from the qualifying revascularization procedure for central data 
verification ............................................................................................................ 128
15.2.1.7
Change 7: Text amendments for clarity and consistency...................................... 128
15.2.2
Changes to the protocol text..................................................................................... 129
15.2.2.1
Title Page............................................................................................................... 129
15.2.2.2
Synopsis ................................................................................................................ 130
15.2.2.3
Definitions and medical terms............................................................................... 132
15.2.2.4
Section 4. Study objectives ................................................................................... 133
15.2.2.5
Section 6.2 Exclusion criteria................................................................................ 133
15.2.2.6
Section 7.3 Treatment assignment ........................................................................ 135
15.2.2.7
Section 8.1 Prior and concomitant therapy ........................................................... 135
15.2.2.8
Section 9.1 Tabular schedule of evaluations......................................................... 136
15.2.2.9
Section 9.2.1.1 Screening Visit (ScV): 30 days before, or up to 10 days after 
qualifying revascularization procedure ................................................................. 137
15.2.2.10 Section 9.3.3 Definition of qualifying revascularization procedure ..................... 137
15.2.2.11 Section 9.4.1 Assessments and procedures at occurrence of primary efficacy 
events..................................................................................................................... 138
15.2.2.12 Section 9.4.3.2 Secondary efficacy variables........................................................ 138
15.2.2.13 Section 9.6.1.3.3 Reporting of serious adverse events and study-specific 
exemptions ............................................................................................................ 139
Table of tables
Table 8–1: Comparative antithrombotic effect at given time points following 
rivaroxaban 2.5 mg administration to subcutaneous enoxaparin doses ................ 41
Table 9–1: Schedule of assessments - amended....................................................................... 44
Table of figures
Figure 5–1:Study design - amended ........................................................................................ 27


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List of abbreviations - amended
Adapted via Amendment 4
ABI
Ankle-Brachial Index
ACCF
American College of Cardiology Foundation
ACCP
American College of Chest Physicians
ACS
Acute coronary syndrome
AE(s)
Adverse event(s)
AF
Atrial fibrillation
AHA
American Heart Association
ALI
Acute limb ischemia
ALT
Alanine transaminase
APCC
Activated Prothrombin Complex Concentrate
ARO
Academic Research Organization
ASA
Acetylic salicylic acid
AST
Alanine Aminotransferase
ATLAS ACS
Anti-Xa Therapy to Lower cardiovascular events in Addition to standard therapy 
in Subjects with Acute Coronary Syndrome trial
BARC
Bleeding Academic Research Consortium
BHC
Bayer HealthCare
bid
Bis in die (twice daily)
BMI
Body Mass Index
CABG
Coronary artery bypass graft
CAD
Coronary artery disease
CAPRIE
Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (trial)
CHARISMA
Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, 
Management, and Avoidance (trial)
CI
Confidence interval
CLI
Critical limb ischemia
COMPASS
Cardiovascular OutcoMes for People using Anticoagulation StrategieS (a 
randomized controlled trial of rivaroxaban for the prevention of major 
cardiovascular events in patients with coronary or peripheral artery disease)
CRF/eCRF
Case report form/electronic CRF
CRO
Contract Research Organization
CT
Computed tomography
CV
Cardiovascular
CVD
Cerebral Vascular Disease
CYP2C19
Cytochrome P450 isoenzyme 2C19
CYP3A4
Cytochrome P450 isoenzyme 3A4
DAPT
Dual anti-platelet therapy
DVT
Deep vein thrombosis
EC
Executive Committee
ECG
Electrocardiogram
EDC
Electronic Data Capturing
eGFR
estimated glomerular filtration rate


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EOT
End of treatment
EQ-5D
European Quality of Life-5 Dimensions questionnaire
ESC
European Society of Cardiology
EU
European Union
FDA
Food and Drug Administration
FXa
Clotting factor Xa
GCL
Global Clinical Leader
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HDL
High density lipoprotein
HDPE
High-density polyethylene
HbA1c
Glycosylated hemoglobin
HIV
Human Immunodeficiency Virus
HR
Hazard ratio
IB
Investigator's brochure
ICAC
Independent Central Adjudication Committee
ICF
Informed consent form
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
ISC
International Steering Committee
ISTH
International Society on Thrombosis and Haemostasis
ITT
Intent to treat
IxRS
Interactive web/voice response system
kg
kilogram
LDL
Low density lipoprotein
LMWH
Low molecular weight heparin
MDRD
Modification of Diet in Renal Disease (formula)
MedDRA
Medical Dictionary for Regulatory Activities 
mg
Milligram
MI
Myocardial infarction
mL
Milliliter
mmol
Millimole
MRI
Magnetic resonance imaging
NOAC
Non vitamin K antagonist oral anticoagulant
NSAID
Non-steroid anti-inflammatory drug
od
Once a day
OR
Odds ratio
P2Y12 
P2Y12 receptor antagonist (antiplatelet agent)
PAD
Peripheral artery disease
PBRER
Periodic benefit-risk evaluation report
PCI
Percutaneous coronary intervention


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PE
Pulmonary embolism
P-gp
P-glycoprotein
PS-FU
Post-study treatment follow-up visit
PSUR
Periodic safety update report
PV
Pharmacovigilance
QoL
Quality of life
REACH
Reduction of Atherothrombosis for Continued Health
RR
Relative risk
RxV
Randomization visit
SAE(s)
Serious adverse event(s)
SAP
Statistical analysis plan
SAS
Statistical analysis system
ScV
Screening visit
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SUSAR
Suspected unexpected serious adverse reaction
TBI
Toe-Brachial Index
TIA
Transient ischemic attack
TIMI
Thrombolysis in Myocardial Infarction (study group)
TOSCA
Tools for syntactic corpus analysis
TRA2P-TIMI
The Trial to Assess the Effects of vorapaxar in Preventing Heart Attack and 
Stroke in Patients With Atherosclerosis
UFH
Unfractionated heparin
UK
United Kingdom
US/USA
United States of America
VOYAGER PAD
Vascular Outcomes studY of ASA alonG with rivaroxaban in Endovascular or 
surgical limb Revascularization for peripheral artery disease (PAD)
VKA
Vitamin K Antagonist
VTE
Venous thromboembolism
WAVE
Warfarin and Antiplatelet Vascular Evaluation trial
WIQ
Walking Impairment Questionnaire
WHO
World Health Organization


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Definitions of medical terms - amended
Dropout
A patient who discontinues study participation 
prematurely for any reason, if the patient has already been 
randomized.
Endovascular procedure13
Refers to catheter-based and hybrid procedures (those 
procedures involving aspects of both endovascular and 
surgical revascularizations) for PAD.
Index leg14
Refers to the leg receiving the qualifying revascularization 
for randomization into this trial. 
Qualifying revascularization15
Refers to the procedure by which the patient qualifies for 
the study. 
Screening failure
A patient who, for any reason (e.g., failure to satisfy the 
selection criteria), terminates the study before 
randomization.
Study ASA
Refers to the background treatment with ASA 100 mg od.
Study medication
Refers to either rivaroxaban or placebo.
Successful procedure
Refers to qualifying revascularization (regardless of type 
of procedure that is considered:
1) a technical success with no immediate plan for re-
intervention and per the investigator’s discretion, the 
patient can safely be placed on an anticoagulant at the 
time of randomization and 
2) has demonstrated graft or vascular patency prior to the 
time of randomization.
Surgical procedure16
Refers to open surgical procedure in the lower extremity 
for PAD. This can include a variety of procedures, bypass 
conduit materials, and extra-anatomic operations.
                                                
13 Definition revised with Protocol Amendment 4 (change nos. 4 and 17) and Protocol Amendment 5 (see 
change no. 4).
14 Definition revised with Protocol Amendment 4 (change no. 7).
15 Definition revised with Protocol Amendment 4 (change no. 6).
16 Definition revised with Protocol Amendment 4 (change no. 4) and Protocol Amendment 5 (see change no. 4).


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3.
Introduction
3.1
Background - amended
Disease characteristics
PAD refers to the atherosclerotic obstruction of the major arteries supplying the lower 
extremities, sometimes also referred to as lower extremity artery disease. Atherosclerosis of 
the peripheral circulation, with underlying atheroma and chronic inflammation, leads to 
progressive occlusion of medium and large arteries, with additional risks of embolism or 
thrombus formation. Abrupt occlusions and plaque rupture may lead to acute complications 
such as acute limb ischemia (ALI), similar to an acute coronary syndrome in the coronary 
circulation [Becker et al. 2011].
Most recent estimates suggest that PAD has now reached pandemic proportion with more 
than 200 million people living with PAD in 2010, over 40 million in Europe and over 14 
million in North and South America. While the condition is generally uncommon in patients 
younger than 40 years of age, it affects one in 10 individuals aged 70 years or older and one in 
6 individuals aged 80 years or older [Fowkes et al. 2013]. In the United States alone, more 
than 8.5 million individuals are affected by this condition [Go et al. 2014].
Cardiovascular risks associated with PAD
It is now well established that symptoms, severity, and acuteness of PAD are major 
determinants of subsequent risk of cardiovascular (CV) events and mortality. Independent of 
symptoms, patients diagnosed with PAD are at an increased risk of subsequent myocardial 
infarction (MI) and stroke, and are 6 times more likely to die within 10 years than those 
without PAD [Criqui et al. 1992, Morris et al. 2014]. 
In the multinational, prospective Reduction of Atherothrombosis for Continued Health 
(REACH) registry, among the 53,211 symptomatic individuals with established coronary 
artery disease (CAD), cerebral vascular disease (CVD), or PAD, stable patients with PAD had 
a numerically higher risk of vascular death, MI, or stroke compared with stable patients with 
CAD at 1 year (5.4% vs. 4.5%) and at 3 years (14.8% vs. 11.6%) [Abola et al. 2012]. Patients 
with severe PAD requiring amputations are at even higher risk of CV complications [Abola et 
al. 2012, Jones et al. 2013]. Similarly, PAD patients requiring surgical revascularizations are 
at increased risk of CV complications, especially in the first year following the procedure. 
Patients treated surgically typically have more severe limb symptoms such as severe 
claudication, ischemic rest pain, and ischemic ulceration that has not responded to 
endovascular revascularizations [Moxey et al. 2011]. This is in addition to increased risk of 
perioperative MI and CV events often associated with vascular surgeries [Fleisher et al. 2014, 
Kristensen et al. 2014]. Even among the less invasive endovascular procedures, in-hospital 
CV complications and mortality remain high [Vogel et al. 2011].
Ischemic limb risks associated with PAD
The most common initial symptom from underlying progressive atherosclerotic occlusion of 
the peripheral vasculature is leg pain on exertion or intermittent claudication. In patients with 
more severe disease, critical limb ischemia (CLI) can present with pain at rest, ulceration, 
tissue loss, and/or non-healing ulcers and gangrene. The incidence of CLI is estimated to be 


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approximately 500 to 1000 new cases per year per million people, with significant growth 
expected due to aging of the population and the increased prevalence of diabetes [Fowkes et 
al. 2013, Tendera et al. 2011]. Patients diagnosed with CLI are at increased risk of major 
amputation, impaired physical function, and a marked reduction in the quality of life [Abola 
et al. 2012, Mangiafico and Mangiafico 2011]. More acutely, PAD patients may present with 
acute atherothrombotic occlusions resulting in ALI, a condition marked by a sudden decrease 
in limb perfusion that threatens the immediate viability of the affected limb.
Historically, 1-year mortality among CLI patients is approximately 10%, with loss of limb 
around 20% without revascularization [Conte et al. 2009]. However, even with 
revascularization, ALI and CLI patients remain at risk of subsequent need for amputation and 
death [de Donato et al. 2006, Goodney et al. 2010]. In a recent analysis that evaluated all 
admissions for lower extremity thromboembolism (1.76 million cases) resulting either from 
ALI or acute exacerbation of CLI over a 20-year period in the National Hospital Discharge 
Survey from 1998 to 2007, while there was notable improvement in outcomes, in-hospital 
mortality remained high at approximately 6%, with overall in-hospital amputation rate at 
approximately 7% [Korabathina et al. 2013].
3.2
Drug management of PAD
Use of antiplatelet drugs in PAD
While ASA remains the cornerstone therapy and the most recommended treatment for the 
secondary prevention of atherothrombotic events, its efficacy has been increasingly 
questioned [Anderson et al. 2013, Baigent et al. 2009, Berger et al. 2009, Tendera et al. 2011, 
Wong and White 2011, Wong et al. 2013]. The benefits of clopidogrel compared with ASA, 
as observed in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events 
(CAPRIE) trial (n=19,185), appeared modest at best in the overall cohort, with an 8.7% 
relative risk (RR) reduction of composite outcomes of ischemic stroke, MI, or vascular death 
at 3 year (p=0.043). Interestingly, observed benefits were not consistent across the subgroups 
of CAD, CVD, and PAD, with the efficacy driven primarily by those PAD patients with a 
history of MI [CAPRIE-Steering-Committee 1996]. In the subsequent Clopidogrel for High 
Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance 
(CHARISMA) trial (n=15,603), when clopidogrel was added to ASA, not only were 
additional benefits not observed in the overall trial, but also benefits were not reproduced in 
the PAD group [Bhatt et al. 2007, Bhatt et al. 2006, Cacoub et al. 2009]. As a result, 
clopidogrel use in PAD is largely limited as a single agent, an alternative to ASA, while
benefits of dual antiplatelet therapy (DAPT) have not been confirmed, particularly since 
CHARISMA was a negative trial. Monotherapy of clopidogrel, as a therapeutic option in 
PAD patients is further complicated by recent revelations about interactions with proton pump 
inhibitors such as omeprazole or esomeprazole and Cytochrome P450 isoenzyme 2C19
(CYP2C19) polymorphism [Wedemeyer and Blume 2014].
Most recently, in the TRA2°P-TIMI 50 trial, vorapaxar (a novel antiplatelet agent) added to 
standard of care that included ASA and clopidogrel was associated with an overall 13% RR 
reduction of composite outcomes of CV death, MI, or stroke, but at a cost of a significant 
increase in moderate or severe bleeding including intracranial hemorrhage. Among the subset 
of patients whose qualifying diagnosis was PAD (n=3,787), no significant treatment effect 


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was observed (Hazard Ratio [HR]: 0.94; 95%-CI: 0.78 to 1.14; p=0.53) while moderate or 
severe bleeding was significantly increased (HR: 1.62; 95%-CI: 1.21 to 2.18; p=0.001) along 
with a trend toward increase in intracranial hemorrhage [Bonaca et al. 2013, Morrow et al. 
2012]. Interestingly, in a post-hoc exploratory analysis, vorapaxar significantly reduced the 
risk of limb ischemic events, including hospitalization for acute limb ischemia (2.3% vs. 
3.9%; HR: 0.58; 95%-CI: 0.39 to 0.86; p=0.006) and peripheral revascularization (18.4% vs. 
22.2%; HR: 0.84; 95%-CI: 0.73 to 0.97; p=0.017). These findings confirmed for the first time 
that these limb events are likely thrombotic in nature and are potentially modifiable by 
antithrombotics.
Use of anticoagulants in PAD
Anticoagulants such as warfarin or phenprocoumon alone or in combination with single 
antiplatelet therapy are effective for the secondary prevention of CV events in patients with 
CAD, but at the cost of increased bleeding [Anand and Yusuf 2003, Andreotti et al. 2006, 
Smith et al. 2011].
In the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial, 2,161 patients with lower 
extremity and carotid atherosclerotic vascular disease were randomized to antiplatelet therapy 
alone (ASA) versus antiplatelet therapy plus full dose warfarin (target INR 2.0-3.0) [Anand et 
al. 2007, WAVE-Investigators 2006]. Over 80 % of the patients had PAD (intermittent 
claudication plus objective evidence of atherosclerosis). There was no reduction in the 
primary outcome of CV death, MI, or stroke, or the co-primary outcome which included CV 
death, MI, Stroke, and severe coronary or limb ischemia requiring urgent intervention. 
Importantly, there was a 3.5-fold increase in life-threatening bleeding in the warfarin plus 
ASA group vs. ASA alone, including an excess of intracranial hemorrhage.
Since the potential benefits of vitamin K antagonists (VKA) are often offset by increased 
bleeding, especially in PAD patients, there is a Grade 1A recommendation in the American 
College of Chest Physicians 2008 guidelines against the use of anticoagulants in patients with 
PAD [Sobel and Verhaeghe 2008], and Grade 1B recommendation against its use in PAD 
[ACCP 2012 guidelines]. Nevertheless, there may be a limited role for VKA in improving 
outcomes following infra-inguinal bypass surgeries, and the ESC guideline on the 
management of PAD has a Class IIb recommendation for anticoagulation with VKAs 
following autologous infrainguinal bypass based on a subgroup analysis of the DUTCH 
Bypass Oral Anticoagulants or Aspirin trial [Tendera et al. 2011].
Use of revascularization procedures in PAD
Revascularization (either endovascular or surgical) is the treatment of choice in symptomatic 
patients who are suitable candidates based on clinical history, presentation (e.g., ALI or CLI), 
and target lesions, as described in the Trans-Atlantic Inter-Society Consensus Document II 
[Norgren et al. 2007]. With the advent of improved technology and wide-spread accessibility, 
endovascular therapy is fast becoming the first-line treatment. Given the sequential nature of 
these procedures, surgical patients today are generally sicker and have more severe disease. 
Clinical failures in endovascular therapy also remain high because less ideal or high risk 
patients are offered at least a trial of the less invasive endovascular treatment. In terms of 
concomitant treatment, the endovascular patients are more likely to be on short term (1 
month) empiric DAPT. Because of this potential difference in natural history and therefore 


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event rates, type of procedure (endovascular or surgical) is proposed as a stratification factor 
in the present study.
Current treatment guidelines for patients with PAD
At present, due to paucity and low quality of data, the international guidelines of the 
ACCF/AHA [Anderson et al. 2013] and ESC [Tendera et al. 2011] are divergent regarding 
their recommendations on optimal antithrombotic therapy in PAD patients, with 
recommendations often extrapolated from studies from patients with stable CAD or ACS, or 
from expert opinions. For the primary prevention of cardiovascular events, low-dose ASA 
(dose range 75 mg/day to 150 mg/day) is the treatment of choice (Class IA), while clopidogrel 
(75 mg/day) may be an alternative. ACCP 2012 CHEST guidelines recommend single 
antiplatelet use over DAPT post angioplasty and stent in PAD [Alonso-Coello et al. 2012].
For antithrombotic therapy following interventions, DAPT or ASA plus clopidogrel is often 
used for a period of one month after infra-inguinal implantation of a bare-metal stent or in 
case of below-knee bypass with a prosthetic graft. After revascularization procedures, 
antithrombotic therapy with ASA is generally recommended; a combination with ASA and 
dipyridamole could be considered after infra-inguinal bypass surgery. VKAs are generally not 
recommended except in the case of bypass graft surgery when a native conduit is used, but 
this recommendation is controversial (Class IIb; ESC only).
Summary of currently unmet medical needs
Overall, the currently available treatment options for PAD and evidence-based knowledge on 
certain patient subsets are suboptimal. Given that the prevalence of conventional 
cardiovascular risk factors for PAD is increasing, it is likely that the incidence of PAD would 
grow even more dramatically overtime. The loss of mobility, functional decline, and 
cardiovascular events, represents a major public health challenge. New and effective 
treatments are urgently needed to reverse these trends [Biancari 2013, Fowkes et al. 2013].
3.3
Rationale of the study
Given its effectiveness across a broad spectrum of arterial and venous conditions, rivaroxaban 
has the potential to reduce the burden of a number of thrombosis-related conditions, and to be 
more effective than prior therapies such as VKAs or aspirin at preventing thrombotic vascular 
events of a cardiovascular and peripheral vascular nature. Rivaroxaban's mechanism of action, 
its predictable dose response, its clinically proven anti-ischemic and antithrombotic benefits 
and its demonstrated beneficial effects on the prevention of stent thrombosis, suggest that it 
will impact both the traditional coronary outcomes such as CV death, MI, and stroke, and 
peripheral vascular events such as major amputation and ALI, often associated with early or 
late procedural failures. Thus, rivaroxaban seems promising for the prevention of coronary 
atherothrombotic events as well as peripheral vascular events in symptomatic PAD patients 
who are undergoing peripheral revascularization procedures.
The hypothesis of the present study is that rivaroxaban, when compared to placebo, additional 
to standard of care therapy using low-dose ASA, has the potential to reduce the incidence of 
the traditional CV outcomes (i.e., CV death, MI, and stroke) as well as lower limb vascular 
events, such as ALI and major amputation also in the critical population of symptomatic PAD 
patients requiring lower extremity revascularization procedures.


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3.4
Benefit/risk assessment
Currently available treatment options have been inadequately evaluated and appear 
insufficient to address the thrombotic complications observed in this distinct population, i.e. 
PAD patients with a recent lower extremity revascularization procedure. Thus, the potential 
reduction of major thrombotic events by rivaroxaban is of clinical importance and this 
research substantially contributes to the knowledge and treatment optimization in these 
critically ill patients who require lower extremity revascularization procedures.
The choice of standard of care therapy in this study (administered to all study patients) takes 
into account the current practice and guideline recommendations to allow the use of ASA 
alone or in transient combination with clopidogrel. In this specific population of patients who 
have undergone peripheral revascularization procedures, the study mandates the use of ASA 
in all patients, with the additional clopidogrel for dual antiplatelet therapy permissible (at the 
discretion of the investigator).
All study efficacy endpoints are clinically meaningful, have been developed and composed on 
a solid scientific basis, and are established measures in clinical trials. In order to ensure 
consistent and valid data evaluation, an ICAC will review and adjudicate all potential study 
endpoints at regular intervals.
Inherently, the prevailing risk on treatment with rivaroxaban is bleeding, which is a 
recognized complication shared by all anticoagulants. However, patients enrolled in the 
present study will be closely monitored for the occurrence of bleeding events including peri-
procedural bleedings. An IDMC will regularly evaluate for any imbalances between groups 
with a focus on peri-procedural bleedings. 
The safety profile of rivaroxaban is based on an extensive database of safety information 
collected in a substantial clinical development program, which has enrolled as of Sep 2015 
more than 108,000 subjects have been enrolled in interventional clinical trials (completed and 
ongoing Phase I, Phase II, Phase III and Phase IV) including more than 60,000 subjects 
treated with rivaroxaban. In addition, the steadily amassing post-marketing data summarized 
in numerous Periodic Safety Update Reports (PSURs)/Periodic Benefit-Risk Evaluation
Reports (PBRERs), corresponding to an estimated cumulative patient exposure of 3.7 million 
patient years, provides further reassurance about rivaroxaban benefit-risk balance in the real-
life setting. In conclusion, no undue safety risks are expected from the interventional drug 
treatment with rivaroxaban in the present study. Further details can be found in the latest 
available version of the investigator's brochure, which contains comprehensive information on 
the study drug.17
Overall, it is believed that the potential benefits for both participating patients and society 
clearly outweigh the potential harm that could arise from participation in this study. 
Complementary to the ongoing COMPASS study of over 21,000 patients with a history of 
CAD or PAD, in which outcomes of treatment with rivaroxaban 5 mg bid vs rivaroxaban 
2.5 mg bid and ASA 100 mg od vs aspirin 100 mg od in stable PAD patients are currently 
being investigated, the present VOYAGER study is expected to help gain deeper insight into 
                                                
17 Sentence was added with Protocol Amendment 4 (change no. 16).


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the natural history of PAD and help to optimize treatment in symptomatic PAD patients 
undergoing lower extremity revascularization procedures.
4.
Study objectives - amended
The primary efficacy objective of the study is:

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of major thrombotic vascular events (defined as MI, ischemic stroke, CV
death, ALI, and major amputation of a vascular etiology) in symptomatic PAD 
patients with a recent lower extremity revascularization procedure.
The primary safety objective of the study is:

to evaluate the overall safety and tolerability of rivaroxaban added to ASA compared 
to ASA alone.
The secondary efficacy objectives of the study are:

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of MI, ischemic stroke, coronary heart disease mortality, ALI, and major 
amputation of a vascular etiology;

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of an unplanned index limb revascularization for recurrent limb ischemia
(subsequent index leg revascularizations that were not planned or considered as part of 
the initial treatment plan at the time of randomization);18

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of vascular hospitalizations for a coronary or peripheral event (either limb) of 
a thrombotic nature;

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of MI, ischemic stroke, all-cause mortality, ALI, and major amputation of a 
vascular etiology;

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of MI, all-cause stroke, CV death, ALI, and major amputation of a vascular 
etiology;

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of all-cause mortality.

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of venous thromboembolic (VTE) events19.
                                                
18 Text revised with Protocol Amendment 4 (change no. 8) and Protocol Amendment 5 (see change no. 2).
19 The last 2 secondary objectives were revised with Protocol Amendment 4 (change no. 17)


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5.
Study design - amended
This study is an international multicenter, randomized, placebo-controlled, double-blind, 
event-driven phase 3 study.
Following provision of informed consent, patients who fulfill all inclusion criteria and meet 
none of the exclusion criteria will be treated with ASA 100 mg od20 and randomly allocated 
by an interactive voice/web response system (IxRS) in a ratio of 1:1 to additional treatment 
with either rivaroxaban 2.5 mg or placebo bid (see Figure 5–1). The randomization will be 
stratified by type of procedure and use of clopidogrel (i.e., (i.) surgical vs. (ii.) endovascular 
with clopidogrel vs. (iii.) endovascular without clopidogrel), and treatments will be balanced 
within a country for each stratum by block randomization. Randomization and study treatment 
should commence as soon as possible but no later than 10 days21 after a successful qualifying 
revascularization procedure and once hemostasis has been assured. All randomized patients 
will receive study medication (either rivaroxaban or placebo) and study ASA in a sufficient 
quantity until the next scheduled on-site visit and detailed instructions for its administration.
The first study visit is a screening visit to be performed within 30 days prior to or no more 
than 10 days after the qualifying revascularization. The second study visit is the 
randomization visit (randomization will be assigned as T0 on the time axis). The first study 
drug dose should be administered as close to the time of the randomization visit as possible
(See Section 7.4 for additional guidance on dosing at randomization). The screening and 
randomization visits can be combined into one visit if all tests required for the assessment of 
all eligibility criteria are available and randomization and dosing can be performed on a single 
day.22
The subsequent on-site study visits at the investigational study site will be completed at 1, 3, 
6, and 12 months (Visits 1-4) after T0, and then every 6 months after Visit 4 until the EOT 
visit.
The study is event-driven, and thus, all patients will be treated (or followed-up in the case of 
permanent discontinuation of study medication) until the EOT visit. It is estimated that 
approximately 6,500 patients (3,250 per treatment group) are needed to be enrolled in order to 
have 1,015 patients experiencing a positively-adjudicated primary efficacy outcome event (for 
underlying statistical assumptions see Section 10.4). However, this duration may vary 
depending on the recruitment rate as well as the primary event rate. Due to the event-driven 
study design, no firm treatment duration can be stipulated for an individual patient. However, 
the estimated maximum treatment period for an individual patient is approximately 42 
months, and the mean treatment duration is expected to be approximately 30 months.
The EOT visit will be performed as soon as possible after announcement of study end or upon 
individual premature termination of the study. All efforts must be taken to engage patients 
to continue to be followed until the end of the trial preferably by regular site visits, or at 
                                                
20 In the following, the background treatment with ASA 100 mg/day will be referred to as "study ASA".
21 Prior to Protocol Amendment 4, “10 days” was “7 days” (change no. 2).
22 Paragraph modified with Protocol Amendment 4 (changes no. 3 and 17).


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least by phone contacts, see Section 6.3.1. In all patients, a telephone post-study treatment 
follow-up visit will be performed one month after the EOT visit.
Patients who have discontinued study drug treatment prematurely will continue to be followed 
according to the regular visit schedule, and study efficacy outcome events, bleeding events, 
and vital status must be assessed in these patients until the end of the study via either clinic 
visits or telephone contacts (see Section 6.3.1).
Throughout the study and at all on-site visits, patients will be assessed for the occurrence of 
study efficacy outcome events and bleeding events. All events including study efficacy 
outcome, bleeding, and AEs/SAEs meeting the study-specific definitions will be recorded 
once informed consent (ICF) has been signed and until the post-study treatment follow-up 
visit. Suspected clinical study outcomes (study efficacy outcome and bleeding events) will be 
assessed independently by an Independent Clinical Adjudication Committee (ICAC) blinded 
to treatment allocation, and the adjudication results will be the basis for the final study 
analyses. In addition, an Independent Data Monitoring Committee (IDMC) will monitor 
patient safety during the study and give recommendations to the Executive Committee (EC).
There will be one formal interim analysis, which will occur when approximately 67% of the 
planned primary efficacy outcomes have accrued and adjudicated.
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit of the last patient for all centers in the respective 
country has occurred. However, as the primary efficacy outcome of this study is event-driven 
and requires adjudication by an ICAC, the end of the study as a whole will only be reached 
when the last efficacy outcome event has been adjudicated for patients from all participating 
clinical sites (EU and non-EU).
The primary completion date for this study according to the FDA Amendment Act is specified 
in a separate document (not part of this study protocol).
Figure 5–1: Study design - amended23
                                                
23 Figure updated with Protocol Amendment 4 (changes nos. 2 and 3)


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6.
Study population
The study population consists of symptomatic PAD patients of either sex at the age of at least 
50 years that have had an endovascular or surgical revascularization. Patients who will be 
enrolled in this study must meet all of the inclusion criteria and none of the exclusion criteria 
listed in the following Section 6.1 and Section 6.2, respectively.
6.1
Inclusion criteria - amended
1.
Age ≥50 years;
2.
24Documented moderate to severe symptomatic lower extremity atherosclerotic 
peripheral artery disease as evidenced by ALL of the following:
a.
clinically, by functional limitations in walking activity, ischemic rest pain, or 
ischemic ulceration,
b.
anatomically, by imaging evidence of peripheral artery disease distal to the external 
iliac artery in the index leg within 12 months prior to or at the time of the 
qualifying revascularization
AND
c.
hemodynamically in either leg (within 12 months prior to, or at the time of, the 
qualifying revascularization) by:

an ABI ≤ 0.80 or TBI ≤ 0.60 for patients without a prior history of limb 
revascularization,
OR

an ABI ≤ 0.85 or TBI ≤ 0.65 for patients with a prior history of limb 
revascularization;
3.
Technically successful peripheral revascularization distal to the external iliac artery 
(surgical and/or endovascular; for definition see Section 9.3.3) for symptomatic PAD 
within the last 10 days prior to randomization25;
4.
Written informed consent by patient or his/her legal representative;
5.
Patient understands and is willing and able to comply with the study instructions and 
follow-up visit;
6.
Negative serum pregnancy test (in women of childbearing potential only);
                                                
24 Inclusion criterion 2 revised with Protocol Amendment 4 (changes no. 4,5 and 20a, b, c)
25 Inclusion criterion 3 revised with Protocol Amendment 4 (changes no. 2 and 4).


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7.
26Women of reproductive potential must agree to use adequate contraception* when 
sexually active. This applies for the time period between signing of the informed 
consent form (ICF) to the last administration of study drug.
(*The definition of adequate contraception [with a failure rate of less than 1% per 
year] will be based on the judgment of the investigator and on local requirements. 
Acceptable methods of contraception include, but are not limited to: oral 
contraceptives, contraceptive injections, intrauterine device, double barrier method, 
male partner sterilization
6.2
Exclusion criteria - amended
- Exclusion criteria related to PAD:
1. Patients undergoing revascularization for asymptomatic PAD or mild claudication 
without functional limitation27 of the index leg
2. Patients undergoing revascularization of the index leg to treat an asymptomatic or 
minimally symptomatic restenosis of a bypass graft or target lesion restenosis;
3. Prior revascularization on the index leg within 10 days28 of the qualifying 
revascularization;
4. Acute limb ischemia (ALI) within 2 weeks prior to the qualifying revascularization.
5. Patients with major tissue loss (defined as significant ulceration/gangrene proximal to 
the metatarsal heads, i.e. heel or midfoot)29 in either leg;
- Exclusion criteria related to concomitant and study treatment:
6. Patients requiring treatment with ASA at doses >100 mg;
7. Planned dual antiplatelet therapy (DAPT) use for the qualifying revascularization 
procedure of clopidogrel in addition to ASA for >6 months after the qualifying 
revascularization procedure; it is strongly recommended that any course of clopidogrel is 
kept to the minimum necessary in accordance with local standard of care and 
international practice guidelines (typically 30 days, or up to 60 days  for some drug-
coated products or devices), and is only allowed for up to 6 months for complex 
procedures or devices that in the investigator’s opinion require longer use; see 
section 8.1 for further guidance on clopidogrel; 30
8. Planned*use of any additional antiplatelet agent other than clopidogrel and ASA after 
the qualifying revascularization procedure
(*This exclusion criterion refers to the clinical condition at the time of randomization. 
                                                
26 Inclusion criterion 7 revised with Protocol Amendment 4 (change  no. 21)
27 Exclusion criterion 1 revised with Protocol Amendment 4 (change no. 15)
28 Exclusion criterion 3 revised with Protocol Amendment 4 (change no. 7).
29 Exclusion criterion added with Protocol Amendment 4 (change no. 15)
30Exclusion criterion 7 revised with Protocol Amendment 4 (change no. 17) and Protocol Amendment 5 (change 
no. 3).


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The use of DAPT with ASA plus clopidogrel, for new indication(s) occurring after 
randomization is permitted); 31
9. Any active clinical condition requiring systemic anticoagulation after the qualifying 
revascularization;
10. Hypersensitivity or any other contraindication listed in the local labeling for ASA or 
rivaroxaban;
11. Systemic treatment with strong inhibitors of both Cytochrome P450 isoenzyme 3A4 
(CYP3A4) and p-glycoprotein (P-gp) inhibitors (e.g., systemic azole antimycotics, such 
as ketoconazole [fluconazole is permitted], and human immunodeficiency virus [HIV]-
protease inhibitors, such as ritonavir), or strong inducers of CYP3A4 (e.g., rifampicin, 
rifabutin, phenobarbital, phenytoin and carbamazepine) anticipated after randomization 
or during the study. 31
- Exclusion criteria related to bleeding risks or systemic conditions:
12. Medical history or active clinically significant bleeding, lesions, or conditions within the 
last 6 months prior to randomization, considered to be a significant risk for major 
bleeding (this may include current medically confirmed gastrointestinal ulceration, 
presence of malignant neoplasms at high risk of bleeding, current or recent brain or 
spinal injury, known esophageal varices, vascular aneurysms of the large arteries or 
major intraspinal or intracerebral vascular abnormalities32);
13. Any known hepatic disease associated with coagulopathy or bleeding risk;
14. Any condition requiring dialysis or renal replacement therapy, or a renal impairment at 
screening assessed with an estimated glomerular filtration rate <15 mL/min/1.73 m2*
(*if a patient's eGFR is <30 mL/min/1.73 m2 prior to the procedure, it must remain to be 
>15 mL/min/1.73 m2 72 hours after the procedure to enroll and randomize the patient);
31
15. Confirmed acute coronary syndrome (ACS) within 30 days prior to randomization;
16. Major trauma or accidents within 30 days prior to randomization;
17. Any medically documented history of intracranial hemorrhage, stroke, or transient 
ischemic attack (TIA);
18. Known active malignancy (as determined through review of medical history), excluding 
local skin cancer (basal or squamous cell carcinoma);
19. Poorly controlled diabetes (at the discretion of the investigator);
20. Severe uncontrolled hypertension (at the discretion of investigator);
21. Overall life expectancy < 1 year.
- Other exclusion criteria:
                                                
31Exclusion criteria modified via Protocol Amendment 5 (change no. 7).
32Exclusion criterion 12 revised with Protocol Amendment 4 (change no. 17).


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22. Previous assignment to treatment during this study;
23. Previous (within 30 days) or concomitant participation in another clinical study with 
investigational33 product (s);
24. Close affiliation with the investigational site; e.g., a close relative of the investigator, 
dependent person (e.g., employee or student of the investigational site).
25. Breast feeding34
6.3
Discontinuation of study medication by subjects and withdrawal 
criteria
6.3.1
Discontinuation and withdrawal - amended
An excessive rate of patient discontinuations from either treatment or "dropouts" from the 
study may render the trial uninterpretable. In this trial, ascertainment of study efficacy 
outcome events, bleeding events, and vital status data are crucial to the primary analysis and 
must be collected until the end of the study, even if patients are no longer taking study 
medication. Therefore, all efforts must be taken to engage patients to comply with all 
study procedures and to continue to be followed until the end of the trial. Additionally, 
study medication compliance will be assessed as defined in Section 7.7.
Patients must be withdrawn from study drug, if any of the following occurs:

at their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons (even though providing a reason is 
encouraged), a patient may decline to participate further. The patient will not suffer 
any disadvantage as a result,

pregnancy,
Patients may be withdrawn from study drug, if any of the following occurs35:

if, in the investigator's opinion, continuation of the study drug would be harmful to the 
patient's well-being (e.g. significant decline in cognitive function or renal failure with 
eGFR<15 mL/min/1.73 m2),

at the specific request of the sponsor and in liaison with the investigator (e.g., safety 
concerns).
Depending on the time point of withdrawal, a withdrawn patient is referred to as either 
“screening failure” or “dropout” as specified below:
Screening failure: a patient who, for any reason (e.g., failure to satisfy the selection criteria), 
terminates the study before randomization.
Dropout: a patient who discontinues study participation prematurely for any reason, if the 
patient has already been randomized. 
                                                
33 Exclusion criterion 23 revised with Protocol Amendment 4 (change no. 17)
34 Exclusion criterion 25 added with Protocol Amendment 4 (change no. 18)
35 Sentence was added with Protocol Amendment 4 (change no. 16).


