Conditions: Neoplasms
Keywords: Cancer Rivaroxaban Venous thromboembolism
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 841
Healthy volunteers: no

Brief summary:
The purpose of this study is to demonstrate that rivaroxaban is superior to placebo for reducing the risk of the primary composite outcome as defined by objectively confirmed symptomatic lower extremity proximal deep vein thrombosis (DVT), asymptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal pulmonary embolism (PE), incidental PE, and venous thromboembolism (VTE)-related death in ambulatory adult participants with various cancer types receiving systemic cancer therapy who are at high risk of developing a VTE.

Detailed description:
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, superiority study comparing the efficacy and safety of rivaroxaban with placebo for primary prophylaxis of venous thromboembolism (VTE) in ambulatory adult participants, with various cancer types who are scheduled to initiate systemic cancer therapy. The study consists of 3 Phases: Screening Phase (14 Days), double-blind treatment Phase (180 Days) and follow up Phase (30 Days). The duration of participation in the study for each participant is approximately 32 weeks.

Arms:
arm 1: Participants will be administered rivaroxaban 10 milligram (mg) tablet orally once daily for 180 days. arm 2: Participants will be administered matching placebo tablet orally once daily for 180 days.

Interventions: intervention 1: Rivaroxaban intervention 2: Placebo
Intervention descriptions: intervention 1: Rivaroxaban 10 milligram (mg) tablet will be administered orally once daily for 180 days. intervention 2: Placebo tablet will be administered orally once daily for 180 days.

Protocol document:
Prot_001.pdf: 
1
Status: Approved, Date: 16 February 2018
Janssen Scientific Affairs*
Clinical Protocol
Efficacy and Safety of Rivaroxaban Prophylaxis Compared with Placebo in Ambulatory 
Cancer Patients Initiating Systemic Cancer Therapy and at High Risk for Venous 
Thromboembolism
Protocol BAY59-7939/39039039STM4001/18262 Phase 3b
AMENDMENT-4
JNJ39039039/BAY59-7939 (Rivaroxaban)
* Rivaroxaban (BAY-59-7939, JNJ-39039039) is being co-developed under collaboration and license 
agreement between Bayer HealthCare AG (BHC) and Ortho McNeil Pharmaceuticals, Inc. (OMP) dated 
October 1, 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 trial. 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 NV. The term "sponsor" or "designee" is used throughout the 
protocol to represent these various legal entities that have been identified to perform various clinical trial 
services; the actual sponsor or designee is identified on the Contact Information page that accompanies 
this protocol.
This study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER: 2015-001630-21
Status:
Approved
Date:
16 February 2018
Prepared by:
Janssen Scientific Affairs, LLC
EDMS number:
EDMS-ERI-102610148: 6.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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Approved, Date: 16 February 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT FIGURES ........................................................................................................................ 4
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS.................................................................................................................................................. 21
TIME AND EVENTS SCHEDULE .............................................................................................................. 31
ABBREVIATIONS ...................................................................................................................................... 33
1.
INTRODUCTION................................................................................................................................ 35
1.1.
Background .................................................................................................................................... 35
1.2.
Overall Rationale for the Study...................................................................................................... 37
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 39
2.1.
Objectives ...................................................................................................................................... 39
2.2.
Hypothesis ..................................................................................................................................... 40
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 40
3.1.
Overview of Study Design.............................................................................................................. 40
3.2.
Study Design Rationale.................................................................................................................. 44
4.
SUBJECT POPULATION.................................................................................................................. 48
4.1.
Inclusion Criteria ............................................................................................................................ 48
4.2.
Exclusion Criteria ........................................................................................................................... 50
4.3.
Prohibitions and Restrictions ......................................................................................................... 52
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 53
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 54
7.
TREATMENT COMPLIANCE............................................................................................................ 55
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 55
9.
STUDY EVALUATIONS .................................................................................................................... 58
9.1.
Study Procedures........................................................................................................................... 58
9.1.1.
Overview..................................................................................................................................... 58
9.1.2.
Screening Phase ........................................................................................................................ 58
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 59
9.1.4.
Post-treatment Phase (Follow Up) (Day 181 – Day 210)........................................................... 61
9.2.
Efficacy Evaluations and Outcomes .............................................................................................. 62
9.2.1.
Efficacy Evaluations and Outcomes........................................................................................... 62
9.2.1.1.
Definitions................................................................................................................................ 64
9.2.2.
Efficacy Endpoints ...................................................................................................................... 65
9.2.3.
Approach to the Subject with an Efficacy Outcome Event ......................................................... 66
9.3.
Safety Evaluations ......................................................................................................................... 66
9.3.1.
Bleeding Events.......................................................................................................................... 66
9.3.1.1.
Management of Study Drug for Bleeding Events .................................................................... 67
9.3.2.
Other Safety Assessments ......................................................................................................... 68
9.3.2.1.
Adverse Events ....................................................................................................................... 68
9.3.2.2.
Clinical Laboratory Tests......................................................................................................... 68
9.3.2.3.
Vital Signs................................................................................................................................ 69
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9.3.2.4.
Medical History and Physical Examination.............................................................................. 69
9.4.
Biomarkers ..................................................................................................................................... 70
9.4.1.
Evaluations ................................................................................................................................. 70
9.5.
Pharmacokinetics........................................................................................................................... 70
9.5.1.
Pharmacokinetic Sample Collection and Handling..................................................................... 70
9.5.2.
Analytical Procedures................................................................................................................. 70
9.5.3.
Pharmacokinetic Parameters ..................................................................................................... 70
9.6.
Health Care Resource Utilization................................................................................................... 71
9.7.
Other Evaluations........................................................................................................................... 71
9.8.
Sample Collection and Handling.................................................................................................... 71
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 71
10.1.
Completion ..................................................................................................................................... 71
10.2.
Discontinuation of Study Treatment............................................................................................... 72
10.2.1.
Temporary Interruption of Study Treatment ............................................................................... 72
10.2.2.
Permanent Discontinuation of Study Treatment......................................................................... 74
10.2.3.
Medication Transition Management ........................................................................................... 76
10.2.4.
Withdrawal from the Study.......................................................................................................... 76
11.
STATISTICAL METHODS................................................................................................................. 77
11.1.
Analysis Populations and Observation Periods ............................................................................. 77
11.2.
Sample Size Determination ........................................................................................................... 78
11.3.
Handling of Missing Data ............................................................................................................... 79
11.4.
Interim Analysis.............................................................................................................................. 79
11.5.
Efficacy and Safety Analyses......................................................................................................... 80
11.5.1.
Safety Endpoints, Laboratory, and Vital Signs Data Analysis.................................................... 82
11.6.
Biomarker Analyses ....................................................................................................................... 82
11.7.
Pharmacokinetic Analysis .............................................................................................................. 82
11.8.
Health Care Resource Utilization................................................................................................... 82
11.9.
Committees .................................................................................................................................... 82
11.9.1.
Executive Committee.................................................................................................................. 83
11.9.2.
Independent Data Monitoring Committee................................................................................... 83
11.9.3.
Clinical Endpoint Committee....................................................................................................... 83
12.
ADVERSE EVENT REPORTING ...................................................................................................... 83
12.1.
Warnings/Precautions................................................................................................................. 84
12.2.
Definitions ...................................................................................................................................... 84
12.2.1.
Adverse Event Definitions and Classifications ........................................................................... 84
12.2.2.
Attribution Definitions.................................................................................................................. 85
12.2.3.
Severity Criteria .......................................................................................................................... 86
12.3.
Special Reporting Situations.......................................................................................................... 86
12.4.
Procedures..................................................................................................................................... 87
12.4.1.
All Adverse Events...................................................................................................................... 87
12.4.2.
Serious Adverse Events ............................................................................................................. 88
12.4.3.
Pregnancy................................................................................................................................... 89
12.5.
Contacting Sponsor Regarding Safety........................................................................................... 89
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 89
13.1.
Procedures..................................................................................................................................... 90
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 90
14.
STUDY DRUG INFORMATION......................................................................................................... 90
14.1.
Physical Description of Study Drug(s) ........................................................................................... 90
14.2.
Packaging ...................................................................................................................................... 90
14.3.
Labeling.......................................................................................................................................... 90
14.4.
Preparation, Handling, and Storage............................................................................................... 90
14.5.
Drug Accountability ........................................................................................................................ 90
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15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 91
16.
ETHICAL ASPECTS ......................................................................................................................... 91
16.1.
Study-Specific Design Considerations........................................................................................... 91
16.2.
Regulatory Ethics Compliance....................................................................................................... 92
16.2.1.
Investigator Responsibilities ....................................................................................................... 92
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 92
16.2.3.
Informed Consent ....................................................................................................................... 94
16.2.4.
Privacy of Personal Data ............................................................................................................ 95
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 95
16.2.6.
Country Selection ....................................................................................................................... 95
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 96
17.1.
Protocol Amendments.................................................................................................................... 96
17.2.
Regulatory Documentation ............................................................................................................ 96
17.2.1.
Regulatory Approval/Notification ................................................................................................ 96
17.2.2.
Required Prestudy Documentation............................................................................................. 96
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 97
17.4.
Source Documentation................................................................................................................... 97
17.5.
Case Report Form Completion ...................................................................................................... 98
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 99
17.7.
Record Retention ........................................................................................................................... 99
17.8.
Monitoring .................................................................................................................................... 100
17.9.
Study Completion/Termination..................................................................................................... 100
17.9.1.
Study Completion ..................................................................................................................... 100
17.9.2.
Study Termination..................................................................................................................... 101
17.10.
On-Site Audits .............................................................................................................................. 101
17.11.
Use of Information and Publication.............................................................................................. 101
REFERENCES.......................................................................................................................................... 103
INVESTIGATOR AGREEMENT ............................................................................................................... 112
LIST OF ATTACHMENTS
Attachment 1:
Reporting of Efficacy Endpoints, Adverse Events, and Serious Adverse Events........ 106
Attachment 2: 
Calculation of Creatinine Clearance ............................................................................ 107
Attachment 3: 
Cancer-Associated Venous Thromboembolism Risk Score........................................ 108
Attachment 4: 
Functional Status Assessment Tool ............................................................................ 109
Attachment 5: 
The MDRD Formula for Calculation of GFR................................................................ 110
Attachment 6: 
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Equation 
for Estimating GFR ...................................................................................................... 111
LIST OF IN-TEXT FIGURES
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 44
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PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
13 May 2015
Amendment-1
31 August 2015
Amendment-2
16 September 2015
Amendment-3
18 July 2016
Amendment-4
16 February 2018
Amendments below are listed beginning with the most recent amendment.
Amendment-4 (16 February 2018)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to include lower extremity 
symptomatic distal deep venous thrombosis (DVT) in the composite primary efficacy endpoint and individual 
composite secondary efficacy endpoint as these events are clinically important and can lead to proximal DVT and/or 
pulmonary embolism (PE) in cancer patients, and to indicate that towards the end of the enrollment phase, 
approximately 800 subjects were planned to be randomized into the study due to the high subject discontinuation 
rate.
Applicable Section(s)
Description of Change(s)
Rationale: Symptomatic lower extremity distal DVT was included in the composite primary efficacy endpoint and 
composite secondary efficacy endpoint as these events are clinically important and can lead to proximal DVT and/or 
PE.
Synopsis Objectives
and Hypothesis, 
Efficacy Evaluations, 
Statistical Methods
2.1. Objectives; 2.2. 
Hypothesis; 3.2.
Study Design 
Rationale; 9.2.1. 
Efficacy Evaluations 
and Outcomes; 9.2.2. 
Efficacy Endpoints;
11.5. Efficacy and 
Safety Analyses; 
Attachment 1: 
Reporting of Efficacy 
Endpoints, Adverse 
Events, and Serious 
Adverse Events
Added symptomatic lower extremity distal DVT to the composite primary efficacy 
endpoint and composite secondary efficacy endpoint, and where applicable, deleted it as 
an individual component from other secondary efficacy endpoints.
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Applicable Section(s)
Description of Change(s)
Rationale: Due to the high subject discontinuation rate, additional subjects were planned to be randomized into the 
study towards the end of the enrollment phase.
Synopsis Overview of 
Study Design, 
Statistical Methods;
3.1. Overview of 
Study Design;
11.2. Sample Size 
Determination
Specified that towards the end of the enrollment phase, approximately 800 subjects were
planned to be randomized into the study due to the high subject discontinuation rate.
Rationale:  Clarifications were made to the statistical analyses methods and corrections were made to the efficacy 
evaluations/outcomes and endpoints.
Synopsis Statistical 
Methods; 11.5. 
Efficacy and Safety 
Analyses; 11.5.1. 
Safety Endpoints, 
Laboratory, and Vital 
Signs Data Analysis
Deleted pooling of data across both strata from the primary efficacy composite endpoint 
analysis. Added that the Cox’s proportional hazards model will be stratified for the 
primary safety endpoint of time to a major bleeding event.
9.2.1. Efficacy 
Evaluations
and Outcomes; 9.2.2. 
Efficacy 
Endpoints
Symptomatic proximal upper extremity DVT was corrected to symptomatic upper 
extremity DVT and non-fatal PE was corrected to symptomatic non-fatal PE.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical and formatting changes were made.
Amendment-3 (18 July 2016)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union in that it does not 
significantly impact the safety or physical/mental integrity of subject, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for the amendment is to provide further clarifications 
and ensure consistency within the protocol. Modifications include, but are not limited to, changes to allow for the 
rescreening of subjects, the removal of the requirement related to the use of a double-barrier method of birth control, 
the correction of the physical description of the study drug, and an update to the adverse event (AE) and serious 
adverse event (SAE) collection and reporting requirements.
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Applicable Section(s)
Description of Change(s)
Rationale: Symptomatic lower extremity distal deep vein thrombosis (DVT) has been added to the secondary 
objectives and evaluations.
Synopsis, Secondary 
Objectives; Synopsis, 
Efficacy Evaluations; 
2.1. Objectives 
(Secondary Objectives); 
9.2.1. Efficacy Evaluations 
and Outcomes; 
9.2.2. Efficacy Endpoints
Revised the secondary efficacy objectives and evaluations to include the evaluation of 
the individual components of the primary efficacy composite variable, (ie, confirmed 
fatal/non-fatal arterial thromboembolism [ATE] events, confirmed fatal/non-fatal 
visceral venous thromboembolism [VTE] events, symptomatic lower extremity distal 
DVT, a composite of symptomatic lower extremity proximal DVT, asymptomatic 
lower extremity proximal DVT, symptomatic upper extremity DVT, symptomatic 
non-fatal pulmonary embolism (PE), incidental PE, and all-cause mortality, and a 
composite of symptomatic lower extremity proximal DVT, symptomatic lower 
extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, 
and VTE-related deaths).
Rationale: Clarification has been provided regarding the rate of stratification.
Synopsis, Overview of 
Study Design; 
3.1, Overview of Study 
Design; 11.2. Sample Size 
Determination
Made minor text changes to clarify the rate of stratification.
Rationale: Clarification has been provided regarding the date of randomization.
Synopsis, Overview of 
Study Design; Time and 
Events Schedule; 
3.1. Overview of Study 
Design; 5. Treatment 
Allocation and Blinding 
(Randomization 
Procedures); 
9.1.3. Double-Blind 
Treatment Phase 
(Day 1/Day of 
Randomization)
Made changes to clarify that the date of randomization is considered the date that the 
subject is assigned to study drug in the Interactive Web Response System (IWRS) 
while Day 1 is considered the date that the study drug is initiated.
Rationale: Clarification has been provided regarding the visit window for the duration of treatment during the 
double-blind treatment period.
Synopsis, Overview of 
Study Design; 
3.1. Overview of Study 
Design
Made changes to clarify that subjects will be instructed to take the study drug for a 
fixed duration of 180 days (3 days).
Throughout the protocol
Removed references to visit windows when specifically associated with study visits 
on Day 180 and Day 210.
Rationale: Modifications have been made to clarify the role of the Clinical Endpoint Committee (CEC) and the 
events to be adjudicated.
Synopsis, Overview of 
Study Design; Synopsis, 
Efficacy Evaluations; 
Synopsis, Statistical 
Methods (Efficacy and 
Safety Analyses); 
3.1. Overview of Study 
Design; 3.2. Study Design 
Rationale (Choice of 
Efficacy Outcome/
Endpoint); 
9.1.3. Double-Blind 
Made changes to specify that the CEC is blinded, to provide additional details 
regarding the purpose of the CEC, and to provide consistency regarding the events 
that will be adjudicated, including all routine compression ultrasounds.
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Applicable Section(s)
Description of Change(s)
Treatment Phase 
(Double-Blind Treatment 
Period [Day 1-Day 180]);
9.2.1. Efficacy Evaluations 
and Outcomes; 
9.2.1.1. Definitions; 
9.2.2. Efficacy Endpoints; 
9.4.1. Bleeding Events; 
11.2. Sample Size 
Determination; 
11.5. Efficacy and Safety 
Analyses; 11.9.3. Clinical 
Endpoint Committee; 
12.4.1. All Adverse Events
Rationale: Modifications have been made to clarify the role of the Independent Data Monitoring Committee 
(IDMC) and the information that it will review.
Synopsis, Overview of 
Study Design; Synopsis, 
Statistical Methods 
(Interim Analysis); 
3.1. Overview of Study 
Design; 5. Treatment 
Allocation and Blinding 
(Unblinding); 11.4. Interim 
Analysis; 
11.9.2. Independent Data 
Monitoring Committee; 
12. Adverse Event
Reporting
Made changes to specify that the IDMC is unblinded and that it will periodically 
assess the safety of subjects and evaluate efficacy.
Rationale: An option to allow for the rescreening of subjects has been added.
Synopsis, Overview of
Study Design;
3.1. Overview of Study
Design; 9.1.2. Screening 
Phase
Added text indicating that subjects may be rescreened once and specified that 
screening procedures must be repeated if rescreening is performed after the initial 
2-week screening period.
Rationale: Modifications have been provided to clarify that chemotherapy does not have to last for 6 months for 
the subject to be eligible; however, the intent to treat for 6 months is required.
Synopsis, Dosage and 
Administration; 
4.1. Inclusion Criteria
(Criterion 6); 6. Dosage 
and Administration
Added text indicating that systemic cancer therapy will be initiated within 1 week of 
receiving the first dose of study drug, with the intention of receiving the systemic 
cancer therapy during the double-blind treatment period for a duration determined by 
the treating oncologist according to standard protocols of clinical care.
Rationale: Further clarification has been provided to explain that temporary drug interruptions can lead to 
permanent discontinuation if >14 days.
Synopsis, Dosage and 
Administration; 
(Interruption of Study 
Drug); 8. Prestudy and 
Concomitant Therapy 
(Prohibited Therapy); 
10.2.1. Temporary 
Interruption of Study 
Added text indicating that subjects who miss >14 consecutive days of study drug will 
need to permanently discontinue the study drug.
In Section 10.2.1, Temporary Interruption of Study Treatment, included the list of 
prohibited therapies that will lead to temporary interruption of the study drug instead 
of including a cross reference to Section 8, Prestudy and Concomitant Therapy.
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Applicable Section(s)
Description of Change(s)
Treatment; 
10.2.2. Permanent 
Discontinuation of Study 
Treatment
Rationale: Definition of the per-protocol population has been clarified.
Synopsis, Statistical 
Methods (Study 
Population/Analysis Sets)
Added text to define the per-protocol population as a subset of the intent-to-treat (ITT) 
population, with the condition that subjects with major protocol deviations will be 
excluded from the per-protocol population.
Rationale: Clarification has been provided regarding the analysis of the key secondary efficacy endpoints.
Synopsis, Statistical 
Methods (Primary Efficacy 
Composite Endpoint 
Analysis); 11.5. Efficacy 
and Safety Analyses
Added text to explain that key secondary efficacy endpoints will be analyzed in a 
similar fashion as the primary efficacy endpoint.
Rationale: Clarification has been provided regarding the use of historical laboratory data
Time and Events Schedule; 
9.1.2. Screening Phase; 
9.4.2.2. Clinical 
Laboratory Tests
Removed references to local laboratories to clarify that historical standard-of-care 
laboratory results may be used during the screening visit to determine subject 
eligibility.
Rationale: Use of the Modification of Diet in Renal Disease formula has been included to determine adequate renal 
function.
Time and Events Schedule; 
4.1. Inclusion Criteria
Added text indicating that creatinine clearance (CrCl) can be calculated using the 
Cockcroft-Gault formula or the Modification of Diet in Renal Disease formula.
Attachment 5
The Modification of Diet in Renal Disease formula has been provided.
Attachment 6
The CKD-EPI equation for estimating eGFR has been provided.
Rationale: Text added to clarify that isolated distal DVT events will not be included in the primary efficacy 
outcome due to controversy regarding overall clinical significance.
3.2. Study Design 
Rationale (Rationale for 
Mandatory Bilateral Lower 
Extremity Venous 
Compression 
Ultrasonography)
Specified that the primary efficacy outcome will not include isolated distal DVT 
events.
Rationale: A revision to the standard inclusion criterion relating to the use of double-barrier contraception has been 
made for rivaroxaban.
4.1. Inclusion Criteria
(Criteria 8 and 10); 
4.3. Prohibitions and 
Restrictions (Criterion 2)
Revised text regarding appropriate and adequate methods of birth control for men.
Rationale: A revision was made for consistency with other sections of the protocol
4.1. Inclusion Criteria 
(Criterion 1)
Added qualifier that subjects must be ambulatory men and women.
Rationale: A revision was made to align the inclusion criterion with the language in the informed consent form 
(ICF).
4.1. Inclusion Criteria 
(Criterion 10)
Modified text regarding male contraception to align with the ICF.
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Applicable Section(s)
Description of Change(s)
Rationale: Examples of P2Y12 inhibitors have been added for clarity.
4.2. Exclusion Criteria
(Criterion 13)
Added clopidogrel, prasugrel, and ticagrelor as examples of P2Y12 inhibitors.
Rationale: Compression stockings are permitted regardless of the setting
4.3. Prohibitions and 
Restrictions (Criterion 3)
Added text to indicate that compression stocking may be used during the course of the 
study.
Rationale: Clarification has been provided to ensure that subjects do not stop taking the study drug if using an 
inhibitor as this will result in decreased concentrations of the study drug.
8. Prestudy and 
Concomitant Therapy 
(Prohibited Therapy)
Deleted reference to combined P-glycoprotein (P-gp) and strong cytochrome P450 
(CYP) 3A4 inducers from the list of prohibited medications and added it to the list of 
therapies to be avoided during the study.
Rationale: Thromboprophylaxis with mechanical devices is prohibited because they could potentially interfere with 
the efficacy assessments.
8. Prestudy and 
Concomitant Therapy 
(Prohibited Therapy)
Moved the criterion from the list of prohibited therapies and qualified the reason for 
prohibition.
Rationale: Modifications have been made to clarify DVT locations.
9.2.1.1. Definitions
Definitions have been updated regarding DVT location.
Rationale: The sections related to biomarkers were consolidated to minimize duplication.
9.3. Biomarkers
Duplicate section was deleted and text moved to Section 9.5.1, Evaluations.
Rationale: Modifications have been made to clarify that clinically significant bleeding events include both major 
and relevant non-major bleeding events
9.4.1.1. Management of 
Study Drug for Bleeding 
Events
Added text specifying that the study drug should be stopped or the subject managed 
per the guidelines for both major and relevant non-major clinically significant 
bleeding events.
Rationale: Tympanic temperature readings may be used in the study.
9.4.2.3. Vital Signs
Tympanic temperature has been added to the list of vital signs measurements.
Rationale: Modifications to the subject completion definitions have been provided to specify that subjects who 
discontinue the study drug should remain in the study and continue the study visits, if possible, regardless of the 
reason for discontinuation and to ensure consistency throughout the protocol.
Synopsis, Overview of 
Study Design; 
3.1. Overview of Study 
Design; 10.1. Completion; 
10.2.2. Permanent 
Discontinuation of Study 
Treatment
Made changes to the definitions for completion of the double-blind treatment period, 
completion of the study, and not completing the study. Removed the definition for 
completion of the treatment period to avoid duplication with the definition for 
completion of the double-blind treatment period. Clarified that subjects who 
permanently discontinue the study should complete an unscheduled end-of-treatment 
(EOT) visit as soon as possible from the time that the study drug was discontinued and 
that subjects will required to complete all remaining study visits and procedures, 
including the Day 180/EOT and Day 210/end-of-study (EOS) visits.
Rationale: The physical description of the study drug is not correct for this study.
14.1. Physical Description 
of Study Drug(s)
Made changes to correct the physical description of the study drug.
Rationale: Modifications have been made for consistency with the SAP.
11.1. Analysis Populations 
and Observation Periods
The subject population has been updated to include all randomized subjects instead of 
those with a valid informed consent.
NCT02555878