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Reasons for discontinuing study medication should be solicited and documented. Study 
medication or study ASA will not be routinely discontinued in patients reaching a 
potential primary efficacy event unless there is a safety concern or a clear indication for 
an alternative antithrombotic therapy, as determined by the local investigator.
If study medication and/or study ASA will be temporarily interrupted or permanently 
discontinued, the investigator will document the reason on the electronic case report form 
(eCRF), and if applicable in the patient’s medical records/source documents. The study 
medication and/or study ASA will be restarted as soon as medically justified (in the opinion 
of the investigator). There is no defined maximum limit for temporary treatment interruption, 
however, the date of temporary treatment discontinuation, date of re-starting treatment and the 
reason for temporary discontinuation will be documented in the eCRF.
All patients who permanently discontinue study medication and/or study ASA and have 
not withdrawn consent will remain in the study, and are expected to complete all on-site 
study visits as originally scheduled. If a patient permanently discontinues study medication 
and is unwilling or unable to attend regular study visits at the study site, the investigator and 
patient must determine which of the follow-up options the patient is able and willing to 
comply with. The patient will be approached to provide consent for further follow-up at the 
time of withdrawal. Options for follow-up of these patients are listed below, in descending 
order of preference:
1. Patient will be contacted by phone at the regular study visit intervals.
2. Patient allows his/her general practitioner (with a signed release of medical 
information) or a family relative to be contacted (if allowed in respective country) at 
the regular study visit intervals.
3. Patient will be contacted once at the end of the study.
4. No further contact.
For patients who withdraw consent for any kind of follow-up, the patient’s vital status will be 
obtained at study end through applicable information sources according to local guidelines 
and as allowed by local regulations. In all cases, the reason for withdrawal must be recorded 
in the eCRF and in the patient's medical records.
If a patient fails to return for a study visit or is suspected to be lost to follow-up, the 
investigator should explore all possible options to contact the patient. The investigator should 
ask the patient at the time of enrollment for the contact details of an alternate contact (e.g.,
relative or friend) in case the patient cannot be reached. The site must document all attempts 
to try to contact the patient and alternate contact in the medical records/source documents. If 
all attempts fail (depending on local legislation), publically available information such as 
death registries or other registries may be accessed or private investigation to locate a patient
may be initiated.
Any patient removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable.
6.3.2
Replacement
No patient replacements are permitted in this study.


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6.4
Subject identification
Each patient will be allocated a unique patient identification number after informed consent is 
obtained, and an additional randomization number will be assigned by IxRS at the time of 
randomization. This randomization number will allow subsequent identification of treatment 
allocation.
The patient number is a 9 digit number consisting of:
Digits 1 to 2 
=  Country code
Digits 3 to 5
=  Center number within the country
(Digits 1 to 5
=  Trial unit)
Digits 6 to 9
=  Current patient number within the center
7.
Treatments
7.1
Treatments to be administered - amended
Study treatment assignment will be double-blind. Study treatment consists of study 
medication (rivaroxaban or matching placebo) in addition to study ASA, which is also 
dispensed by the study. Eligible study patients will be randomized in a ratio of 1:1 to one of 
the 2 following treatment arms:
Rivaroxaban group:
Rivaroxaban 2.5 mg bid (5 mg/day, immediate-release film-coated tablets for oral 
administration)
+
ASA 100 mg od (enteric coated tablets for oral administration)
Reference group:
Rivaroxaban-matching placebo bid (tablets for oral administration)
+
ASA 100 mg od (enteric coated tablets for oral administration)
In either treatment group, post-procedural concomitant treatment with clopidogrel will be 
allowed as described in section 8.1.36
The estimated mean treatment duration will be 30 months (maximum treatment duration 
42 months) in either treatment arm.
7.2
Identity of study treatment
Study medication and study ASA will be labeled according to the requirements of local law 
and legislation. Label text will be approved according to the Sponsor's agreed procedures, and 
a copy of the labels will be made available to the study site upon request.
                                                
36 Text revised with Protocol Amendment 4 (change no. 17)


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For all study medication and study ASA, a system of numbering in accordance with all 
requirements of Good Manufacturing Practice (GMP) will be used, ensuring that each dose of 
study medication and study ASA can be traced back to the respective bulk batch of the 
ingredients. Lists linking all numbering levels will be maintained by the Sponsor's Quality 
Assurance group.
A complete record of batch numbers and expiry dates of all study medication and study ASA 
as well as the labels will be maintained in the Sponsor's study file.
7.3
Treatment assignment - amended
Allocation to treatment arms will be done centrally by IxRS. Allocation will be performed in 
a ratio of 1:1 to each study treatment arm and will be stratified in one of 3 strata by:

surgical revascularization,

endovascular revascularization with clopidogrel,

endovascular revascularization without clopidogrel.
Given potential differences in natural history resulting from procedure type, variation in 
medical practice, and concomitant therapy that may affect treatment outcome.
The clopidogrel use defining the randomization strata refers to actual clopidogrel use, at 
randomization, as adjunct treatment for the qualifying revascularization. 37 Specific 
procedures for treatment assignment through the IxRS will be described in the IxRS manual.
7.4
Dosage and administration - amended
Patients will be provided with high-density polyethylene (HDPE) bottles containing 
immediate-release film-coated tablets of study medication rivaroxaban 2.5 mg (or matching 
placebo) and HDPE bottles containing enteric-coated tablets of study ASA 100 mg. The dose 
amount distributed per on-site visit will be sufficient to cover a period of between the study 
visits at the investigational site.
All study medication treatments will be taken orally. Study medication (rivaroxaban or 
placebo) will be taken twice daily (generally in the morning and in the evening, 
approximately 12 hours apart) and study ASA will be taken once daily, generally in the 
morning.
If a dose of study medication 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 or placebo should be taken according to schedule. A missed dose from a previous 
calendar day should not be taken with the current dose.
For patients using a parenteral anticoagulant, the timing of the first dose of study medication 
administration should be no sooner than: 2 hours after final dose bivalirudin, 4 hours after 
final dose of intravenous unfractionated heparin, eptifibatide, or tirofiban, 12 hours after final 
                                                
37 Text modified via Protocol Amendment 5 (change no. 7)


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dose of other intravenous or subcutaneous anticoagulants (e.g., enoxaparin, dalteparin) and 
24 hours after final dose of abciximab or fondaparinux. Depending on the patient and the 
clinical setting, initiation of study medication in a patient with low risk of bleeding, who is on 
low dose subcutaneous anticoagulants sooner than 12 hours may be appropriate and 
permissible (consult Study Helpline).
Clopidogrel (at a dose that is consistent with the site/country’s standard of care) may be used 
at the discretion of the investigator, as described in Section 8.1.38
7.4.1
Dose modifications
The investigator should interrupt study medication and/or study ASA for a given patient if 
continuation is deemed to be detrimental to the patient’s well-being. All patients who 
interrupt study medication and/or study ASA should resume treatment when possible. If there 
is concern that the patient may be intolerant of study treatments or if the patient is reluctant to 
take the full dose of study medication, a possible approach to restarting study medications is 
to reduce the frequency of dosing to once-daily or alternate-daily.
Irrespective of whether or not treatment is resumed, all patients must be followed according to 
the study protocol until the end of the study. Permanent study drug discontinuation should be 
recorded on the eCRF, giving the date and primary reason for stopping the study medication 
and/or study ASA. If one of the study treatments needs to be interrupted, other study 
treatments should be continued. For example, if study medication is interrupted, study ASA 
should be continued.
This section provides a general guide for investigators on the management of patients who 
develop intercurrent illnesses or bleeding during the course of the study. The guidance 
provided in this section does not replace clinical judgment nor usual care in determining the 
appropriate management strategy for individual patients.
The following sections provide general guidance for use of rivaroxaban. For use of ASA, 
please refer to applicable guidelines and local production information. 
7.4.2
Guidance for the treatment of subjects who require an invasive 
procedure
If a patient 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 medication must be 
interrupted.
Dosing recommendations before and after invasive procedures and surgical intervention
If an invasive procedure or surgical intervention is required, study medication should be 
stopped at least 12 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. Study medication 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.
                                                
38 Text revised with Protocol Amendment 4 (change no. 17)


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7.4.3
Guidance for the treatment of subjects who require coronary artery 
bypass graft (CABG) surgery – amended
Patients who are scheduled for CABG surgery during the course of the trial, ideally should 
interrupt study medication at least 12 hours before coronary artery bypass graft surgery in 
order to minimize the risk of bleeding.
Study medication may be interrupted and/or non-study ASA may be used at the discretion of 
the investigator. The timing of resumption of study medication after surgery is at the 
discretion of the investigator but, in general, study medication or study ASA should be 
resumed once the chest tubes are removed and hemostasis is assured. Study medication 
should be interrupted if patients require systemic anticoagulation.39 In all cases, the goal 
should be to resume study medication as soon as it is clinically warranted prior to being 
discharged from the hospital.
7.4.4
Guidance for the treatment of subjects who develop an acute coronary 
syndrome and those who require percutaneous coronary intervention 
with stenting - amended
40 Study medication should be temporarily interrupted in patients who require anticoagulant 
or DAPT because of an ACS event or for percutaneous coronary intervention (PCI) with 
stenting. Peri-procedurally, standard antiplatelet therapy, including ASA and clopidogrel (or 
other P2Y12 antagonists such as prasugrel or ticagrelor) can be administered according to 
usual practice. Study ASA may be continued. Standard anticoagulant therapy can be initiated
without regard to the timing of the most recent dose of study medication because the dose of 
rivaroxaban being tested in this trial is significantly lower than the 15 or 20 mg dose 
administered for stroke prevention in non-valvular atrial fibrillation and the half-life of 
rivaroxaban is short, only 5-13 hours.
Following the procedure, the decision and timing to resume study medication are at the 
discretion of the treating physician and the investigator. If medically indicated, study 
medication may be used along with DAPT with clopidogrel as described in section 8.1, or 
interrupted until patient no longer requires DAPT.
7.4.5
Guidance for the treatment of subjects who overdose on study 
medication
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 patients.
7.4.6
Guidance for the treatment of subjects who experience a major bleed
The management of bleeding in patients receiving study medication is supportive, as 
rivaroxaban does not have a specific antidote. Temporary discontinuation of rivaroxaban is 
                                                
39 Text revised with Protocol Amendment 4 (change no. 17)
40 Text revised with Protocol Amendment 4 (change no. 17)


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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, as in 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, activated prothrombin complex 
concentrate (APCC), or recombinant factor VIIa partially restore hemostasis following 
treatment with factor Xa inhibitors such as rivaroxaban, and a randomized trial involving 
healthy patients treated with rivaroxaban has demonstrated that prothrombin complex 
concentrates reverse prolongation of the prothrombin time. Rivaroxaban cannot be dialyzed as 
it is highly protein bound.
7.4.7
Guidance for the treatment of subjects who have impaired 
renal function
Patients with impaired  renal function (i.e. <60 mL/min/1.73 m2 but ≥15 mL/min/1.73 m2 are 
eligible for the study (see Section 6.2). If a patient's eGFR is <30 mL/min/1.73 m2 prior to the 
index procedure, to enroll and randomize the patient the eGFR must be confirmed to ensure 
that the eGFR remains >15 mL/min/1.73 m2, at least 72 hours after the procedure. 
During the study, in subjects with baseline eGFR <30 mL/min/1.73 m2, renal function should 
be monitored as per standard of care, tailored to the need of the subject. Study medication 
should be interrupted or permanently discontinued if the eGFR should fall below 
15 mL/min/1.73 m2.
7.5
Blinding
Study medication (rivaroxaban or matching placebo) assignment will be double-blind. Study 
treatment consists of study medication (rivaroxaban or matching placebo) in addition to study 
ASA. Additional details of emergency unblinding procedure can be found in the IxRS 
operation manual.
Unblinding should only be undertaken by the investigator when it is deemed medically 
necessary for the patient’s safety and will be done via the IxRS system. If there is an 
uncertainty with respect to an unblinding decision, the investigator may contact the 24-hour 
Study Helpline (independent of the sponsor). 
However, the Study Helpline contact should not delay emergency treatment of the patient. 
Examples that should trigger a Helpline discussion include life-threatening bleeding or 
bleeding requiring surgical intervention. 
In compliance with applicable regulations, in the event of a SUSAR (see Section 9.6.1.4) 
related to the blinded treatment, the patient’s treatment code will usually be unblinded before 
reporting to the health authorities, ethic committees, and investigators.
7.6
Drug logistics and accountability
All study medication and study ASA need to be stored at the investigational site according to 
the labeled storage advice and in accordance with Good Clinical Practice (GCP) and GMP 
requirements. Study medication and study ASA should not be stored above 30°C. The study
medication and study ASA are to be kept in a limited access and secure area that cannot be 


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accessed by unauthorized personnel. Site personnel will confirm receipt of study medication 
and study ASA via IxRS and will use study medication and study ASA only for this study and 
in accordance with this protocol. Receipt, distribution, return, and destruction (if any) of the 
study medication and study ASA must be properly documented according to local regulation 
and specified procedures.
Written instructions on medication destruction for unused study medication and study ASA 
returned to the sites by the patient as well as undispensed study medication and study ASA
will be made available to affected parties as applicable.
7.7
Treatment compliance
Treatment compliance for the study medication and study ASA will be assessed at each study 
visits by interview and by counting the tablets returned by the patient to the site and will be 
documented in the eCRF. Any discrepancies between actual and expected amount of returned 
study medication and study ASA must be discussed with the patient at the time of the visit, 
and any explanation must be documented in the eCRF and, if appropriate, in the patient’s 
medical record.
The date of first dose, the last dose, and dose interruptions of either study medication or study 
ASA will be reported in the eCRF. Patients with temporary interruption of study medication 
and/or ASA for medical reasons should restart study medication and/or study ASA 
administration again as soon as medically indicated. 
8.
Non-study therapy
8.1
Prior and concomitant therapy - amended
Generally, all prior (within 30 days prior to randomization41) and concomitantly taken drugs 
(as specified in the eCRF) need to be recorded in the eCRF. During the study, concomitant 
therapy will be recorded at the study visits, or at the time of occurrence of any efficacy 
outcome events, bleeding events, and SAEs. In addition, any remedial therapy for non-
serious-AEs (if AEs are subject to reporting) should be documented.
Clopidogrel and other non-study antiplatelet treatment42
Patients who enter the study receiving additional antiplatelet therapy will have non-study 
antiplatelet therapy discontinued when study medication is started. 
If deemed required by the investigator, the use of clopidogrel concomitantly with study drugs 
is allowed at the time of randomization. It is strongly recommended that any course of 
clopidogrel is kept to the minimum necessary to comply with local standard of care and 
international practice guidelines (typically 30 days, or up to 60 days for some drug-coated 
products or devices). Clopidogrel will not be supplied as a study medication.
During the course of the study, for enrolled patients who require use of clopidogrel for a new 
indication (e.g., indication for PCI with or without stenting), use of clopidogrel is allowed 
                                                
41 Text revised with Protocol Amendment 4 (change no. 17)
42 Text in this section was revised with Protocol Amendment 4 (change no. 9) and Protocol Amendment 5 
(change no. 3).


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(see Section 7.4.4). At the discretion of the investigator, study medication may be used along 
with clopidogrel or interrupted until the patient no longer requires clopidogrel.  The duration 
of clopidogrel use should follow standard of care and applicable international guidelines.  
Treatment with other P2Y12 antagonists, such as prasugrel or ticagrelor may be administered 
according to usual practice, but the study drug must be interrupted if such drugs are used 
long-term.
The concomitant use of non-steroid anti-inflammatory drugs (NSAIDs) and non-study 
antiplatelet therapy during the study (except clopidogrel in the initial study phase) is strongly 
discouraged since it increases the risk for bleeding. However, if an NSAID drug is indicated, 
the lowest possible dosage must be selected.
For patients at risk for ulcerative gastrointestinal disease or bleeding or who develop 
symptoms of these complications during the study, an appropriate gastro-protective 
prophylactic treatment may be recommended by the investigator, but will not be supplied as 
study medication.
Systemic anticoagulation
The following drugs are regarded as relevant in terms of influencing coagulation:

unfractionated heparin and its derivatives (i.e., including low molecular weight 
heparin (LMWH)),

vitamin K antagonists,

novel or Non-VKA oral anticoagulants (NOACs),

fibrinolytic treatment is allowed during the intervention/surgery, but it must be 
stopped no later than 24 hours before randomization into the trial.
The use of any of these drugs needs to be recorded in the eCRF.
Patients with a foreseeable need for systemic anticoagulation after the qualifying 
revascularization procedure should not be enrolled in the study (see Section 6.2). Patients who 
develop a need for anticoagulant therapy during the study period (e.g., thromboprophylaxis in 
patients undergoing major orthopedic surgery, acute VTE, atrial fibrillation, mechanical aortic 
valve replacement, etc.) must interrupt study treatment with rivaroxaban or placebo, while 
study ASA might be continued at the discretion of the investigator. Study treatment should be 
restarted in patients who no longer have a need for non-study anticoagulant therapy as soon as 
possible after the discontinuation of the non-study anticoagulant therapy (e.g., after 
completion of anticoagulant thromboprophylaxis or anticoagulant treatment for VTE).
Bridging or temporary overlap of study medication with anticoagulant therapy may be 
appropriate, considering the patient’s need, risk, and clinical setting.  In case of questions, 
please consult the Study Helpline.


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Prohibited therapy while on study medication

systemic treatment with strong inhibitors of both CYP3A4 and P-gp inhibitors (e.g., 
systemic azole antimycotics43, such as ketoconazole, and human immunodeficiency 
virus [HIV]-protease inhibitors, such as ritonavir), or strong inducers of CYP3A4 
(e.g., rifampicin, rifabutin, phenobarbital, phenytoin and carbamazepine) at the time of 
screening or their anticipated use during the study;

use of antiplatelet therapy other than the protocol specified background antiplatelet 
therapy of study ASA or clopidogrel is prohibited during the study. This includes 
drugs with known significant antiplatelet effects such as cilostazol, prasugrel and 
ticagrelor. 44

additional anticoagulant(s) (e.g., warfarin sodium or vitamin K antagonists, heparins, 
Factor II or Xa inhibitors) concomitantly with study medication are prohibited.45

NSAID (except ASA) may be used concomitantly on a temporary basis, but should be 
avoided for chronic use (> 4 weeks) during the study;

any non-study ASA use will not be permitted. For management of CABG and PCI 
during the study, refer to Section 7.4.3 and Section 7.4.4. Other non-ASA medications 
should be used for conditions such as pain relief and fever reduction.
These prohibited therapies may be administered on a temporary basis in combination with the 
study drug if deemed medically appropriate. In general,46 the investigator should consider 
temporarily discontinuing study medication if the treatment could result in an increased risk 
of bleeding (e.g., strong inhibitors of both CYP3A4 and P-gp, or anticoagulants). Study drug 
medication may be restarted after the prohibited therapy has been discontinued and after 
completion of a suitable washout period at the investigator’s discretion. 
Study medication should be temporarily interrupted, if the patient:

undergoes PCI, CABG, or any other surgical procedure, or medical condition that may 
require temporary interruption of study drug, or use of prohibited therapy due to bleeding 
risk or use of open-label anticoagulants,

experiences a significant bleeding event,

develops a new neurological deficit or significant alteration in mental status,

develops a platelet count <50,000/L,

has any serious adverse event possibly related to or exacerbated by study drug 
administration,

requires a prohibited therapy on a temporary basis.
                                                
43 Systemic treatment with fluconazole is permitted.
44 Bullet point revised with Protocol Amendment 4 (change no. 22a).
45 Bullet point revised with Protocol Amendment 4 (change no. 22b and 22c).
46 Text revised with Protocol Amendment 4 (change no. 17).


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Study medication can be resumed at a time when in the opinion of the investigator it is safe to 
do so.
Discontinuation of Study Drug for a Vascular Procedure
Table 8–1 depicts the approximate equivalent dose of subcutaneous enoxaparin (mg/kg) 
relative to rivaroxaban 2.5 mg at given time points following its administration, and should be 
used to assist the investigator in deciding which dose of enoxaparin or equivalent dose of 
another antithrombotic agent to administer in the event when a patient may have to undergo 
an emergency interventional coronary procedure or pharmacologic reperfusion while 
receiving study drug. 
Table 8–1: Comparative antithrombotic effect at given time points following 
rivaroxaban 2.5 mg administration to subcutaneous enoxaparin doses
Time after 2.5 mg Rivaroxaban 
Administration
Equivalent Enoxaparin Dose
3 h
0.15 mg/kg
6 h
0.1 mg/kg
> 9 h
0 mg/kg
Source: [Mega et al. 2012] 47
When thrombolysis is required within 3 hours of the last study drug administration, it may be 
necessary to unblind the patient at the discretion of the investigator to estimate the dose of 
enoxaparin to be administered; in the case the patient is in the rivaroxaban treatment group, 
the subcutaneous dose of enoxaparin should be adopted as given in Table 8–1. 
In case of urgent PCI for acute ischemic event, the investigator should discontinue study 
medication and initiate therapy with non-study ASA prior to PCI with non-enteric coated 
formulation. The loading dose of non-study ASA may be considered. In addition, consider 
intravenous administration of 0.5 mg/kg of enoxaparin or its antithrombotic equivalent in 
patients who undergo PCI. In the event that a patient requires a non-emergency 
revascularization procedure (PCI or CABG), study medication should be stopped 
approximately 24 hours before the procedure, if possible, and appropriate anticoagulant or 
antiplatelet therapy should be instituted as medically indicated (including DAPT). 
48Depending on the bleeding risk, the patient may, at the discretion of the managing 
physician, resume study medication thereafter, but no earlier than approximately 12 hours 
after the arterial sheath has been removed (for patients undergoing PCI) or after the post-
procedural drains have been removed (for patients undergoing CABG surgery), and the last 
dose of parenteral anticoagulant therapy has been administered.
                                                
47 Table derived from Attachment 6 of the study protocol of the ATLAS ACS 2 TIMI 51 trial (The second trial 
of Anti-Xa Therapy to Lower cardiovascular events in Addition to standard therapy in Subjects with Acute 
Coronary Syndrome), which is online accessible through the website of the New England Journal of Medicine in 
the supplementary material section (last accessed on 14-FEB-2015):
<http://www.nejm.org/doi/suppl/10.1056/NEJMoa1112277/suppl_file/nejmoa1112277_protocol.pdf>
48 First sentence was removed with Protocol Amendment 4 (change no. 22d).


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8.2
Post-study therapy
After discontinuation of study medication (either at study end or in case of permanent 
premature discontinuation), initiation of standard of care therapy is the responsibility and at 
the discretion of the investigator.
8.3
Background non-antithrombotic therapy
Given the prevalence of potentially modifiable risk factors and concomitant conditions such 
as diabetes, hyperlipidemia, hypertension, or smoking in this study population, aggressive 
treatment and life-style modification are clinically warranted. It is recommended that patients 
be treated in accordance to standard of care and applicable international/local guidelines.
9.
Procedures and variables
9.1
Tabular schedule of evaluations - amended
Please note: As this is an event-driven study, patients participating in this study will have 
different numbers of study visits.
Patients will be assessed for study participation prior to, or after, the qualifying 
revascularization whereas this procedure is not considered to be a study visit. 49On-site study 
visits for the patients at the investigational site are planned at Screening, Randomization, 1, 3, 
6, and 12 months after randomization, and then every 6 months until the end of the study. 
Upon announcement of study end, patients will come to the clinic for a final on-site EOT visit 
followed by a telephone contact (post-study treatment follow-up visit) one month later. 
The following visit abbreviations are used in the description of the visit schedule:
ScV:
Screening visit (to be performed up to 30 days prior to but no later than 10 days 
after Rev; screening procedures can be performed over multiple days if 
necessary)50
Rev:
Day of the qualifying revascularization procedure (not considered a study visit).
RxV:
Randomization visit (time point of randomization = [T0]), to be performed as soon 
as possible but no later than 10 days51 after Rev once hemostasis is assured.
V1:
Visit 1, to be performed 1 month after RxV with an accepted time window of 
± 10 days.
V2-4:
Visits 2, 3, and 4; to be performed 3, 6, and 12 months after RxV with an accepted 
time window of ± 4 weeks.
V5-Vx:
Visit 5 to Visit 5+n (where n is the number of additional treatment phase on-site 
visits beyond Visit 5) to be performed at regular intervals of 6 months with an 
accepted time window of ± 4 weeks; continued until individual premature 
                                                
49 Sentence revised with Protocol Amendment 4 (change no. 17).
50 Revised with Protocol Amendment 4 (change no. 3).
51 Prior to Protocol Amendment 4, 10 days was 7 days (change no. 2).


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permanent termination of the study (not study drug treatment; see Section 6.3) or 
announcement of study end.
EOT:
End of treatment visit, to be performed within 4 weeks after announcement of study 
end or upon individual termination of the study (not premature study drug 
discontinuation; see Section 6.3). No further study medication will be dispensed at 
this visit.
PS-FU:
Post-study treatment follow-up visit by phone call, to be performed one month after 
the EOT visit with an accepted time window of ± 1 week.
52Clinic visits or procedures should be scheduled as close to the specified interval as possible, 
and preferably within the defined window. If it is not possible for the patient to return within 
the visit "window", or perform the required study procedures especially due to unforeseen 
circumstance or technical feasibility beyond the control of the patient or the study center, then 
the visit or procedure should be scheduled as close to the interval as is convenient for the 
patient and the study center.  
                                                
52 Paragraph revised with Protocol Amendment 4 (change no. 17).


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Table 9–1: Schedule of assessments - amended
Timelines
ScV a
Qualifying 
revascular
-ization
(Rev)
RxV a
(T0)
Treatment Phase
PS-FU
1 Mo post EOT
V1 
V2
V3
V4
V5-Vx
EOT
visit  b
1 Mo
3 Mo
6 Mo
12 Mo
every 6 Mo
Visit Window 
(weeks if not otherwise 
specified)
-30 days before, to 
+10 days after, Rev53
Up to +10 days 
after Rev54
±10 days
±4
±4
±4
±4
±1
Type of Visit 
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit

Informed consent
●
Demographics
●
Medical / surgical history 
●
Laboratory tests c
●
Serum pregnancy test d
●
Inclusion/Exclusion
●
Revascularization 
procedure (surgical or 
endovascular)
♦
Documentation of 
revascularization details
●55
Randomization (IxRS)
●
Concomitant medications e
●
●
●
●
●
●
●
●
1st study drug 
●
Drug dispense 
●
●
●
●
●
●
Drug accountability
●
●
●
●
●
●
Vital Signs
●
●
●
●
●
●
●
●
Study efficacy outcomes
●
Study safety outcomes 
(bleeding events)
●
AE/SAE reporting f
●
●
●
●
●
●
●
●
●
ABI/TBIh
● g
●
●
●
●
●
●
(footnotes are provided on the next page)
Questionnaires (EQ-5D, 
●
●
●
●
●
●
●
                                                
53 Schedule revised with Protocol Amendment 4 (change no. 2).
54 Schedule revised with Protocol Amendment 4 (change no. 3). 
55 Schedule revised with Protocol Amendment 4 (change no. 17).
continuous reporting
continuous reporting


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Table 9–1: Schedule of assessments - amended
Timelines
ScV a
Qualifying 
revascular
-ization
(Rev)
RxV a
(T0)
Treatment Phase
PS-FU
1 Mo post EOT
V1 
V2
V3
V4
V5-Vx
EOT
visit  b
1 Mo
3 Mo
6 Mo
12 Mo
every 6 Mo
Visit Window 
(weeks if not otherwise 
specified)
-30 days before, to 
+10 days after, Rev53
Up to +10 days 
after Rev54
±10 days
±4
±4
±4
±4
±1
WIQ, HCRU) PAD 
symptom status56
Vital status
●
57  ♦= non-study procedure (change no. 17); ●= study procedure to be performed at specified visits; = post-study treatment telephone contact
Abbreviations: ABI/TBI = Ankle (Toe) - Brachial - Index; AE = adverse event; EOT = end of treatment; EQ-5D = European Quality of Life-5 Dimensions 
questionnaire; IxRS = Interactive Voice and Web Response System; Mo = month; V = visit; Rx = randomization; SAE = serious adverse event; 
Sc = Screening; WIQ = Walking Impairment Questionnaire, HCRU= HealthCare Research Utilization (see Section 9.7.3) (change no.17)
a:
Screening visit can be performed at the same time as randomization visit, if all required tests for eligibility criteria are available at that time. Screening period 
is 30 days before or up to 10 days (change no. 3) after the revascularization procedure. Randomization should be done as soon as possible (but within 10 
days [change no. 2]) after the qualifying revascularization procedure.
b:
End of treatment visit is to be performed within 4 weeks after announcement of study end, or once the patient has permanently withdrawn from the study.
c:
Laboratory tests required to verify the eligibility criteria (creatinine/eGFR) are to be collected per the site’s standard of care and assessed through a local lab.
Creatinine/eGFR must not be older than 30 days prior to the qualifying revascularization (change no. 10). If the patient’s eGFR is <30 mL/min/1.73 m2 prior 
to the procedure, it must remain to be >15 mL/min/1.73 m2  72 hours after the procedure in order (change no. 17) to enroll and randomize the patient.  
d:
Required in women of childbearing potential only.  A pregnancy test must not be older than 7 days prior to randomization.
e:
Planned post-procedural concomitant clopidogrel allowed at the discretion of the investigator, see Section 8.1
f:
Only AE/ SAEs not exempted from adverse event reporting and specified in the protocol need to be documented (see Section 9.6.1.3 (change no.17).58
g:
ABI/TBI values used at screening may be historical (captured in the patient’s medical history), but must not be older than 12 months prior to the qualifying 
revascularization procedure (change no. 5). If an ABI/TBI is performed during screening to assess eligibility, it must be completed prior to, or at the time of,
the qualifying revascularization (change no. 6).59
h:    ABI/TBI assessments performed after informed consent is obtained must be performed per the guidance in the ABI/TBI Site Manual.60
                                                
56 Schedule revised with Protocol Amendment 4 (change no. 12).
57 Single footnotes of Table 9-1 were revised with Protocol Amendment 4.  All changes are included behind the respective text for better readability.
58 Footnote revised with Protocol Amendment 5 (change no. 7).
59 Footnote revised with Protocol Amendment 5 (change no. 7).
60 Footnote added with Protocol Amendment 5 (change no 5).


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9.2
Visit description
9.2.1
Timing of assessments
9.2.1.1
Screening Visit (ScV): 30 days before, or up to 10 days after qualifying 
revascularization procedure - amended
61The ScV is required to assess the eligibility of the patient. After obtaining signed informed 
consent, the investigator will review or perform all medical evaluations required to verify the 
patient’s eligibility for study participation as defined in the inclusion and exclusion criteria. 
Adverse events reporting begins once the informed consent has been signed.
Demographic data and medical history (including PAD risk factors and vascular disease 
history) will be recorded at Screening. Laboratory tests should be performed according to the 
site specific standards, but must, at minimum, include creatinine and eGFR, and a serum 
pregnancy test in women of childbearing potential. Results of laboratory measurements 
(ideally obtained during the hospital admission for the qualifying revascularization) should 
not be older than 30 days prior to the qualifying revascularization; otherwise, tests would need 
to be repeated. If the site’s local laboratory report does not provide eGFR, this value should be 
calculated (e.g. using the Modification of Diet in Renal Disease [MDRD] formula). All 
laboratory tests will be performed locally as no central laboratory is involved in this study.
The following measures/documentations will be performed at the screening visit:

obtaining informed consent;

documentation of demographic characteristics (for details see Section 9.3.1);

documentation of medical history (for details see Section 9.3.2) and surgical history;

review laboratory test data for the patient, if creatinine/eGFR assessments were 
performed more than 30 days prior to the qualifying revascularization, they must be 
redrawn and if serum pregnancy test (females with childbearing potential only)62was 
performed more than 7 days ago prior to the qualifying revascularization a repeat 
pregnancy test must be performed;

evaluate for all inclusion- and exclusion criteria;

documentation of prior (within the last 30 days prior to randomization63) and 
concomitant medication. Chronic treatment with prescription antiplatelet therapies 
(except already ongoing treatment with low-dose ASA that can be continued as study 
ASA 100 mg od) should be stopped at the time of randomization;

assess vital signs (blood pressure, pulse rate);

check for the occurrence of AEs/SAEs since the signing of the ICF (only AEs/SAEs 
not exempted from AE/SAE reporting need to be reported; for details see 
Section 9.6.1.3);
                                                
61 First two paragraphs revised with Protocol Amendment 4 (changes no. 3 and 10).
62 Sentence revised with Protocol Amendment 4 (change no. 17).
63 Sentence revised with Protocol Amendment 4 (changes no. 10 and 17).


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
perform ABI (or TBI) if no ABI/TBI data are available for the patient within the last 
12 months64 prior to the qualifying revascularization; ABI/TBI assessments performed 
after informed consent is obtained must be performed per the guidance in the ABI/TBI 
Site Manual.65
If the patient is eligible for study participation, the site investigator should make all 
organizational arrangements required for prompt randomization of the patient to study 
treatment as soon as feasible, but no more than 1066days after the qualifying revascularization 
procedure (for treatments to be administered, see Section 7.1).
9.2.1.2
Randomization visit (RxV): 0-10 days after the qualifying 
revascularization procedure - amended
67After meeting all inclusion criteria and none of the exclusion criteria, eligible patients will 
be randomized by accessing the IxRS system and receive study medication and study ASA as 
soon as feasible, but no more than 10 days after the qualifying revascularization procedure. 
The first dose of study medication should be given immediately, but no more than 24 hours 
after randomization, if study drug can be safely administered (see Section 7.4). Planned 
additional treatment with clopidogrel after the qualifying revascularization procedure is 
allowed at the discretion of the investigator, as described in section 8.1.68
The following measures/documentations will be performed at the randomization visit:

randomization of patient (must be performed prior to all other randomization study 
visit procedures);69

documentation of the details about the qualifying revascularization and its success;70

If laboratory evaluations have been performed and are available per standard or usual 
care of the subjects in the recent past that reflect baseline hematologic, glucose 
metabolic, liver, and renal functions, record the relevant and available indices in the 
eCRF (HbA1c, total cholesterol, HDL cholesterol, LDL cholesterol, ALT(SGPT), 
AST(SGOT), total bilirubin, hemoglobin, hematocrit, platelet count). The serum 
creatinine value used to assess eligibility and corresponding eGFR should also be 
entered;71

dispensing of study medication and study ASA with patient instruction;

administration of first study medication treatment dose (on-site);

documentation of any changes in concomitant medication since the last study visit;

assess vital signs (blood pressure, pulse rate);
                                                
64 Timepoint for ABI (TBI) changed with Protocol Amendment 4 (changes no. 5 and 10).
65 This bullet point was modified with Protocol Amendment 5 (change no. 5).
66 Sentence revised with Protocol Amendment 4 (change no. 3).
67 Section revised with Protocol Amendment 4 (changes no. 2 and 17)
68 Last two sentences revised with Protocol Amendment 4 (change no. 17).
69 Sentence revised with Protocol Amendment 4 (change no. 17).
70 Sentence revised with Protocol Amendment 4 (change no. 17).
71 Bullet added with protocol Amendment 4 (change no. 19)


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
check for the occurrence of study efficacy outcome events since the last study visit
(these pre-randomization events should be documented on the outcome pages and 
forwarded by expedited means to the Sponsor's PV; see Section 9.6.1.3);

check for the occurrence of study safety outcome events (bleeding events) since the 
last study visit (these pre-randomization events should be documented on the outcome 
pages and forwarded by expedited means to the Sponsor's PV; see Section 9.6.1.3);

check for the occurrence of AEs/SAEs since the last study visit; for events exempted 
from AE/SAE reporting, see Section 9.6.1.3);

assess the patient’s PAD Symptom Status. 
(This assessment, as well as the QoL assessment and Walking Impairment 
Questionnaire, should reflect the time period prior to the qualifying revascularization 
procedure);72

QoL assessment with EQ-5D;

Walking Impairment Questionnaire;

remind patient to return with the study medication and study ASA dispensed bottles at 
their next visit.
Note: Screening and randomization visits can be combined into one single visit, provided 
that all required information for the patient eligibility assessment are available at that 
time (e.g., eGFR values). Study endpoint evaluations and safety evaluations will start from 
time of signing the ICF. The patient will be instructed to report any hospitalization or other 
significant illness to the investigator on an ongoing basis during the entire course of the study 
in order to allow a timely reporting of study efficacy outcome events, bleeding events, and 
other AEs/SAEs.
9.2.1.3
Treatment phase: Regular study visits from Visit 1 onwards - amended
Patients will return to the study site for the first on-treatment visit one month following 
randomization (Visit 1, with a permitted time window of ± 10 days). Further regular treatment 
visits (all with a permitted time window of ± 4weeks) will be performed 3 months (Visit 2), 
6 months (Visit 3), and 12 months (Visit 4) after randomization, and then every 6 months until 
the study end will be announced (see Table 9–1).
At each on-site visit in the treatment phase, patients will be asked about the occurrence of 
potential study efficacy outcome events, bleeding events, and AEs/SAEs. If a suspected study 
efficacy outcome event or bleeding event is reported, the respective eCRF page will be 
completed and an adjudication package expeditiously compiled and submitted to the ICAC.
The following measures/documentations will be performed at each study visit:

check for the occurrence of study efficacy outcome events since the last study visit;

check for the occurrence of bleeding events since the last study visit;
                                                
72 Last sentence added with Protocol Amendment 4 (change no. 12).


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
complete all eCRF outcome event, bleeding event and Health Care Resource 
Utilization (HCRU see Section 9.7.3) pages if applicable73

check for the occurrence of AEs/SAEs since the last study visit (for events exempted 
from AE/SAE reporting, see Section 9.6.1.3);

document any changes in concomitant medications since the last study visit;

assess the patient’s PAD Symptom Status;74

If the following laboratory evaluations have been performed since the last study visit 
and are available in the medical record, it is requested that this information be 
recorded in the eCRF: HbA1c, creatinine, total cholesterol, HDL cholesterol, LDL 
cholesterol, ALT(SGPT), AST(SGOT), total bilirubin, hemoglobin, hematocrit,
platelet count;75

QoL assessment with EQ-5D (questionnaires should be completed before the other 
visit procedures);

Walking Impairment Questionnaire (questionnaires should be completed before the 
other visit procedures);

assess vital signs (blood pressure, pulse rate);

perform ABI (or TBI);76

collect study medication and study ASA bottles dispensed at the previous visit and 
count and document number of returned tablets. Document any treatment 
interruptions, if applicable;

dispense new bottles of study medication and study ASA with patient instructions;

remind patient to return with the study medication and study ASA dispensed bottles at 
their next visit.
9.2.1.4
End of treatment (EOT) visit - amended
Once the Sponsor announces the end of the study, all patients must return to their study site 
within 4 weeks in order to complete the EOT visit. Study medication and study ASA will be 
stopped at this visit, and it will be left to the discretion of the investigator to initiate any 
antiplatelet or anticoagulation therapy during the transition of care to the patient’s personal 
physicians.
Likewise, an EOT visit should be performed in those patients who leave the study 
permanently in spite of any attempts to hold the patient on study observation (see 
Section 6.3.1).77
The following measures/documentations will be performed at the final on-site visit:
                                                
73 Bullet added with Protocol Amendment 4 (change no. 17)
74 Bullet added with Protocol Amendment 4 (change no. 12)
75 Bullet added with Protocol Amendment 4 (change no. 19)
76 Prior to Protocol Amendment 4, this was “perform ABI (or TBI for non-compressible tibial arteries)” (change 
no. 5).
77 Wording revised with Protocol Amendment 4 (change no. 17)


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
check for the occurrence of study efficacy and safety outcome events since the last 
study visit and obtain all supportive information required to complete assessment of 
these outcome events;

check for the occurrence of AEs/SAEs since the last study visit (for events exempted 
from AE/SAE reporting, see Section 9.6.1.3);

documentation of any changes in concomitant medication since the last study visit;

assess the patient’s PAD Symptom Status;78

QoL assessment with EQ-5D (questionnaires should be completed before the other 
visit procedures);

Walking Impairment Questionnaire (questionnaires should be completed before the 
other visit procedures);

assess vital signs (blood pressure, pulse rate);79

perform ABI (or TBI);80

collect study medication and study ASA bottles dispensed at the previous visit and 
count and document number of returned tablets. Document any treatment 
interruptions, if applicable;

arrangement of final post-study treatment follow-up phone call.
9.2.1.5
Post-study treatment follow-up visit (PS-FU): one month post-EOT 
(± 1 week)
Patients will be contacted by telephone one month after the EOT visit to allow for collection 
of final safety data and patient’s vital status at study end.
9.3
Population characteristics
9.3.1
Demographics
The following demographic data will be recorded in the eCRF at the screening visit:

age,

sex,

race/ethnicity,

body weight (kg),

body height (cm),

calculated BMI.
                                                
78 Bullet added with Protocol Amendment 4 (change no. 12)
79 Bullet moved with Protocol Amendmend 4 (change no. 17)
80 Prior to Protocol Amendment 4, this was “perform ABI (or TBI for non-compressible tibial arteries)” (change 
no. 5).