JNJ39039039/BAY59-7939 (Rivaroxaban)
Clinical Protocol BAY59-7939/39039039STM4001/18262 Amendment-4
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Approved, Date: 16 February 2018
Applicable Section(s)
Description of Change(s)
11.5. Efficacy and Safety 
Analyses
Key subgroups have been modified.
Rationale: Minor modifications have been made to clarify the initial estimates of expected VTE rates.
Synopsis, Sample Size 
Determination; 
11.2. Sample Size 
Determination
Changes were made to clarify and align the text throughout the document.
Rationale: Modifications were made to clarify that at 80% power, the subpopulation sample size will need to show 
a somewhat larger effect size (ie, difference in incidence rates between the 2 treatment arms) to be statistically 
significant. For the APC group, this effect size is estimated to be at least 14%.
11.2. Sample Size 
Determination
Added text specifying that the differences in incidence rates between the 2 treatment 
groups will be slightly larger.
Rationale: Modifications have been made to align the attribution definitions for AEs with the electronic case report 
form (eCRF) data capture.
12.2.2. Attribution 
Definitions
Changed the term “unlikely” to “doubtful” and added definitions for “life-threatening” 
and “death”.
Rationale: Updates have been made to the AE and SAE collection and reporting requirements given that 
adjudication is being performed by the CEC for outcome events.
12.4.1. All Adverse Events
Made changes to clarify that suspected outcome events will be captured in the eCRF 
and will be waived from SAE collection and unblinding, and exempted from 
expedited reporting. Symptomatic lower extremity distal DVT was added to the list of 
events and it was clarified that this list also includes all bleeding events, not just those 
that are major and clinically relevant non-major bleeding events. Also removed the 
requirement to collect any non-VTE- or non-ATE-related death or non-clinically 
relevant bleeding event as a SAE in the eCRF.
Attachment 1, Reporting of 
Efficacy Endpoints, 
Adverse Events, and 
Serious Adverse Events
Table was updated.
Rationale: Text was included in the wrong section of the protocol.
9.6.4. Pharmacokinetic 
Analysis; 9.7. Health Care 
Resource Utilization
Moved text associated with the analysis of data to Section 11, Statistical Methods.
Rationale: Updates have been made to align text in the Time and Events Schedule to the rest of the protocol.
Time and Events Schedule 
(Footnotes i and j)
Reference to the Cockroft-Gault formula was removed from Footnote i and a 
cross reference to the CKD-EPI (Attachment 6) was made in Footnote j.
Time and Events Schedule 
(Footnote o)
Footnote o was deleted as it was not associated with and assessment in the table and 
the instructions are clearly stated in the protocol. Renumbered subsequent footnotes 
accordingly.
Rationale: Modifications have been made for consistency with the current version of the protocol template.
Throughout the protocol
Template changes have been applied, as appropriate.
Rationale: Modifications have been made to correct inconsistencies in text and to remove text deleted from 
previous amendments.
Throughout the protocol
Made changes to harmonize wording in sections that discuss similar topics and deleted 
statements that were inadvertently missed in previous amendments.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
NCT02555878


JNJ39039039/BAY59-7939 (Rivaroxaban)
Clinical Protocol BAY59-7939/39039039STM4001/18262 Amendment-4
12
Approved, Date: 16 February 2018
Applicable Section(s)
Description of Change(s)
Amendment-2 (16 September 2015)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union in that is does not significantly 
impact the safety or physical/mental integrity of subject, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for the amendment is to correct the physical 
description of the study drug being provided and to allow for flexibility in the initiation of the first dose of study 
drug relative to randomization with IWRS.
Applicable Section(s)
Description of Change(s)
Rationale: To allow for flexibility in the initiation of the first dose of study drug relative to randomization with 
IWRS, a window for starting study drug was added.
Synopsis (Overview of 
Study Design); Section 3.1 
Overview of Study Design; 
Time and Events Schedule 
(footnote “f”); Section 5 
Treatment Allocation and 
Blinding (Randomization 
Procedures); Section 6.0 
Dosage and 
Administration; Section 
9.1.3 Double-Blind 
Treatment Phase (Day 
1/Day of Randomization)
The following sentence has been added throughout the protocol as indicated. ‘Subjects 
will have up to 4 days from the point of being randomly assigned study drug within
IWRS to initiate their study drug treatment in order to accommodate those subjects 
who will be receiving their study drug from a centralized drug depot but every effort 
should be made to initiate study drug within 1 day.’
Rationale: The sentence in the 5th paragraph was removed as it is repeated above in that same paragraph. 
Section 3.1 Overview of 
Study Design
The last sentence in the paragraph was removed, ‘Imaging from routine care (eg, CT 
scans ordered primarily for staging or restaging of malignancy) will be adjudicated for 
asymptomatic PE or DVT events’.
Rationale: To correct the physical description of the study drug that is actually being provided for this study
Section 14.1 Physical 
Description
The following sentence has been added. ‘The study drug supplied for this study is 
rivaroxaban 10 mg and matching placebo, provided as round, light red tablets. It will 
be manufactured and provided under the responsibility of the sponsor. Refer to the 
Investigator’s Brochure for a list of excipients.’
The following sentences have been deleted ‘The rivaroxaban supplied for this study 
are the tablet formulations containing 10 mg of active drug. The round, light red, 
tablets will be over-encapsulated in size 00 capsule shells. The tablets are immediate 
release dosage forms with rapid dissolution characteristics under in vitro test 
conditions. Each tablet contains the active ingredient rivaroxaban and the excipients; 
croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, 
hypromellose, and sodium lauryl sulfate. The tablets are film-coated with 
hypromellose, macrogol, and titanium dioxide/ ferric oxide red.’ 
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Rationale: Correction of error in biomarker sampling timing.
Synopsis (Biomarker 
Evaluations)
Blood samples will be collected from subjects at Screening Randomization, Weeks 8 
and 16 visits and Day 180/EOT to measure levels of circulating D-dimer, P-selectin, 
and Tissue Factor.
NCT02555878