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9.3.2
Medical history
Medical history findings (i.e., previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator at the screening visit:
o
not pertaining to the study indication,
o
start before signing of the informed consent,
o
considered relevant for the patient’s study eligibility.
Special attention must be paid to the PAD-related medical history:

PAD-related and cardiovascular disease history (MI, angina, intermittent claudication, 
diabetes, renal dysfunction, heart failure, pacemaker, defibrillator, TIA, stroke, 
hypertension, etc.);

PAD-related and cardiovascular surgical and endovascular disease history (coronary 
percutaneous transluminal coronary angioplasty, atherectomy, PCI, coronary artery 
bypass graft, peripheral artery bypass surgery, peripheral percutaneous transluminal 
angioplasty, limb or foot amputation, etc.);

Medical history of bleeding risk and bleeding (liver diseases, gastrointestinal diseases
with bleeding, erosions, ulceration, obstruction, perforation; previous bleeding 
requiring transfusion, etc.).
Instructions on the differentiation between (i) medical history and (ii) adverse events can be 
found in Section 9.6.1.1.
9.3.3
Definition of qualifying revascularization procedure - amended
81For the purposes of the current study, the qualifying revascularization procedure (surgical or 
endovascular) must include a technically successful procedure distal to the external iliac 
artery in the past 10 days, and hemostasis must be assured.
Patients under consideration for this trial may have a treatment plan that focuses on a single 
procedure or staged procedures where not all revascularizations will necessarily be completed 
at one time. Preferably, the qualifying revascularization should be the last planned procedure.
Surgical procedure: open surgical procedures in the lower extremity for PAD. This can 
include a variety of procedures, bypass conduit materials, and extra-anatomic operations.
Endovascular procedure: catheter-based procedures and hybrid procedures (those 
procedures involving aspects of both endovascular and surgical revascularizations) for PAD.
The details about the qualifying revascularization procedure will be recorded at the 
randomization visit in the eCRF. 
Successful procedure: the qualifying revascularization (regardless of type of procedure) 
procedure must be deemed technically successful by meeting the following criteria:

technical success of the procedure with no immediate plan for re-intervention and per 
the investigator’s discretion, the patient can safely be placed on an anticoagulant at the 
time of randomization;
                                                
81 Section revised with Protocol Amendment 4 (change no. 4, 6, 7, 14 and 17) and Protocol Amendment 5 (see 
change no. 4).


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
demonstrated graft or vascular patency of the qualifying revascularization procedure 
prior to randomization. Graft or vascular patency is at the discretion of the investigator 
and can be demonstrated by a variety of means including imaging, hemodynamic 
and/or physical findings.
Sites may be required to submit source documents from the qualifying revascularization 
procedure for central data verification. 82
9.4
Efficacy
9.4.1
Assessments and procedures at occurrence of primary efficacy events -
amended
In addition to the interviews performed during the regular on-site visits, all study patients are 
requested to inform the site as soon as possible if they have been hospitalized (regardless of 
reason) or have experienced other significant adverse medical events in order to ensure timely 
identification of potential study efficacy outcome events and bleeding events.
The analysis of study efficacy outcome events will be based on events as adjudicated by the 
ICAC. Thus, the occurrence of study efficacy outcome events must be reported on 
Outcome/CV Event reporting forms, as described in the Endpoint Event Site Manual83, and 
will undergo adjudication by the ICAC. All potential coronary ischemic events, 
cerebrovascular events and peripheral ischemic events should also be reported on the 
Outcome/CV Event reporting forms.84
The following events will be assessed for primary efficacy (for event definition see 
Section 9.4.2):

MI,

Ischemic stroke,

CV death,

ALI,

Major amputation due to a vascular etiology.
Please note that these study efficacy outcome in addition to bleeding events are exempted 
from AE/SAE reporting (see Section 9.6.1.3.3).
In addition to investigator-identified study efficacy outcome and bleeding events, safety data 
will be reviewed regularly for potential major vascular thrombotic events. In particular,
Medical Dictionary for Regulatory Activities (MedDRA) preferred terms assigned to 
investigator-reported AEs will be screened for potential study efficacy outcome and bleeding 
events and investigators may then be asked to further investigate whether or not a study 
efficacy outcome or bleeding event occurred and potentially initiate the outcomes reporting 
process.
Study efficacy outcome events will be continuously collected from signing of the ICF to study 
end (including the post-study treatment follow-up call).
                                                
82 Sentence added with Protocol Amendment 5 (change no. 6).
83 Sentence revised with Protocol Amendment 5 (change no. 7).
84 Sentence revised with Protocol Amendment 4 (change no. 23).


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9.4.2
Definition of study efficacy outcome events
85The following definitions are provided for the purposes of this study:
Myocardial infarction (MI): the definition of acute MI is based on the evidence of 
myocardial necrosis in a clinical setting consistent with acute myocardial ischemia, using the 
universal MI definition [Thygesen et al. 2012].
Ischemic stroke: the definition of ischemic stroke will be an acute episode of neurological 
dysfunction caused by focal or global brain vascular injury and includes all strokes that are
not of a primary hemorrhagic etiology. This includes fatal and non-fatal strokes.
Cardiovascular (CV) death: all deaths will be assumed CV in nature unless a non-CV cause 
can be clearly shown.
Acute limb ischemia (ALI): for the current study, ALI is defined as clinical history and 
presentation consistent with a sudden significant worsening of limb perfusion requiring 
hospitalization and

a new pulse deficit with associated rest pain, pallor, paresthesia, or paralysis and either
o
confirmation of arterial obstruction by imaging, limb hemodynamics, 
intraoperative findings, or pathological evaluation
OR
o
requiring thrombolysis, thrombectomy, or urgent revascularization.
Major amputation due to a vascular etiology: for the current study, this is operationally 
defined as above-the-ankle amputation that is:

non-traumatic
AND

due to a vascular etiology which includes worsening perfusion of the limb but 
excludes foot sepsis as the primary indication for amputation.
Detailed definitions for these efficacy outcomes are provided in a separate ICAC charter.
9.4.3
Efficacy variables
9.4.3.1
Primary efficacy variable
The primary efficacy outcome of the study is a composite endpoint consisting of:

the time from randomization to the first occurrence of any component of the following 
major thrombotic vascular events: MI, ischemic stroke, CV death, ALI, and major 
amputation due to a vascular etiology.
9.4.3.2
Secondary efficacy variables - amended
The secondary efficacy variables of the study are:

time from randomization to the first occurrence of MI, ischemic stroke, coronary heart 
disease mortality, ALI, and major amputation of a vascular etiology;
                                                
85 Paragraphs about ischemic stroke, acute limb ischemia, and major amputation due to a vascular etiology 
revised with Protocol Amendment 4 (change no. 24).


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
time from randomization to the first occurrence of an unplanned index limb 
revascularization for recurrent limb ischemia (subsequent index leg revascularization 
that was not planned or considered as part of the initial treatment plan at the time of 
randomization);86

time from randomization to the first occurrence of hospitalization for a coronary or 
peripheral cause (either lower limb) of a thrombotic nature;

time from randomization to the first occurrence of MI, ischemic stroke, all-cause 
mortality, ALI, and major amputation of a vascular etiology;

time from randomization to the first occurrence of MI, all-cause stroke, CV death, 
ALI, and major amputation of a vascular etiology;

time from randomization to the first occurrence of all-cause mortality.

time from randomization to the first occurrence of venous thromboembolic (VTE) 
events;
9.4.3.3
Other efficacy variables - amended
Other efficacy variables of the study are:

time from randomization to the first occurrence of all subsequent limb
revascularizations of a lower extremity that were not planned or considered as part of 
the initial treatment plan at the time of randomization;87

time from randomization to the first occurrence of above ankle amputation of the 
index leg or major re-intervention (e.g., new bypass graft, jump/interposition graft 
revision, or thrombectomy/thrombolysis);

time from randomization to the first occurrence of all-cause amputations;

patient reported outcomes using disease and non-disease specific questionnaires (EQ-
5D and WIQ)

serial changes in limb hemodynamics (ABI/TBI).88
9.5
Pharmacokinetics / pharmacodynamics
No pharmacokinetic/pharmacodynamic evaluation will be performed.
9.6
Safety
9.6.1
Adverse events
Introductory note: Due to the broad knowledge about the safety of rivaroxaban based on the 
comprehensive clinical and post-marketing safety databases available to date, rules for 
recording and expedited reporting of AEs/SAEs will follow a targeted approach89 in order to 
                                                
86 Bullet revised with Protocol Amendment 4 (change no. 8) and Protocol Amendment 5 (change no. 2).
87 Bullet revised with Protocol Amendment 4 (change no. 8).
88 Bullet added with Protocol Amendment 4 (change no. 13).
89 Principles of targeted safety data collection are laid down in the FDA Draft Guidance for Industry 
"Determining the Extent of Safety Data Collection Needed in Late Stage Premarket and Post approval Clinical 
Investigations" (February 2012)


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facilitate the study documentation. The exemptions from AE/SAE documentation and SAE 
reporting are described in Section 9.6.1.3.2 and Section 9.6.1.3.3.
9.6.1.1
Definitions
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
A surgical procedure that was planned prior to the start of the study by any physician treating 
the patient should not be recorded as an AE (however, the condition for which the surgery is 
required may still be considered an AE).
In the following differentiation between medical history and AEs, the term "condition" may 
include abnormal e.g., physical examination findings, symptoms, diseases, laboratory, ECG.

Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g., seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g., allergic pollinosis).
Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events. This includes intercurrent illnesses.
Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a. Results in death.
b. Is life-threatening.
The term ‘life-threatening’ in the definition refers to an event in which the patient was 
at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization.
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:
the admission results in a hospital stay of less than 12 hours
the admission is pre-planned (e.g., elective or scheduled surgery arranged prior 
to the start of the study; admission is part of the study procedures as described in 
Section 9.2)
the admission is not associated with an AE 
(e.g., social hospitalization for purposes of respite care).
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fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability / incapacity.
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly / birth defect.
f.
Is another serious or important medical event as judged by the investigator.
9.6.1.2
Classifications for adverse event assessment
All AEs requiring documentation will be assessed and documented by the investigator 
according to the categories detailed below.
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the eCRF.
Causality should be assessed as detailed in the eCRF. If the investigator feels that the event 
cannot be firmly attributed to one of the study treatments (e.g., owing to a suspected 
underlying interaction), the same assessment will be documented for each study treatment.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are "yes" or "no".
An assessment of "no" would include:
1. the existence of a highly likely alternative explanation, e.g., mechanical bleeding at 
surgical site.
or
2. non-plausibility, e.g., the patient is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
diagnosed a few days after the first drug administration.
An assessment of "yes" indicates that the AE is reasonably associated with the use of the 
study treatment.
Important factors to be considered in assessing the relationship of the AE to study treatment 
include:
the temporal sequence from drug administration: The event should occur after the drug is 
given. The length of time from drug exposure to event should be evaluated in the clinical 
context of the event.


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Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge): Patient’s response after de-challenge or re-challenge should be considered 
in view of the usual clinical course of the event in question.
Underlying, concomitant, intercurrent diseases: Each event should be evaluated in the 
context of the natural history and course of the disease being treated and any other disease 
the patient may have.
Concomitant medication or treatment: The other drugs the patient is taking or the 
treatment the patient receives should be examined to determine whether any of them 
might have caused the event in question.
Known response pattern for this class of drug: Clinical/preclinical.
Exposure to physical and/or mental stresses: The exposure to stress might induce adverse 
changes in the patient and provide a logical and better explanation for the event.
The pharmacology and pharmacokinetics of the study treatment: The pharmacokinetic 
properties (absorption, distribution, metabolism and excretion) of the study treatment, 
coupled with the individual patient’s pharmacodynamics should be considered.
9.6.1.2.3
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below. The study treatment action should be recorded as detailed in the eCRF.

none,

drug withdrawn,

drug interrupted,

not applicable (e.g., study drugs already discontinued),

unknown.
9.6.1.2.4
Other specific treatment(s) of adverse events

none,

remedial drug therapy,

other non-drug treatment (e.g., surgery, endovascular interventions).
9.6.1.2.5
Outcome
The outcome of the AE is to be documented as follows:

recovered/resolved,

recovering/resolving,

recovered/resolved with sequelae,

not recovered/not resolved,

fatal,

unknown.


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9.6.1.2.6
Intensity - amended
90The intensity of an AE is to be classified according to the following categories:

mild,

moderate,

severe.
9.6.1.3
Targeted safety data collection
Targeted safety data collection is aimed to improve the value of safety data collected by 
focusing on patient safety and to concentrate the attention on key data to improve clarity of 
safety reports.
9.6.1.3.1
Assessment of bleeding events
Bleeding events, which are specific safety outcomes of this study, will be continuously 
monitored from signing of the ICF until post-study treatment follow-up visit.
All bleeding events will be reported on the designated bleeding reporting forms in the eCRF. 
Since bleeding events are recorded as safety outcome and the risk profile of rivaroxaban has 
been established in multiple previous studies, these events are not required to be recorded as 
an AE/SAE and thus are exempted from SAE reporting. 
Bleeding occurring after randomization that is related to the index revascularization procedure 
(e.g. bleeding requiring an unplanned surgical take-back operation to manage91) will also be 
reported, including details of the management of the bleeding event and any limb 
complications (e.g., resulting in major amputation or compartment syndrome requiring 
surgical management). These events will be reviewed by the IDMC on a regular basis and not 
reported as SAEs.
Potential major bleedings occurring after randomization will undergo adjudication by the 
ICAC. Major bleeding as adjudicated per TIMI classification is considered the primary safety 
outcome of the study, but other bleeding types (e.g., based on BARC and ISTH criteria) will 
also be evaluated as defined in the ICAC charter.
9.6.1.3.1.1
Primary safety outcome - occurrence of major bleeding as per TIMI 
definition
The primary safety outcome will be major bleeding events according to the TIMI 
classification.
Additional information on the definition of major bleedings can be found in the ICAC charter.
9.6.1.3.1.2
Secondary safety outcomes
In addition to the TIMI classification, bleeding events will be assessed using the BARC and 
the ISTH classifications, as defined in the ICAC charter.
                                                
90 This section was added with Protocol Amendment 4 because it was erroneously omitted from the original 
version (change no. 16).
91 Text revised with Protocol Amendment 4 (change no. 17).


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9.6.1.3.2
Assessments and documentation of adverse events – amended
The investigator has to record on the respective eCRF pages all AEs occurring in the period 
between the signing of the ICF and the end of the follow-up phase (i.e., post-study treatment 
follow-up visit by phone at 4 weeks after the EOT visit) according to the guidelines outlined 
in Sections 9.6.1.3.2 and 9.6.1.3.3.92 After the end of the follow-up phase there is no 
requirement to actively collect AEs including deaths. In case of permanent discontinuation of 
study medication, AEs other than outcome events must be reported up to one month after the
last dose of study medication intake.
The type of information that should be assessed and recorded by the investigator for each AE 
requiring documentation is listed in Section 9.6.1.2. "Death" should not be recorded as an AE 
on the AE page. Instead, "death" is the outcome of underlying AE(s). For all serious adverse 
events (SAEs), the Sponsor has to carry out a separate assessment for expectedness, 
seriousness and causal relationship to study drug.
In the current study, a targeted approach will be followed for AE/SAE documentation and 
reporting. Regarding non-serious AEs, this basically means that only
i) non-serious AEs leading to screening failure (pre-randomization),
ii) non-serious AEs leading to permanent discontinuation of study-drug treatment (post-
randomization), and
iii) any non-serious AEs of particular concern to the investigator
will be captured on the AE page of the eCRF (but these events do not require further reporting 
to the Sponsor’s pharmacovigilance (PV) department).93 Other non-serious AEs will not be 
collected because of the large available safety database for rivaroxaban.
The handling of SAEs is described in the following Section 9.6.1.3.3.
9.6.1.3.3
Reporting of serious adverse events and study-specific exemptions -
amended
The common definition of SAEs is given in Section 9.6.1.1. Each SAE must be followed up 
until resolution or stabilization by submission of updated reports to the designated recipient.
The efficacy and safety outcomes in this study will be collected in the eCRF and regularly 
monitored by the IDMC during the entire course of the study in a timely adequate manner. 
Due to this targeted surveillance, no AE documentation and no expedited SAE reporting will 
be performed for these events. Consequently, they will neither be un-blinded nor reported to 
regulatory authorities, IECs, or investigators. The IDMC will periodically review and assess 
all safety data for imbalances in safety outcomes. It is believed that in this way patient safety 
can continue to be monitored throughout the duration of the trial, along with study integrity. If 
unexpected safety issues are identified, specific amendments will be implemented.
The following rules should be followed:
1. Primary and secondary efficacy outcome events occurring after randomization will 
not be recorded on the AE page and not be reported as SAEs to Sponsor's PV 
                                                
92 Cross-references added by Amendment 4 (change no. 17).
93 Wording changed by Amendment 4 (change no. 17).


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department, but they will be collected on the specific eCRF pages as an efficacy 
outcome event.
2. Safety outcome events (i.e., bleeding events occurring after signing of the ICF) will 
not be recorded on the AE page and not be reported as SAEs to Sponsor's PV 
department, but they will be collected on the specific eCRF pages as a safety outcome 
event. 94
3. All other SAEs (including complications of efficacy or safety outcome events) that 
fulfill the seriousness criteria provided in Section 9.6.1.1 need to be collected on the 
eCRF (AE page) and reported as SAEs to the PV department. All SAEs that fulfill 
SUSAR criteria will be reported to the concerned authorities by expedited means (see 
Section 9.6.1.4).
4. Pregnancies need to be captured and reported to the Sponsor's PV department within 
24 hours, even if classified as non-serious (see Section 9.6.2).
Investigator’s notification of the Sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator's reporting obligations for SAEs. This information, including all relevant contact 
details, is summarized in the investigator site file. This information will be updated as needed.
The investigator must report immediately (i.e., within 24 hours of the investigator’s 
awareness) all SAEs not exempted from SAE reporting occurring during the observation 
period to the recipient detailed in the instructions for SAE reporting included in the 
investigator site file. For this, an AE page in the eCRF as well as the complementary pages 
provided in the investigator site file must be completed for each SAE. 
The investigator is responsible for continuing to follow all SAE reports (whether or not 
related to study drug) until resolution or until the event is considered chronic and/or stable by 
the investigator and/or other physician who has the responsibility for the patient’s medical 
care. Follow-up SAE reports will be reported according to the same timelines as initial 
reports, as soon as new significant information becomes available (in conformity with the 
Sponsor's PV guidance).
SAEs occurring after the protocol-defined observation period will be processed by the 
Sponsor according to all applicable regulations.
Notification of the IECs / IRBs
Notification of the IECs / IRBs about all relevant events (e.g., SAEs, SUSARs) will be 
performed by the Sponsor and/or by the investigator according to all applicable regulations 
and policies.
Notification of the authorities
The processing and reporting of all relevant events (e.g., SAEs, SUSARs) to the authorities 
will be done by the Sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The Sponsor will inform all investigational sites about reported relevant events (e.g., 
SUSARs) according to all applicable regulations.
                                                
94 No. 2 changed with Protocol Amendment 5 (change no. 7).


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9.6.1.4
Expected adverse events
For this study, the applicable reference document is the most current version of the 
Investigator's Brochure (IB).
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB. If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the Sponsor according to the applicable 
reference document (IB) and according to all local regulations. All SAEs that fulfill the 
SUSAR criteria as defined by the International Conference on Harmonization (ICH) E2A 
Guideline will be reported to the concerned authorities by expedited means.
In compliance with applicable regulations, in the event of a SUSAR, the patient’s treatment 
code will usually be unblinded before reporting to the competent authorities, IECs/IRBs. For 
reporting to investigators, the treatment blind, if possible, will be kept.
9.6.2
Pregnancies
Pregnancy (and its outcome) in a patient or in the patient’s partner need to be captured and 
reported to Sponsor’s PV department within 24 hours even if classified as non-serious. If the 
pregnancy/outcome of pregnancy fulfills SUSAR criteria, the outcome of the pregnancy will 
be reported to the concerned authorities by expedited means.
The outcome of the pregnancy should be followed up carefully, and any outcome of the 
mother and the child at delivery should be reported. For a pregnancy in the partner of a male 
study patient, all efforts will be made to obtain similar information on course and outcome, 
patient to the partner’s consent.
For all reports, the forms provided are to be used. The investigator should submit them within
the same timelines as an SAE.
9.6.3
Further safety – amended
In this study, vital signs assessments will be performed at each study visit as further safety 
measures. Vital signs (systolic and diastolic blood pressure, pulse rate) will be measured 
either in a supine or sitting position (preferably in the same position per patient) after a 
minimum of 5 minutes rest.  
It is also generally expected that study visit assessments of subjects occurs under the direct 
supervision of medically qualified personnel such as a physician to determine the need for 
additional evaluations. It is expected that laboratory surveillance should follow standard of 
care, tailored to the specific need and clinical indications of the subjects. As part of standard 
in-hospital, perioperative, and chronic care of such patients with known vascular conditions, 
repeat and in some cases frequent laboratory testing may be required. Record the relevant 
laboratory parameters on the corresponding eCRFs.95
9.7
Other procedures and variables
9.7.1
European Quality of Life-5 Dimensions Questionnaire - amended
For the quality of life assessment the European Quality of Life-5 Dimensions Questionnaire 
(EQ-5D) will be used as a standardized measure of health outcomes. The assessment is 
                                                
95 Paragraph was added with Protocol Amendment 4 (change no. 19)


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applicable to a wide range of health conditions and treatments and it provides a simple 
descriptive profile and a single index value for health status. The EQ-5D is primarily designed 
for self-completion by patients.
The EQ-5D will be administered at the randomization visit, and subsequently at each on-site 
visit.96
9.7.2
Walking Impairment Questionnaire - amended
The Walking Impairment Questionnaire (WIQ) is an effective and validated tool to assess the 
objective improvement or deterioration in the daily walking ability of PAD patients [Nicolai
et al. 2009]. Assessments will be performed at the randomization visit, and subsequently at 
each on-site visit.97
9.7.3
Health resource use - amended
98Health care resource utilization data related to all efficacy and safety outcomes events 
referred to as Health Care Resource Utilization (HCRU) will be collected for all patients 
during the study using the Health Care Resource Utilization form in the eCRF. These may
include: hospitalizations (total days length of stay, intensive care unit/cardiac care unit days, 
ward type), emergency room visits, unscheduled out-patient physician consultations, visits 
related to bleeding, surgeries, other and selected procedures (inpatient and outpatient), and 
days off-work. Country-specific cost data may be linked at a later stage.
9.7.4
PAD Symptom Status - amended
99The PAD Symptom Status assessment is a graded scale used to assess the severity of 
chronic PAD. This assessment tool, adapted from the commonly-used Rutherford 
classification of chronic limb ischemia [Rutherford et al. 1997], categorizes subjects’ 
condition into one of six strata of chronic limb ischemia severity ranging from asymptomatic 
to tissue loss beyond the digits of the foot. This assessment will be completed by the 
investigator at the Randomization visit, and subsequently at each on-site visit.
9.8
Appropriateness of procedures / measurements
With the exception of routine laboratory assessments performed at Screening, no invasive 
procedures are planned for this study. All study visits will be used to collect safety and 
outcome data that are considered appropriate measures for this event-driven trial (see 
Section 3.3).
10.
Statistical methods and determination of sample size
10.1
General considerations
A general description of the statistical methods is outlined below. A Statistical Analysis Plan 
(SAP) will be provided in a separate document and will contain a more technical and detailed 
description of the planned analyses. The core SAP is targeted to be finalized prior to study 
enrollment. Amendments and/or appendices to the core SAP will provide more details on the 
                                                
96 Sentence was revised with Protocol Amendment 4 (change no. 17)
97 Sentence was revised with Protocol Amendment 4 (change no. 17)
98 This section was modified with Protocol Amendment 4 (change no. 17).
99 This section was added with Protocol Amendment 4 (change no. 12)


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coding guidelines, data-handling, and output tables and figures. These SAP-associated 
documents are targeted for completion 6 months before the planned interim analysis.
Analyses will be performed using SAS software (SAS Institute Inc., Cary, North Carolina, 
USA); the version used will be specified in the SAP.
10.2
Analysis sets
The efficacy analyses will be based on the intent-to-treat (ITT) population, which comprises 
all randomized patients. In the ICH E9 guideline this is also termed the Full Analysis Set. 
Patients will be categorized to the group to which they were assigned by the IxRS; i.e., they 
will be analyzed as randomized.
The safety analyses will be based upon the safety analysis set, which comprises all treated 
patients, i.e., randomized patients who received at least one dose of study drug. For the 
purpose of safety analyses, patients will be categorized to the group to which they were 
assigned by the IxRS unless the incorrect treatment was received throughout the study. In this 
case, patients will be analyzed for safety as actually treated.
10.3
Variables and planned statistical analyses
10.3.1
Variables
The efficacy outcome variables of this study are defined in Section 9.4.3.1 (primary efficacy 
variable), Section 9.4.3.2 (secondary efficacy variables), and Section 9.4.3.3 (other efficacy 
variables). The ITT data scope (primary data scope for the efficacy analyses) will include all 
outcome events observed from randomization until the efficacy cut-off date. The follow-up 
period for each patient will be as long and complete as possible.
The safety outcomes of this study are defined in Section 9.6.1.3. The on-treatment data scope 
(primary data scope for the assessments of the aforementioned safety variables) will include 
all outcome events observed from randomization until 2 days following permanent 
discontinuation of the study drug.
10.3.2
Planned subgroups
Subgroup analyses based on demographic characteristics (such as age, sex, race, etc.) and 
baseline randomization stratum are planned. Additional subgroups will be specified in the 
SAP.
10.3.3
Statistical and analytical plans
10.3.3.1
Analysis of the primary efficacy variable
The primary efficacy analysis will be based on the time from randomization to the first 
occurrence of any of the components of the primary efficacy outcome (independently 
adjudicated) including CV death, MI, ischemic stroke, major amputation, and ALI, using the 
ITT principle (i.e., patients as randomized [Full Analysis Set] considering all events until the 
efficacy cut-off date).
The null hypothesis will be:
H0, PE: SR(t) = SA(t) for all time points t ≥0, (i.e., "there is no difference between the 
rivaroxaban added to ASA group and the ASA alone group regarding the primary 
efficacy outcome for all time points"),
and the one-sided alternative hypothesis will be:


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H1, PE: SR(t) >SA(t) for at least one time point t ≥0, and SR(t) ≥SA(t) for all time points 
t ≥0, (i.e., "there is a difference between the two groups in favor of rivaroxaban 
regarding the primary efficacy outcome for at least one time point"),
where SR denotes the survival function of the rivaroxaban added to ASA group and SA denotes 
the survival function of the ASA alone group.
The rivaroxaban added to ASA group will be compared to the ASA alone group using a log-
rank test stratified by type of procedure and use of clopidogrel ((i.) surgical vs. (ii.) 
endovascular with clopidogrel vs. (iii.) endovascular without clopidogrel) with treatment as 
fixed factor. Superiority of rivaroxaban over placebo will be declared, if the associated one-
sided null hypothesis is rejected in favor of rivaroxaban at the 2.5% significance level.
Kaplan-Meier estimates of cumulative risk and cumulative hazard functions will be provided 
to evaluate the timing of event occurrence in the different treatment groups and the 
consistency of the respective treatment effects for all time points.
The RR reduction will be estimated using a Cox proportional hazards model, stratified by type 
of procedure and use of clopidogrel, with treatment as the only covariate. The point estimate 
and corresponding 95% confidence interval (CI) for the hazard ratio (HR, rivaroxaban added 
to ASA vs. ASA alone) will be reported. The plausibility of proportional hazards assumption 
will be assessed by visually comparing the plot of the log of cumulative hazard between 
treatments and by additionally adding a treatment by logarithm-transformed time interaction 
into the Cox model.
10.3.3.2
Analysis of the secondary and other efficacy variables
The secondary efficacy variables are provided in Section 9.4.3.2 and the other efficacy 
variables are presented in Section 9.4.3.3. 
The secondary efficacy variables will be analyzed similarly to the primary efficacy variable.
If the superiority of rivaroxaban for the primary variable is declared, the secondary efficacy 
variables will be tested in the sequential order as listed in in Section 9.4.3.2.
The other efficacy variables will be analyzed similarly to the primary efficacy variables 
except for the patient reported outcomes and considered exploratory.
10.3.3.3
Analysis of safety outcomes and regular adverse events
Time to the first occurrence of the primary safety outcome (i.e., TIMI major bleeding) will be 
compared using a Cox proportional hazards model stratified by type of procedure and 
clopidogrel use with treatment group as a covariate. The analysis will be conducted in the 
safety analysis set and for the on-treatment data scope. The other time-to-event safety 
outcomes will be analyzed similarly.
Adverse events reported as per study-specific rules for event exemption (Section 9.6.1.3) will 
be analyzed by MedDRA system organ class and preferred term level using tabulated 
summaries with absolute and relative frequencies.
10.3.3.4
Analysis of subgroups
Analyses for the primary efficacy and safety outcomes for the subgroups as listed in 
Section 10.3.2 will be performed based on the same analysis sets and data scopes as in the 
main analyses, and presented descriptively. Homogeneity of treatment effect in subgroups, 
both in magnitude and direction, will be assessed.


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10.3.3.5
Handling of missing data
All efforts will be made to collect complete data for all patients randomized in this study
including visits by telephone contact. Patients will be followed to the study end and all 
required data will be collected, regardless of their compliance with study medications or 
visits.
When an event date is not complete, the date will be estimated to be the middle date within 
the period that the event is known to have occurred, e.g., if the event is known to have 
occurred in the first week of a month, then the date in the middle of that week will be used; if 
no information is known then the date in the middle of the plausible time period will be used, 
based on the last contact with the patient prior to the event and the date of contact when 
information about the event was known.
If a patient experiences a fatal event that is not part of a specific endpoint under analysis, the 
patient will be considered as having been censored at the earlier date of efficacy cut-off or the 
time of death. If a patient is lost to follow-up or has withdrawn consent and has not 
experienced any endpoint events under analysis, the patient will be counted as censored at the 
last contact date prior to the date of efficacy cut-off, with complete information of the 
endpoint being analyzed (e.g., for analysis of the primary endpoint, information regarding all 
components of the primary endpoint need to available at the contact date).
10.4
Determination of sample size
The study is event-driven and it is estimated that approximately 6,500 patients (3,250 per 
treatment group) need to be randomized in order to have 1,015 patients experiencing a 
confirmed primary efficacy outcome event. This number of events will allow the 
demonstration of superiority of rivaroxaban compared to placebo with regard to the primary 
outcome with a power of 90% and a one-sided level of significance α=0.025 under the 
following assumptions:

the effect size (Hazard Ratio) for rivaroxaban 2.5 mg bid plus study ASA 100 mg od 
vs. placebo plus study ASA 100 mg od is HR=0.8;

the annualized event rate in the control arm is approximately 7.5% per year;

the rate of patients with permanent discontinuation of study drug (rivaroxaban plus 
ASA switching to ASA alone or an equally effective treatment regimen) is 
approximately 5.5% in the 1st year, 8% in the 2nd year, 12% in the 3rd year (4% 1st half 
+ 8% 2nd half), and 8% every half year afterwards;

the rate of patients lost to follow-up or with non-CV death is approximately 1.5% per 
year;

the duration of the enrollment period is 18 months (approximately 15% in the 1st
6 months, 30% in the 2nd 6 months, and 55% in the 3rd 6 months) and 2 years of 
follow-up from last patient-randomized until the efficacy cut-off date.
The event rates used for this sample size estimation are extrapolated from recent studies such 
as the TRA2oP-TIMI 50 trial. Based on the TRA2oP-TIMI 50 study, both the CV and limb 
events are estimated at an annualized rate of approximately 4% each, with both CV and limb 
events being higher in those patients who had a history of prior peripheral revascularization 
procedure [Bonaca et al. 2013]. It is assumed that, given the acuity of the population based on 
underlying symptoms and CLI presentation, the proximity to the revascularization procedure, 
and the fact that the patients in this study will all have a revascularization procedure, the short 


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and intermediate term events would be considerably higher. Also these CV and limb events 
are generally considered non-overlapping and non-competing.
Inherently, the number of patients enrolled may be adjusted based on the observed overall 
event rate of the primary efficacy outcomes during the study. Sample size estimation was 
based on PASS 11100 [Hintze 2011].
10.5
Planned interim analyses
The IDMC will monitor the study for greater than expected efficacy and for safety. There will 
be one formal pre-planned interim analysis to assess greater than expected efficacy, which 
will be performed when approximately 67% of the planned primary efficacy outcome events 
have accrued. Based on that analysis, the study may be stopped early, if there is 
overwhelming superiority of rivaroxaban (p<0.001, 2-sided) for primary efficacy endpoint 
(following the Haybittle-Peto approach). Due to the conservative amount of alpha spent at 
interim, no alpha adjustment will be made for the final efficacy analyses [Haybittle 1971].
Also, secondary efficacy and safety will be considered. The study will be stopped early if the 
totality of data suggests an overwhelming benefit of rivaroxaban added to ASA over ASA 
alone. No formal boundaries have been set for terminating the study for safety reasons; but 
clear, consistent, and persistent evidence of net harm that overwhelms any benefit should be 
apparent through periodic assessment by the IDMC.
Details on the modalities of the interim analyses and decision rules will be specified in the 
IDMC charter.
11.
Data handling and quality assurance
11.1
Data recording
101Data required according to this protocol will be recorded by trained investigational site 
personnel via data entry into the internet based validated EDC software system RAVE from
Medidata Solutions. RAVE allows for the application of software logic to set-up data entry 
screens and data checks to ensure the completeness and accuracy of the data entered by the 
site personnel.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All study personnel seeking access must go through a thorough RAVE 
training process before they are granted access to RAVE for use in clinical studies. Training 
records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
Data entries made in the RAVE EDC screens are supported by source documents maintained 
for all subjects enrolled in this study.
Source documentation
Sites must implement processes to ensure that all data entered into the eCRF are supported by 
source documentation. A source document checklist will be used at the site to identify the 
                                                
100 Reference added with Protocol Amendment 4 (change no. 17)
101 Section revised with Protocol Amendment 4 (change no. 17).


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source data for all data points collected, in accordance with the latest version of the protocol 
and study agreements102. 
Data recorded from screening failures
Data of ‘only screened patients’ will be recorded at least as source data, as far as the reason 
for the premature discontinuation is identifiable. At minimum, the following data should be 
recorded in the eCRF:

demographic information (patient number; year of birth / age; sex; race / ethnicity),

date of informed consent,

reason for premature discontinuation,

date of last visit.
These data will be transferred to the respective database.
For screening failures with an SAE, the following data should be collected in the eCRF in 
addition to the data specified above:
all information about the SAE,
all information related to the SAE such as: 

concomitant medication,

medical history,

other information needed for SAE complementary page.
11.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
Generally, the sponsor/designee will monitor the site activity to verify that the:

data are authentic, accurate, and complete,

safety and rights of patients are being protected,

study is conducted in accordance with the currently approved protocol (including 
study treatment being used in accordance with the protocol),

any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
11.3
Data processing
The data collection tool for this study will be a validated electronic system called Medidata 
RAVE. Patient data necessary for analysis and reporting will be entered / transmitted into a 
                                                
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validated database or data system (e.g., Tools for syntactic corpus analysis [TOSCA]; SAS). 
Clinical data management will be performed in accordance with the applicable 
sponsor’s/CRO’s standards and data cleaning procedures. This is applicable for data recorded 
on the eCRF as well as for data from other sources (e.g. IxRS, ICAC, Laboratory).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
11.4
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study.
11.5
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice. Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change (e.g.,
relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof) at 
any time, which may be due but not limited to 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 the review by the IDMC,
results of parallel clinical studies,
if the study conduct (e.g., recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the study within a reasonable 
time frame.