JNJ39039039/BAY59-7939 (Rivaroxaban)
Clinical Protocol BAY59-7939/39039039STM4001/18262 Amendment-4
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Approved, Date: 16 February 2018
Amendment-1 (31 August 2015)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union in that is does not significantly 
impact the safety or physical/mental integrity of subject, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for the amendment is to include time-to-event 
analyses and additional protocol recommendations based on regulatory authority input.
Applicable Section(s)
Description of Change(s)
Rationale: Inclusion of time-to-event analyses based on regulatory authority input for the primary efficacy 
composite endpoint.
Synopsis; Section 3.2 
Study Design 
Rationale; Section 
9.2.2 Efficacy 
Endpoints; Section 11 
Statistical Methods; 
Section 11.5 Efficacy 
and Safety Analyses
This analysis will be performed on a time-to-first-event basis during the observation 
period up to Day 180 (+3 days), using a stratified Cox proportional hazard model 
(stratification factor: advanced pancreatic cancer [APC] or non-APC) including treatment 
group as a categorical exploratory variable with 2 levels (ie, rivaroxaban, placebo) and 
include the pooled data across both strata based on the Intent-to-treat [ITT] analysis set.
Rationale: Input received from the regulatory authorities to include methodology of handling of missing data.
Section 11.3 Handling 
of Missing Data
Addition of Section
Rationale: Input received from regulatory authorities to increase the sample size.
Synopsis (Overview 
of Study Design, 
Sample Size 
Determination), 
Section 3.1 Overview 
of Study Design, 
Section 11.2 Sample 
Size Determination
The sample size was increased from 625 to 700 subjects.
Rationale:  Input received from the regulatory authorities concerning biomarker evaluation.
Synopsis (Exploratory
Objectives, Biomarker 
Evaluations, Time and
Events Schedule,
footnote m); Section 
2.1 Objectives; 
Section 9.5.1 
Evaluations
Netosis (NETs) was deleted and Tissue Factor was added.
NCT02555878


JNJ39039039/BAY59-7939 (Rivaroxaban)
Clinical Protocol BAY59-7939/39039039STM4001/18262 Amendment-4
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Approved, Date: 16 February 2018
Applicable Section(s)
Description of Change(s)
Rationale:  Clarification of the role of the local imaging laboratory. Compression ultrasonography examinations 
will be assessed at a local imaging laboratory by a site designated radiologist. All diagnostic imaging for all events 
will be done locally and adjudication will be centralized.
Synopsis (Overview 
of Study Design) 
Time and Events 
Schedule, footnotes a 
and e;
Section 3.1 
Overview of Study 
Design; Section 9.1.2
Screening Phase
A local reader will be responsible to determine that an event has occurred. The Clinical 
Endpoints Committee (CEC) will adjudicate all events.
In Overview of Study Design in Synopsis: The local imaging laboratory independent CEC 
will also assess all ultrasound examinations to ensure uniformity of asymptomatic event 
ascertainment.
Rationale:  Timing of the Day 180/End-of-Treatment [EOT] visit window was modified to be more conducive to 
scheduling subjects’ procedures.
Synopsis (Overview 
of Study Design; Time 
and Events Schedule 
[Day 180/EOT visit]),
footnotes b, k, and l, 
Section 3.1 Overview 
of Study Design, 
Section 10.1 
Completion
Subjects will be instructed to take study drug for a fixed duration of 180 days and will 
then complete the Day 180/EOT Visit. The Day 180/EOT Visit will be completed within a 
window of ±3 days. 
Rationale: Timing of the bilateral lower duplex venous compression ultrasonography at the Day 180/EOT visit was 
modified to be more conducive to scheduling subjects’ procedures.
Synopsis (Overview 
of Study Design, 
Time and Events 
Schedule footnote l); 
Section 3.1 Overview 
of Study Design, 
Section 9.1.3 Double-
blind Treatment Phase
”The Day 180/EOT Visit will be completed within a window of ±3 days. The CU planned 
for the Day 180/EOT Visit must occur within this window and before the last dose of 
study drug. Subjects who discontinue early will have an unscheduled EOT visit and will 
have up to 2 days after the last dose of study drug to have the CU completed but every 
effort should be made to have it done as soon as possible after the last dose. A CU should 
not be performed at all if it is not possible to have it completed within 2 days of the last 
dose of study drug.
Rationale:  Clarifications to exclusion criteria were made.
Section 4.2 Exclusion 
Criteria
Criterion #2 was modified to known history of brain metastases; Criterion #8 was 
removed Previously diagnosed/treated venous thromboembolism (VTE) ≤30 days prior to 
randomization; Criterion # 14 (atrial fibrillation was provided for clarity as an example); 
Criterion #19 was removed as it was duplicated in Criterion #14
Rationale: Clarification of dual antiplatelet therapy bullet; addition of new bullet for prohibited anticoagulant
therapy; clarification on modification of pre-existing therapy; prohibition of single and dual P2Y12 antagonist 
antiplatelet therapy due to the increased risk of bleeding
Section 4.2 Exclusion 
Criteria, #13 
Criterion; Section 8.0 
Prestudy and 
Concomitant Therapy
Modification to: P2Y12 receptor antagonist antiplatelet therapy, daily nonsteroidal anti-
inflammatory drugs, or other medications known to increase the risk of bleeding (a daily 
dose of ≤100 mg of aspirin is permitted)
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Approved, Date: 16 February 2018
Applicable Section(s)
Description of Change(s)
Rationale:  Clarification on types of prestudy and concomitant therapies that will be collected was added.
Time and Events 
Schedule, footnote 
“k”; Section 8.0 
Prestudy and 
Concomitant Therapy
All concomitant therapies taken throughout the double-blind treatment period for the 
treatment of AEs/SAEs, prohibited medications, additional medications as listed in 
Section 8 and systemic cancer therapy and radiotherapy must be recorded in the eCRF 
except supplements such as fish oil, herbal medicines and vitamins. In addition, 
concomitant therapies should also be recorded beyond the Day 180/EOT visit only in 
conjunction with SAEs that meet the criteria outlined in Section 12.4.2. Serious Adverse 
Events.
Rationale: Language was added to add flexibility to use local laboratory tests to determine eligibility if previously 
drawn labs are already available during the Screening period.
Time and Events 
Schedule footnote “e”
An IWRS will be used to randomly assign subjects to treatment. Randomization may be 
completed once clinical laboratory results and imaging results (CU) from the local reader 
are available to confirm subject eligibility. Note: Local laboratory results may be used for 
the screening visit to confirm eligibility; these results must be documented in the subjects’ 
source documentation. In this case, subjects will be randomized on Day 1 based on the 
results from the local laboratory that confirms eligibility; however, screening blood 
samples must still be collected and sent to the central laboratory for analysis. 
Subsequently, if the screening results from the central laboratory are exclusionary the 
local laboratory results will take precedence and must be recorded in the eCRF to 
document eligibility.
Rationale: Language was modified to allow for standard-of-care in the event of diagnosis of a suspected DVT or 
PE.
Synopsis (Overview 
of Study Design), 
Section 3.1 Overview 
of Study Design
If a subject has a suspected efficacy outcome event during the study, the treating physician 
should exercise clinical judgment and follow guidelines to apply the standard-of-care.
Unblinding of study drug should not be necessary, as anticoagulation regiments do not 
require adjustment regardless of use of placebo vs rivaroxaban when administered in the 
dose used in this study.
Section 9.2.3 Approach to the Subject with an Efficacy Outcome Event, was added
Rationale: Additional details provided regarding study drug discontinuation were added.
Section 10.3 
Permanent 
Discontinuation of 
Study Treatment
Subjects missing more than 14 consecutive days of taking study drug will be discontinued 
from further study therapy and censored for the time-to-event analyses. These subjects 
will not be restricted from seeking appropriate medical care available outside the protocol, 
but will be encouraged to make every effort to continue with their scheduled study visits 
until the planned end of their study duration.
Rationale: Details were provided on all-cause mortality data collection based on input received from the regulatory 
authorities.
Section 9.2.1 Efficacy 
Evaluations and 
Outcomes
All-cause mortality will be recorded
NCT02555878