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The investigator has the right to close his/her center at any time. In this case, it may be
explored whether patients can still be further followed-up for outcome events and vital status 
or whether patients could be switched to another investigational site.
For any of the above closures, the following applies:
•
closures should occur only after consultation between involved parties. Final decision 
on the closure must be in writing,
•
all affected institutions (e.g., IEC(s)/IRB(s); competent authority(ies); study center; head 
of study center) must be informed as applicable according to local law,
•
all study materials (except documentation that has to remain stored at site) must be 
returned to the Sponsor. The investigator will retain all other documents until 
notification is given by the Sponsor for destruction,
•
in the event of a partial study closure, ongoing patients, including those in post study 
follow-up, must be taken care of in an ethical manner.
13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate. This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.
13.1.1
Investigators
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained, and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g., health authority, ethics committee, sponsor) 
before patient recruitment may start at the respective center. Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
13.1.2
Study personnel
Study personnel relevant for the centers will be available in each center’s investigator site file.
13.1.3
External data evaluation bodies
Four study committees will be established in order to ensure a proper study conduct according 
to the state of the art as well as independent, consistent, and high-quality data review. 
Separate charters will be prepared for all study committees overseeing the study including the 
personnel, responsibilities, procedures, and meeting frequencies. Generally, the committees 
are:


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Executive Committee (EC)
The EC will consist of academic and sponsor members. The EC has the final decision 
responsibility and will provide scientific input into the overall trial design and specific trial 
methodologies. In addition, the EC will contribute to the development of the statistical 
analysis plans and will serve as the publication committee. It will be actively engaged in 
discussions with regulatory authorities, will be responsible for identifying and populating the
key trial committees and will actively participate in site selection. The EC will meet regularly 
during the study conduct and provide key input into ongoing trial operations, will work with 
the Sponsor and CRO/ARO to identify issues in trial conduct with a focus on resolution of 
those issues. Communication with trial committees, national lead investigators, and trial sites 
will be overseen by the EC. Likewise, any recommendations in trial conduct from the IDMC 
or changes in the protocol will be overseen by the EC. 
International Steering Committee (ISC)
The International Steering Committee (ISC) will consist of the 2 co-principal investigators, 
National Lead Investigators from all countries, and sponsor representatives. The ISC will be 
responsible for all scientific aspects of the study and will ensure that study execution and 
management of the study are of the highest quality. The ISC will convene regularly to discuss 
and report on ongoing supervision of the study.
Independent Data Monitoring Committee (IDMC)
The primary role of the IDMC is to ensure the safety of the patients in the ongoing study. The 
IDMC will comprise a chair, co-chair, and members who have recognized expertise in clinical 
trials, neurologic or cardiovascular disease, and/or biostatistics; and who are not members of 
the ISC, or involved as investigators or otherwise in the trial.
Independent Central Adjudication Committee (ICAC)
The Independent Central Adjudication Committee (ICAC) will comprise of members with 
appropriate clinical and methodological expertise, blinded to study medication assignment, 
who will be responsible for adjudication and classification of outcome events in the study.
13.2
Funding and financial disclosure
Funding
This study will be funded by the Sponsor Bayer HealthCare AG103 and Janssen 
Pharmaceuticals Inc. 
Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research patients has to provide a financial disclosure 
according to all applicable legal requirements. All relevant documentation will be filed in the 
trial master file.
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the Declaration 
                                                
103 Text revised with Protocol Amendment 4 (change no. 17).


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of Helsinki. The study will also be carried out in keeping with applicable local law(s) and 
regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the IEC/IRB approval 
must be obtained and also forwarded to the sponsor. 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 
EC/IRB members involved in the vote and a statement to confirm that the IEC/IRB is 
organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial patients without prior IEC/IRB/sponsor approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor. Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Subject information and consent
All relevant information on the study will be summarized in an integrated patient information 
sheet and ICF provided by the sponsor. A sample patient information and ICF is provided as a 
document separate to this protocol.
Based on this patient information sheet, the investigator or designee will explain all relevant 
aspects of the study to each patient, prior to his/her entry into the study (i.e., before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.
Each patient will be informed about the following aspects of premature withdrawal:
•
each patient has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
•
The patient’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2.1.4 to be conducted after withdrawal of consent. 
•
The patient’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the statistical analysis plan.
•
Patient-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g., image reading, analysis of biological specimen such 
as blood, urine, or tissues); these data would also be retained and statistically analyzed 
in accordance with the statistical analysis plan. The patient has the right to object to 
the generation and processing of this post-withdrawal data. For this, he/she needs to 


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sign a corresponding declaration of objection; alternatively, the patient’s oral objection 
may be documented in the patient’s source data.
Each patient will have ample time and opportunity to ask questions.
Only if the patient voluntarily agrees to sign the ICF and has done so, may he/she enter the 
study. Additionally, the investigator will personally sign and date the form. The patient will 
receive a copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or patient´s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
If the patient is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of the sponsor and the 
investigator). This is to be documented by a signature from the informing physician as well as 
by a signature from the witness.
For adults under legal protection, consent shall be given by the legal guardian(s). The consent 
of an adult under legal protection shall also be requested where such a person is able to 
express his/her own will. His/her refusal or the withdrawal of his/her consent may not be 
disregarded.
The ICF and any other written information provided to patients will be revised whenever 
important new information becomes available that may be relevant to the patient’s consent, or 
there is an amendment to the protocol that necessitates a change to the content of the patient
information and/or the written ICF. The investigator will inform the patient of changes in a 
timely manner and will ask the patient to confirm his/her participation in the study by signing 
the revised ICF. Any revised written ICF and written information must receive the IEC/IRB`s 
approval / favorable opinion in advance of use.
13.5
Publication policy and use of data
The results of the VOYAGER PAD study will be published, irrespective of the findings. The 
primary results will be prepared for publication and submitted to a respective journal in a 
timely fashion following final data lock and delivery of all validated tables, figures and 
listings. At the conclusion of the VOYAGER PAD trial, the EC will serve as the main core of 
a Publications Committee and will manage the publication of the primary study results and 
subsequent analyses. The Publications Committee will review all manuscript proposals for 
scientific merit and approve the authorship and content of all proposals. Journal papers 
produced by the EC will comply with the guidelines set forth by the uniform requirements for 
manuscripts submitted to biomedical journals, drawn up by the International Committee of 
Medical Journal Editors, see http://www.icmje.org/. 
The EC will provide the final draft version for publication to the sponsor for review; the EC 
will maintain the authority of final approval of the manuscript to submit for publication. The 
sponsor will have a period of up to 30 days for review and comment prior to submission of 
any manuscripts for publication.
The EC will co-ordinate the timing and authorship of derived publications referring to data 
from this study to ensure that secondary publications do not jeopardize the primary 
publications from this study.


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13.6
Compensation for health damage of subjects / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
13.7
Confidentiality
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Patient names will not be supplied to the sponsor. Only the patient number will be recorded in 
the eCRF, and if the patient name appears on any other document (e.g., pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of 
the informed consent process, the patients will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the patient’s identity will remain confidential.
The investigator will maintain a list to enable patients to be identified.


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14.
Reference list - amended
Abola MT, Bhatt DL, Duval S, et al. Fate of individuals with ischemic amputations 
in the REACH Registry: three-year cardiovascular and limb-related 
outcomes. Atherosclerosis. 2012;221(2):527-35.
Alonso-Coello P, Bellmunt S, McGorrian C, et al. Antithrombotic therapy in 
peripheral artery disease: Antithrombotic Therapy and Prevention of 
Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based 
Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e669S-90S.
Anand S, Yusuf S, Xie C, et al. Oral anticoagulant and antiplatelet therapy and 
peripheral arterial disease. The New England journal of medicine. 
2007;357(3):217-27.
Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. 
Journal of the American College of Cardiology. 2003;41(4 Suppl S):62S-9S.
Anderson JL, Halperin JL, Albert NM, et al. Management of patients with peripheral 
artery disease (compilation of 2005 and 2011 ACCF/AHA guideline 
recommendations): a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines. 
Circulation. 2013;127(13):1425-43.
Andreotti F, Testa L, Biondi-Zoccai GG, et al. Aspirin plus warfarin compared to 
aspirin alone after acute coronary syndromes: an updated and comprehensive 
meta-analysis of 25,307 patients. European heart journal. 2006;27(5):519-26.
Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary
prevention of vascular disease: collaborative meta-analysis of individual 
participant data from randomised trials. Lancet. 2009;373(9678):1849-60.
Becker F, Robert-Ebadi H, Ricco JB, et al. Chapter I: Definitions, epidemiology, 
clinical presentation and prognosis. European journal of vascular and 
endovascular surgery : the official journal of the European Society for 
Vascular Surgery. 2011;42 Suppl 2:S4-12.
Berger JS, Krantz MJ, Kittelson JM, et al. Aspirin for the prevention of 
cardiovascular events in patients with peripheral artery disease: a meta-
analysis of randomized trials. Jama. 2009;301(18):1909-19.
Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, 
stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. 
Journal of the American College of Cardiology. 2007;49(19):1982-8.
Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for 
the prevention of atherothrombotic events. The New England journal of 
medicine. 2006;354(16):1706-17.
Biancari F. Meta-analysis of the prevalence, incidence and natural history of critical 
limb ischemia. The Journal of cardiovascular surgery. 2013;54(6):663-9.
Bonaca MP, Scirica BM, Creager MA, et al. Vorapaxar in patients with peripheral 
artery disease: results from TRA2P-TIMI 50. Circulation. 
2013;127(14):1522-9.


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Cacoub PP, Bhatt DL, Steg PG, et al. Patients with peripheral arterial disease in the 
CHARISMA trial. European heart journal. 2009;30(2):192-201.
CAPRIE-Steering-Committee. A randomised, blinded, trial of clopidogrel versus 
aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering 
Committee. Lancet. 1996;348(9038):1329-39.
Conte MS, Geraghty PJ, Bradbury AW, et al. Suggested objective performance 
goals and clinical trial design for evaluating catheter-based treatment of 
critical limb ischemia. Journal of vascular surgery. 2009;50(6):1462-73.
Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in 
patients with peripheral arterial disease. The New England journal of 
medicine. 1992;326(6):381-6.
de Donato G, Gussoni G, de Donato G, et al. The ILAILL study: iloprost as adjuvant 
to surgery for acute ischemia of lower limbs: a randomized, placebo-
controlled, double-blind study by the italian society for vascular and 
endovascular surgery. Annals of surgery. 2006;244(2):185-93.
Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA Guideline on 
Perioperative Cardiovascular Evaluation and Management of Patients 
Undergoing Noncardiac Surgery: A Report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines. 
Journal of the American College of Cardiology. 2014;0735-1097.
Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence 
and risk factors for peripheral artery disease in 2000 and 2010: a systematic 
review and analysis. Lancet. 2013;382(9901):1329-40.
Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and 
stroke statistics--2014 update: a report from the American Heart Association. 
Circulation. 2014;129(3):399-410.
Goodney PP, Nolan BW, Schanzer A, et al. Factors associated with amputation or 
graft occlusion one year after lower extremity bypass in northern New 
England. Annals of vascular surgery. 2010;24(1):57-68.
Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. 
The British journal of radiology. 1971;44(526):793-7.
Hintze J. Using PASS 11, LLC. Kaysville, Utah, USA. Available: www.ncss.com. 
2011. 104
Jones WS, Patel MR, Dai D, et al. High mortality risks after major lower extremity 
amputation in Medicare patients with peripheral artery disease. American 
heart journal. 2013;165(5):809-15.
Korabathina R, Weintraub AR, Price LL, et al. Twenty-year analysis of trends in the 
incidence and in-hospital mortality for lower-extremity arterial 
thromboembolism. Circulation. 2013;128(2):115-21.
                                                
104 Reference added with Protocol Amendment 4 (change no. 17)


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Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA Guidelines on non-cardiac 
surgery: cardiovascular assessment and management: The Joint Task Force 
on non-cardiac surgery: cardiovascular assessment and management of the 
European Society of Cardiology (ESC) and the European Society of 
Anaesthesiology (ESA). European heart journal. 2014;35(35):2383-431.
Mangiafico RA, Mangiafico M. Medical treatment of critical limb ischemia: current 
state and future directions. Current vascular pharmacology. 2011;9(6):658-
76.
Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent 
acute coronary syndrome. The New England journal of medicine. 
2012;366(1):9-19.
Morris DR, Rodriguez AJ, Moxon JV, et al. Association of lower extremity 
performance with cardiovascular and all-cause mortality in patients with 
peripheral artery disease: a systematic review and meta-analysis. Journal of 
the American Heart Association. 2014;3(4).
Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary 
prevention of atherothrombotic events. The New England journal of 
medicine. 2012;366(15):1404-13.
Moxey PW, Hofman D, Hinchliffe RJ, et al. Trends and outcomes after surgical 
lower limb revascularization in England. The British journal of surgery. 
2011;98(10):1373-82.
Nicolai SP, Kruidenier LM, Rouwet EV, et al. The walking impairment 
questionnaire: an effective tool to assess the effect of treatment in patients 
with intermittent claudication. Journal of vascular surgery. 2009;50(1):89-94.
Norgren L, Hiatt WR, Harris KA, et al. TASC II section F on revascularization in 
PAD. Journal of endovascular therapy : an official journal of the 
International Society of Endovascular Specialists. 2007;14(5):743-4.
Rutherford RB, Baker JD, Ernst C, et al. Recommended standards for reports 
dealing with lower extremity ischemia: revised version. Journal of vascular 
surgery. 1997;26(3):517-38. 105
Smith SC, Jr., Benjamin EJ, Bonow RO, et al. AHA/ACCF Secondary Prevention 
and Risk Reduction Therapy for Patients with Coronary and other 
Atherosclerotic Vascular Disease: 2011 update: a guideline from the 
American Heart Association and American College of Cardiology 
Foundation. Circulation. 2011;124(22):2458-73.
Sobel M, Verhaeghe R. Antithrombotic therapy for peripheral artery occlusive 
disease*: American college of chest physicians evidence-based clinical 
practice guidelines (8th edition). Chest. 2008;133(6_suppl):815S-43S.
Tendera M, Aboyans V, Bartelink ML, et al. ESC Guidelines on the diagnosis and 
treatment of peripheral artery diseases: Document covering atherosclerotic 
disease of extracranial carotid and vertebral, mesenteric, renal, upper and 
                                                
105 Reference added with Protocol Amendment 4 (change no. 12)


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lower extremity arteries: the Task Force on the Diagnosis and Treatment of 
Peripheral Artery Diseases of the European Society of Cardiology (ESC). 
European heart journal. 2011;32(22):2851-906.
Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial 
infarction. European heart journal. 2012;33(20):2551-67.
Vogel TR, Dombrovskiy VY, Carson JL, et al. In-hospital and 30-day outcomes 
after tibioperoneal interventions in the US Medicare population with critical 
limb ischemia. Journal of vascular surgery. 2011;54(1):109-15.
WAVE-Investigators. The effects of oral anticoagulants in patients with peripheral 
arterial disease: rationale, design, and baseline characteristics of the Warfarin 
and Antiplatelet Vascular Evaluation (WAVE) trial, including a meta-
analysis of trials. American heart journal. 2006;151(1):1-9.
Wedemeyer RS, Blume H. Pharmacokinetic drug interaction profiles of proton pump 
inhibitors: an update. Drug safety : an international journal of medical 
toxicology and drug experience. 2014;37(4):201-11.
Wong CK, White HD. Antithrombotic therapy in ST-segment elevation myocardial 
infarction. Expert opinion on pharmacotherapy. 2011;12(2):213-23.
Wong MC, Tam WW, Cheung CS, et al. Drug adherence and the incidence of 
coronary heart disease- and stroke-specific mortality among 218,047 patients
newly prescribed an antihypertensive medication: a five-year cohort study. 
International journal of cardiology. 2013;168(2):928-33.


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15.
Protocol amendments
15.1
Amendment 4
15.1.1
Overview of changes to the study
Amendment 4 is the first global amendment to the original clinical study protocol 17454 
Version 1.0, dated 23 March 2015.
Change 1: Administrative change
Rationale: The Sponsor’s study medical expert has changed. Instead of 
 
 has taken over this task.
Section affected include:

Title page
Change 2: The timing from randomization from the qualifying revascularization has 
changed from no later than 7 days to no later than 10 days
Rationale: It has been recognized that many subjects are discharged either the same day or the 
following day after their qualifying revascularization. In consideration of the difficulty of 
having subjects travel to the clinical research site so quickly after a revascularization 
procedure, the timing from the qualifying revascularization to randomization has been 
extended from 7 days to 10 days to facilitate enrollment.
Sections affected include:

Section 2, Synopsis (Methodology)

Section 5, Study design (also Figure 5-1)

Section 6.1, Inclusion criteria (criterion 3)

Section 9.1, Tabular schedule of evaluation (Table 9-1, footnote a)

Section 9.2.1.2, Randomization visit (RxV)
Change 3: The timing of screening was changed from up to 7 days after the qualifying 
revascularization to up to 30 days before, to up to 10 days after the qualifying 
revascularization (-30 days to +10 days) 
Rationale: This change provides the opportunity to consent subjects prior to the qualifying 
revascularization procedure. It is felt to be more beneficial for the consent process and 
enrollment to be able to approach subjects pre-operatively. This will also provide more of an 
opportunity to complete the required eligibility procedures that may not have been performed 
prior to the revascularization.  
Sections affected include:

Section 2, Synopsis (Methodology)

Section 5, Study design 

Section 9.1, Tabular schedule of evaluation (Table 9-1, footnote a)
PPD
PPD


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
Section 9.2.1.1, Screening visit (ScV)
Change 4: The anatomic location of eligible PAD was changed from “infra-inguinal” to 
“distal to the external iliac artery”.  
Rationale: “Infra-inguinal” was interpreted as distal to the common femoral artery. This 
change allows isolated common femoral procedures which has been recognized to include 
common practice patterns in certain geographic areas. The inclusion of this anatomic location 
is also felt to potentially benefit from study intervention and will contribute to enrollment of 
the study. 
Sections affected include:

Section 2, Synopsis (Diagnosis and main criteria for inclusion/exclusion)

Definition of medical terms (Endovascular / Surgical procedure)

Section 6.1, Inclusion criteria (criteria 2b and 3)

Section 9.3.3, Definition of qualifying revascularization procedure
Change 5: The ABI/TBI inclusion criterion was clarified.
Rationale: Qualifying symptoms and evidence of anatomic disease is specific to the leg 
undergoing revascularization. ABI/TBI criterion can be from either leg. A qualifying ABI or 
TBI from either leg can qualify a patient for the study, as this is felt to be sufficient to identify 
subjects with clinically significant PAD but also recognizes the fact that there is not a perfect 
correlation between ABI/TBI severity and symptom severity. There is no longer the 
requirement for non-compressible ABI result to allow TBI assessment, as this recognizes the 
scenario whereby the ABI rises in the setting of progressive arterial calcification, prior to 
becoming non-compressible.
Sections affected include:

Section 2, Synopsis (Diagnosis and main criteria for inclusion/exclusion)

Section 6.1, Inclusion criteria (criterion 2c)

Section 9.1, Tabular schedule of evaluation (Table 9-1, footnote g)

Section 9.2.1.1, Screening (Visit) (ScV)

Section 9.2.1.3, Treatment phase: Regular study visits from Visit 1 onwards

Section 9.2.1.4, End of treatment (EOT) visit
Change 6: The definition of qualifying revascularization was clarified and altered.
Rationale: Formerly was described as the last planned procedure if multiple procedures are 
performed on one leg, and silent on bilateral procedures. Changed to subjects are eligible to 
enroll after any qualifying revascularization on either leg; recommending (not requiring) last 
planned procedure if multiple procedures are planned. The change made to the ‘Definitions of 
medical terms’ simplifies the definition and consolidates the description of determinants of 
the qualifying revascularization into one section 9.3.3. This change is also felt to eliminate 


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ambiguity of the stated preference for enrollment after the last planned procedure in the 
setting of a staged revascularization treatment plan and the prior statement of defining the 
index leg as the most symptomatic leg. It is recognized that staged treatment plans often 
address the most severe lesions first and the less severe lesions with subsequent procedures.  
Sections affected include:

Definition of medical terms, Qualifying revascularization

Section 9.1, Tabular schedule of evaluations (Table 9-1, footnote g)

Section 9.3.3, Definition of qualifying revascularization procedure
Change 7: Subjects with prior revascularization on the index leg within 8 weeks of the 
qualifying revascularization were to be excluded from the study. The timeframe was 
changed to 10 days of the qualifying revascularization to accommodate staged treatment 
plans. The definition of the index leg was also simplified to reflect changes in the 
protocol regarding staged revascularization treatment plans and the recognized 
difficulty in identifying the most symptomatic leg in some cases.
Rationale: To be consistent with Change 2 and Change 6.
Sections affected include:

Section 2, Synopsis (Diagnosis and main criteria for inclusion/exclusion)

Definition of medical terms (Index leg)

Section 6.2, Exclusion criteria (criterion 3)

Section 9.3.3, Definition of qualifying revascularization procedure
Change 8: The secondary and exploratory efficacy endpoints dealing with 
revascularization was revised to specify that the endpoint is only for subsequent 
revascularizations that were not planned or considered as part of the treatment plan at 
the time of randomization. 
Rationale: To be consistent with change 6, this was further clarified to clearly delineate 
planned and staged subsequent revascularizations from unplanned revascularizations on the 
index leg for the purposes of analysis of a secondary efficacy endpoint.
Sections affected include:

Section 2, Synopsis (Study objective[s] and Primary and secondary variable[s])

Section 4, Study objectives

Section 9.4.3.2, Secondary efficacy variables

Section 9.4.3.3, Other efficacy variables


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Change 9: The guidance on DAPT following the qualifying revascularization was
revised to allow the use of >30 days, or >60 days in cases of labeled indication for a 
device, if the investigator determines that a medical need arises that warrants a longer 
course of clopidogrel therapy.
Rationale: This allows the investigator to increase the duration of DAPT if the clinical need 
arises during the course of initial DAPT in select cases by documenting this justification in the 
medical record. The aim here is to allow for investigator discretion and reflect real world 
practice without having this being a protocol violation.
Sections affected include:

Section 8.1, Prior and concomitant therapy
Change 10: The timeframe of the laboratory tests required to verify eligibility criteria 
(creatinine/eGFR) was changed from within 7 days prior to  the qualifying 
revascularization to within 30 days  prior to the qualifying revascularization.
Rationale: This was changed to be more consistent with practice patterns. 
Sections affected include:

Section 9.1, Tabular schedule of evaluations (Table 9-1, footnote c)

Section 9.2.1.1, Screening visit (ScV)
Change 11: The rules for study drug interruption due to prohibited medications were 
clarified.
Rationale: To correct conflicting information as well as to provide additional guidance on 
concomitant use of prohibited medications in the interest of subject safety.
Sections affected include:

Section 7.4.4, Guidance for the treatment of subjects who develop an acute coronary 
syndrome and those who require percutaneous coronary intervention with stenting
Change 12: The assessment of PAD Symptom Status was added to the randomization 
and all follow-up visits
Rationale: To correct an omission of the original protocol.
Sections affected include:

Section 9.1, Tabular schedule of evaluations (Table 9-1)

Section 9.2.1.2, Randomization visit (RxV)

Section 9.2.1.3, Treatment phase: Regular study visits from Visit 1 onwards

Section 9.2.1.4, End of treatment (EOT) visit

Section 9.7.4, PAD Symptom Status (new section)

Section 14, Reference list


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Change 13: Serial changes in limb hemodynamics (ABI/TBI) was added as an 
exploratory endpoint.
Rationale: To describe an additional planned analysis of study data.
Section affected include:

Section 9.4.3.3, Other efficacy variables
Change 14: The description of “successful procedure” was revised.
Rationale: Definition further clarified to reflect what is expected to meet this criteria.
Section affected include:

Section 9.3.3, Definition of qualifying revascularization procedure
Change 15: The following was added as an exclusion criterion: “Patients with major 
tissue loss (defined as significant ulceration/gangrene proximal to the metatarsal heads, 
i.e. heel or midfoot) in either leg” .The previous protocol excluded major tissue loss of 
the index leg in exclusion criterion #1.  The reference to “major tissue loss” in exclusion 
criterion #1 was removed and incorporated into the new, broadened exclusion criterion 
(#5) which now excludes major tissue loss of either leg.
Rationale: These patients are felt to have an end stage condition that is beyond the point of 
deriving benefit from study intervention.
Section affected include:

Synopsis (Diagnosis and main criteria for inclusion/exclusion)

Section 6.2, Exclusion criteria (criteria 1 and 5)
Change 16: Standard text from the protocol template was added / deleted
Rationale: The standard text was erroneously omitted from the original protocol or standard 
text was erroneously added twice in the same section or added to the wrong section.
Section affected include:

Section 3.4, Background (sentence added)

Section 6.3.1, Discontinuation and withdrawal (sentence added) 

Section 7.4.1 Dose Modification (sentence deleted and added to Section 3.4)

Section 9.6.1.2.6, Intensity (section added)

Section 11.1, Data recording (sentence deleted)


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Change 17: Minor clarifications and edits for consistency were made.
Rationale: These minor changes were made to ensure consistency and clarity throughout the 
document.
Section affected include:

Section 2, Synopsis (Study objectives, Background treatment, Diagnosis and main 
criteria for inclusion / exclusion, Methodology)

Definition of medical terms

Section 4, Study objectives

Section 16.2, Exclusion criteria (criteria 7, 12, 23)

Section 7.1, Treatment to be administered

Section 7.4, Dosage and administration

Section 7.4.3, Guidance for the treatment of subjects who require coronary artery 
bypass graft (CABG) surgery

Section 7.4.1, Dose modification

Section 7.4.4, Guidance for the treatment of subjects who develop an acute coronary 
syndrome and those who require percutaneous coronary intervention with stenting

Section 8.1, Prior and concomitant therapy

Section 9.1, Tabular schedule of evaluations (Table 9-1, abbreviations and footnotes c
and f)

Section 9.2.1.1, Screening visit (ScV)

Section 9.2.1.2, Randomization visit (RxV)

Section 9.2.1.3 Treatment phase: Regular study visits from Visit 1 onwards

Section 9.2.1.4, End of treatment (EOT) visit

Section 9.3.3, Definition of qualifying revascularization

Section 9.6.1.3.1, Assessment of bleeding events

Section 9.6.1.3.2, Assessment and documentation of adverse events

Section 9.7.1, European Quality of Life-5 Dimensions Questionnaires

Section 9.7.2, Walking Impairment Questionnaire

Section 9.7.3, Health resource use

Section 13.2, Funding and financial disclosure

´Section 10.4, Determination of sample size

Section 11.1, Data Recording

Section 14, Reference list


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Change 18:  “Breast feeding” as additional exclusion criterion added
Rationale:  This exclusion criterion was added to be consistent with the package labelling of 
study medications.
Section affected include:

Section 6.2 Exclusion criteria (criterion 25)
Change 19:  Documentation of laboratory evaluations
Rationale:  The request for a documentation of the laboratory evaluations was added to reflect 
the standard medical care. This change will also add uniformity of data collection across all 
sites, as rare countries have regulatory bodies that have required the additional collection of 
laboratory evaluations for safety monitoring. Since these laboratory evaluations are not 
mandated in the product labeling of rivaroxaban, the intent was to not mandate these 
procedures to maintain consistency with the product labeling. This may also serve to 
demonstrate that the study population is receiving optimal medical care for cardiac risk factor 
modification. Local reference ranges will be added at the site level.
Section affected include:

Section 9.2.1.2, Randomization visit (RxV)

Section 9.2.1.3, Treatment phase: Regular study visits from Visit 1 onwards

Section 9.6.3, Further safety
Change 20:  Further clarification of definition of inclusion criteria for PAD
Rationale: This change includes 3 justifications:
a) “Atherosclerotic” was added to clarify that the etiology of PAD should be 
atherosclerotic- related rather than an alternative etiology that may respond differently 
to this treatment
b) “Occlusive” was removed and the wording “peripheral” was added for consistency and 
further clarity.  The word “arterial” was changed to “artery” for consistency.
c) The timeframe of prior ABI/TBI testing for inclusion has been extended to 
“12 months” to more align with practice patterns and is not felt to impact the patient 
population being enrolled.
Section affected include:

Section 2, Synopsis (Diagnosis and main criteria for inclusion/exclusion)

Section 6.1, Inclusion criteria


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Change 21:  Inclusion criteria 7 was modified by removing the requirement of men to 
use contraception
Rationale: This is consistent with the product labeling and existing data demonstrating no 
known genotoxic effects of rivaroxaban.
Based on information in the IB for Rivaroxaban, contraception is not required for male 
subjects enrolled in the study nor their female partners. The language for this inclusion criteria 
for female subjects of child-bearing potential will be modified to be consistent with other 
similar rivaroxaban studies presently enrolling.
The language for Change 21 and Inclusion criteria 7 was changed to the following: ‘Women 
of reproductive potential must agree to use adequate contraception* when sexually active. 
This applies for the time period between signing of the informed consent form (ICF) to the 
last administration of study drug.’
Section affected include:

Section 6.1, Inclusion criteria (criterion 7)
Change 22:  Further clarification of prohibited therapies
Rationale: This change includes 4 justifications:
a) The use of prasugrel and ticagrelor was specifically added to the list of prohibited 
antiplatelet therapy in the interest of patients safety
b) The wording for “heparins” added for completeness and consistency
c) The sentence “Study medication shall be discontinued in patients who develop any 
condition which requires permanent or long term anticoagulation (e.g., DVT, atrial 
fibrillation)“ was removed as it was felt to be redundant and removed for clarity and 
consistency
d) The sentence “After PCI or CABG, treatment with DAPT should be considered for at 
least 48 hours.” was removed as it was felt to have been placed in the protocol in error.
Section affected include:

Section 8.1, Prior and concomitant therapy
Change 23:  Further guidance on reporting of clinical outcome events
Rationale: A sentence was added to inform investigators of the expectation that any clinical 
outcome event that could possibly be considered as such an event should also be reported for 
consideration by the ICAC.
Section affected include:

Section 9.4.1, Assessments and procedures at occurrence of primary efficacy events


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Change 24: Further clarification of definition of study efficacy outcome events
Rationale:  Minor changes were made to event definitions to be consistent with the outcome 
event definitions in the adjudication charter.
Section affected include:

Section 9.4.2, Definition of study efficacy outcome events
Change 25: Deletion of Appendix 16.1
Rationale: The decision was made to not pursue the duplex ultrasound substudy.
Section affected include:

Section 9.2.1.3, Treatment phase: Regular study visit from Visit 1 onwards

Section 9-1, Tabular schedule of evaluations

Section 16.1 Vascular ultrasound substudy


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15.1.2
Changes to the protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol, Version 1.0. In the display of modifications, the “old 
text” refers to the protocol version preceding this amendment; deletions are crossed out.  
Additions are underlined in the “new text” or “added text.”
15.1.2.1
Title page
The title page was modified based on amendment change 1.
Old Text: 
[…]
Sponsor’s study medical 
expert:
Bayer Vital GmbH, 51368 Leverkusen, Germany
Phone No. 
New Text: 
[…]
Sponsor’s study medical 
expert:
Bayer HealthCare Pharmaceuticals Inc.
100 Bayer Blvd, PO Box 915
Whippany, NJ 07981-0915; United States
Phone No. 
15.1.2.2
Section 2.  Synopsis, Study objective(s)
Section revised per amendment change 8.
Old Text: 
[…]
Secondary efficacy objectives:
•
to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of index limb revascularization;
[…]
•
to evaluate the efficacy of rivaroxaban in reducing the risk of venous thromboembolic 
(VTE) events;
•
to evaluate the efficacy of rivaroxaban in reducing the risk of all-cause mortality.
PPD
PPD
PPD
PPD


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New Text: 
[…]
Secondary efficacy objectives:
•
to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of index limb revascularization (subsequent index leg revascularizations that 
were not planned or considered as part of the initial treatment plan at the time of 
randomization);
[…]
•
to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of venous thromboembolic (VTE) events;
•
to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of all-cause mortality. 
15.1.2.3
Section 2.  Synopsis, Background treatment
Section revised per amendment change 17.
Old Text: 
All study patients will receive treatment with open label ASA 100 mg orally once daily (od) 
during the entire course of the study; additional treatment with clopidogrel may be 
administered for a planned duration of 30 days following the qualifying revascularization 
procedure, at the discretion of the investigator. This extended use will be limited to a labeled 
indication for a device (e.g., stent) and will not exceed 60 days.
New Text: 
All study patients will receive treatment with open label ASA 100 mg orally once daily (od) 
during the entire course of the study; additional treatment with clopidogrel may be 
administered for a planned duration of up to 30 days after the qualifying revascularization 
procedure (or up to 60 days for a labeled indication [e.g. drug coated stent or balloon]), at the 
discretion of the investigator
15.1.2.4
Section 2.  Synopsis, Diagnosis and main criteria for inclusion/exclusion
Section revised per amendment changes 4, 5, 7, 17 and 20.
Old Text: 
Main inclusion criteria are:
•
age ≥50,
•
documented moderate to severe symptomatic lower extremity peripheral artery 
occlusive disease as evidenced by ALL of the following:
a. clinically, by functional limitations in walking activity, ischemic rest pain, or 
ischemic ulceration, 
b. anatomically, by imaging evidence of arterial occlusive disease below the inguinal 
ligament within 6 months prior to or at the time of the qualifying revascularization, 


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AND
c. hemodynamically (within 6 months prior to, or at the time of, the qualifying 
revascularization) by:

an ABI ≤ 0.80 or TBI ≤ 0.60 of the index leg (in the event of non-compressible 
ankle arteries) for patients without a prior history of limb revascularization on 
the index leg,
OR

an ABI ≤ 0.85 or TBI ≤ 0.65 of the index leg (in the event of non-compressible 
ankle arteries) for patients with a prior history of limb revascularization on the 
index leg.
Main exclusion criteria are:
•
patients undergoing revascularization for asymptomatic PAD, mild claudication 
without functional limitation or major tissue loss (including severe ischemic ulcers or 
gangrene) of the index leg,
•
patients undergoing revascularization of the index leg to treat an asymptomatic or 
minimally symptomatic restenosis of a bypass graft or target lesion restenosis,
•
prior revascularization on the index leg within 8 weeks of the qualifying 
revascularization,
•
Planned dual antiplatelet therapy (DAPT) use for the qualifying revascularization 
procedure of clopidogrel in addition to ASA for >30 days after the qualifying 
revascularization procedure
•
Planned DAPT use for any other indication(s) with any P2Y12 antagonists in addition 
to ASA after the qualifying revascularization procedure
New Text: 
Main inclusion criteria are:
•
age ≥50,
•
documented moderate to severe symptomatic lower extremity atherosclerotic
peripheral artery disease as evidenced by ALL of the following:
a. clinically, by functional limitations in walking activity, ischemic rest pain, or 
ischemic ulceration,
b. anatomically, by imaging evidence of peripheral artery disease distal to the external 
iliac artery in the index leg within 12 months prior to or at the time of the 
qualifying revascularization, 
AND
c. hemodynamically in either leg (within 12 months prior to, or at the time of, the 
qualifying revascularization) by:

an ABI ≤ 0.80 or TBI ≤ 0.60 for patients without a prior history of limb 
revascularization,
OR

an ABI ≤ 0.85 or TBI ≤ 0.65 for patients with a prior history of limb 
revascularization.
Main exclusion criteria are:
•
patients undergoing revascularization for asymptomatic PAD, or mild claudication 


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without functional limitation,
•
patients undergoing revascularization of the index leg to treat an asymptomatic or 
minimally symptomatic restenosis of a bypass graft or target lesion restenosis,
•
prior revascularization on the index leg within 10 days of the qualifying 
revascularization,
•
Planned dual antiplatelet therapy (DAPT) use for the qualifying revascularization 
procedure of clopidogrel in addition to ASA for >30 days after the qualifying 
revascularization procedure (or > 60 days for a labeled indication [e.g. drug coated 
stent or ballon]) (*Planned use of clopidogrel not exceeding 60 days for a labeled 
indication for a device [e.g., stent or balloon] may be allowed; see section 8.1 for 
further guidance on clopidogrel),
•
Planned DAPT use for any other indication(s) with any P2Y12 antagonists in addition 
to ASA after the qualifying revascularization procedure
15.1.2.5
Section 2.  Synopsis, Methodology
Section revised per amendment changes 2 and 3.
Old Text: 
[…]
Randomization will be stratified by type of procedure and use of clopidogrel (i.e., (i.) surgical 
vs. (ii.) endovascular with clopidogrel vs. (iii.) endovascular without clopidogrel), and 
treatments will be balanced within a country for each stratum by block randomization. 
Randomization and study treatment will commence as soon as possible but no later than 
7 days after the qualifying revascularization.
The first study visit is a screening visit to be performed within 7 days after the qualifying 
revascularization. The second study visit is the randomization visit, which should be 
performed as soon as possible (but no later than 7 days) after the qualifying revascularization.
The first dose of study drug will be taken at the randomization visit
New Text: 
[…]
Randomization will be stratified by type of procedure and use of clopidogrel (i.e., (i.) surgical 
vs. (ii.) endovascular with clopidogrel vs. (iii.) endovascular without clopidogrel), and 
treatments will be balanced within a country for each stratum by block randomization. 
Randomization and study treatment will commence as soon as possible but no later than 
10 days after the qualifying revascularization.
The first study visit is a screening visit to be performed within 30 days prior to or no more 
than 10 days after the qualifying revascularization. The second study visit is the 
randomization visit, which should be performed as soon as possible (but no later than 10 days) 
after the qualifying revascularization. The first dose of study drug should be taken at the 
randomization visit


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15.1.2.6
Section 2.  Synopsis, Primary and secondary variable(s)
Section revised per amendment change 8.
Old Text: 
[…]
The secondary efficacy variables of the study will be:

time from randomization to the first occurrence of an index limb revascularization;
New Text: 
[…]
The secondary efficacy variables of the study will be:
•
time from randomization to the first occurrence of an index leg limb revascularization
(subsequent to index procedure that was not planned or considered part of the initial 
treatment plan at the time of randomization);
15.1.2.7
Definition of medical terms
Section revised per amendment changes 4, 6 and 7.
Old Text: 
[…]
Endovascular procedure
Refers to catheter-based and hybrid procedures (those 
procedures involving aspects of both endovascular and 
surgical revascularizations).
Index leg
Refers to the leg receiving the qualifying revascularization 
for randomization into this trial. In the event that 
revascularization is planned on both legs, the index leg will 
be defined as the most symptomatic one.
Qualifying revascularization
Refers to the procedure by which the patient qualifies for the 
study. The qualifying revascularization procedure for 
patients that require multiple attempts at revascularization 
on the index leg and lesion must be the last of the 
planned/foreseeable revascularizations.
[…]
Surgical procedure
Refers to surgical bypass procedure in the lower extremity 
for PAD below the inguinal ligament. This can include a 
variety of bypass conduit materials and extra-anatomic 
operations.


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New Text: 
[…]
Endovascular procedure
Refers to catheter-based and hybrid procedures (those 
procedures involving aspects of both endovascular and 
surgical revascularizations) for PAD distal to the external 
iliac artery.
Index leg
Refers to the leg receiving the qualifying revascularization 
for randomization into this trial.
Qualifying revascularization
Refers to the procedure by which the patient qualifies for the 
study.
[…]
Surgical procedure
Refers to surgical bypass procedure in the lower extremity 
for PAD distal to the external iliac artery. This can include a 
variety of bypass conduit materials and extra-anatomic 
operations.
15.1.2.8
Section 3.4.  Benefit/risk assessment
Section revised per amendment change 16.
Old Text: 
[…]
The safety profile of rivaroxaban is based on an extensive database of safety information 
collected in a substantial clinical development program, which has enrolled over 84,000 
patients into phase 2 and 3 clinical trials alone, including over 47,000 patients treated with 
rivaroxaban. In addition, the steadily amassing post-marketing data summarized in numerous 
Periodic Safety Update Reports (PSURs)/Periodic Benefit-Risk Evaluation Reports 
(PBRERs), corresponding to an estimated cumulative patient exposure of 3.7 million patient 
years, provides further reassurance about rivaroxaban benefit-risk balance in the real-life 
setting. In conclusion, no undue safety risks are expected from the interventional drug 
treatment with rivaroxaban in the present study.
New Text: 
[…]
The safety profile of rivaroxaban is based on an extensive database of safety information 
collected in a substantial clinical development program, which has enrolled as of Sep 2015 
more than 108,000 subjects have been enrolled in interventional clinical trials (completed and 
ongoing Phase I, Phase II, Phase III and Phase IV) including more than 60,000 subjects
treated with rivaroxaban. In addition, the steadily amassing post-marketing data summarized 
in numerous Periodic Safety Update Reports (PSURs)/Periodic Benefit-Risk Evaluation 
Reports (PBRERs), corresponding to an estimated cumulative patient exposure of 3.7 million 
patient years, provides further reassurance about rivaroxaban benefit-risk balance in the real-
life setting. In conclusion, no undue safety risks are expected from the interventional drug 


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treatment with rivaroxaban in the present study. Further details can be found in the latest 
available version of the investigator's brochure, which contains comprehensive information on 
the study drug.106
15.1.2.9
Section 4.  Study objectives
Section revised per amendment change 8.
Old Text: 
[…]
The secondary efficacy objectives of the study are:

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of index limb revascularization;
[…]
•
to evaluate the efficacy of rivaroxaban in reducing the risk of venous thromboembolic 
(VTE) events;
•
to evaluate the efficacy of rivaroxaban in reducing the risk of all-cause mortality.
New Text: 
[…]
The secondary efficacy objectives of the study are:

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of index limb revascularization (subsequent index leg revascularizations that 
were not planned or considered as part of the initial treatment plan at the time of 
randomization);
•
[…]to evaluate whether rivaroxaban added to ASA is superior to ASA alone in 
reducing the risk of venous thromboembolic (VTE) events;
•
to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of all-cause mortality. 
15.1.2.10 Section 5.  Study design
Section revised per amendment changes 2, 3 and 17.
Old Text: 
[…]
….Randomization and study treatment should commence as soon as possible but no later than 
7 days after a successful qualifying revascularization procedure and once hemostasis has been 
assured. All randomized patients will receive study medication (either rivaroxaban or placebo) 
and study ASA in a sufficient quantity until the next scheduled on-site visit and detailed 
instructions for its administration.
                                                
106 Sentence was added with Protocol Amendment 4 (change no. 16).


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The first study visit is a screening visit to be performed within 7 days after the qualifying 
revascularization. The second study visit is the randomization visit (randomization will be 
assigned as T0 on the time axis). The first study drug dose will be taken at the randomization 
visit. The screening and randomization visits can be combined into one visit if all tests 
required for the assessment of all eligibility criteria are available and randomization and 
dosing can be performed on a single day. 
[…]
Figure 5-1:  Study design
New Text: 
[…]
….Randomization and study treatment should commence as soon as possible but no later than 
10 days after a successful qualifying revascularization procedure and once hemostasis has 
been assured. All randomized patients will receive study medication (either rivaroxaban or 
placebo) and study ASA in a sufficient quantity until the next scheduled on-site visit and 
detailed instructions for its administration.
The first study visit is a screening visit to be performed within 30 days prior to or no more 
than 10 days after the qualifying revascularization. The second study visit is the 
randomization visit (randomization will be assigned as T0 on the time axis). The first study 
drug dose should be administered as close to the time of the randomization visit as possible 
(See Section 7.4 for additional guidance on dosing at randomization). The screening and 
randomization visits can be combined into one visit if all tests required for the assessment of 
all eligibility criteria are available and randomization and dosing can be performed on a single 
day. 
[…]


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Figure 5-1:  Study design
15.1.2.11 Section 6.1.  Inclusion criteria
Section revised per amendment changes 2, 4, 5, and 20a-c.
Old Text: 
[…]
2.
Documented moderate to severe symptomatic lower extremity peripheral artery 
occlusive disease as evidenced by ALL of the following:
a.
clinically, by functional limitations in walking activity, ischemic rest pain, or 
ischemic ulceration,
b.
anatomically, by imaging evidence of occlusive PAD below the inguinal ligament
within 6 months prior to or at the time of the qualifying revascularization,
AND
c.
hemodynamically (within 6 months prior to, or at the time of, the qualifying 
revascularization) by:

an ABI ≤ 0.80 or TBI ≤ 0.60 of the index leg (in the event of non-
compressible ankle arteries) for patients without a prior history of limb 
revascularization on the index leg,
OR

an ABI ≤ 0.85 or TBI ≤ 0.65 of the index leg (in the event of non-
compressible ankle arteries) for patients with a prior history of limb 
revascularization on the index leg.
3.
Technically successful peripheral infra-inguinal revascularization (surgical and/or 
endovascular; for definition see Section 9.3.3) for symptomatic PAD within the last 7
days prior to randomization;
[…]
7.
Women and men of reproductive potential must agree to use adequate contraception* 
when sexually active. This applies for the time period between signing of the informed 
consent form (ICF) and after the last administration of study drug.


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(*The definition of adequate contraception will be based on the judgment of the 
investigator and on local requirements. Acceptable methods of contraception 
include, but are not limited to, (i) condoms (male or female) with or without a 
spermicidal agent; (ii) diaphragm or cervical cap with spermicide; (iii) intra-uterine 
device; (iv) hormone-based contraception. Patients must agree to utilize two reliable 
and acceptable methods of contraception simultaneously).
[…]
New Text: 
[…]
2.
Documented moderate to severe symptomatic lower extremity atherosclerotic peripheral 
artery disease as evidenced by ALL of the following:
a. clinically, by functional limitations in walking activity, ischemic rest pain, or 
ischemic ulceration,
b. anatomically, by imaging evidence of peripheral artery disease distal to the external 
iliac artery in the index leg within 12 months prior to or at the time of the 
qualifying revascularization, 
AND
c. hemodynamically in either leg (within 12 months prior to, or at the time of, the 
qualifying revascularization) by:

an ABI ≤ 0.80 or TBI ≤ 0.60 for patients without a prior history of limb 
revascularization,
OR

an ABI ≤ 0.85 or TBI ≤ 0.65 for patients with a prior history of limb 
revascularization.
3.
Technically successful peripheral revascularization distal to the external iliac artery
(surgical and/or endovascular; for definition see Section 9.3.3) for symptomatic PAD 
within the last 10 days prior to randomization;
[…]
7.
Women of reproductive potential must agree to use adequate contraception* when 
sexually active. This applies for the time period between signing of the informed 
consent form (ICF) to the last administration of study drug.
(*The definition of adequate contraception [with a failure rate of less than 1% per 
year] will be based on the judgment of the investigator and on local requirements. 
Acceptable methods of contraception include, but are not limited to: oral 
contraceptives, contraceptive injections, intrauterine device, double barrier method, 
male partner sterilization).
[…]


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15.1.2.12 Section 6.2  Exclusion criteria
Section revised per amendment changes 7, 15, 17 and 18.
Old Text: 
1. Patients undergoing revascularization for asymptomatic PAD, mild claudication without 
functional limitation or major tissue loss (including severe ischemic ulcers or gangrene) of 
the index leg;
[…]
3. Prior revascularization on the index leg within 8 weeks of the qualifying revascularization;
[…]
- Exclusion criteria related to concomitant and study treatment:
5. Patients requiring treatment with ASA at doses >100 mg;
6. Planned dual antiplatelet therapy (DAPT) use for the qualifying revascularization 
procedure of clopidogrel in addition to ASA for >30 days* after the qualifying 
revascularization procedure
*Use of clopidogrel not exceeding 60 days for a labeled indication for a device [e.g., stent 
or balloon] may be allowed with written justification of the investigator)
[…]
12. Medical history or active clinically significant bleeding, lesions, or conditions within the 
last 6 months prior to randomization, considered to be a significant risk for major bleeding 
(this may include current medically confirmed gastrointestinal ulceration, presence of 
malignant neoplasms at high risk of bleeding, current or recent brain or spinal injury, known 
esophageal varices, vascular aneurysms of the large arteries or major intraspinal or 
intracerebral vascular abnormalities; patients without any medical history of gastrointestinal 
disease may be exempted from this exclusion criterion);
[…]
23. Previous (within 30 days) or concomitant participation in another clinical study with 
investigational medicinal product
24. Close affiliation with the investigational site; e.g., a close relative of the investigator, 
dependent person (e.g., employee or student of the investigational site).
New Text: 
1. Patients undergoing revascularization for asymptomatic PAD or mild claudication without 
functional limitation of the index leg;
[…]
3. Prior revascularization on the index leg within 10 days of the qualifying revascularization;
[…]
5. Patients with major tissue loss (defined as significant ulceration/gangrene proximal to the 
metatarsal heads, i.e. heel or midfoot) in either leg.
- Exclusion criteria related to concomitant and study treatment:


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6. Patients requiring treatment with ASA at doses >100 mg;
7. Planned dual antiplatelet therapy (DAPT) use for the qualifying revascularization 
procedure of clopidogrel in addition to ASA for >30 days* after the qualifying 
revascularization procedure (or > 60 days for a labeled indication [e.g. drug coated stent or 
balloon])
*Planned use of clopidogrel not exceeding 60 days for a labeled indication for a device 
[e.g., stent or balloon] may be allowed; see section 8.1 for further guidance on 
clopidogrel)
[…]
12. Medical history or active clinically significant bleeding, lesions, or conditions within the 
last 6 months prior to randomization, considered to be a significant risk for major bleeding 
(this may include current medically confirmed gastrointestinal ulceration, presence of 
malignant neoplasms at high risk of bleeding, current or recent brain or spinal injury, known 
esophageal varices, vascular aneurysms of the large arteries or major intraspinal or 
intracerebral vascular abnormalities);
[…]
23. Previous (within 30 days) or concomitant participation in another clinical study with
investigational product
24. Close affiliation with the investigational site; e.g., a close relative of the investigator, 
dependent person (e.g., employee or student of the investigational site).
25. Breast feeding
15.1.2.13 Section 6.3.1 Discontinuation and withdrawal
Section revised per amendment change 16.
Old Text: 
[…]

pregnancy

if, in the investigator's opinion, continuation of the study drug would be harmful to the 
patient's well-being (e.g. significant decline in cognitive function or renal failure with 
eGFR <15 mL/min/1.73 m2),

at the specific request of the sponsor and in liaison with the investigator (e.g., safety 
concerns).
[…]
New Text: 
[…]

pregnancy
Patients may be withdrawn from study drug, if any of the following occurs:


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
if, in the investigator's opinion, continuation of the study drug would be harmful to the 
patient's well-being (e.g. significant decline in cognitive function or renal failure with 
eGFR <15 mL/min/1.73 m2),

at the specific request of the sponsor and in liaison with the investigator (e.g., safety 
concerns).
15.1.2.14 Section 7.1.  Treatments to be administered
Section revised per amendment change 17.
Old Text: 
[…]
In either treatment group, post-procedural concomitant treatment with clopidogrel will be 
allowed for a planned maximum period of 30 days following the qualifying revascularization 
procedure. Justification will need to be provided if the investigator would like to treat the 
patient with clopidogrel for longer than 30 days following the revascularization. This 
extended use will be limited to a labeled indication for the device (e.g., stent) and will not 
exceed 60 days. Clopidogrel will not be part of or provided as study medication.
New Text: 
[…]
In either treatment group, post-procedural concomitant treatment with clopidogrel will be
allowed as described in Section 8.1.
15.1.2.15 Section 7.4.  Dosage and administration
Section revised per amendment change 17.
Old Text: 
[…]
Clopidogrel (at a dose that is consistent with the site/country’s standard of care) may be used 
for DAPT in either treatment group for a planned period of up to 30 days (or up to 60 days, if 
justified; see Section 7.1) after the qualifying revascularization procedure at the discretion of 
the investigator.
New Text: 
[…]
Clopidogrel (at a dose that is consistent with the site/country’s standard of care) may be used 
at the discretion of the investigator as described in Section 8.1.
15.1.2.16 Section 7.4.1  Dosage modifications
Section revised per amendment change 16.


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Old Text: 
[…]
The following sections provide general guidance for use of rivaroxaban. For further details, 
please refer to the investigator brochure (IB) and/or applicable local product information. For 
use of ASA, please refer to applicable guidelines and local production information. 
New Text: 
[…]
The following sections provide general guidance for use of rivaroxaban. For use of ASA, 
please refer to applicable guidelines and local production information. 
15.1.2.17 Section 7.4.4.  Guidance for the treatment of subjects who develop an 
acute coronary syndrome and those who require percutaneous 
coronary intervention with stenting
Section revised per amendment change 17.
Old Text: 
Study medication should be temporarily interrupted in patients who require anticoagulant or 
DAPT because of an ACS or need for percutaneous coronary intervention (PCI) with stenting. 
Peri-procedurally, standard antiplatelet therapy, including ASA and clopidogrel (or other 
P2Y12 antagonists such as prasugrel or ticagrelor) can be administered according to usual 
practice. Study ASA may be continued. Standard anticoagulant therapy can be used without 
regard to the timing of the most recent dose of study medication because the dose of 
rivaroxaban being tested in this trial is significantly lower than the 15 or 20 mg dose 
administered for stroke prevention in atrial non-valvular fibrillation and the half-life of 
rivaroxaban is short, only 5-13 hours.
Following the procedure, decision and timing to resume study medication are at the discretion 
of the treating physician and the investigator. If medically indicated, study medication may be 
used along with DAPT or interrupted until patient no longer requires DAPT.
New Text: 
Study medication should be temporarily interrupted in patients who require anticoagulant or 
DAPT because of an ACS event or for percutaneous coronary intervention (PCI) with 
stenting. Peri-procedurally, standard antiplatelet therapy, including ASA and clopidogrel (or 
other P2Y12 antagonists such as prasugrel or ticagrelor) can be administered according to 
usual practice. Study ASA may be continued. Standard anticoagulant therapy can be initiated
without regard to the timing of the most recent dose of study medication because the dose of 
rivaroxaban being tested in this trial is significantly lower than the 15 or 20 mg dose 
administered for stroke prevention in non-valvular atrial fibrillation and the half-life of 
rivaroxaban is short, only 5-13 hours.
Following the procedure, the decision and timing to resume study medication are at the 
discretion of the treating physician and the investigator. If medically indicated, study 


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medication may be used along with DAPT with clopidogrel as described in Section 8.1, or 
interrupted until patient no longer requires DAPT.
15.1.2.18 Section 8.1. Prior and concomitant therapy
Section revised per amendment changes 9, 17 and 22 a-d.
Old Text: 
Generally, all prior (within 30 days prior to screening) and concomitantly taken drugs (as 
specified in the eCRF) need to be recorded in the eCRF.
[…]
In addition, any remedial therapy for non-serious-AEs (if AEs are subject to documentation) 
should be documented.
Clopidogrel and other non-study antiplatelet treatment
Patients who enter the study receiving additional antiplatelet therapy will have non-study 
antiplatelet therapy discontinued when study medication is started. The use of clopidogrel for 
a planned duration of 30 days following the qualifying revascularization procedure is allowed 
if deemed required by the investigator, but will not be supplied as a study medication. 
Justification will need to be provided if the investigator would like to treat the patient with 
clopidogrel for longer than 30 days following the revascularization. This extended use will be 
limited to a labeled indication for the device (e.g., stent) and will not exceed 60 days.
Patients who require use of clopidogrel during the course of the study after the qualifying 
revascularization procedure (e.g., indication for PCI with or without stenting), use of 
clopidogrel or DAPT is allowed (see Section 7.4.4). If medically indicated, study medication 
may be used along with DAPT or interrupted until the patient no longer requires DAPT.
[…]
Prohibited therapy while on study medication
[…]

use of antiplatelet therapy other than the protocol specified background antiplatelet 
therapy of study ASA or clopidogrel is prohibited during the study. This includes 
drugs with known significant antiplatelet effects such as cilostazol;

additional anticoagulant(s) (e.g., warfarin sodium or vitamin K antagonists, Factor II 
or Xa inhibitors) concomitantly with study medication are prohibited. Study 
medication shall be discontinued in patients who develop any condition which requires 
permanent or long term anticoagulation (e.g., DVT, atrial fibrillation. 
[…]
These prohibited therapies may be administered on a temporary basis, and if administered the 
investigator should consider temporarily discontinuing study medication if the treatment could 
result in an increased risk of bleeding (e.g., strong inhibitors of both CYP3A4 and P-gp, or 
anticoagulants).
[…]


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Discontinuation of Study Drug for a Vascular Procedure
[…]
After PCI or CABG, treatment with DAPT should be considered for at least 48 hours.
Depending on the bleeding risk, the patient may, at the discretion of the managing physician, 
resume study medication thereafter, but no earlier than approximately 12 hours after the 
arterial sheath has been removed (for patients undergoing PCI) or after the post-procedural 
drains have been removed (for patients undergoing CABG surgery), and the last dose of 
parenteral anticoagulant therapy has been administered.
[…]
New Text: 
Generally, all prior (within 30 days prior to randomization) and concomitantly taken drugs (as 
specified in the eCRF) need to be recorded in the eCRF
[…]
In addition, any remedial therapy for non-serious-AEs (if AEs are subject to reporting) should 
be documented.
Clopidogrel and other non-study antiplatelet treatment
Patients who enter the study receiving additional antiplatelet therapy will have non-study 
antiplatelet therapy discontinued when study medication is started. 
If deemed required by the investigator, the use of clopidogrel for a planned duration of up to 
30 days following the qualifying revascularization procedure, or planned duration of up to 60 
days in the case of a labeled indication for a device (e.g. drug-coated stent or balloon), is 
allowed. Justification will need to be documented during the course of this planned use of 
clopidogrel if the investigator determines that a medical need arises that warrants that 
clopidogrel be administered for >30 days following the qualifying revascularization, or >60 
days in the case of a device. Clopidogrel will not be supplied as a study medication.
During the course of the study, for enrolled patients who require use of clopidogrel for a new 
indication (e.g., indication for PCI with or without stenting), use of clopidogrel is allowed (see 
Section 7.4.4). At the discretion of the investigator, study medication may be used along with 
clopidogrel or interrupted until the patient no longer requires clopidogrel.  The duration of 
clopidogrel use should follow standard of care and applicable international guidelines.  
Treatment with other P2Y12 antagonists, such as prasugrel or ticagrelor may be administered 
according to usual practice, but the study drug must be interrupted if such drugs are used long-
term.
[…]
Prohibited therapy while on study medication
[…]

use of antiplatelet therapy other than the protocol specified background antiplatelet 
therapy of study ASA or clopidogrel is prohibited during the study. This includes 
drugs with known significant antiplatelet effects such as cilostazol, prasugrel, and 
ticagrelor;


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
additional anticoagulant(s) (e.g., warfarin sodium or vitamin K antagonists, heparins,
Factor II or Xa inhibitors) concomitantly with study medication are prohibited. 
[…]
These prohibited therapies may be administered on a temporary basis in combination with the 
study drug if deemed medically appropriate. In general, the investigator should consider 
temporarily discontinuing study medication if the treatment could result in an increased risk of 
bleeding (e.g., strong inhibitors of both CYP3A4 and P-gp, or anticoagulants). 
[…]
Discontinuation of Study Drug for a Vascular Procedure
[…]
Depending on the bleeding risk, the patient may, at the discretion of the managing physician, 
resume study medication thereafter, but no earlier than approximately 12 hours after the 
arterial sheath has been removed (for patients undergoing PCI) or after the post-procedural 
drains have been removed (for patients undergoing CABG surgery), and the last dose of 
parenteral anticoagulant therapy has been administered.
[…]
15.1.2.19 Section 9.1.  Tabular schedule of evaluations
Section revised per amendment changes 2, 3,5, 6, 10, 12, and 17.
Old Text: 
[…]
Patients will be assessed for study participation after the qualifying revascularization whereas 
this procedure is not considered to be a study visit. On-site study visits for the patients at the 
investigational site are planned at Screening, Randomization, 1, 3, 6, and 12 months after 
randomization, and then every 6 months until the end of the study. Upon announcement of 
study end, patients will come to the clinic for a final on-site EOT visit followed by a 
telephone contact (post-study treatment follow-up visit) one month later. 
The following visit abbreviations are used in the description of the visit schedule:
Rev:
Day of the qualifying revascularization procedure (not considered a study visit).
ScV:
Screening visit (to be performed within 7 days after Rev; screening procedures can 
be performed over multiple days if necessary).
RxV:
Randomization visit (time point of randomization = [T0]), to be performed as soon 
as possible but no later than 7 days after Rev once hemostasis is assured.
[…]
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 patient to return within the visit 
"window", especially due to unforeseen circumstance beyond the control of the patient or the 
study center, then the visit should be scheduled as close to the interval as is convenient for the 
patient and the study center.


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At selected qualified sites, a duplex ultrasound evaluated of the treated leg may be performed 
to measure lumen diameter and vessel patency in order to understand mechanistic effects of 
study treatment (see Appendix 16.1).


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Table 9-1:
Schedule of assessments
Timelines
Qualifying 
revascular-
ization
(Rev)
ScV a
RxV a
(T0)
Treatment Phase
PS-FU
1 Mo post EOT
V1 
V2
V3
V4
V5-Vx
EOT
visit  b
1 Mo
3 Mo
6 Mo
12 Mo
every 6 
Mo
Visit Window 
(weeks if not otherwise 
specified)
Up to +7 days 
after Rev
Up to +7 days 
after Rev
±10 
days
±4
±4
±4
±4
±1
Type of Visit 
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit

Informed consent
●
Demographics
●
Medical / surgical history 
●
Laboratory tests c
●
Serum pregnancy test d
●
Inclusion/Exclusion
●
Revascularization procedure 
(surgical or endovascular)
♦
Documentation of 
revascularization details
●
Randomization (IxRS)
●
Concomitant medications e
●
●
●
●
●
●
●
●
1st study drug 
●
Drug dispense 
●
●
●
●
●
●
Drug accountability
●
●
●
●
●
●
Vital Signs
●
●
●
●
●
●
●
●
Study efficacy outcomes
●
Study safety outcomes 
(bleeding events)
●
AE/SAE reporting f
●
●
●
●
●
●
●
●
●
ABI/TBI
● g
●
●
●
●
●
●
●
Questionnaires (EQ-5D, WIQ, 
PRO)
● h
●
●
●
●
●
●
Vital status
●
Duplex Ultrasound j
●
●
(footnotes are provided on the next page)
continuous reporting
continuous reporting


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♦= procedure before study (not study-related); ●= study procedure to be performed at specified visits; = post-study treatment telephone contact
Abbreviations: ABI/TBI = Ankle (Toe) - Brachial - Index; AE = adverse event; EOT = end of treatment; EQ-5D = European Quality of Life-5 Dimensions 
questionnaire; IxRS = Interactive Voice and Web Response System; Mo = month; V = visit; Rx = randomization; SAE = serious adverse event; 
Sc = Screening; WIQ = Walking Impairment Questionnaire, PRO = patient-reported outcomes data
a:
Screening visit can be performed at the same time as randomization visit, if all required tests for eligibility criteria are available at that time. Maximum 
screening period is 7 days after the revascularization procedure. Randomization should be done as soon as possible (but within 7 days) after the qualifying 
revascularization procedure.
b:
End of treatment visit is to be performed within 4 weeks after announcement of study end, or once the patient has permanently withdrawn from the study.
c:
Laboratory tests required to verify the eligibility criteria (creatinine/eGFR, serum pregnancy test) are to be collected per the site’s standard of care and 
assessed through a local lab and must not be older than 7 days prior to randomization. If the patient’s eGFR is <30 mL/min/1.73 m2 prior to the procedure, it 
must remain to be >15 mL/min/1.73 m2  72 hours after the procedure to enroll and randomize the patient.
d:
Required in women of childbearing potential only.
e:
Planned post-procedural concomitant clopidogrel allowed for a maximum period of 30 days (an extended use of up to 60 days will be accepted in a labeled 
indication; see Section 7.1).
f:
Only AE/ SAEs not exempted from adverse event reporting and specified in the need to be documented (see Section 9.6.1.2.6).
g:
ABI/TBI values used at screening may be historical (captured in the patient’s medical history), but must not be older than 6 months prior to the qualifying 
revascularization procedure.
h:
Baseline assessments can be performed either at the screening visit or the randomization visit.
j:
Duplex ultrasound of the treated limb(s) (at selected sites only).


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New Text: 
[…]
Patients will be assessed for study participation prior to, or after, the qualifying 
revascularization whereas this procedure is not considered to be a study visit. On-site study 
visits for the patients at the investigational site are planned at Screening, Randomization, 1, 3, 
6, and 12 months after randomization, and then every 6 months until the end of the study. 
Upon announcement of study end, patients will come to the clinic for a final on-site EOT visit 
followed by a telephone contact (post-study treatment follow-up visit) one month later. 
The following visit abbreviations are used in the description of the visit schedule:
ScV:
Screening visit (to be performed up to 30 days prior to but no later than 10 days 
after Rev; screening procedures can be performed over multiple days if necessary).
Rev:
Day of the qualifying revascularization procedure (not considered a study visit).
RxV:
Randomization visit (time point of randomization = [T0]), to be performed as soon 
as possible but no later than 10 days after Rev once hemostasis is assured.
[…]
Clinic visits or procedures should be scheduled as close to the specified interval as possible, 
and preferably within the defined window. If it is not possible for the patient to return within 
the visit "window," or perform the required study procedures, especially due to unforeseen 
circumstance or technical feasibility beyond the control of the patient or the study center, then 
the visit or procedure should be scheduled as close to the interval as is convenient for the 
patient and the study center.  
The new schedule of assessment includes the changes according to amendment 4. The 
respective footnotes, however, were not repeated in the new text version for better readability.  
Please refer to the revised schedule of assessment in Section 9.1


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Table 9-1: Schedule of assessments - amended
Timelines
ScV a
Qualifying 
revascular-
ization
(Rev)
RxV a
(T0)
Treatment Phase
PS-FU
1 Mo post EOT
V1 
V2
V3
V4
V5-Vx
EOT
visit  b
1 Mo
3 Mo
6 Mo
12 Mo
every 6 
Mo
Visit Window 
(weeks if not otherwise 
specified)
-30 days before, to 
+10 days after, Rev
Up to +10 days 
after Rev
±10 days
±4
±4
±4
±4
±1
Type of Visit 
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit

Informed consent
●
Demographics
●
Medical / surgical history 
●
Laboratory tests c
●
Serum pregnancy test d
●
Inclusion/Exclusion
●
Revascularization 
procedure (surgical or 
endovascular)
♦
Documentation of 
revascularization details
●46
Randomization (IxRS)
●
Concomitant medications 
e
●
●
●
●
●
●
●
●
1st study drug 
●
Drug dispense 
●
●
●
●
●
●
Drug accountability
●
●
●
●
●
●
Vital Signs
●
●
●
●
●
●
●
●
Study efficacy outcomes
●
Study safety outcomes 
(bleeding events)
●
AE/SAE reporting f
●
●
●
●
●
●
●
●
●
ABI/TBI
● g
●
●
●
●
●
●
Questionnaires (EQ-5D, 
WIQ, HCRU)
PAD symptom status
●
●
●
●
●
●
●
Vital status
●
continuous reporting
continuous reporting


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Table 9-1: Schedule of assessments - amended
Timelines
ScV a
Qualifying 
revascular-
ization
(Rev)
RxV a
(T0)
Treatment Phase
PS-FU
1 Mo post EOT
V1 
V2
V3
V4
V5-Vx
EOT
visit  b
1 Mo
3 Mo
6 Mo
12 Mo
every 6 
Mo
Visit Window 
(weeks if not otherwise 
specified)
-30 days before, to 
+10 days after, Rev
Up to +10 days 
after Rev
±10 days
±4
±4
±4
±4
±1
♦= non-study procedure (change no. 17); ●= study procedure to be performed at specified visits; = post-study treatment telephone contact
Abbreviations: ABI/TBI = Ankle (Toe) - Brachial - Index; AE = adverse event; EOT = end of treatment; EQ-5D = European Quality of Life-5 Dimensions 
questionnaire; IxRS = Interactive Voice and Web Response System; Mo = month; V = visit; Rx = randomization; SAE = serious adverse event; 
Sc = Screening; WIQ = Walking Impairment Questionnaire, HCRU=Health Care Research Utilization data (see Section 9.7.3) (change 17)
a:
Screening visit can be performed at the same time as randomization visit, if all required tests for eligibility criteria are available at that time. Screening period 
is 30 days before or up to 10 days (change no. 3) after the revascularization procedure. Randomization should be done as soon as possible (but within 10
days [change no. 2]) after the qualifying revascularization procedure.
b:
End of treatment visit is to be performed within 4 weeks after announcement of study end, or once the patient has permanently withdrawn from the study.
c:
Laboratory tests required to verify the eligibility criteria (creatinine/eGFR) are to be collected per the site’s standard of care and assessed through a local lab.
Creatinine/eGFR must not be older than 30 days prior to the qualifying revascularization (change no. 10). If the patient’s eGFR is <30 mL/min/1.73 m2 prior 
to the procedure, it must remain to be >15 mL/min/1.73 m2  72 hours after the procedure in order (change no. 17) to enroll and randomize the patient.
d:
Required in women of childbearing potential only.  A pregnancy test must not be older than 7 days prior to randomization.
e:
Planned post-procedural concomitant clopidogrel allowed at the discretion of the investigator, see Section 8.1
f:
Only AE/ SAEs not exempted from adverse event reporting and specified in the need to be documented (see Section 9.6.1.3) (change no 17).
g:
ABI/TBI values used at screening may be historical (captured in the patient’s medical history), but must not be older than 12 months prior to the qualifying 
revascularization procedure (change no. 5). If an ABI/TBI is performed during screening to assess eligibility, it must be completed prior to the qualifying 
revascularization (change no. 6).


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15.1.2.20 Section 9.2.1.1.  Screening Visit (ScV)
Section revised per amendment changes 3, 5, 10 and 17.
Old Text: 
9.2.1.1  Screening Visit (ScV): after qualifying revascularization procedure (study Day --
-7 to study Day 0)
Once a patient has received a lower limb revascularization procedure that qualify him/her for 
the study, he/she should be screened for eligibility for study participation. The ScV is required 
to assess the eligibility of the patient. After obtaining signed informed consent, the 
investigator will review or perform all medical evaluations required to verify the patient’s 
eligibility for study participation as defined in the inclusion and exclusion criteria. Adverse 
events reporting begins once the informed consent has been signed.
Demographic data and medical history (including PAD risk factors and vascular disease 
history) will be recorded at Screening. Laboratory tests should be performed according to the 
site specific standards, but must, at minimum, include creatinine and eGFR, and a serum 
pregnancy test in women of childbearing potential. Results of laboratory measurements 
(ideally obtained during the hospital admission for the qualifying revascularization) should 
not be older than 7 days prior to the qualifying revascularization; otherwise, tests would need 
to be repeated. If the site’s local laboratory report does not provide eGFR, this value should be 
calculated (e.g. using the Modification of Diet in Renal Disease [MDRD] formula). All 
laboratory tests will be performed locally as no central laboratory is involved in this study.
The following measures/documentations will be performed at the screening visit:

obtaining informed consent;

documentation of demographic characteristics (for details see Section 9.3.1);

documentation of the details about the qualifying revascularization and its success;

documentation of medical history (for details see Section 9.3.2) and surgical history;

review laboratory test data for the patient, if creatinine/eGFR assessments were 
performed more than 7 days prior to the qualifying revascularization, they must be 
redrawn;

serum pregnancy test (in females with childbearing potential only);

evaluate for all inclusion- and exclusion criteria;

documentation of prior (within the last 30 days prior to screening) and concomitant 
medication. Chronic treatment with prescription antiplatelet therapies (except already 
ongoing treatment with low-dose ASA that can be continued as study 
ASA 100 mg od) should be stopped;

assess vital signs (blood pressure, pulse rate);

check for the occurrence of AEs/SAEs since the signing of the ICF (only AEs/SAEs 
not exempted from AE/SAE reporting need to be reported; for details see 
Section 9.6.1.2.6);

perform ABI (or TBI for non-compressible tibial arteries) if no ABI/TBI data is
available for the patient within the last 6 months prior to screening;


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
QoL assessment with EQ-5D (this assessment can be performed at either the screening 
visit or the randomization visit);

Walking Impairment Questionnaire (this assessment can be performed at either the 
screening visit or the randomization visit).
If the patient is eligible for study participation, the site investigator should make all 
organizational arrangements required for prompt randomization of the patient to study 
treatment as soon as feasible, but no more than 7 days after the qualifying revascularization 
procedure (for treatments to be administered, see Section 7.1).
New Text: 
9.2.1.1  Screening Visit (ScV): 30 days before, or up to 10 days after qualifying 
revascularization procedure 
The ScV is required to assess the eligibility of the patient. After obtaining signed informed 
consent, the investigator will review or perform all medical evaluations required to verify the 
patient’s eligibility for study participation as defined in the inclusion and exclusion criteria. 
Adverse events reporting begins once the informed consent has been signed.
Demographic data and medical history (including PAD risk factors and vascular disease 
history) will be recorded at Screening. Laboratory tests should be performed according to the 
site specific standards, but must, at minimum, include creatinine and eGFR, and a serum 
pregnancy test in women of childbearing potential. Results of laboratory measurements 
(ideally obtained during the hospital admission for the qualifying revascularization) should 
not be older than 30 days prior to the qualifying revascularization; otherwise, tests would need 
to be repeated. If the site’s local laboratory report does not provide eGFR, this value should be 
calculated (e.g. using the Modification of Diet in Renal Disease [MDRD] formula). All 
laboratory tests will be performed locally as no central laboratory is involved in this study.
The following measures/documentations will be performed at the screening visit:

obtaining informed consent;

documentation of demographic characteristics (for details see Section 9.3.1);

documentation of medical history (for details see Section 9.3.2) and surgical history;

review laboratory test data for the patient, if creatinine/eGFR assessments were 
performed more than 30 days prior to the qualifying revascularization, they must be 
redrawn and if serum pregnancy test (females with childbearing potential only) was 
performed more than 7 days ago prior to the qualifying revascularization a repeat 
pregnancy test must be performed; 

evaluate for all inclusion- and exclusion criteria;

documentation of prior (within the last 30 days prior to randomization) and 
concomitant medication. Chronic treatment with prescription antiplatelet therapies 
(except already ongoing treatment with low-dose ASA that can be continued as study 
ASA 100 mg od) should be stopped at the time of randomization;

assess vital signs (blood pressure, pulse rate);


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
check for the occurrence of AEs/SAEs since the signing of the ICF (only AEs/SAEs 
not exempted from AE/SAE reporting need to be reported; for details see 
Section 9.6.1.3);

perform ABI (or TBI) if no ABI/TBI data are available for the patient within the last 
12 months prior to the qualifying revascularization.
If the patient is eligible for study participation, the site investigator should make all 
organizational arrangements required for prompt randomization of the patient to study 
treatment as soon as feasible, but no more than 10 days after the qualifying revascularization 
procedure (for treatments to be administered, see Section 7.1).
15.1.2.21 Section 9.2.1.2.  Randomization visit (RxV) 0-10 days after the 
qualifying revascularization procedure - amended
Section revised per amendment changes 2,12, 17 and 19.
Old Text: 
9.2.1.2  Randomization visit (RxV): 0-7 days after the qualifying revascularization 
procedure 
After meeting all inclusion criteria and none of the exclusion criteria, eligible patients will be 
randomized by accessing the IxRS system and receive study medication and study ASA as 
soon as feasible, but no more than 7 days after the qualifying revascularization procedure. The 
first dose of study medication will be given immediately after randomization. Planned 
additional treatment with clopidogrel for up to 30 days (or up to 60 days, if justified by a 
labeled indication; see Section 7.1) after the qualifying revascularization procedure is allowed 
at the discretion of the investigator.
The following measures/documentations will be performed at the randomization visit (study 
visit procedures should be performed in the order in which they are listed):

randomization of patient;

dispensing of study medication and study ASA with patient instruction;

administration of first study medication treatment dose (on-site);

documentation of any changes in concomitant medication since the last study visit;

assess vital signs (blood pressure, pulse rate);

check for the occurrence of study efficacy outcome events since the last study visit 
(these pre-randomization events should be documented on the outcome pages and 
forwarded by expedited means to the Sponsor's PV; see Section 9.6.1.2.6);

check for the occurrence of study safety outcome events (bleeding events) since the 
last study visit (these pre-randomization events should be documented on the outcome 
pages and forwarded by expedited means to the Sponsor's PV; see Section 9.6.1.2.6);

check for the occurrence of AEs/SAEs since the last study visit; for events exempted 
from AE/SAE reporting, see Section 9.6.1.2.6);

perform ABI (or TBI for non-compressible tibial arteries);


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
QoL assessment with EQ-5D (this assessment can be performed at either the screening 
visit or the randomization visit);

Walking Impairment Questionnaire (this assessment can be performed at either the 
screening visit or the randomization visit);

remind patient to return with the study medication and study ASA dispensed bottles at 
their next visit.
New Text: 
9.2.1.2  Randomization visit (RxV): 0-10 days after the qualifying revascularization 
procedure 
After meeting all inclusion criteria and none of the exclusion criteria, eligible patients will be 
randomized by accessing the IxRS system and receive study medication and study ASA as 
soon as feasible, but no more than 10 days after the qualifying revascularization procedure. 
The first dose of study medication should be given immediately, but no more than 24 hours
after randomization, if study drug can be safely administered (see Section 7.4). Planned 
additional treatment with clopidogrel after the qualifying revascularization procedure is 
allowed at the discretion of the investigator as described in Section 8.1.
The following measures/documentations will be performed at the randomization visit:

randomization of patient (must be performed prior to all other randomization study 
visit procedures);

documentation of the details about the qualifying revascularization and its success;

If laboratory evaluations have been performed and are available per standard or usual 
care of the subjects in the recent past that reflect baseline hematologic, glucose 
metabolic, liver, and renal functions, record the relevant and available indices in the 
eCRF (HbA1c, total cholesterol, HDL cholesterol, LDL cholesterol, ALT(SGPT), 
AST(SGOT), total bilirubin, hemoglobin, hematocrit, platelet count). The serum 
creatinine value used to assess eligibility and corresponding eGFR should also be 
entered;

dispensing of study medication and study ASA with patient instruction;

administration of first study medication treatment dose (on-site);

documentation of any changes in concomitant medication since the last study visit;

assess vital signs (blood pressure, pulse rate);

check for the occurrence of study efficacy outcome events since the last study visit 
(these pre-randomization events should be documented on the outcome pages and 
forwarded by expedited means to the Sponsor's PV; see Section 9.6.1.3;

check for the occurrence of study safety outcome events (bleeding events) since the 
last study visit (these pre-randomization events should be documented on the outcome 
pages and forwarded by expedited means to the Sponsor's PV; see Section 9.6.1.3);

check for the occurrence of AEs/SAEs since the last study visit; for events exempted 
from AE/SAE reporting, see Section 9.6.1.3;


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
assess the patient’s PAD Symptom Status 
(This assessment, as well as the QoL assessment and Walking Impairment 
Questionnaire, should reflect the time period prior to the qualifying revascularization 
procedure);

QoL assessment with EQ-5D;

Walking Impairment Questionnaire;

remind patient to return with the study medication and study ASA dispensed bottles at 
their next visit.
[…]
15.1.2.22 Section 9.2.1.3.  Treatment phase:  Regular study visits from Visit 1 
onwards
Section revised per amendment changes 5, 12, 17 and 19.
Old Text: 
[…]
At each on-site visit in the treatment phase visit, patients will be asked about the occurrence of 
potential study efficacy outcome events, bleeding events, and AEs/SAEs.
[…]
The following measures/documentations will be performed at each study visit:

check for the occurrence of study efficacy outcome events since the last study visit;

check for the occurrence of bleeding events since the last study visit;

check for the occurrence of AEs/SAEs since the last study visit (for events exempted 
from AE/SAE reporting, see Section 9.6.1.2.6);
[…]

assess vital signs (blood pressure, pulse rate);

perform ABI (or TBI for non-compressible tibial arteries);
[…]

Walking Impairment Questionnaire (questionnaires should be completed before the 
other visit procedures);
[…]
In addition, duplex ultrasound of the treated limb(s) may be performed at one (Visit 1) and 
6 months (Visit 3) after randomization (at selected sites only; see Appendix 16.1).