JNJ39039039/BAY59-7939 (Rivaroxaban)
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Approved, Date: 16 February 2018
Applicable Section(s)
Description of Change(s)
Rationale:  Additional details were provided on the primary composite endpoint (analysis, endpoints, and 
objectives) based on input received from internal authorities.
Synopsis (Primary 
Objectives, 
Hypothesis, Efficacy 
Evaluations, Primary 
Composite Endpoint 
Analysis); Section 
9.2.1 Efficacy 
Evaluations and 
Outcomes; Section 
9.2.2 Efficacy 
Endpoints
The primary efficacy analysis will include composite events (eg, objectively 
confirmed symptomatic lower extremity proximal DVT, asymptomatic lower 
extremity proximal DVT, symptomatic upper extremity DVT, symptomatic 
non-fatal PE, incidental PE and VTE-related death) occurring from 
randomization up to Day 180 (+3 days) for all randomly assigned subjects in 
the study. 
Rationale:  Additional definitions to secondary endpoints were added based on regulatory input.
Synopsis (Secondary 
Objectives; Efficacy 
Evaluations), Section 
9.2.2 Efficacy 
Endpoints
The key secondary efficacy endpoints include symptomatic VTE events (DVT/PE), 
VTE-related deaths and all-cause mortality from time to randomization to Day 180 
(+3 days).
Other secondary efficacy objectives include the evaluation of the individual components 
of the primary efficacy composite variable analyzed separately, a composite of confirmed 
fatal/non-fatal arterial thromboembolism (ATE) events, a composite of confirmed 
fatal/non-fatal visceral VTE events, and a composite of symptomatic lower extremity 
proximal DVT, asymptomatic lower extremity proximal DVT, symptomatic upper 
extremity DVT, non-fatal PE, incidental PE and all-cause mortality.
Rationale: Additional details were provided for the clinical events relevant to the efficacy endpoints.
Synopsis (Overview 
of Study Design); 
Time and Events 
Schedule, footnote 
“o”; Section 9.1.1, 
Overview; Section 
9.1.3, Double-blind 
Treatment Phase; 
Section 10.3, 
Permanent 
Discontinuation of 
Study Treatment
If the subject is unwilling or unable to return for any visits, or is lost-to-follow up, the 
investigator should collect as much follow-up information as possible for each remaining 
visit according to the Time and Events Schedule, including contacting the subject or 
legally acceptable representative by telephone or by mail to determine vital status and 
outcome ascertainment, as agreed to by the subject during the informed consent process. 
The site must document all attempts to try to contact the subject in the source documents.
Rationale:  Recommendations were received from regulatory authorities to include concept of targeted safety 
collection and reporting of adverse events/serious adverse events as in our other sponsored studies. 
Attachment 1 (revised)
NCT02555878


JNJ39039039/BAY59-7939 (Rivaroxaban)
Clinical Protocol BAY59-7939/39039039STM4001/18262 Amendment-4
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Approved, Date: 16 February 2018
Applicable Section(s)
Description of Change(s)
Rationale:  Regulatory authorities requested a single blood draw at Week 8 to estimate exposure to rivaroxaban.
Synopsis (Exploratory 
Objectives); Time and 
Events Schedule; 
Time and Events 
Schedule footnote n); 
Section 2.1 
Objectives; Section 
9.6 Pharmacokinetics; 
Section 9.6.1 
Pharmacokinetic
Sample Collection and 
Handling; Section 
9.6.2 Analytical 
Procedures; Section 
9.6.3 Pharmacokinetic 
Parameters; Section 
9.6.4 Pharmacokinetic 
Analyses
These are new sections added based on the request for PK sampling.
Rationale:  Health Care Resource Utilization section was added based on input received from internal subject 
matter experts.
Synopsis (Exploratory 
Objectives); Time and 
Events Schedule
footnote p; Section 2.1 
Objectives; Section 
9.7 Health Care 
Resource Utilization; 
Section 11.7 Health 
Care Resource 
Utilization
Health care resource utilization (HCRU) data will be collected as part of the endpoint 
assessments, at Weeks 8 and 16, and Day 180/EOT, for all patients, or until study drug 
discontinuation. The data collection will be specific to the study outcomes of DVT, PE, or 
bleeding, including visits to health care providers, hospitalization, length of 
hospitalization, and use of diagnostic procedures.
Rationale:  Regulatory authorities made comments regarding temporary discontinuations during hospitalizations 
and suggested subjects remain on study drug.
Synopsis (Interruption 
of Study Drug); 
Section 10.2.1 
Temporary 
Interruption of Study 
Treatment
In case of major surgery or major bleeding risk procedure, the investigator may consider 
holding the prior day study dose [skip both, day before and day of surgery, doses of study 
drug], weighing the risk of bleeding against that of VTE. Consider bridging with parental 
anticoagulation if necessary. Study drug should be restarted after the surgical or other 
procedures as soon as adequate hemostasis has been established. Study drug should be 
restarted after the surgical or other procedures as soon as adequate hemostasis has been 
established, noting that the time to onset of therapeutic effect is short. The investigator 
may consider resuming study therapy 24 hours after achieving hemostasis for 
low-bleeding risk or minor surgical procedures, and at 48 hours in case of major or 
high-risk bleeding procedures, noting that the time to onset of therapeutic effect is short.
Rationale: Clarification on procedures for premature discontinuation was added.
Section 10.2.1 
Temporary 
Interruption of Study 
Treatment
Subjects who have a study drug interruption of >14 days must be discontinued form study 
drug treatment. 
NCT02555878