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New Text: 
[…]
At each on-site visit in the treatment phase, patients will be asked about the occurrence of 
potential study efficacy outcome events, bleeding events, and AEs/SAEs.
[…]
The following measures/documentations will be performed at each study visit:

check for the occurrence of study efficacy outcome events since the last study visit;

check for the occurrence of bleeding events since the last study visit;

Complete all eCRF outcome event, bleeding event and Health Care Resource 
Utilization (HCRU, see section 9.7.3) pages if applicable

check for the occurrence of AEs/SAEs since the last study visit (for events exempted 
from AE/SAE reporting, see Section 9.6.1.3; 
[…]

Assess the patient’s PAD Symptom Status;

If the following laboratory evaluations have been performed since the last study visit 
and are available in the medical record, it is requested that this information be 
recorded in the eCRF: HbA1c, creatinine, total cholesterol, HDL cholesterol, LDL 
cholesterol, ALT(SGPT), AST(SGOT), total bilirubin, hemoglobin, hematocrit, 
platelet count;
[…]

Walking Impairment Questionnaire (questionnaires should be completed before the 
other visit procedures);

assess vital signs (blood pressure, pulse rate);

perform ABI (or TBI);
[…]
15.1.2.23 Section 9.2.1.4.  End of treatment (EOT) visit
Section revised per amendment changes 5, 12 and 17.
Old Text: 
[…]
Likewise, an EOT visit should be performed in those patients who will leave the study 
permanently in spite of any attempts to hold the patient on study observation (see 
Section 6.3.1).
[…]

documentation of any changes in concomitant medication since the last study visit;

assess vital signs (blood pressure, pulse rate);

perform ABI (or TBI for non-compressible tibial arteries);


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
QoL assessment with EQ-5D (questionnaires should be completed before the other 
visit procedures);

Walking Impairment Questionnaire (questionnaires should be completed before the 
other visit procedures);

collect study medication and study ASA bottles dispensed at the previous visit and 
count and document number of returned tablets. Document any treatment 
interruptions, if applicable;
[…]
New Text: 
[…]
Likewise, an EOT visit should be performed in those patients who leave the study 
permanently in spite of any attempts to hold the patient on study observation (see 
Section 6.3.1).
[…]

documentation of any changes in concomitant medication since the last study visit;

Assess the patient’s PAD Symptom Status;

QoL assessment with EQ-5D (questionnaires should be completed before the other 
visit procedures);

Walking Impairment Questionnaire (questionnaires should be completed before the 
other visit procedures);

assess vital signs (blood pressure, pulse rate);

perform ABI (or TBI);

collect study medication and study ASA bottles dispensed at the previous visit and 
count and document number of returned tablets. Document any treatment 
interruptions, if applicable;
[…]
15.1.2.24 Section 9.3.3.  Definition of qualifying revascularization procedure
Section revised per amendment changes 4, 6, 7, 14 and 17.
Old Text: 
For the purposes of the current study, the qualifying revascularization procedure (surgical or 
endovascular) must be technically successful and hemostasis must be assured prior to 
randomization.
The qualifying revascularization procedure for patients that require multiple attempts at 
revascularization on the index leg and lesion must be the last of the planned/foreseeable 
revascularizations.


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Surgical procedure: surgical bypass procedures in the lower extremity for PAD below the 
inguinal ligament. This can include a variety of bypass conduit materials and extra-anatomic 
operations.
Endovascular procedure: catheter-based procedures and hybrid procedures (those 
procedures involving aspects of both endovascular and surgical revascularizations). The 
details about the qualifying revascularization procedure will be recorded at the screening visit 
in the eCRF. 
Successful procedure: the qualifying revascularization (regardless of type of procedure) 
procedure must be deemed technically successful by meeting the following criteria:

technical success of the procedure with no immediate plan for re-intervention and per 
the investigator’s discretion, the patient can safely be placed on an anticoagulant at the 
time of randomization;

demonstrated graft or vascular patency of the qualifying revascularization procedure 
immediately prior to the time of randomization.
New Text: 
For the purposes of the current study, the qualifying revascularization procedure (surgical or 
endovascular) must be a technically successful procedure in the past 10 days and hemostasis 
must be assured.
Patients under consideration for this trial may have a treatment plan that focuses on a single 
procedure or staged procedures where not all revascularizations will necessarily be completed 
at one time. Preferably, the qualifying revascularization should be the last planned procedure.
Surgical procedure: surgical bypass procedures in the lower extremity for PAD distal to the 
external iliac artery. This can include a variety of bypass conduit materials and extra-anatomic 
operations.
Endovascular procedure: catheter-based procedures distal to the external iliac artery and 
hybrid procedures (those procedures involving aspects of both endovascular and surgical 
revascularizations). 
The details about the qualifying revascularization procedure will be recorded at the 
randomization visit in the eCRF. 
Successful procedure: the qualifying revascularization (regardless of type of procedure) 
procedure must be deemed technically successful by meeting the following criteria:

technical success of the procedure with no immediate plan for re-intervention and per 
the investigator’s discretion, the patient can safely be placed on an anticoagulant at the 
time of randomization;

demonstrated graft or vascular patency of the qualifying revascularization procedure 
prior to randomization. Graft or vascular patency is at the discretion of the investigator 
and can be demonstrated by a variety of means including imaging, hemodynamic 
and/or physical findings.


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15.1.2.25 Section 9.4.1  Assessments and procedures at occurrences of primary 
efficacy events
Section revised per amendment change 23.
Old Text: 
[…]
The analysis of study efficacy outcome events will be based on events as adjudicated by the 
ICAC. Thus, the occurrence of study efficacy outcome events must be reported on 
Outcome/CV Event reporting forms and will undergo adjudication by the ICAC.
[…]
New text
[…]
The analysis of study efficacy outcome events will be based on events as adjudicated by the 
ICAC. Thus, the occurrence of study efficacy outcome events must be reported on 
Outcome/CV Event reporting forms and will undergo adjudication by the ICAC. All potential 
coronary ischemic events, cerebrovascular events and peripheral ischemic events should also 
be reported on the Outcome/CV Event reporting forms.
[…]
15.1.2.26 Section 9.4.2  Definition of study outcome events
Section revised per amendment change 24.
Old Text: 
[…]
Ischemic stroke: the definition of ischemic stroke will be an acute episode of neurological 
dysfunction caused by focal or global brain vascular injury and includes ischemic stroke, 
hemorrhagic stroke, and undetermined stroke. This includes fatal and non-fatal strokes. In 
case signs and symptoms resolve in less than 24 hours, confirmation of stroke requires 
neuroimaging evidence of acute brain ischemia (i.e., TIA with positive neuroimaging).
[…]
Cardiovascular (CV) death: all deaths will be assumed CV in nature unless a non-CV cause 
can be clearly shown.


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Acute limb ischemia (ALI): for the current study, ALI is defined as clinical history and 
presentation consistent with a sudden significant worsening of limb perfusion and either

Clinical history including a new pulse deficit with associated rest pain, pallor, 
paresthesia, or paralysis
AND
o
confirmation of arterial obstruction by imaging, limb hemodynamics, 
intraoperative findings, or pathological evaluation
OR

requiring thrombolysis, thrombectomy, or urgent bypass. 
[…]
Additonal standard definitions for these efficacy outcomes will be provided in a separate 
ICAC manual.
New text
[…]
Ischemic stroke: the definition of ischemic stroke will be an acute episode of neurological 
dysfunction caused by focal or global brain vascular injury and includes all strokes that are 
not of a primary hemorrhagic etiology. This includes fatal and non-fatal strokes. 
Cardiovascular (CV) death: all deaths will be assumed CV in nature unless a non-CV cause 
can be clearly shown.
Acute limb ischemia (ALI): for the current study, ALI is defined as clinical history and 
presentation consistent with a sudden significant worsening of limb perfusion requiring 
hospitalization and 

a new pulse deficit with associated rest pain, pallor, paresthesia, or paralysis and either
o
confirmation of arterial obstruction by imaging, limb hemodynamics, 
intraoperative findings, or pathological evaluation
OR
o
requiring thrombolysis, thrombectomy, or urgent revascularization.
Major amputation due to a vascular etiology: for the current study, this is operationally 
defined as above-the-ankle amputation that is:

non-traumatic
AND

due to a vascular etiology which includes worsening perfusion of the limb but 
excludes foot sepsis as the primary indication for amputation.
Detailed definitions for these efficacy outcomes are provided in a separate ICAC charter.


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15.1.2.27 Section 9.4.3.2.  Secondary efficacy variables
Section revised per amendment change 8.
Old Text: 
The secondary efficacy variables of the study are:

time from randomization to the first occurrence of an index limb revascularization;
[…]
New Text: 
The secondary efficacy variables of the study are:

time from randomization to the first occurrence of an index limb revascularization 
(subsequent index leg revascularization that was not planned or considered as part of 
the initial treatment plan at the time of randomization);
[…]
15.1.2.28 Section 9.4.3.3.  Other efficacy variables
Section revised per amendment changes 8 and 13.
Old text: 
Other efficacy variables of the study are:

time from randomization to the first occurrence of all limb revascularizations of the 
lower extremity;
[…]
New Text: 
Other efficacy variables of the study are:

time from randomization to the first occurrence of all subsequent limb
revascularizations of the lower extremity that were not planned or considered as part 
of the initial treatment plan at the time of randomization;
[…]

serial changes in limb hemodynamics (ABI/TBI).


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15.1.2.29 Section 9.6.1.2.6.  Intensity (section added)
Section revised per amendment change 16.
New Text: 
9.6.1.2.6  Intensity
The intensity of an AE is to be classified according to the following categories:

mild,

moderate,

severe.
15.1.2.30 Section 9.6.1.3.1.  Assessment of bleeding events
Section revised per amendment change 17.
Old Text: 
[…]
Bleeding occurring after randomization that is related to the index revascularization procedure 
(e.g. bleeding requiring an unplanned surgical take-back operation to manage will also be 
reported), including details of the management of the bleeding event and any limb 
complications (e.g., resulting in major amputation or compartment syndrome requiring 
surgical management).
[…]
New text
[…]
Bleeding occurring after randomization that is related to the index revascularization procedure 
(e.g. bleeding requiring an unplanned surgical take-back operation to manage) will also be 
reported, including details of the management of the bleeding event and any limb 
complications (e.g., resulting in major amputation or compartment syndrome requiring 
surgical management).
[…]
15.1.2.31 Section 9.6.1.3.2.  Assessment and documentation of adverse events
Section revised per amendment change 17.
Old text:
The investigator has to record on the respective eCRF pages all AEs occurring in the period 
between the signing of the ICF and the end of the follow-up phase (i.e., post-study treatment 
follow-up visit by phone at 4 weeks after the EOT visit); after the end of the follow-up phase 
there is no requirement to actively collect AEs including deaths. In case of permanent 
discontinuation of study medication, AEs other than outcome events must be reported up to 
one month after the last dose of study medication intake.


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[…]
In the current study, a targeted approach will be followed for AE/SAE documentation and 
reporting. As regards non-serious AEs, this basically means that only
[…]
New text:
The investigator has to record on the respective eCRF pages all AEs occurring in the period 
between the signing of the ICF and the end of the follow-up phase (i.e., post-study treatment 
follow-up visit by phone at 4 weeks after the EOT visit) according to the guidelines in 
Sections 9.6.1.3.2 and 9.6.1.3.3; after the end of the follow-up phase there is no requirement 
to actively collect AEs including deaths. In case of permanent discontinuation of study 
medication, AEs other than outcome events must be reported up to one month after the last 
dose of study medication intake.
[…]
In the current study, a targeted approach will be followed for AE/SAE documentation and 
reporting. Regarding non-serious AEs, this basically means that only
[…]
15.1.2.32 Section 9.6.3 Further safety
Section revised per amendment change 19
[…]
Added text:
It is also generally expected that study visit assessments of subjects occurs under the direct 
supervision of medically qualified personnel such as a physician to determine the need for 
additional evaluations. It is expected that laboratory surveillance should follow standard of 
care, tailored to the specific need and clinical indications of the subjects. As part of standard 
in-hospital, perioperative, and chronic care of such patients with known cardiovascular or 
other significant medical conditions, repeat and in some cases frequent laboratory testing may 
be required as part of this standard care. Record the relevant laboratory parameters on the 
corresponding eCRFs.
15.1.2.33 Section 9.7.1 European Quality of Life-5 Dimensions Questionnaire
Section revised per amendment change 17.
Old text: 
[…]
The EQ-5D will be administered at either the screening visit or the randomization visit, and 
subsequently at each on-site visit. 
New text: 


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[…]
The EQ-5D will be administered at the randomization visit, and subsequently at each on-site 
visit. 
15.1.2.34 Section 9.7.2 Walking Impairment Questionnaire
Section revised per amendment change 17.
Old text: 
[…]
Assessments will be performed at either the screening visit or the randomization visit, and 
subsequently at each on-site visit.
New text: 
[…]
Assessments will be performed at the randomization visit, and subsequently at each on-site 
visit.
15.1.2.35 Section 9.7.3 Health resource use
Section revised per amendment change 17.
Old Text: 
Health care resource utilization data related to all efficacy and safety outcomes events (PRO) 
will be collected for all patients during the study.
[…]
New text:
Health care resource utilization data related to all efficacy and safety outcomes events referred 
to as Health Care Resource Utilization (HRCU) will be collected for all patients during the 
study using the Health Care Resource Utilization form in the eCRF.
15.1.2.36 Section 9.7.4.  PAD Symptom Status (section added)
Section revised per amendment change 12.
Added Text: 
The PAD Symptom Status assessment is a graded scale used to assess the severity of chronic 
PAD.  This assessment tool, adapted from the commonly-used  Rutherford classification of 
chronic limb ischemia (Rutherford et al. 1997), categorizes subjects’ condition into one of six 
strata of chronic limb ischemia severity ranging from asymptomatic to tissue loss beyond the 
digits of the foot.  This assessment will be completed by the investigator at the Randomization 
visit, and subsequently at each on-site visit. 


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15.1.2.37 Section 10.4.  Determination of sample size
Section revised per amendment change 17
Old text
[…]
Inherently, the number of patients enrolled may be adjusted based on the observed overall 
event rate of the primary efficacy outcomes during the study.
New text
[…]
Inherently, the number of patients enrolled may be adjusted based on the observed overall 
event rate of the primary efficacy outcomes during the study. Sample size estimation was 
based on PASS 11 [Hintze 2011].
15.1.2.38 Section 11.1.  Data recording
Section revised per amendment change 16 and 17.
Old text
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE, which Bayer has licensed 
from Medidata Solutions. Worldwide. RAVE has been validated by Medidata Solutions 
Worldwide and Bayer for use in its clinical studies. RAVE allows for the application of 
software logic to set-up data entry screens and data checks to ensure the completeness and 
accuracy of the data entered by the site personnel. Bayer extensively applies the logic to 
ensure data are complete and reflect the clinical data requirements of the study. Data queries 
resulting from the application of the software logic are resolved by the site personnel. The 
data are stored at a secure host facility maintained by Medidata Solutions Worldwide and 
transferred on a periodic basis to Bayer's internal computer system via a secure Virtual Private 
Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All internal Bayer and external investigator site personnel seeking access 
must go through a thorough RAVE training process before they are granted access to RAVE 
for use in Bayer's clinical studies. Training records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
subjects enrolled in this study.
New text


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Data required according to this protocol will be recorded by trained investigational site 
personnel via data entry into the internet based validated EDC software system RAVE from 
Medidata Solutions. RAVE allows for the application of software logic to set-up data entry 
screens and data checks to ensure the completeness and accuracy of the data entered by the 
site personnel.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All study personnel seeking access must go through a thorough RAVE 
training process before they are granted access to RAVE for use in clinical studies. Training 
records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
Data entries made in the RAVE EDC screens are supported by source documents maintained 
for all subjects enrolled in this study.
Source documentation
Sites must implement processes to ensure that all data entered into the eCRF are supported by 
source documentation. A source document checklist will be used at the site to identify the 
source data for all data points collected, in accordance with the latest version of the protocol 
and study agreements. The investigator or the head of the medical institution (where 
applicable) agrees to allow the monitor direct access to all relevant documents.
New text
Source documentation
Sites must implement processes to ensure that all data entered into the eCRF are supported by 
source documentation. A source document checklist will be used at the site to identify the 
source data for all data points collected, in accordance with the latest version of the protocol 
and study agreements. 
15.1.2.39 Section 13.2.  Funding and financial disclosure
Section revised per amendment change 17.
Old text
This study will be funded by the Sponsor Bayer HealthCare Inc. and Janssen Pharmaceuticals 
Inc. 
New text
This study will be funded by the Sponsor Bayer HealthCare AG and Janssen Pharmaceuticals 
Inc. 


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15.1.2.40 Section 14.  Reference list
Section revised per amendment change 12.
Added Text: 
Rutherford RB, Baker JD, Ernst C, et al. Recommended standards for reports 
dealing with lower extremity ischemia: revised version.  Journal of Vascular 
Surgery. 1997; 26(3):517-38.
Hintze J. Using PASS 11, LLC. Kaysville, Utah, USA. Available: www.ncss.com. 
2011.
15.1.2.41 Section 16 Appendices
Section revised per amendment change 25.
Old text:
16.1 Vascular ultrasound substudy
Based on the scientific understanding of arterial remodeling and associated increased 
thrombotic risk after surgical and endovascular therapy, rivaroxaban has the potential to 
reduce the incidence of atherothrombosis and stenosis in grafts and endovascular 
revascularization patients. Short and long-term success in lower extremity revascularization is 
ideally assessed using non-invasive imaging. Vascular ultrasound is an ideal, portable, and 
widely available noninvasive technique to assess surgical graft patency as well as assess graft 
lumen diameter. 
An ultrasound substudy of the treated leg may be performed at select qualified sites (at 30 
days [Visit 1] and 6 months [Visit 3]) to measure lumen diameter and vessel patency in order 
to understand the mechanistic effects of study treatment. For additional information, please 
refer to the applicable ultrasound study manual.
New text
Section 16 was deleted.


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15.2
Amendment 5
Amendment 5 is the second global amendment to the original clinical study protocol 17454 
Version 1.0, dated 23 March 2015.
15.2.1
Overview of changes to the study
15.2.1.1
Change 1: Change of sponsorship information 
Rationale:
The sponsor was changed from Bayer Healthcare AG to Bayer AG for non-US territory and 
sponsor information for Bayer HealthCare Pharmaceuticals Inc. was added for US-territory. 
Bayer HealthCare AG merged with Bayer AG, an affiliated company within the Bayer Group, 
effective as of 1st July 2016. Thereby, Bayer HealthCare AG ceased to exist and Bayer AG 
became its legal successor and automatically took over all of the Bayer HealthCare AG’s 
rights, obligations and liabilities by law. As a result of the above mentioned merger, Bayer 
AG assumes the role of the sponsor.
Affected sections: Title Page
15.2.1.2
Change 2: Further specification of secondary objective concerning risk 
of index limb revascularization
Rationale: The secondary endpoints were reordered to reflect clinical relevance.  The wording 
of the secondary endpoint that now becomes the second ordered secondary endpoint has been 
modified for clarity to reflect the accommodation of a treatment plan for the qualifying 
revascularization to include the option of a staged procedure plan.
Affected sections:  Synopsis, Section 4. Study objectives, Section 9.4.3.2 Secondary efficacy 
variables
15.2.1.3
Change 3: Changes to exclusion criteria concerning DAPT
Rationale: To adapt to emerging trends in practice patterns across the world and to allow for 
the inclusion of newer devices and procedures now available.
Affected sections: Synopsis, Section 6.2 Exclusion criteria, Section 8.1 Prior and concomitant 
therapy


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15.2.1.4
Change 4: Amendment of definitions for Endovascular procedure and 
Surgical procedure
Rationale: Wording of endovascular and surgical procedure definitions modified for clarity to 
better reflect the definition of hybrid procedures and to make clearer that surgical procedures 
also include other open procedures such as endarterectomy. 
Affected sections: Definitions and medical terms, Section 9.3.3 Definition of qualifying 
revascularization procedure
15.2.1.5
Change 5: Addition of requirement that ABI/TBI assessments done 
after consenting must be performed per ABI/TBI Site Manual
Rationale: Added for consistency such that all procedures done after signing of the informed 
consent and thereafter conform to the same guidelines.
Affected sections: Section 9.1 Tabular schedule of evaluations, Section 9.2.1.1 Screening 
Visit (ScV): 30 days before, or up to 10 days after qualifying revascularization procedure
15.2.1.6
Change 6: Addition of possible requirement for submission of source 
documents from the qualifying revascularization procedure for central 
data verification
Rationale: To allow for the possible collection of source data.
Affected sections: Section 9.3.3 Definition of qualifying revascularization procedure
15.2.1.7
Change 7: Text amendments for clarity and consistency
Rationale: Changes were made to ensure clarity and consistency throughout the document. 
These changes do not affect the overall study concept. In addition, minor corrections were 
made as requested through the Note to File attached to the Protocol Amendment 4 (dated 
10 FEB 2016).
Affected sections: Synopsis, Section 6.2 Exclusion criteria, Section 7.3 Treatment assignment, 
Section 9.1 Tabular schedule of evaluations, Section 9.4.1 Assessments and procedures at 
occurrence of primary efficacy events, Section 9.6.1.3.3 Reporting of serious adverse events 
and study-specific exemptions


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15.2.2
Changes to the protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol, Version 1.0. In the display of modifications, the “old 
text” refers to the protocol version preceding this amendment; deletions are crossed out.  
Additions are underlined in the “new text” or “added text.”
15.2.2.1
Title Page
The title page was modified based on amendment change 1.
Old text:
Clinical study phase:
3
Date: 10 FEB 2016
Registration:
EudraCT: 2014-005569-58
Version no.:
2.0
Sponsor’s study no.:
BAY 59-7939 / 17454
Sponsor:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
New text:
[…]
Clinical study phase:
3
Date: 21 MAR 2017
Registration:
EudraCT: 2014-005569-58
Version no.:
3.0
Sponsor’s study no.:
BAY 59-7939 / 17454
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
[…]


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15.2.2.2
Synopsis
This section was modified based on amendment changes 2, 3 and 7.
Old text:
[…]
Background treatment
All study patients will receive treatment with open label ASA 100 mg orally 
once daily (od) during the entire course of the study; additional treatment with 
clopidogrel may be administered for a planned duration of up to 30 days 
following after the qualifying revascularization procedure (or up to 60 days 
for a labeled indication [e.g. drug coated stent or balloon]), at the discretion of 
the investigator.
[…]
Diagnosis and main criteria for 
inclusion/exclusion
[…]
Main exclusion criteria are:
•
[…]
•
Planned dual anti-platelet therapy (DAPT) use for the qualifying 
revascularization procedure of clopidogrel in addition to ASA for 
>30 days after the qualifying revascularization procedure (or > 60 
days for a labeled indication [e.g. drug coated stent or balloon]) 
(*Planned use of clopidogrel not exceeding 60 days for a labeled 
indication for a device [e.g., stent or balloon] may be allowed; see 
section 8.1 for further guidance on clopidogrel)
•
Planned DAPT use for any other indication(s) with any P2Y12 
antagonists in addition to ASA after the qualifying revascularization 
procedure.
[…]


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New text (incl. changed sequence of bullet points for objectives and variables):
[…]
Study objective(s)
[…]
Secondary efficacy objectives: 
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of MI, ischemic stroke, coronary heart 
disease mortality, ALI, and major amputation of a vascular etiology;
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of an unplanned index limb 
revascularization for recurrent limb ischemia (subsequent index leg 
revascularizations that were not planned or considered as part of the 
initial treatment plan at the time of randomization); 
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of vascular hospitalizations for a coronary 
or peripheral event (either limb) of a thrombotic nature;
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of MI, ischemic stroke, all-cause mortality, 
ALI, and major amputation of a vascular etiology;
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of MI, all-cause stroke, CV death, ALI, 
and major amputation of a vascular etiology;
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of all-cause mortality
•
to evaluate whether rivaroxaban added to ASA is superior to ASA 
alone in reducing the risk of venous thromboembolic (VTE) events
[…]
Background treatment 
All study patients will receive treatment with open label ASA 100 mg orally 
once daily (od) during the entire course of the study; additional treatment with 
clopidogrel may be administered for a planned duration of up to 30 days after 
the qualifying revascularization procedure (or up to 6 months for complex 
procedures or devices in the investigator’s opinion that require longer use); it 
is strongly recommended that any course of clopidogrel is kept to the 
minimum necessary in accordance with local standard of care and 
international practice guidelines (typically 30 days, or up to 60 days for some 
drug-coated products or devices)( see section 8.1for further guidance on 
clopidogrel).
[…]
Diagnosis and main criteria for 
inclusion/exclusion
[…]
Main exclusion criteria are:
•
patients undergoing revascularization for asymptomatic PAD or mild 
claudication without functional limitation of the index leg,
•
[…]
•
Planned dual antiplatelet therapy (DAPT) use for the qualifying 
revascularization procedure of clopidogrel in addition to ASA for >6 
months after the qualifying revascularization procedure; it is strongly 
recommended that any course of clopidogrel is kept to the minimum 
necessary in accordance with local standard of care and international 
practice guidelines (typically 30 days, or up to 60 days  for some 
drug-coated products or devices), and is only allowed for up to 6 
month for complex procedures or devices that in the investigator’s 
opinion require longer use; see section 8.1 for further guidance on 
clopidogrel.
•
Planned use of any additional antiplatelet agent other than 


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clopidogrel and ASA after the qualifying revascularization 
procedure.
[…]
Primary and secondary 
variable(s)
[…]
The secondary efficacy variables of the study will be:
•
time from randomization to the first occurrence of MI, ischemic stroke, 
coronary heart disease mortality, ALI, and major amputation of a 
vascular etiology;
•
time from randomization to the first occurrence of an unplanned index 
limb revascularization for recurrent limb ischemia (subsequent index leg 
revascularizations that were not planned or considered as part of the 
initial treatment plan at the time of randomization); 
•
time from randomization to the first occurrence of hospitalization for a 
coronary or peripheral cause (either lower limb) of a thrombotic nature;
•
time from randomization to the first occurrence of MI, ischemic stroke, 
all-cause mortality, ALI, and major amputation of a vascular etiology;
•
time from randomization to the first occurrence of MI, all-cause stroke, 
CV death, ALI, and major amputation of a vascular etiology;
•
time from randomization to the first occurrence of all-cause mortality.
•
time from randomization to the first occurrence of venous 
thromboembolic (VTE) events;
[…]
15.2.2.3
Definitions and medical terms
This section was modified based on amendment change 4.
Old text:
[…]
Endovascular procedure
Refers to catheter-based and hybrid procedures (those 
procedures involving aspects of both endovascular and 
surgical revascularizations) for PAD distal to the external 
iliac artery.
[…]
Surgical procedure
Refers to surgical bypass procedure in the lower extremity 
for PAD distal to the external iliac artery. This can include 
a variety of bypass conduit materials and extra-anatomic 
operations.
New text:
[…]
Endovascular procedure
Refers to catheter-based and hybrid procedures (those 
procedures involving aspects of both endovascular and 
surgical revascularizations) for PAD.
[…]


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Surgical procedure
Refers to open surgical procedure in the lower extremity 
for PAD. This can include a variety of procedures, bypass 
conduit materials, and extra-anatomic operations.
15.2.2.4
Section 4. Study objectives
This section was modified based on amendment change 2.
New text (incl. changed sequence of bullet points):
The secondary efficacy objectives of the study are:

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of MI, ischemic stroke, coronary heart disease mortality, ALI, and major 
amputation of a vascular etiology;

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of an unplanned index limb revascularization for recurrent limb ischemia 
(subsequent index leg revascularizations that were not planned or considered as part of 
the initial treatment plan at the time of randomization);

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of vascular hospitalizations for a coronary or peripheral event (either limb) of 
a thrombotic nature;

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of MI, ischemic stroke, all-cause mortality, ALI, and major amputation of a 
vascular etiology;

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of MI, all-cause stroke, CV death, ALI, and major amputation of a vascular 
etiology;

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of all-cause mortality.

to evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of venous thromboembolic (VTE) events.
15.2.2.5
Section 6.2 Exclusion criteria
This section was modified based on amendment changes 3 and 7.
Old text:
[…]
7. Planned dual antiplatelet therapy (DAPT) use for the qualifying revascularization 
procedure of clopidogrel in addition to ASA for >30 days* after the qualifying 
revascularization procedure (or > 60 days for a labeled indication [e.g.drug coated stent or 
balloon])


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(*Planned use of clopidogrel not exceeding 60 days for a labeled indication for a device 
[e.g., stent or balloon] may be allowed; see section 8.1 for further guidance on 
clopidogrel)
8. Planned* DAPT use for any other indication(s) with any P2Y12 antagonists (e.g. 
percutaneous coronary interventions) in addition to ASA after the qualifying 
revascularization procedure
(*This exclusion criterion refers to the clinical condition at the time of randomization. The 
use of DAPT with ASA plus P2Y12 antagonists of any type for new indication(s) occurring 
after randomization is permitted; see Section 7.4.4);
[..]
11. Systemic treatment with strong inhibitors of both Cytochrome P450 isoenzyme 3A4 
(CYP3A4) and p-glycoprotein (P-gp) inhibitors (e.g., systemic azole antimycotics, such as 
ketoconazole [fluconazole is permitted], and human immunodeficiency virus [HIV]-
protease inhibitors, such as ritonavir), or strong inducers of CYP3A4 (e.g., rifampicin, 
rifabutin, phenobarbital, phenytoin and carbamazepine) at the time of screening or their
anticipated use during the study.
- Exclusion criteria related to bleeding risks or systemic conditions:
[…]
14. Medical history of chronic renal failure, any condition requiring dialysis or renal 
replacement therapy or a renal impairment at screening assessed with an estimated 
glomerular filtration rate <15 mL/min/1.73 m2*
(*if a patient's eGFR is <30 mL/min/1.73 m2 prior to the procedure, it must remain to be 
>15 mL/min/1.73 m2 72 hours after the procedure to enroll and randomize the patient);
New text:
[…]
7. Planned dual antiplatelet therapy (DAPT) use for the qualifying revascularization 
procedure of clopidogrel in addition to ASA for >6 months after the qualifying 
revascularization procedure; it is strongly recommended that any course of clopidogrel is 
kept to the minimum necessary in accordance with local standard of care and international 
practice guidelines (typically 30 days, or up to 60 days  for some drug-coated products or 
devices) and is only allowed for up to 6 months for complex procedures or devices in the 
investigator’s opinion that require longer use; see section 8.1 for further guidance on 
clopidogrel.
8. Planned* use of any additional antiplatelet agent other than clopidogrel and ASA after the 
qualifying revascularization procedure
(*This exclusion criterion refers to the clinical condition at the time of randomization. The 
use of DAPT with ASA plus clopidogrel, for new indication(s) occurring after 
randomization is permitted) 
[…]
11. Systemic treatment with strong inhibitors of both Cytochrome P450 isoenzyme 3A4 
(CYP3A4) and p-glycoprotein (P-gp) inhibitors (e.g., systemic azole antimycotics, such as 
ketoconazole [fluconazole is permitted], and human immunodeficiency virus [HIV]-
protease inhibitors, such as ritonavir), or strong inducers of CYP3A4 (e.g., rifampicin, 


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rifabutin, phenobarbital, phenytoin and carbamazepine) anticipated after randomization or
during the study. 
- Exclusion criteria related to bleeding risks or systemic conditions:
[…]
14. Any condition requiring dialysis or renal replacement therapy, or a renal impairment at 
screening assessed with an estimated glomerular filtration rate <15 mL/min/1.73 m2*
(*if a patient's eGFR is <30 mL/min/1.73 m2 prior to the procedure, it must remain to be 
>15 mL/min/1.73 m2 72 hours after the procedure to enroll and randomize the patient);
15.2.2.6
Section 7.3 Treatment assignment
This section was modified based on amendment change 7.
New text:
[…]
The clopidogrel use defining the randomization strata refers to actual clopidogrel use, at 
randomization, as adjunct treatment for the qualifying revascularization. Specific procedures 
for treatment assignment through the IxRS will be described in the IxRS manual.
15.2.2.7
Section 8.1 Prior and concomitant therapy
This section was modified based on amendment change 3.
Old text:
[…]
If deemed required by the investigator, the use of clopidogrel for a planned duration of up to 
30 days following the qualifying revascularization procedure, or planned duration of up to 60 
days in the case of a labeled indication for a device (e.g. drug-coated stent or balloon), is 
allowed. Justification will need to be documented during the course of this planned use of 
clopidogrel if the investigator determines that a medical need arises that warrants that 
clopidogrel be administered for >30 days following the qualifying revascularization, or >60 
days in the case of a device. Clopidogrel will not be supplied as a study medication.
[…]
New text:
[…]
If deemed required by the investigator, the use of clopidogrel concomitantly with study drugs 
is allowed at the time of randomization. It is strongly recommended that any course of 
clopidogrel is kept to the minimum necessary to comply with local standard of care and 
international practice guidelines (typically 30 days, or up to 60 days for some drug-coated 
products or devices). Clopidogrel will not be supplied as a study medication. 
[…]


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15.2.2.8
Section 9.1 Tabular schedule of evaluations
This section was modified based on amendment changes 5 and 7.
New text:
Table 9–1: Schedule of assessments - amended
Timelines
ScV a
Qualifying 
revascular
-ization
(Rev)
RxV a
(T0)
Treatment Phase
PS-FU
1 Mo post EOT
V1 
V2
V3
V4
V5-Vx
EOT
visit  b
1 Mo
3 Mo
6 Mo
12 Mo
every 6 Mo
Visit Window 
(weeks if not otherwise 
specified)
-30 days before, to 
+10 days after, Rev
Up to +10 days 
after Rev
±10 days
±4
±4
±4
±4
±1
Type of Visit 
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit

[…]
ABI/TBIh
● g
●
●
●
●
●
●
[…]
[…]
f:     Only AE/ SAEs not exempted from adverse event reporting and specified in the protocol need to be documented (see Section 9.6.1.3 (change no.17).
g:
ABI/TBI values used at screening may be historical (captured in the patient’s medical history), but must not be older than 12 months prior to the qualifying 
revascularization procedure (change no. 5). If an ABI/TBI is performed during screening to assess eligibility, it must be completed prior to, or at the time 
of, the qualifying revascularization (change no. 6).
h:    ABI/TBI assessments performed after informed consent is obtained must be performed per the guidance in the ABI/TBI Site Manual.


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15.2.2.9
Section 9.2.1.1 Screening Visit (ScV): 30 days before, or up to 10 days 
after qualifying revascularization procedure
This section was modified based on amendment change 5.
New text:

[…]

perform ABI (or TBI) if no ABI/TBI data are available for the patient within the last 
12 months prior to the qualifying revascularization; ABI/TBI assessments performed 
after informed consent is obtained must be performed per the guidance in the ABI/TBI 
Site Manual.
15.2.2.10 Section 9.3.3 Definition of qualifying revascularization procedure
This section was modified based on amendment changes 4 and 6.
Old text:
For the purposes of the current study, the qualifying revascularization procedure (surgical or 
endovascular) must be a technically successful procedure in the past 10 days, and hemostasis 
must be assured.
[…]
Surgical procedure: surgical bypass procedures in the lower extremity for PAD distal to the 
external iliac artery. This can include a variety of bypass conduit materials and extra-anatomic 
operations.
Endovascular procedure: catheter-based procedures distal to the external iliac artery and 
hybrid procedures (those procedures involving aspects of both endovascular and surgical 
revascularizations). 
[…]


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New text:
For the purposes of the current study, the qualifying revascularization procedure (surgical or 
endovascular) must include a technically successful procedure distal to the external iliac 
artery in the past 10 days, and hemostasis must be assured.
[…]
Surgical procedure: open surgical procedures in the lower extremity for PAD. This can 
include a variety of procedures, bypass conduit materials, and extra-anatomic operations.
Endovascular procedure: catheter-based procedures and hybrid procedures (those 
procedures involving aspects of both endovascular and surgical revascularizations) for PAD. 
[…]
Sites may be required to submit source documents from the qualifying revascularization 
procedure for central data verification.
15.2.2.11 Section 9.4.1 Assessments and procedures at occurrence of primary 
efficacy events
This section was modified based on amendment change 7.
New text:
The analysis of study efficacy outcome events will be based on events as adjudicated by the 
ICAC. Thus, the occurrence of study efficacy outcome events must be reported on 
Outcome/CV Event reporting forms, as described in the Endpoint Event Site Manual, and will 
undergo adjudication by the ICAC. All potential coronary ischemic events, cerebrovascular 
events and peripheral ischemic events should also be reported on the Outcome/CV Event 
reporting forms.
15.2.2.12 Section 9.4.3.2 Secondary efficacy variables
This section was modified based on amendment change 2.
New text (incl. changed sequence of bullet points):
The secondary efficacy variables of the study are:

time from randomization to the first occurrence of MI, ischemic stroke, coronary heart 
disease mortality, ALI, and major amputation of a vascular etiology;

time from randomization to the first occurrence of an unplanned index limb 
revascularization for recurrent limb ischemia (subsequent index leg revascularization 
that was not planned or considered as part of the initial treatment plan at the time of 
randomization);

time from randomization to the first occurrence of hospitalization for a coronary or 
peripheral cause (either lower limb) of a thrombotic nature;


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
time from randomization to the first occurrence of MI, ischemic stroke, all-cause 
mortality, ALI, and major amputation of a vascular etiology;

time from randomization to the first occurrence of MI, all-cause stroke, CV death, 
ALI, and major amputation of a vascular etiology;

time from randomization to the first occurrence of all-cause mortality.

time from randomization to the first occurrence of venous thromboembolic (VTE) 
events.
15.2.2.13 Section 9.6.1.3.3 Reporting of serious adverse events and study-specific 
exemptions
This section was modified based on amendment change 7.
Old text:
[…]
2. Safety outcome events (i.e., bleeding events occurring after randomization) will not be 
recorded on the AE page and not be reported as SAEs to Sponsor's PV department, but 
they will be collected on the specific eCRF pages as a safety outcome event.
[…]
New text:
[…]
2. Safety outcome events (i.e., bleeding events occurring after signing of the ICF) will not 
be recorded on the AE page and not be reported as SAEs to Sponsor's PV department, but 
they will be collected on the specific eCRF pages as a safety outcome event.
[…]

SAP_000.pdf: 
 
Document Type: 
Study Analysis Plan 
Official Title: 
An international, multicenter, randomized, double-blind, placebo 
controlled phase 3 trial investigating the efficacy and safety of 
rivaroxaban to reduce the risk of major thrombotic vascular events in 
patients with symptomatic peripheral artery disease undergoing 
lower extremity revascularization procedures 
NCT Number: 
NCT02504216 
Document Date: 
24-Jul-2019 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 59-7939 / 17454 
Page: 1 of 36
 
 
An international, multicenter, randomized, double-blind, 
placebo controlled phase 3 trial investigating the efficacy and 
safety of rivaroxaban to reduce the risk of major thrombotic 
vascular events in patients with symptomatic peripheral artery 
disease undergoing lower extremity revascularization procedures 
 
Vascular Outcomes studY of ASA alonG with rivaroxaban in Endovascular or surgical 
limb Revascularization for peripheral artery disease (VOYAGER PAD) 
 
Bayer study drug 
BAY 59-7939/rivaroxaban 
 
Clinical study 
phase: 
III 
Date: 
24 JULY 2019 
Study No.: 
 
BAY 59-7939 /17454 
Version: 
3.0 
Authors: 
 (Version 1.0, 2.0) 
 (Version 1.0, 2.0) 
 (Version 1.0) 
 (Version 2.0) 
 (Version 3.0) 
 
 
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
PPD
PPD
PPD
PPD


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 59-7939 / 17454 
Page: 2 of 36
 
 
Table of Contents 
 
Table of Tables .......................................................................................................................... 3 
Abbreviations ............................................................................................................................ 4 
1. 
Introduction ....................................................................................................................... 6 
2. 
Study Objectives ................................................................................................................ 6 
3. 
Study Design ...................................................................................................................... 7 
4. 
General Statistical Considerations .................................................................................. 8 
4.1 
General Principles ............................................................................................................ 8 
4.2 
Handling of Non-compliance to Study Treatment or Follow up ..................................... 8 
4.3 
Handling of Missing Data ................................................................................................ 9 
4.4 
Interim Analyses and Data Monitoring .......................................................................... 10 
4.5 
Data Rules ...................................................................................................................... 10 
4.5.1 
Analysis Dates ............................................................................................................ 10 
4.5.2 
Data Scopes ................................................................................................................ 11 
4.5.3 
Censoring rules for time-to-event variables ............................................................... 11 
4.6 
Determination of sample size ......................................................................................... 12 
5. 
Analysis Sets ..................................................................................................................... 13 
5.1 
Assignment of analysis sets ........................................................................................... 13 
5.1.1 
Intention-to-treat (ITT) analysis set ............................................................................ 13 
5.1.2 
Safety analysis set (SAF) ............................................................................................ 13 
6. 
Statistical Methodology ................................................................................................... 15 
6.1 
Population characteristics .............................................................................................. 15 
6.1.1 
Disposition .................................................................................................................. 15 
6.1.2 
Demographics ............................................................................................................. 15 
6.1.3 
Medical history ........................................................................................................... 17 
6.1.4 
Protocol Deviations .................................................................................................... 17 
6.1.5 
Prior and Concomitant Medications ........................................................................... 17 
6.1.6 
Extent of Exposure and Compliance .......................................................................... 17 
6.2 
Efficacy .......................................................................................................................... 18 
6.2.1 
Primary efficacy variable ............................................................................................ 18 
6.2.2 
Secondary efficacy variables ...................................................................................... 18 
6.2.3 
Other efficacy variables .............................................................................................. 18 
6.2.4 
Subgroup variables ..................................................................................................... 19 
6.2.5 
Analysis of the primary efficacy variable ................................................................... 20 
6.2.6 
Analysis of secondary efficacy variables ................................................................... 21 
6.2.7 
Analysis of other efficacy variables ........................................................................... 22 
6.2.8 
Exploratory analysis ................................................................................................... 22 
6.2.9 
Subgroup analysis ....................................................................................................... 23 
6.2.10  Sensitivity analyses ..................................................................................................... 24 
6.3 
Pharmacokinetics/pharmacodynamics ........................................................................... 26 
6.4 
Safety ............................................................................................................................. 26 
6.4.1 
Adverse events ............................................................................................................ 26 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 59-7939 / 17454 
Page: 3 of 36
 
 
6.4.2 
Primary safety variable ............................................................................................... 27 
6.4.3 
Secondary safety variables ......................................................................................... 27 
6.4.4 
Other safety variables ................................................................................................. 27 
6.4.5 
Analysis of safety variables ........................................................................................ 27 
6.5 
Other procedures and variables ...................................................................................... 28 
6.6 
Benefit/Risk Assessment ............................................................................................... 28 
7. 
Document history and changes in the planned statistical analysis ............................. 28 
8. 
References ........................................................................................................................ 31 
Appendix A: Study Closeout Procedure and Variables used for Censoring .................... 32 
Appendix B: Definition of Regions ....................................................................................... 33 
Appendix C: Mathematical Details of the Proposed Tipping Point Analysis ................... 33 
Appendix D: Imputation Rules for Missing Dose Date ....................................................... 35 
Appendix E: Components of the Primary Efficacy Outcome by the Investigators ......... 36 
 
 
 
 
Table of Tables 
Table 1 
Sketch of the planned primary and secondary efficacy and safety analyses ......... 14 
Table 2 
Classification of Countries to Regions .................................................................. 33 
 
 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 59-7939 / 17454 
Page: 4 of 36
 
 
Abbreviations 
 
ABI 
Ankle Brachial Index 
AE 
Adverse Event 
ALI 
Acute Limb Ischemia 
ASA 
Acetylsalicylic acid; aspirin 
BARC 
Bleeding Academic Research Consortium 
bid 
Twice daily 
CAD 
Coronary Artery Disease 
CI 
Confidence Interval 
CRF 
Case Report Form 
CV 
Cardiovascular 
e.g. 
for example 
eGFR 
estimated Glomerular Filtration Rate 
ECOD 
Efficacy cut-off date 
EOT 
End-of-treatment 
EQ-5D 
European Quality of Life-5 Dimensions questionnaire 
HR 
Hazard ratio 
ICAC 
Independent Clinical Adjudication Committee 
ICH 
International Conference on Harmonisation 
i.e. 
id est (that is) 
IDMC 
Independent Data Monitoring Committee 
ISTH 
International Society on Thrombosis and Haemostasis 
ITT 
Intention-to-treat 
IxRS 
Interactive web/voice response system 
KM 
Kaplan Meier 
LCEAD 
Last Clinical Event Ascertainment Date 
LDL 
Low-density lipoprotein 
MACE 
Major adverse cardiac events 
MALE 
Major adverse limb events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
NYHA 
New York Hearth Association 
od 
Once daily 
p 
p-value 
PAD 
Peripheral Artery Disease 
PT 
Preferred Term 
RRR 
Relative risk reduction 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
TBI 
Toe Brachial Index 
TE 
Treatment Emergent 
TEAE 
Treatment Emergent Adverse Events 
TIMI 
Thrombolysis in Myocardial Infarction 


 
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TLF 
Tables, listings, and figures 
USA 
United States of America 
vs. 
versus 
VTE 
Venous thromboembolism 
WIQ 
Walking Impairment Questionnaire 
 
 


 
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1. 
Introduction 
Peripheral artery disease (PAD) refers to the atherosclerotic obstruction of the major arteries 
supplying the lower extremities, sometimes also referred to as lower extremity artery disease. 
Atherosclerosis of the peripheral circulation, with underlying atheroma and chronic 
inflammation, leads to progressive occlusion of medium and large arteries, with additional 
risks of embolism or thrombus formation. Abrupt occlusions and plaque rupture may lead to 
acute complications such as acute limb ischemia (ALI), similar to an acute coronary syndrome 
event in the coronary circulation (Becker et al. 2011). 
 
The hypothesis of the VOYAGER study is that rivaroxaban added to standard of care therapy 
of low-dose acetylsalicylic acid (ASA), has the potential to reduce the incidence of the major 
cardiovascular (CV) outcomes (i.e., CV death, myocardial infarction (MI), and ischemic 
stroke) as well as major lower limb vascular events (i.e. ALI and major amputation) in 
symptomatic PAD patients requiring lower extremity revascularization procedures. 
This core statistical analysis plan (SAP) is based on the Global Integrated Clinical Study 
Protocol BAY 59-7939/17454 version 3.0 and contains definitions of analysis sets, key 
derived variables and statistical methods for analysis of efficacy and safety for the 
VOYAGER study. It provides a technical and detailed elaboration of the principal features of 
the planned analyses, e.g., censoring schemes for time-to-event variables. Amendments and/or 
appendices to this core SAP may be used to add additional analysis and provide more details 
on the coding guidelines, data-handling, and output tables and figures. 
Titles, mock-ups, and programming instructions for all statistical output (tables, figures, and 
listings (TLF)) are provided in a separate TLF specifications document. 
 
2. 
Study Objectives 
The primary efficacy objective is: 
 To evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of major thrombotic vascular events (defined as MI, ischemic stroke, CV death, 
ALI, and major amputation of a vascular etiology) in symptomatic PAD patients 
undergoing lower extremity revascularization procedure. 
 
The secondary efficacy objectives are: 
 To evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of MI, ischemic stroke, coronary heart disease mortality, ALI, and major 
amputation of a vascular etiology 
 To evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of an unplanned index limb revascularization for recurrent limb ischemia 
(subsequent index leg revascularizations that were not planned or considered as part of 
the initial treatment plan at the time of randomization) 


 
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 To evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of vascular hospitalizations for a coronary or peripheral event (either limb) of a 
thrombotic nature 
 To evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of MI, ischemic stroke, all-cause mortality, ALI, and major amputation of a 
vascular etiology 
 To evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of MI, all-cause stroke, CV death, ALI, and major amputation of a vascular 
etiology 
 To evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of all-cause mortality 
 To evaluate whether rivaroxaban added to ASA is superior to ASA alone in reducing 
the risk of venous thromboembolic (VTE) events. 
The primary safety objective of the study is:  
 To evaluate the overall safety and tolerability of rivaroxaban added to ASA compared 
to ASA alone. 
 
3. 
Study Design 
This study is an international multicenter, randomized, placebo-controlled, double-blind, 
event-driven phase 3 study. 
Following provision of informed consent, subjects who fulfill all inclusion criteria and meet 
none of the exclusion criteria will be treated with ASA 100 mg once daily (od) and randomly 
allocated by an interactive voice/web response system (IxRS) in a ratio of 1:1 to additional 
treatment with either rivaroxaban 2.5 mg or placebo twice daily (bid). The randomization will 
be stratified by type of procedure and use of clopidogrel (i.e., (i.) surgical vs. (ii) endovascular 
with clopidogrel vs. (iii) endovascular without clopidogrel). Treatments will be balanced 
within a country for each stratum by block randomization. Randomization and study treatment 
should commence as soon as possible but no later than 10 days after a successful qualifying 
revascularization procedure and once hemostasis has been assured. All randomized subjects 
will receive study medication (either rivaroxaban or placebo) and study ASA in a sufficient 
quantity until the next scheduled on-site visit and detailed instructions for its administration. 
 
The study is event-driven, and thus, all subjects will be treated (or followed-up in the case of 
permanent discontinuation of study medication) until the end of treatment (EOT) visit. It is 
estimated that approximately 6,500 subjects (3,250 per treatment group) are needed to be 
enrolled in order to have 1,015 subjects experiencing a confirmed primary efficacy outcome 
event. Due to the event-driven study design, no firm treatment duration can be stipulated for 
an individual subject. The estimated maximum treatment period for an individual subject is 
approximately 42 months, and the mean treatment duration is expected to be approximately 
30 months. However, this duration may vary depending on the recruitment rate as well as the 
primary event rate. 


 
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Subjects who have discontinued study drug treatment prematurely should continue to be 
followed according to the regular visit schedule, and study efficacy outcome events, bleeding 
events and vital status must be assessed in these subjects until the end of the study via either 
clinic visits or telephone contacts.  
 
Throughout the study and at all on-site visits, subjects will be assessed for the occurrence of 
study efficacy outcome events and bleeding events. Suspected clinical study outcomes (study 
efficacy outcome and bleeding events) will be assessed independently by an Independent 
Clinical Adjudication Committee (ICAC) blinded to treatment allocation, and the adjudicated 
results will be the basis for the final study analyses.  
There will be one formal interim analysis, which will occur when approximately 67% of the 
planned primary efficacy outcomes have accrued and adjudicated. 
A simplified schematic of the study design is provided in the following figure: 
 
 
4. 
General Statistical Considerations 
4.1 
General Principles 
All variables will be summarized using descriptive statistical methods. The number of patients 
with data available and missing, mean, standard deviation, minimum, quartiles, median, and 
maximum will be provided for continuous variables, as appropriate. Frequency tables will be 
provided for categorical variables. The decision rules will be based on one-sided superiority 
testing unless otherwise specified, but in addition to the one-sided p-values from the logrank 
test, two-sided p-values will be reported according to general conventions. The statistical 
evaluation will be performed by using the software package SAS release 9.2 or higher (SAS 
Institute Inc., Cary, NC, USA). 
4.2 
Handling of Non-compliance to Study Treatment or Follow up 
A randomized subject who permanently discontinues rivaroxaban or rivaroxaban placebo 
before their planned EOT Visit for any reason is defined as having had a permanent 
discontinuation of study medication (including subjects who were randomized but never 


 
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started taking any study medication). The reason for permanent discontinuation of study 
medication will be collected and summarized. 
A subject will be considered as lost to follow-up for analysis purposes if contact is not 
obtained with the subject despite all possible efforts by the site, and the subject’s vital status is 
not obtained and documented in the database at the end of the study. 
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 case report form (CRF) including best estimate dates of site investigators collected in the 
clinical database.  
Missing or incomplete post-randomization event dates 
All efforts will be made to collect complete data for all subjects randomized in this study 
including visits by telephone contact. Subjects will be followed to the study end and all 
required data will be collected, regardless of their compliance with study medications or 
visits. 
When an event date is not complete, the date will be estimated according to the following 
rules but not earlier than randomization date, 
 If only the onset day is missing, but the month and year are available: 
o If the month and year are the same as the efficacy cut-off date (ECOD), impute 
the date as mean of the first day of the onset month/year and the ECOD 
(rounded up). 
o Otherwise if the month and year are the same as the last contact date alive (see 
Appendix A), impute the date as mean of the first day of the onset month/year 
and the last contact date alive (rounded up). For death event, the last contact 
alive date +1 day will be used as the death date. 
o Otherwise impute the event date as maximum of the date of randomization + 1 
and day 15 of the onset month and year. 
 If the onset day and month is missing, but the year available: 
o The minimum possible date is maximum of randomization date + 1 days and 
January 1st of the onset year. 
o The maximum possible date is the minimum of the ECOD and last contact date 
alive and December 31th of the onset year. 
o Impute the event date as mean of the minimum possible date and the maximum 
possible date (rounded up). 
o For subjects who experienced death in the same year as last contact alive date, 
the last contact alive date +1 day will be used as the death date. 
 If the onset date is complete missing, the onset date will be imputed with the 
randomization date + 1 days. 
 For subjects who experienced death during the study and the death date is completely 
missing, the last contact alive date + 1 day will be used to impute death date. If the last 
contact alive date is missing, the death date will be imputed as ECOD. 


 
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4.4 
Interim Analyses and Data Monitoring 
The Independent Data Monitoring Committee (IDMC) will monitor the study for greater than 
expected efficacy and for safety. There will be one formal pre-planned interim analysis to 
assess greater than expected efficacy, which will be performed when approximately 67% of 
the planned primary efficacy outcome events (~680) have accrued and are adjudicated. Based 
on that analysis, the study may be stopped early, if there is overwhelming superiority of 
rivaroxaban (p<0.001, 2-sided) for the primary efficacy endpoint (following the Haybittle-
Peto approach) (Haybittle 1971]. Details on the approach to the interim analyses and 
refinement of decision rules are specified in the IDMC charter.  
4.5 
Data Rules 
4.5.1 
Analysis Dates 
For the study, the following date and time window are of relevance for the analysis: 
 Efficacy cut-off date:  
The trial is designed to be terminated when 1015 patients have experienced a 
confirmed primary efficacy outcome event. The ECOD is a predicted common date 
when at least 1015 primary efficacy outcomes are expected to have occurred. It is the 
last calendar date acceptable for counting events for the primary analysis.  
 Trial close-out window: 
The time period when all subjects return to the clinic for an EOT visit. All randomized 
subjects should return for their EOT visit after the ECOD. 
For each subject, the following individual dates are of relevance for analysis: 
 Randomization date:  
The date of randomization as recorded in the IxRS system.  
 EOT Visit date: 
The date of the EOT visit. If subjects do not have an EOT visit, the date will be 
missing. 
 Date of last contact: 
The date of the last documented contact with the subject or a third party (including 
data on subject survival status, see Appendix A for details). 
 Date of first dose of study treatment:  
The date of the first dose of rivaroxaban or rivaroxaban placebo, defined as: 
o Date of first dose from the appropriate CRF page capturing the study 
medication (rivaroxaban or rivaroxaban placebo) if this date is complete.  
o Date of the earliest logically possible dose of study medication (rivaroxaban or 
rivaroxaban placebo) administration in cases where the date of first dose is 
missing or incomplete. See Appendix D for details of the imputation rules. 
 Date of last dose of study treatment:  


 
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The date of the last dose of rivaroxaban or rivaroxaban placebo, defined as: 
o Date of last dose from the appropriate CRF page capturing the study 
medication (rivaroxaban or rivaroxaban placebo) if this date is complete.  
o Date of the latest logically possible dose of study medication (rivaroxaban or 
rivaroxaban placebo) administration in cases where the date of last dose is 
missing or incomplete. See Appendix D for details of the imputation rules. 
4.5.2 
Data Scopes 
All analyses are based on two elements:  
1) analysis set, which specifies which subjects will be included in an analysis; and  
2) data scope, which specifies the time window within which data will be included in an 
analysis.  
This section describes the coverage of the event data scopes used for the statistical analyses. 
Analysis sets are described in Section 5. 
Data scope according to intention-to-treat principle (ITT) 
The ITT data scope includes outcome events observed from randomization date until the 
ECOD. Events occurring after the ECOD will not be counted for primary analysis.  This ITT 
data scope will be applied mainly to the analyses of efficacy variables. 
Data scope according to treatment (on-treatment) 
The on-treatment data scope will include all outcome events observed from randomization 
until 2 days following permanent discontinuation of the study drug. This on-treatment data 
scope will be applied mainly to the analyses of safety variables (e.g. bleeding). 
Data scope according to overall study duration for sensitivity analysis 
The overall study duration data scope will include all outcome events observed from 
randomization until the last contact/visit. This data scope will be applied for sensitivity 
analysis only. 
4.5.3 
Censoring rules for time-to-event variables 
All efforts will be made to collect complete data for all subjects randomized in this study 
including visits by telephone contact.  
Censoring rules for analyses according to the ITT principle 
The censoring rule for time to first event analyses depends on the type of endpoint, thereby 
distinguishing between clinical events endpoints (primary efficacy composite and component, 
secondary efficacy and bleeding events) and CV-death / all-cause mortality. 
 
 


 
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Primary efficacy composite 
and components other than 
CV-death 
All-cause mortality, CV-death 
If the subject was randomized 
but has no post-randomization 
clinical event ascertainment 
date the subject will be 
censored : 
At the randomization date  + 1 
day 
Earlier of last contact alive date 
or ECOD 
 
If no last contact alive date, use 
the randomization date  +1 day 
 
Else, if the subject has 
withdrawn from the study but 
objected to further data 
collection the subject will be 
censored : 
At the earlier date of the last 
clinical event ascertainment 
date (LCEAD), date of 
objection to further data 
collection or ECOD  
Earlier of last contact alive date 
from public sources or ECOD 
 
If no last contact alive date 
from public sources, use the 
earlier date objection to further 
data collection  or ECOD  
 
Otherwise, the subject will be 
censored : 
At the earlier date of last 
clinical event ascertainment 
date, date when patient died or 
ECOD 
At the earlier date of last 
contact alive date or ECOD  
Censoring rules for analyses according to the on-treatment principle 
For on-treatment analyses (primary analysis for time to bleeding events, sensitivity analysis 
for primary efficacy endpoint and all secondary efficacy endpoints), patient with at least one 
dose of study medication and without documentation of an event within the on-treatment data 
scope will be censored similarly to the ITT data scope except that the date of last dose of 
study treatment + 2 days will be used as the cap for the time scope instead of ECOD. 
Censoring rules for analyses according to the overall study duration principle 
Above censoring rules for ITT data scope apply except that the date of last clinical event 
ascertainment or last contact alive will be used as the cap for the time scope instead of ECOD. 
See Appendix A for additional details. 
4.6 
Determination of sample size 
The study is event-driven and it is estimated that approximately 6,500 patients (3,250 per 
treatment group) need to be randomized in order to have 1,015 patients experiencing a 
confirmed primary efficacy outcome event. This number of events will allow the 
demonstration of superiority of rivaroxaban compared to placebo with regard to the primary 
outcome with a power of 90% and a one-sided level of significance α=0.025 under the 
following assumptions: 
 The effect size (Hazard Ratio (HR)) for rivaroxaban plus ASA vs. ASA alone is 
HR=0.80. 
 The annualized event rate in the control arm is approximately 7.5% per year. 
 The rate of patients with permanent discontinuation of study drug (rivaroxaban plus 
ASA switching to ASA alone or an equally effective treatment regimen) is 
approximately 5.5% 1st year, 8% 2nd year, 12% 3rd year (4% 1st half year + 8% 2nd half 
year), and 8% every half year afterwards. 


 
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 The rate of patients lost to follow-up or with non-CV death is approximately 1.5% per 
year. 
 The duration of the enrollment period is 18 months (approximately 15% 1st 6 months, 
30% 2nd 6 months, 55% 3rd 6 months) and 2 years of follow-up from last patient-
randomized until the ECOD. 
The number of patients enrolled may be adjusted and the study duration may be adapted based 
on a blinded review of the observed overall event rate of confirmed primary efficacy 
outcomes during the study. 
Sample size estimation was based on PASS 11 (Hintze 2011).  
 
5. 
Analysis Sets 
5.1 
Assignment of analysis sets 
All subjects who have been randomized in the study are valid for assignment to analysis sets. 
5.1.1 
Intention-to-treat (ITT) analysis set 
The intention-to-treat analysis set, also termed full analysis set in the International Conference 
on Harmonization (ICH) E9 guideline, will include all randomized subjects. Subjects will be 
categorized to the treatment group to which they were assigned by the IxRS; i.e., they will be 
analyzed as randomized. 
5.1.2 
Safety analysis set (SAF) 
The SAF will include all randomized subjects who received at least one dose of study 
medication (rivaroxaban or rivaroxaban placebo). Subjects will be categorized to the group to 
which they were assigned by the IxRS unless the incorrect treatment was received throughout 
the study. In this case, subjects will be analyzed for safety as actually treated. 
The planned analyses for the primary and secondary efficacy and safety variables are 
summarized in but not limited to Table 1 below 
 
 


 
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Table 1 
Sketch of the planned primary and secondary efficacy and safety analyses 
Endpoint 
Analysis 
Type 
Analysis 
Set 
(population)
1 
Data 
Scope2 
Censoring 
Rule3 
Analysis 
Method 
Efficacy 
Primary 
 
 
 
 
 
Composite of MI, ischemic 
stroke, CV death, Acute 
Limb Ischemia, major 
amputation due to a 
vascular etiology 
Main 
ITT 
ITT 
ITT 
Stratified log-
rank test, HR 
estimates from 
stratified Cox PH 
model,  KM plot 
Sensitivity 
ITT 
ITT 
ITT 
Cox PH model 
with no 
stratification;  
Cox PH model 
with actual 
stratification;  
robust 
proportional 
hazard estimator; 
tipping point 
analysis 
SAF 
On-
treatment 
On-
treatment 
Stratified log-
rank test, HR 
estimates from 
stratified Cox PH 
model, KM plot  
 
ITT 
Overall 
study 
duration 
Overall 
study 
duration 
Stratified log-
rank test, HR 
estimates from 
stratified Cox PH 
model, KM plot 
Subgroup 
ITT 
 
ITT 
ITT 
HR estimates 
from  stratified 
Cox PH model4, 
forest plot 
 
SAF 
On-
treatment 
On-
treatment 
HR estimates 
from  stratified 
Cox PH model4, 
forest plot 
Secondary 
 
 
 
 
 
All secondary efficacy 
variables. For the list of 
secondary efficacy 
variables, see section 
6.2.2. 
Main 
 
ITT 
 
ITT 
 
ITT 
 
Stratified log-
rank test, HR 
estimates from  
stratified Cox 
PH model,  KM  
plot 
Sensitivit
y 
SAF 
On-
treatment 
On-
treatment 
Stratified log-
rank test, HR 
estimates from  
stratified Cox 
PH model,  KM  
plot 


 
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Endpoint 
Analysis 
Type 
Analysis 
Set 
(population)
1 
Data 
Scope2 
Censoring 
Rule3 
Analysis 
Method 
Safety 
Primary 
 
 
 
 
 
TIMI major bleeding 
Main 
SAF 
On-
treatment 
On-
treatment 
Stratified Cox PH 
model, KM plot 
Supportive 
SAF 
ITT 
ITT 
Stratified Cox PH 
model, KM plot 
 
SAF 
Overall 
study 
duration 
Overall 
study 
duration 
Stratified Cox PH 
model, KM plot 
Subgroup 
SAF 
On-
treatment 
On-
treatment 
Stratified Cox PH 
model4, forest 
plot 
Secondary 
 
 
 
 
 
ISTH major bleeding 
BARC type 3b and above 
bleeding 
Main 
SAF 
On-
treatment 
On-
treatment 
Stratified Cox PH 
model, KM plot 
Note:  Details of the planned analyses are provided in section 6. 
1. 
Intention-to-treat (ITT) analysis set – all randomized subjects. Treatment assigned as randomized; Safety analysis 
set (SAF) – all randomized subjects who received at least one dose of study medication. Treatment assigned as 
treated. See section 5.1 for details. 
2. 
ITT data scope – all outcome events observed from randomization until efficacy cut-off date; On-treatment data 
scope – all outcome events observed from randomization until 2 days following permanent discontinuation of the 
study drug (rivaroxaban or rivaroxaban placebo). See section 4.5.2 for details. Overall study duration scope - all 
outcome events observed post randomization including post-study treatment follow-up. 
3. 
See section 4.5.3 and Appendix A for details regarding the censoring rules according to each data scope.  
4. 
Not stratified for subgroups related to type of procedure and clopidogrel use. See sections 6.2.4, 6.2.9 and 6.4.5 
fordetails. 
6. 
Statistical Methodology 
6.1 
Population characteristics 
6.1.1 
Disposition 
The following will be tabulated overall and/or by treatment group: 
 Study sample sizes (All enrolled subjects, ITT, and SAF)  
 Study sample sizes by region, country, and site 
 Subject disposition 
 Number of subjects and primary reasons for screening failures (only overall) 
 Number of subjects and primary reasons for permanent discontinuation of study 
medication (by treatment group and overall for ITT and SAF) 
 Number of subjects and primary reasons for discontinuation from intended study 
treatment period (by treatment group and overall for ITT and SAF) 
6.1.2 
Demographics 
The following demographic and baseline characteristics will be summarized by treatment 
group and overall in ITT and SAF. Summary statistics will be presented for metric variables.  
Frequency tables will be presented for categorical variables. Subjects will be considered 
fragile if age >75 years or weight ≤50 kg or baseline eGFR <50 mL/min. 
 Age (<55; ≥55 to <65; ≥65 to ≤75; >75 years) 


 
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 Age (<65; ≥65 to <75; ≥75 years)  
 Age (<65; ≥65 to <85; ≥85 years) 
 Sex (male, female) 
 Race (White; Black or African American; Asian; American Indian or Alaska Native; 
Native Hawaiian or Other Pacific Islander; Not reported; Multiple) 
 Type of qualifying procedure and clopidogrel use, per IxRS assignment (surgical; 
endovascular with clopidogrel; endovascular without clopidogrel) 
 Qualifying revascularization procedure per IxRS (surgical; endovascular ) 
 Geographic Region (North America, Western Europe, Eastern Europe, Asia Pacific, 
South America, see Appendix B for details) 
 Geographic Region (US, non-US) 
 Weight (≤60 kg; >60 kg) 
 estimated Glomerular Filtration Rate (eGFR) (<60 ml/min/1.73m2 , ≥60 
ml/min/1.73m2) 
 eGFR (<15 ml/min/1.73m2, ≥15 to <30 ml/min/1.73m2, ≥30 to <60 ml/min/1.73m2, 
≥60 ml/min/1.73m2) 
 eGFR (<30 ml/min/1.73m2, ≥30 to ≤50 ml/min/1.73m2, >50 to ≤80 ml/min/1.73m2, 
>80 ml/min/1.73m2) 
 Fragile subjects (yes, no) 
 Qualifying revascularization procedure, actual (surgical; endovascular including 
hybrid) 
 Clopidogrel use in relation to qualifying revascularization procedure (yes, no) 
   Time from qualifying revascularization procedure to randomization, actual (≤median, 
>median) 
 Type of qualifying procedure and clopidogrel use, actual (surgical; endovascular 
including hybrid with clopidogrel; endovascular including hybrid without clopidogrel) 
 Clopidogrel use continued after randomization (none, ≤30 days, >30 days) 
 Prior coronary artery disease (CAD) (yes; no) 
 Prior MI (yes; no) 
 Prior limb revascularization (yes; no)  
 Carotid artery disease history (yes; no) 
 Critical limb ischemia (yes; no) 
 Intermittent claudication present within past 12 months (yes; no) 
 History of heart failure (yes; no) 
 Classification of heart failure (NYHA class I, class II, class III, class IV) 


 
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 Diabetes mellitus (yes; no) 
 Smoking status (former, never, current)  
 Hypertension (yes; no) 
 Hyperlipidemia (yes; no) 
 Baseline Ankle Brachial Index (ABI) (at Month 1 visit) (≤0.80; >0.80)   
 Baseline Toe Brachial Index (TBI) (at Month 1 visit) (≤0.60; >0.60)  
In addition, age, days from actual qualifying revascularization procedure to randomization and 
baseline Low-density lipoprotein (LDL) will be treated as continuous variable and 
summarized descriptively. Other baseline characteristics may be added. 
6.1.3 
Medical history 
Medical history will be presented by the pre-specified terms as listed in the CRF. Medical 
history data will be evaluated by frequency tables, showing the number of subjects with 
medical history findings (i.e., listed conditions of previous diagnoses, diseases, or surgeries 
based on the CRF) that started before signing of the informed consent and that are considered 
relevant to the study. 
6.1.4 
Protocol Deviations 
A summary of protocol deviations related to in- and exclusion criteria will be given by 
frequency tables. The summary will be based on ITT.  
6.1.5 
Prior and Concomitant Medications  
Prior and concomitant medications will be presented by the pre-specified terms as listed in the 
CRF. Frequency tables by type of medication will be provided for prior medications prior to 
randomization and for concomitant medication post-randomization. The summaries will be by 
treatment group and overall based on ITT. 
6.1.6 
Extent of Exposure and Compliance 
All summaries related to intake of study medication (rivaroxaban or rivaroxaban placebo) will 
be by treatment group based on SAF. 
The treatment duration (date of last study medication- date of first study medication+1 day) 
will be summarized descriptively. Additionally the number of subjects by treatment duration 
category will be given (≤3 months, >3-≤6 months, >6-≤9 months, >9-≤12 months, >12-≤18 
months, >18-≤24 months, >24 months). 
The time on study medication (treatment duration excluding days off study medication) will 
be calculated and summarized descriptively. 
The number of tablets taken will be summarized descriptively, as well as corresponding extent 
of exposure (number of tablets taken*dose). 
Compliance (or adherence, defined as 100*number of tablets taken / number of tablets 
planned) will be presented by visit as entered in the CRF and summarized for the whole study. 
The number of subjects with at least 80% compliance will be presented.  