JNJ39039039/BAY59-7939 (Rivaroxaban)
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Approved, Date: 16 February 2018
Applicable Section(s)
Description of Change(s)
Rationale:  Additional statistical details on analyses set and periods were added.
Section 11.1 Analysis 
Populations and 
Observation Periods
On-treatment: this observation period includes data from the first dose of study drug to 
2 days after the last dose of the study drug, inclusively. For time-to-event analyses, 
subjects who do not experience endpoint events during this period will be censored on the 
last dose date +2 days or at the last day of their completed unscheduled EOT assessments 
for study outcomes during the treatment period whichever occurs first.
Rationale:  Changes were made to include time-to-event analysis based on regulatory authority input for the main 
safety endpoint.
Section 11.5.1 Safety 
Endpoints, Laboratory 
and Vital Signs Data 
Analysis
The main safety endpoint includes time to a major bleeding event in treated subjects in 
each randomized treatment group.
Rationale:  Clarification on IDMC data review process was added.
Section 11.9.2 
Independent Data 
Monitoring 
Committee
The IDMC will monitor unblinded data following a charter.
Rationale:  Recommendations received from regulatory authorities to remove potential outcome events.
Section 12.2.1 
Adverse Event
Definitions and 
Classifications
Section was deleted
Rationale: Staging details were added to the Time and Events Schedule for subjects with lymphoma.
Time and Events
Schedule
Addition of Ann Arbor staging. 
Rationale:  The ECOG performance status and CVC status are no longer necessary at the Day 210/EOS visit.
Time and Events
Schedule
Removed ECOG performance status and CVC status at Day 210
Rationale:  Coagulation testing is required at the screening visit.
Time and Events 
Schedule;
Section 9.1.1 
Overview
Coagulation analysis (2 mL) was added to the section. 
Rationale:  Additional safety monitoring added to ensure that either the investigator or a qualified subinvestigator
will be required to see each subject at every study visit for clinical assessment of the subject’s status.
Synopsis (Overview 
of Study Design);
Section 3.1 Overview 
of Study Design; 
Section 9.1.3 
Double-blind 
Treatment Phase
Either the PI or a qualified subinvestigator will be required to see each subject at every 
study visit for clinical assessment of the subject’s status.
NCT02555878


JNJ39039039/BAY59-7939 (Rivaroxaban)
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Approved, Date: 16 February 2018
Applicable Section(s)
Description of Change(s)
Rationale:  Request was received from regulatory authorities for inclusion of eGFR.
Synopsis (Time and 
Events Schedule
footnote j);
Attachment 5
eGFR will be calculated using the Modification of Diet in Renal Disease formula 
(see Attachment 5).
Rationale:  Samples will not be stored beyond 5 years.
Section 16.2.5.
Long-Term
Retention of Samples 
for Additional Future
Research
Samples collected in this study may be stored for up to 5 years (or according to local 
regulations) for future research and will not include molecular biological or genetic 
studies.
Rationale:  Further clarification provided on the definitions for the different types of DVTs.
Section 9.2.1.1 
Definitions
The following definitions will be applied by the CEC based on objective confirmation. 
Asymptomatic lower extremity proximal DVT
The presence, in subjects who are asymptomatic or otherwise unaware of and lack clinical 
signs for a DVT located in the proximal veins of lower extremities (proximal to the deep 
calf veins eg, external iliac, common femoral vein, proximal femoral vein, distal femoral 
vein, popliteal vein), as evidenced by a positively diagnosed and adjudicated CU. If the 
CU is deemed to be of unsatisfactory quality, confirmation may be done by venography if 
ordered by the investigator or qualified designee.
Symptomatic lower extremity proximal DVT
The adjudicated presence, in subjects who are symptomatic or otherwise aware of and/or 
have clinical signs for a DVT located in the proximal deep veins of the lower extremities 
(proximal to the deep calf veins, eg, external iliac, common femoral vein, proximal 
femoral vein, distal femoral vein, popliteal vein), as evidenced by the final clinical 
diagnosis including a positively adjudicated CU. If the CU is deemed to be of 
unsatisfactory quality, confirmation can be done by venography if ordered by the 
investigator or qualified designee.
Symptomatic Upper Extremity DVT
The adjudicated presence, in subjects who are symptomatic or otherwise aware of and/or 
have clinical signs for a DVT located in the proximal veins of the upper extremities as 
confirmed by abnormal CU. 
Note: Thrombosis of the central line will not be considered as suspicion of DVT unless the 
patient presents with symptoms (eg, swelling, erythema, pain, distal paresthesia, neck 
swelling, headache, congestion of subcutaneous collateral veins).
Symptomatic non-fatal PE
The adjudicated presence, in subjects who are symptomatic or otherwise aware of and/or 
have clinical signs for a PE objectively confirmed by CT scan.
Visceral VTE
Thrombi formed in portal, splenic, superior mesenteric, inferior mesenteric, hepatic, 
gonadal, renal veins or inferior vena cava as evidenced by CT scan.
NCT02555878


JNJ39039039/BAY59-7939 (Rivaroxaban)
Clinical Protocol BAY59-7939/39039039STM4001/18262 Amendment-4
20
Approved, Date: 16 February 2018
Applicable Section(s)
Description of Change(s)
Rationale:  Further defined reporting of adverse events.
Section 12.4.1 All 
Adverse Events
These events include:
Symptomatic lower extremity proximal DVT
Asymptomatic lower extremity proximal DVT
Symptomatic upper extremity DVT
Symptomatic non-fatal PE
Incidental PE
VTE-related death
ATE events (eg, MI, stroke)
Visceral VTE
Major bleeding events and clinically relevant non-major bleeding events. 
The serious adverse events need to be reported to the sponsor within the appropriate 
timeline as described in Section 12.2.1, Serious Adverse Events.
Adverse events leading to permanent study drug discontinuation
All SAEs that are not considered endpoint events as listed above
While one of the outcome measures is all-cause mortality, any non-VTE or non-ATE 
related death will be reported as a SAE.
Non-clinically relevant bleeding events
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Rationale:  References were not used in the protocol.
References Section
The following references were deleted: 11, 13, 14, 17, 18, 19, 26, 30, 33, 42, 45, 56, 59, 
and 61
NCT02555878