 
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6.2 
Efficacy 
6.2.1 
Primary efficacy variable 
The primary efficacy variable is the time from randomization to first occurrence of any of the 
components of the composite outcome, including: 
 MI 
 ischemic stroke 
 CV death 
 ALI 
 major amputation due to a vascular etiology   
 
6.2.2 
Secondary efficacy variables 
The secondary efficacy variables of this study are: 
 time from randomization to the first occurrence of MI, ischemic stroke, coronary heart 
disease mortality, ALI, and major amputation of a vascular etiology 
 time from randomization to the first occurrence of an unplanned index limb 
revascularization for recurrent limb ischemia (subsequent index leg revascularization 
that was not planned or considered as part of the initial treatment plan at the time of 
randomization) 
  time from randomization to the first occurrence of hospitalization for a coronary or 
peripheral cause (either lower limb) of a thrombotic nature 
 time from randomization to the first occurrence of MI, ischemic stroke, all-cause 
mortality, ALI, and major amputation of a vascular etiology 
 time from randomization to the first occurrence of MI, all-cause stroke, CV death, ALI, 
and major amputation of a vascular etiology 
 time from randomization to the first occurrence of all-cause mortality 
 time from randomization to the first occurrence of VTE events 
6.2.3 
Other efficacy variables 
The other efficacy variables of this study are: 
 time from randomization to the first occurrence of all subsequent limb 
revascularizations of the lower extremity that were not planned or considered as part 
of the initial treatment plan at the time of randomization. 
 time from randomization to the first occurrence of all-cause amputations; 
 patient reported outcomes using disease and non-disease specific questionnaires 
(European Quality of Life-5 Dimensions questionnaire (EQ-5D) and Walking 
Impairment Questionnaire (WIQ)). 
 serial changes in limb hemodynamics (ABI and TBI). 


 
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6.2.4 
Subgroup variables 
The following subgroup analyses based on baseline and demographic characteristics are 
planned for the treatment comparisons of the primary efficacy and safety outcomes: 
 Age (<55; ≥55 to <65; ≥65 to ≤75; >75 years) 
 Age (<65; ≥65 to <75; ≥75 years) 
 Age (<65; ≥65 to <85; ≥85 years) 
 Sex (male; female) 
 Race (White; Black or African American; Asian; Other) 
 Type of qualifying procedure and clopidogrel use, per IxRS assignment:  (surgical; 
endovascular with clopidogrel; endovascular without clopidogrel) 
 Qualifying revascularization procedure per IxRS (surgical; endovascular ) 
 Geographic Region (North America; Western Europe; Eastern Europe; Asia Pacific; 
South America, see Appendix B for details) 
 Geographic Region (US, non-US) 
 Weight (≤60 kg; >60 kg) 
 estimated Glomerular Filtration Rate (eGFR) (<60 ml/min/1.73m2 , ≥60 
ml/min/1.73m2) 
 eGFR (<15 ml/min/1.73m2, ≥15 to <30 ml/min/1.73m2, ≥30 to <60 ml/min/1.73m2, ≥60 
ml/min/1.73m2) 
 eGFR (<30 ml/min/1.73m2, ≥30 to ≤50 ml/min/1.73m2, >50 to ≤80 ml/min/1.73m2, >80 
ml/min/1.73m2) 
 Fragile subjects (yes, no) 
 Qualifying revascularization procedure, actual (surgical; endovascular including 
hybrid) 
 Clopidogrel use in relation to qualifying revascularization procedure (yes, no) 
 Type of qualifying procedure and clopidogrel use, actual (surgical; endovascular 
including hybrid with clopidogrel; endovascular including hybrid without clopidogrel )  
 Clopidogrel use continued after randomization (<30 days, >=30 days, none) 
 Prior coronary artery disease (CAD) (yes; no) 
 Prior MI (yes; no) 
 Prior MI and age < 65 years (yes, no) 
 Prior MI and reduced renal function, i.e., eGFR <60 mL/min (yes, no) 
 Carotid artery disease history (yes; no) 
 Prior limb revascularization (yes; no) 
 History of heart failure (yes; no) 


 
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 Diabetes mellitus(yes; no) 
 Smoking status (former, never, current)  
 Hypertension (yes; no) 
 Hyperlipidemia (yes; no) 
 Baseline (Month 1 visit)  
o ABI ≤0.80 or TBI ≤0.60;  
o ABI >0.80 and TBI >0.60;  
o TBI and ABI not done  
6.2.5 
Analysis of the primary efficacy variable 
The primary analysis will be based on the time from randomization to the first occurrence of 
any of the components of the primary efficacy outcome (independently adjudicated), using the 
ITT analysis set and ITT data scope.  
 
The null hypothesis will be: 
H0, PE: SR(t) = SA(t) for all time points t ≥0, (i.e., "there is no difference between the 
rivaroxaban added to ASA group and the ASA alone group regarding the primary 
efficacy outcome for all time points"), 
and the one-sided alternative hypothesis will be: 
H1, PE: SR(t) >SA(t) for at least one time point t ≥0, and SR(t) ≥SA(t) for all time points 
t ≥0, (i.e., "there is a difference between the two groups in favor of rivaroxaban 
regarding the primary efficacy outcome for at least one time point"), 
where SR denotes the survival function of the rivaroxaban added to ASA group and SA 
denotes the survival function of the ASA alone group. 
 
The rivaroxaban added to ASA group will be compared to the ASA alone group using a log-
rank test stratified by type of procedure and clopidogrel use ((i.) surgical vs. (ii.) endovascular 
with clopidogrel vs. (iii.) endovascular without clopidogrel per IxRS assignment) with 
treatment as a fixed factor. Superiority of rivaroxaban over placebo will be declared, if the 
associated one-sided null hypothesis is rejected in favor of rivaroxaban at the 2.5% 
significance level. 
 
Kaplan-Meier (KM) estimates of cumulative risk and cumulative hazard functions will be 
provided to evaluate the timing of event occurrence in the different treatment groups and the 
consistency of the respective treatment effects for all time points. 
The following SAS program code will be used for the log-rank test and Kaplan-Meier 
estimates:  


 
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PROC LIFETEST DATA = <dataset> ALPHA=0.05 METHOD=KM NELSON; 
  STRATA stratumn / GROUP=trtgrpn TEST=(LOGRANK) TREND; 
  TIME ttevalue * ttecnsr(0); 
RUN; 
 
/* 
where 
dataset  = name of dataset including all ITT subjects   
trtgrpn  = variable coding randomized treatment group 
ttevalue = time to first occurrence of primary efficacy outcome event 
ttecnsr  = censoring index (0 = right-censored, 1 = event) 
stratumn = variable for stratification factor */ 
 
 
The relative risk reduction (RRR) will be estimated using a Cox proportional hazards (Cox 
PH) model, stratified by type of procedure and use of clopidogrel per IxRS assignment, with 
treatment as the only covariate. The point estimate and corresponding 95% confidence 
interval (CI) for the hazard ratio (HR, rivaroxaban added to ASA vs. ASA alone) will be 
reported. The plausibility of proportional hazards assumption will be assessed by visually 
comparing the plot of the log of cumulative hazard between treatments and by additionally 
adding a treatment by logarithm-transformed time interaction into the Cox PH model.  
 
The following SAS program code will be used for the Cox proportional hazards model:  
 
 
PROC PHREG DATA = <dataset>; 
  MODEL ttevalue * ttecnsr(0) = trtgrpn / RL TIES=EFRON ALPHA=0.05; 
  STRATA stratumn; 
RUN; 
 
/* 
where 
dataset  = name of dataset including all ITT subjects  
trtgrpn  = variable coding randomized treatment group 
ttevalue = time to first occurrence of primary efficacy outcome event 
ttecnsr  = censoring index (0 = right-censored, 1 = event) 
stratumn = variable for stratification factor  
*/ 
 
 
Additional procedure options controlling the output may be added to the program codes. 
6.2.6 
Analysis of secondary efficacy variables 
If the primary efficacy outcome is statistically significant, the secondary efficacy outcomes 
will be tested in a sequential manner according to the order as listed in Section 6.2.2 with one-
sided alpha of 0.025. If an individual test during any step is not statistically significant, further 
treatment comparison may continue (i.e., reporting of p-values) but significance will not be 
claimed. This hierarchical testing procedure will control the global Type 1 error level. 


 
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The analysis of the secondary variables will be based on the ITT analysis set and ITT data 
scope, including events as adjudicated by the ICAC or reported by investigators if not being 
adjudicated.   
The statistical hypotheses for the secondary efficacy outcomes are defined similarly as for the 
primary efficacy outcome. The analysis methods will be similar to those described for the 
primary efficacy outcome.  
6.2.7 
Analysis of other efficacy variables 
The analysis of the other variables will be based on the ITT analysis set and ITT data scope, 
including events as adjudicated by the ICAC or reported by investigators if not being 
adjudicated. These analyses will be considered exploratory.  
The analysis methods will be similar to those described for the primary efficacy outcome 
except for patient reported outcomes.  
For EQ-5D and WIQ, the change from baseline of the mobility domain of EQ-5D and each 
domain of WIQ (pain [PAD specific question and Q1 of differential diagnosis], distance, 
speed, stair climbing) will be analyzed using an ANCOVA model with baseline value as a 
covariate and treatment as the only fixed effect. Baseline is the last measurement prior to or at 
randomization. 
For limb hemodynamics (ABI and TBI separately), the changes from baseline will be 
analyzed using an ANCOVA model with baseline value as a covariate and treatment as the 
only fixed effect. Since the ABI and TBI is expected to improve after qualifying 
revascularization and decrease gradually over time, baseline value is defined as the 
measurement at month 1 visit. 
Summary statistics of EQ-5D, WIQ and ABI and TBI actual and change from baseline values 
will also be provided by visit. 
6.2.8 
Exploratory analysis 
Exploratory analysis of the individual components of the primary and secondary efficacy 
outcomes will be analyzed similarly to the primary efficacy outcome. Composite outcomes 
major adverse cardiac events (MACE, ie.  CV death, MI and ischemic stroke) and major 
adverse limb events (MALE, i.e.  ALI and  major amputation due to a vascular etiology) will 
be analyzed similarly to the primary efficacy outcome. 
To account for the multiple components of the primary efficacy endpoint, all event analysis 
will be evaluated in ITT data scopes and on-treatment data scopes by fitting frailty model with 
gamma distribution of the shared frailty terms as an extension of the Cox accounting for 
correlation of the events within a subject (see Hougaard, 2000; Wienke, 2011; Austin, 2017), 
with treatment as the only covariate. In addition, model with log-normal distribution of the 
shared frailty terms will be fitted. Another extension of the Cox model is the Andersen-Gill 
model, which assumes that each recurrence is an independent event (Andersen, 1982). To 
account for the intra-subject correlation, models with robust standard error estimator will be 
fitted according to Lin’s method (Lin et al. 2000). 
The primary efficacy endpoint will be explored for the following subgroups 
Qualifying endovascular techniques  
o Balloon angioplasty (drug-coated and not coated), yes/no 


 
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o Angioplasty with stent (bare metal, drug-coated, covered) yes/no 
o Atherectomy 
o Thrombolysis 
 Time from qualifying revascularization procedure to randomization (<median; 
>=median) 
 History of lower limb amputation 
o Major ischemic amputation with or without other amputation 
o Minor ischemic amputation with or without non-ischemic amputation 
o Nonischemic amputation only 
o No amputation 
The frequency will be presented descriptively (and with forest plots). The hazard ratio for the 
treatment effect will be estimated separately within each level of a subgroup using the Cox 
proportional hazards model without stratification. 
The following variable will also be explored: 
 Time from randomization to the first occurrence of MI types  
 Any revascularization after randomization regardless of the side as reported by the 
investigator  
 Any index leg revascularization as reported by the investigator 
In addition, ABI and TBI will be further explored to understand the effect of natural history 
and drug effect on hemodynamics.  Examples include: 
 Change in ABI and TBI post randomization excluding values after subsequent 
revascularization by subgroup (endovascular versus surgical)  
 Change in ABI and TBI post randomization in patients with subsequent intervention 
versus those who do not undergo subsequent intervention 
To explore the robustness of the treatment effect over time, landmark analyses will be 
performed for the primary endpoint according to landmark periods of randomization to 3-
month, 3-month to 1-year and 1-year to the end of treatment phase and randomization to 6-
month, 6-month to 1 year and 1-year to end of treatment phase (Van Houwelingen 2007). 
Additional time point after 1-year may be added depending on the actual study duration. For 
each landmark period, the hazard ratio will be estimated using a Cox PH model stratified by 
type of procedure and use of clopidogrel (per IxRS assignment) with treatment as the only 
covariate, the corresponding 95% CI will be provided, and Kaplan-Meier (KM) plot of 
cumulative risk will be generated, respectively.  The hazard ratio will also be calculated for 
the two main components (MACE versus MALE) of the primary endpoint.  
6.2.9 
Subgroup analysis 
Patients with actual qualifying revascularization procedure 
In addition to the stratification based on the IxRS assignment, the study will be analyzed 
based on the actual qualifying revascularization procedure and actual clopidogrel use in 
relation to qualifying revascularization as follows: 


 
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 surgical, 
 endovascular including hybrid with clopidogrel, 
 endovascular including hybrid without clopidogrel. 
Patients with hybrid procedures are classified as endovascular revascularization. We plan to 
determine the treatment effect among patients in each of the above strata (actual 
classification). Treatment groups will be compared using Cox proportional hazards model 
with treatment as a covariate for the primary (also the individual components) and secondary 
efficacy endpoints, using the ITT analysis set and ITT data scope. The point estimate and 
corresponding 95% CI for the hazard ratio (HR, rivaroxaban added to ASA vs. ASA alone) 
will be reported. Additional analyses on other endpoints may be performed based on both per 
IxRS assignment and actual type of qualifying procedure and clopidogrel use. 
Other subgroups  
The analyses for the other subgroups (as defined in section 6.2.4) will be performed based on 
the same analysis sets and data scopes as in the main analyses for the primary efficacy 
outcome (also the individual components). The results will be presented descriptively (and 
with forest plots). The hazard ratio for the treatment effect will be estimated separately within 
each level of a subgroup variable using the Cox proportional hazards model stratified by type 
of procedure and clopidogrel use (per IxRS assignment) (except for subgroups related to 
qualifying revascularization procedure or clopidogrel use) with treatment as a covariate.  
Additionally, homogeneity of treatment effect in subgroups, both in magnitude and direction, 
will be assessed by adding a covariate for the subgroup variable and the corresponding 
treatment-subgroup interaction to the respective Cox proportional hazards model. This further 
investigation includes the likelihood ratio test proposed by Gail to test for qualitative 
interaction (Gail et al. 1985). 
As the number of subgroup analyses may be large, the probability of observing at least one 
spurious interaction is high despite the lack of a biological or pharmacological basis for 
expecting an interaction. Thus, any interaction with a p-value below the 5% type I error level 
in the analysis of primary outcome will be interpreted as “flag” to prompt further investigation 
into the consistency of the pattern within secondary and related outcomes. 
The analyses for the subgroups as defined in section 6.2.4 will also be performed based on the 
same analysis set and data scope as in the main analysis for the secondary efficacy outcomes 
(also the individual components). 
6.2.10 
Sensitivity analyses  
To support the primary study results and to assess the robustness of the primary analysis, 
several sensitivity analyses will be performed. 
The primary efficacy variable will be analyzed based on the ITT analysis set and ITT data 
scope 
 using the Cox proportional hazard model with actual stratification 
 using the Cox proportional hazard model without stratification 
 Using a proportional hazards estimator that is robust to departures from  proportional 
hazard (Boyd et al. 2012) 


 
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The primary efficacy outcome (also the individual components) as adjudicated by ICAC will 
also be analyzed using the same Cox PH model as described in section 6.2.5 based on SAF 
and on-treatment data scope. The same analysis will be repeated based on ITT analysis set and 
overall study duration including post-study treatment follow-up. All subjects who are event 
free will be censored at the date of last clinical event ascertainment or last contact.  
The primary efficacy outcome as reported by investigator will be analyzed similarly based on 
the ITT analysis set and ITT data scope. 
For the individual components of investigator reported primary efficacy outcome see 
Appendix E. 
In addition, the secondary efficacy outcomes as adjudicated by ICAC (if applicable) will be 
analyzed using the same Cox PH model as described in section 6.2.5 based on the SAF and 
on-treatment data scope.  
If the sensitivity analyses are much different from the primary analysis, additional analyses 
may be performed to further investigate the inconsistency. 
Concordance of ICAC and investigator reports on the primary efficacy endpoint events will be 
provided for the combined treatment group. 
Sensitivity analyses to address the potential impact of missing data 
Although extensive effort will be made to reduce the number of subjects with missing follow-
up, it is expected that there will be missing vital status and event information in some 
subjects. Subjects who are not followed up until the ECOD (consent withdrawal, objection to 
further data collection, and lost to follow up) before the development of primary efficacy 
events will be considered missing. 
Sensitivity analyses will be performed for the primary efficacy endpoint based on the ITT 
analysis set and ITT data scope to evaluate the potential impact of missing data on analysis 
results and robustness of study conclusions. 
To evaluate the plausibility of informative censoring, distributions of baseline demographics 
and other characteristics will be compared between subjects with and without missing data, 
taking into account treatment and regardless of treatment.  
Potential impact of missing data will be evaluated by imputation, where the event process will 
be imputed in missing follow-up periods (ie. time from last clinical event ascertainment date 
until ECOD in subjects without a primary efficacy endpoint prior to the ECOD). The 
robustness of the treatment effect with respect to missing data will be evaluated with a tipping 
point analysis (see Appendix C for mathematical details). In this analysis, we will: 
1. Estimate the hazard at time of loss to follow-up among subjects in ITT analysis set, 
adjusting for treatment group, stratification factors, and the following baseline 
covariates: 
 age (<65; ≥65 to <75; ≥75 years) 
 diabetes mellitus (yes, no) 
 prior coronary artery disease (yes, no) 
2. Inflate the hazard only in the rivaroxaban group by a set of inflation factors; assuming 
non-informative censoring in the control group 


 
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3. Perform simulations to impute events to the end of the study using standard multiple 
imputation rules, and compute the hazard ratio and two-sided 95% CI using the 
primary Cox proportional model 
4. Given the study results is statistically significant in favor of rivaroxaban, increase the 
inflation factor (by repeating steps 2 and 3) until the upper limit of the two-sided 95% 
CI for the hazard ratio crosses 1.0; this will be the “tipping point” 
The tipping point will show how much higher the event risk after drop-out would need to be 
in the rivaroxaban group so that statistical significance is lost.   
In addition, the extent of missing information will be described by the fraction of subjects 
with missing data and the fraction of unobserved rivaroxaban or rivaroxaban placebo follow-
up subject-years. 
6.3 
Pharmacokinetics/pharmacodynamics 
Not applicable 
6.4 
Safety 
6.4.1 
Adverse events 
Because the safety profile of rivaroxaban has been well established in previous large and 
extensive trials, this study will collect limited AE data. Adverse events (AEs) will be coded 
by Medical Dictionary for Regulatory Activities (MedDRA).  The version number of 
MedDRA used for the analyses will be stored in the clinical database. A listing will be 
provided linking the original investigator terms and the coded terms. 
Analyses of reported adverse events will be performed based on the SAF and on-treatment 
data scope.   
In case of uncertainty (e.g., missing or incomplete dates), AEs will be classified as “treatment 
emergent” (TE) following the worst case approach.  
An overall summary of AEs and treatment-emergent (TE) AEs (only considering study 
medication of rivaroxaban or rivaroxaban placebo) will be generated by treatment group and 
overall.  
Incidences of subjects with treatment emergent adverse events (TEAEs), drug-related and/or 
serious TEAEs, and TEAEs causing discontinuation of study drug will be summarized by 
treatment grouped by MedDRA Primary System Organ Class (SOC) and Preferred Term 
(PT).  In addition, the incidence of pre-treatment AEs and AEs during the post study treatment 
follow up will be tabulated. 
Serious adverse events (SAEs), AEs leading to discontinuation and AEs of special safety 
interest (if applicable) will be listed.  The date, relative day (to start of study medication) and 
phase of the study (pre-treatment, during treatment, post-treatment) will be included. 
Further summaries of AEs by maximum intensity and worst outcome will be provided, 
consistent with Bayer Global Medical Standards. 
Specific to Japan, outcome events (i.e. bleeding, efficacy outcome events) are reported as an 
(S)AEs as required by PMDA, thus (TE)AEs and SAEs will be further presented for Japan 
only subjects vs. non-Japan subjects. 


 
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6.4.2 
Primary safety variable 
The primary safety variable is the time from randomization to the major bleeding events 
according to the thrombolysis in myocardial infarction (TIMI) classification, as defined in the 
ICAC charter. 
6.4.3 
Secondary safety variables 
The secondary safety variables are: 
 the time from randomization to the major bleeding events according to the International 
Society on Thrombosis and Haemostasis (ISTH) classification 
 the time from randomization to the type 3b and above bleeding events according to the 
Bleeding Academic Research Consortium (BARC) classification 
Bleeding definitions can be found in the ICAC charter. 
6.4.4 
Other safety variables 
Other safety variables include vital signs (systolic and diastolic blood pressure, pulse rate).  
6.4.5 
Analysis of safety variables 
The analysis of the primary and secondary safety variables will be based on the SAF and on-
treatment data scope.  
Time to the first occurrence of the primary safety endpoint (i.e., TIMI major bleeding) will be 
compared using a Cox proportional hazards model stratified by type of procedure and use of 
clopidogrel (per IxRS assignment) with treatment group as a covariate. A plot of cumulative 
event rate derived by Kaplan-Meier estimate will be provided to show event rate and 
treatment effect by time.  
The secondary safety outcome variables will be analyzed similarly. 
As supportive analyses, the primary safety variable will be analyzed as described above based 
on the SAF and ITT data scope as well as overall study duration including post-study 
treatment follow-up. In addition, the primary safety variable will be analyzed according to the 
actual qualifying revascularization procedure (section 6.2.9) and in subgroups as described in 
section 6.2.4. Number of subjects with multiple TIMI major bleedings will also be 
summarized in frequency table. 
As exploratory analyses, landmark analysis similar to those as described in section 6.2.8 will 
also be performed for the primary safety variable. 
Additionally number of patients with bleeding leading to permanent drug discontinuation will 
be summarized by bleeding sites.  
Concordance of ICAC and investigator reports on the TIMI major bleeding events will be 
provided for the combined treatment group. 
Other safety variables will be summarized descriptively. 
Any pregnancy occurring in a study subject during the subject’s participation in this study will 
be displayed. 


 
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6.5 
Other procedures and variables 
The other procedures and variables include: 
 Health care resource utilization data  
 PAD symptom status 
For these variables, additional analyses other than those specified in sections 6.2.7 and 6.2.8 
may be performed and reported separately. 
6.6 
Benefit/Risk Assessment 
The benefit-risk analyses are structured to allow an integrated evaluation of the key benefits 
and risks in the study. They are complementary to the efficacy and safety analyses described 
previously in this document and not intended for hypothesis testing. These analyses will be 
performed in patient populations with the same follow up. Details of these analyses will be 
described in a separate document (supplemental statistical analysis plan for benefit-risk). 
The benefit-risk evaluation will be based on the comparison of the time-to-first-event rates 
(rivaroxaban added to ASA vs. ASA alone), for events intended to be prevented (benefits) and 
events that may be caused (risks). Individual outcome measures balanced and weighed by 
clinical significance and severity will be compared to evaluate the trade-off between 
prevention of thrombotic vascular events versus harm (i.e. bleeding). These outcome 
measures include the individual components of the primary efficacy outcome, risk 
measurements include the hemorrhagic events of the efficacy endpoint and bleedings 
according to TIMI classification. To have a comprehensive benefit-risk evaluation, several 
quantification methods will be used.  
 Results of the above analysis do not preclude additional benefit/risk assessment in other 
endpoints. The overall benefit-risk profile of the study drug will be interpreted in 
consideration of the totality of the data. 
 
7. 
Document history and changes in the planned statistical analysis 
Version 
Date 
Action 
Draft SAP 
submitted to FDA 
12 June 2015 
 
Version 1.0 
7 April 2016 
Updates based on protocol amendment #4 and 
FDA feedback on planned sensitivity analyses 
to assess the impact of missing data 
 
Version 2.0 
14 May 2018 
 
 
 
 
 Order of secondary efficacy endpoints 
were changed according to Global 
Integrated Clinical Study Protocol version 
3.0 
 Efficacy cut-off date and censoring rules 
for efficacy endpoints were modified in 


 
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Version 
Date 
Action 
 
section 4.5.1, 4.5.3 and Appendix A 
 Added a few more subgroup variables in 
section 6.2.4 
 Added more exploratory analyses (e.g. 
MACE/MALE endpoints,  landmark 
analysis for primary efficacy endpoint) in 
section 6.2.8 
 Added more sensitivity analyses of 
primary and secondary efficacy endpoints 
in section 6.2.10 
 Added AEs analyses for Japan vs. non-
Japan patients in section 6.4.1, and 
supportive analyses in section 6.4.5.  
 Updated benefit/risk analysis in section 6.6 
 Added Appendix B for the definition of 
regions 
 Added Appendix C to describe the 
mathematical details of the tipping point 
analysis 
  
Version 3.0 
24 July 2019 
None of the edits in this SAP version is 
considered to change the primary efficacy 
analysis and other analyses as described in the 
SAP version 2.0, but includes further 
clarifications and additional analyses.  
Editorial, administrative, and typographical 
corrections were made that do not affect the 
overall SAP. These changes are not described 
in this section. 
The following changes are introduced in SAP 
version 3.0: 
 Added information on imputation rules for 
the missing or incomplete post-
randomization event dates in section 4.3 
 Added information on derivation of the 
first dose and last dose date of study 
treatment in section 4.5.1.  
 Added analysis in data scopes with overall 
study duration for sensitivity analysis in 
section 4.5.2 
 Added information on censoring rules for 
efficacy endpoints in section 4.5.3 and 


 
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Version 
Date 
Action 
Appendix A 
 Added analysis on SAF with on-treatment 
data scope for secondary efficacy 
endpoints, subgroup variables, and 
changed sensitivity analysis for primary 
efficacy endpoints with on-treatment data 
scope from ITT to SAF in Table 1 
 Updated some demographic variables in 
section 6.1.2 
 Updated other efficacy variables in section 
6.2.3 
 Updated some subgroup variables in 
section 6.2.4 
 Updated SAS code to display both one-
sided and two-sided p values in section 
6.2.5 
 Updated exploratory analysis with detailed 
statistical model information in the 
multiple occurrences of the primary 
efficacy endpoints analysis and references 
in section 6.2.8 
 Updated exploratory analysis in the 
subgroup variables in section 6.2.8  
 Added additional landmark analysis on the 
time period from randomization to 6-
month, 6-month to 1 year and 1-year to 
end of treatment phase in section 6.2.8 
 Added likelihood ratio test analysis to test 
for interaction terms in the subgroup 
analysis in section 6.2.9 
 Added sensitivity analyses on individual 
components of primary efficacy endpoints 
on SAF and on-treatment data scope in 
section 6.2.10 
 Updated sensitivity analyses on the 
missing data tipping point analysis by 
including the additional baseline covariates 
in the Cox model in section 6.2.10 
 Removed European quality of life 5 
dimensions questionnaire and walking 
impairment questionnaire variables in 
section 6.5. Those variables were  


 
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Version 
Date 
Action 
mentioned in section 6.2.3 
 Updated Efficacy cut-off date, timelines, 
and censoring variables in Appendix A 
 Added Appendix D for the detailed 
information on imputation rules for 
missing dose date  
 Added Appendix E for the definition on 
the components of the primary efficacy 
outcome by the investigators 
 
 
8. 
References 
Andersen, PK and Gill, RD: Cox’s Regression Model for Counting Processes: A 
Large Sample Study. Annals of Statistics, 1982; 10:1100-1120. 
Austin PC. A Tutorial on Multilevel Survival Analysis: Methods, Models and 
Applications. Int Stat Rev. 2017;85(2):185–203. doi:10.1111/insr.12214. 
Becker F, Robert-Ebadi H, Ricco JB, et al. Chapter I: Definitions, epidemiology, 
clinical presentation and prognosis. European journal of vascular and 
endovascular surgery: the official journal of the European Society for 
Vascular Surgery. 2011; 42 Suppl 2:S4-12 
Boyd, AP, Kittelson, JM, Gillen, DL. Estimation of treatment effect under 
nonproportional hazards and covariate dependent censoring. Statistics in 
Medicine. (2012) 31(28):3504-15 
Gail M., Simon R. Testing for qualitative interactions between treatment effects and 
patient subsets. Biometrics 1985, 41:361-372. 
Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. 
Brit J Radiology 1971, 44:793-7 
Hintze, J. PASS 2011. NCSS, LLC Kaysville, Utah. 2011. 
Hougaard, P. Analysis of Multivariate Survival Data. New York: Springer-Verlag; 
2000. 
Lin DY, Wei LJ, Yang I, Ying Z. Semiparametric regression for the mean and rate 
functions of recurrent events. J R Stat Soc B 2000;62:711–30. 
Van Houwelingen HC. Dynamic prediction by landmarking in event history 
analysis. Scandinavian Journal of Statistics. 2007 Mar 1;34(1):70-85. 
Wienke, A. Frailty Models in Survival Analysis. Boca Raton, FL: Chapman & 
Hall/CRC; 2011. 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 59-7939 / 17454 
Page: 32 of 36
 
 
Appendix A: Study Closeout Procedure and Variables used for Censoring 
 
 
 
 
 
 
 
 
 
 
 
Note: The dates and timeline shown are for illustration purpose only. ECOD= Efficacy cut-off date, EOT Visit=end of treatment 
visit, PS-FU Visit=Post-study treatment follow-up visit (phone call), DBL=database lock 
The executive committee will monitor the accrual of the number of primary events, and when 
appropriate predict and define an ECOD at which time the pre-defined target number of 
events for the primary composite endpoint are expected to have occurred. All randomized 
patients should return for their End of Treatment (EOT) visit after the ECOD.  
Events that occur after the ECOD will also be collected and adjudicated. These events will be 
included in sensitivity analyses but not the primary analysis.  
For the implementation of the censoring rules below variables are defined to distinguish 
between a patient’s last contact with information relating to clinical events versus CV-death / 
all-cause mortality. 
 Date of objection to further data collection 
This date will be given only for those subjects who expressed objection to further data 
collection after withdrawal of informed consent.  
 Last clinical event ascertainment date 
The latest date from regular or unscheduled post-randomization visits or contacts with 
assessment of clinical events or latest adjudicated clinical event start date.  
 Date of last contact alive  
The date of the last documented contact with the subject or a third party (including 
data on subject survival status) derived from the maximum (last clinical event 
ascertainment date, SAEs date, vital status date, consent withdrawn date or date of 
objection to further data collection). The resulting maximum date is capped by the 
death date if the patient died or by the date of clean database. In addition, the date of 
last contact alive will be the day before the death date, if available, for subjects who 
die. 
PS-FU 
visit 
(30 d) 
Regular visit schedule  
Patient on study drug 
2019 
DBL 
Aug 
Nov 
Feb 
Jul 
Sep 
Oct 
Dec 
Jan 
Mar 
Apr 
Jun 
ECOD  
Site communications 
Monthly alerts as the 
ECOD estimates 
become refined 
2020 
May 
EOT 
visit  
(30 d) 
ECOD will be 
before the 
EOT visit 
CDB  
(30 d) 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 59-7939 / 17454 
Page: 33 of 36
 
 
Appendix B: Definition of Regions 
Countries will be assigned to regions as shown in Table 2 below. If additional countries 
participate in the trial, their assignment to a region will be specified in the table/listing/figure 
specification document before unblinding. 
Table 2 
Classification of Countries to Regions 
Region  
Countries 
North America  
Canada, USA 
Western Europe  
Austria, Belgium, Denmark, Finland, France, Germany, Italy, 
Netherlands, Portugal, Spain, Sweden, Switzerland, United Kingdom 
Eastern Europe  
Bulgaria, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, 
Romania, Russia, Serbia, Slovakia, Ukraine 
Asia Pacific 
China, Japan, South Korea, Taiwan, Thailand 
South America 
Argentina, Brazil  
Appendix C: Mathematical Details of the Proposed Tipping Point Analysis 
The robustness of the treatment effect with respect to missing data will be evaluated with a 
tipping point analysis for the primary efficacy variable. A methodology similar to pattern-
mixture-models will be employed, where a Weibull survival model will be fitted to impute 
outcome for subjects who are lost-to-follow-up (or withdrawn consent with no further 
information) (Little 2016).  
 
1. Estimate the hazard at time of loss to follow-up, adjusting for treatment group, 
covariates and stratification factors  
 
a. The log survival time w=log(t) is modeled using SAS LIFEREG procedure by 
fitting a Weibull distribution to all subjects, adjusting for treatment group, 
covariates and stratification factors. The  survival function has the form 















w
w
S
exp
exp
)
(
0
, 
where µ (differs for treatment, covariates, and stratum) and σ (scale) are estimated 
from the SAS output. 
 
b. Re-parametrize the Weibull distribution with survival function  
S (t) = exp (– (t/λ) β), 
where λ is the scale parameter and β is the shape parameter. Obtain the estimates 
of λ and β as 
      λ = exp (µ) 
β = 1/σ. 
c. Obtain the observed hazard rate for individual subjects using the hazard function  
h (t|λ, β) = (β/λ) (t/λ) β-1. 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 59-7939 / 17454 
Page: 34 of 36
 
 
2. Inflate the hazard only in the rivaroxaban group by a set of inflation factors; assuming 
non-informative censoring in the control group  
 
Let k be the inflation factor, the inflated hazard rate in the rivaroxaban group is 
h* (t|λ, β)  = k×(β/λ) (t/λ) β-1 
and the new scale parameter is  
λ* = λ/ (k1/β) 
by solving λ* from k×(β/λ) (t/λ) β-1 = (β/ λ*) (t/ λ*) β-1, while fixing the shape parameter 
β. 
The hazard rate in the control group remains unchanged. 
3. Perform simulations to impute events to the end of the study using standard multiple 
imputation rules (Rubin 1987), and compute the hazard ratio and two-sided 95% CI 
using the primary Cox proportional model 
 
For subjects who are lost-to-follow up (or withdrawn consent with no further information), 
and who did not experience a primary efficacy endpoint prior to the ECOD, random variables 
will be simulated using the conditional time to event distribution after the last contact date 
(LC) (defined as earlier date of last clinical event ascertainment date, date of the objection to 
further data collection) given that no event was observed before.  
 
Let x be the time from the last contact date (LC) to the event date, the conditional probability 
of having an event given no event observed before LC is  
.
)
(
)
(
1
)
(
)
Pr(
1
)
|
Pr(
1
)
|
Pr(
LC
S
LC
x
S
LC
t
P
LC
x
t
LC
t
LC
x
t
LC
t
LC
x
t
y

















 
Using the estimated scale parameter λ* and shape parameter β from Weibull distribution in 
step 2, the above becomes 
y = 1– exp (– ((x+LC)/λ*) β) / exp (– (LC/λ*) β), 
    log (1–y) = – ((x+LC)/λ*) β + (LC/λ*) β 
 x = λ*((LC/λ*) β – log (1–y)) 1/β – LC.  
If y is generated as a random variable with uniform distribution between 0 and 1, the random 
variable x can be generated using the inverse transformation technique from the formula 
above. 
 
If this randomly generated variable has a value less than the elapsed time between the last 
contact date and the efficacy cut of date, the subject will be counted as having observed an 
event at the last contact date plus the random variable. Otherwise, the subject is re-adjusted to 
be censored at the ECOD. 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 59-7939 / 17454 
Page: 35 of 36
 
 
 
These imputed events will be added to the observed events in the study for both treatments 
and the primary efficacy variable will be re-analyzed. This process will be repeated 1000 
times. The hazard ratio with 95% CI will be estimated for each imputed data set and then 
combined using standard multiple imputation combining rules. 
 
4. Given the study results is statistically significant in favor of rivaroxaban, increase the 
inflation factor (by repeating steps 2 and 3) until the upper limit of the two-sided 95% 
CI for the hazard ratio crosses 1.0; this will be the “tipping point”. 
 
Reference: 
Little, RL, Wang, J., Sun, X. et. al. The treatment of missing data in a large cardiovascular 
clinical outcomes study. Clinical Trials, 2016 vol. 13 no. 3 344-351 
Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley, 1987 
Appendix D: Imputation Rules for Missing Dose Date 
First dose date is missing or incomplete 
Action 
Only day of first dose date is missing 
Impute the first dose date as maximum (date of 
randomization+1 day, 01.month.year) 
Month and day of first dose date is missing 
Impute the first dose date as randomization 
+ 1 day. 
First dose date is complete missing but last 
dose date is available 
Impute the first dose date as randomization 
+ 1 day. 
First dose date and last dose date is missing 
The patient never took the study medicine 
Last dose date is missing or incomplete 
Action 
Only day of last dose date is missing 
 
Impute the last dose date using last day of 
the month  
 
Derive last dose date as minimum of (the 
date of last contact, imputed last dose 
date, the date of death, or the maximum of 
(ECOD, EOT visit date)) but no earlier 
than the date of first dose. 
Month and day of last dose date is missing 
 
Impute the last dose date using last day of 
the year 
 
Derive last dose date as minimum of (the 
date of last contact, imputed last dose 
date, the date of death, or the maximum of 
(ECOD, EOT visit date)) but no earlier 
than the date of first dose. 
Last dose date is complete missing but first 
dose date is available 
Impute last dose date as minimum of (the date 
of last contact, the date of death, or the 
maximum of (ECOD, EOT visit date)) but no 
earlier than the date of first dose. 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 59-7939 / 17454 
Page: 36 of 36
 
 
Appendix E: Components of the Primary Efficacy Outcome by the 
Investigators 
 CV death: Either any death in the main category “Cardiovascular cause” or within the 
“Other cause” main category including any death indicated by the investigator that the 
cause was unknown.  
 MI: coronary ischemic event diagnosis in 
o Non-stemi 
o Stemi 
 Ischemia stroke: stroke type in 
o Primary ischemic stroke 
o Primary ischemic stroke with hemorrhagic conversion 
o Unknown stroke type 
 Acute limb ischemia 
 Amputation: reason for amputation in primary acute limb ischemia and primary 
vascular disease progression with site of leg in 
o Above the knee 
o Below the knee, ankle disarticulation 
o Below the knee, transtibial