JNJ39039039/BAY59-7939 (Rivaroxaban)
Clinical Protocol BAY59-7939/39039039STM4001/18262 Amendment-4
21
Approved, Date: 16 February 2018
SYNOPSIS
Efficacy and Safety of Rivaroxaban Prophylaxis Compared with Placebo in Ambulatory 
Cancer Patients Initiating Systemic Cancer Therapy and at High Risk for Venous 
Thromboembolism
Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. 
The risk of VTE is particularly high in the first few months following the diagnosis of cancer and 
there is an increased risk for VTE in patients initiating systemic cancer therapy and with 
late-stage metastatic disease. Current guidelines do not recommend the routine use of 
VTE prophylaxis in most ambulatory patients with cancer due to limited randomized controlled
trial (RCT) data and uncertainty on the benefit/risk in the ambulatory cancer population. 
Rivaroxaban is a potent, orally administered and highly selective direct inhibitor of activated 
factor X (FXa) and has been shown to be effective in preventing VTE in patients undergoing 
hip/knee replacement surgery as well as reducing VTE recurrence in patients with deep vein 
thrombosis (DVT) and pulmonary embolism (PE). The aim of this clinical study is to evaluate 
the efficacy and safety of rivaroxaban versus placebo for primary thromboprophylaxis in 
ambulatory cancer patients at a high risk for VTE undergoing systemic cancer therapy.
OBJECTIVES AND HYPOTHESIS
Primary Objectives
The primary efficacy objective is to demonstrate that rivaroxaban is superior to placebo for
reducing the risk of the primary composite outcome as defined by objectively confirmed 
symptomatic lower extremity proximal DVT, asymptomatic lower extremity proximal DVT, 
symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-
fatal PE, incidental PE, and VTE-related death in ambulatory adult subjects with various cancer 
types receiving systemic cancer therapy who are at high risk of developing a VTE.
Secondary Objectives
The key secondary efficacy objectives of this study are to compare the efficacy of rivaroxaban
with placebo for reducing the risk of symptomatic VTE events and VTE-related deaths, and 
all-cause mortality in ambulatory adult subjects with various cancer types receiving systemic 
cancer therapy who are at high risk of developing a VTE. Other secondary efficacy objectives 
include the evaluation of the individual components of the primary efficacy composite variable, 
confirmed fatal/non-fatal arterial thromboembolism (ATE) events, confirmed fatal/non-fatal 
visceral VTE events, 
a composite of symptomatic lower extremity proximal DVT, 
asymptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, 
symptomatic upper extremity DVT, symptomatic non-fatal PE, incidental PE, and all-cause 
mortality, and a composite of symptomatic lower extremity proximal DVT, symptomatic lower 
extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, and VTE-
related deaths.
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JNJ39039039/BAY59-7939 (Rivaroxaban)
Clinical Protocol BAY59-7939/39039039STM4001/18262 Amendment-4
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Approved, Date: 16 February 2018
Safety Objectives
The primary safety objective of this study is to assess major bleeding events (as defined by the 
International Society on Thrombosis and Haemsotasis [ISTH]). In addition, clinically relevant 
non-major bleeding, minor bleeding, and any bleeding (defined as major, clinically relevant 
non-major, and minor bleeding) will be assessed as measured by the ISTH definition.
Exploratory Objectives
The exploratory objectives of this study are: 

To assess inflammation- and hypercoagulability-related biomarkers including D-dimer, 
P-selectin, and Tissue Factor

To analyze the steady state pharmacokinetics (PK) and exposure response of rivaroxaban 

To collect health care resource utilization (HCRU) data that may be used in future 
economic modeling (the construction and reporting of the economic model will be 
conducted separately from this study)
Hypothesis
The primary hypothesis of this study is that prophylactic treatment with rivaroxaban 
administered at a dose of 10 mg once daily for up to 6 months will be superior to placebo in 
reducing the risk of objectively confirmed symptomatic lower extremity proximal DVT, 
asymptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, 
symptomatic upper extremity DVT, symptomatic non-fatal PE, incidental PE, and VTE-related 
death in ambulatory adult subjects with various cancer types receiving systemic cancer therapy 
who are at high risk of developing a VTE.
OVERVIEW OF STUDY DESIGN
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, superiority 
study comparing the efficacy and safety of rivaroxaban with placebo for primary prophylaxis of 
VTE (defined as DVT and/or PE) in ambulatory adult men and women, 18 years of age and 
older, with various cancer types who are scheduled to initiate systemic cancer therapy as a 
component of their standard-of-care anticancer regimen, who have a baseline Khorana 
thromboembolic risk score of ≥2, and are judged by the investigator or qualified designee to be 
an 
appropriate 
candidate 
for 
treatment 
with 
either 
placebo 
or 
rivaroxaban 
for
thromboprophylaxis based on their clinical status.
Initially, a target of approximately 700 subjects were to be randomly assigned into the study in a 
1:1 ratio to 1 of 2 treatment groups with approximately 350 subjects per treatment group, with an 
assumed rate of discontinuation of approximately 20% from the study. Towards the end of the 
enrollment phase, approximately 800 subjects were planned to be randomized into the study due 
to the high subject discontinuation rate. In addition, subjects will be stratified at randomization 
by tumor type (advanced pancreatic cancer [APC] or non-APC); it is estimated that
approximately 25% of the subjects randomly assigned are those with APC.
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The study consists of 3 periods: a 2-week screening period, a 180-day double-blind treatment 
period with an end-of-treatment (EOT) visit, and a 30-day post-treatment follow-up period with a
Day 210/end-of-study (EOS) visit. The duration of participation in the study for each subject is 
approximately 32 weeks. 
At the screening visit (Day -14 to -1), designated study personnel will explain the nature of the 
study, including all relevant details, and obtain written informed consent from the subject before 
initiation of any study-related procedures. Once all required screening procedures are completed, 
qualifying laboratory results are received, and bilateral lower extremity venous duplex 
compression ultrasonography (CU) results are received from the local reader, subjects will be 
asked to return to the study site as soon as possible, but no more than 14 days after the screening 
visit, for the randomization (Day 1) visit. Subjects found to have baseline DVT on screening CU 
or incidental DVT or PE as identified from routine care imaging (eg, spiral computed 
tomography [CT] scans ordered primarily for staging or restaging of malignancy) within 30 days 
prior to randomization will not be eligible for randomization. Subjects may be rescreened once, 
if not randomized after the initial screening. All screening procedures must be repeated if 
rescreening is performed after the initial 2-week screening period.
Eligible subjects will be randomly assigned by an Interactive Web Response System (IWRS), in 
a 1:1 ratio to receive 1 of 2 treatments during the double-blind treatment period: 
rivaroxaban 10 mg orally once daily or placebo 10 mg orally once daily for a maximum of 
180 days
(±3 days).
Subjects will be stratified at randomization by tumor type 
(APC or non-APC) and will be instructed to take the study drug for a fixed duration of 180 days 
(±3 days). Subjects will have up to 4 days to complete the Day 1 visit from the point of being 
randomly assigned to the study drug within IWRS (date of randomization) to initiate their study 
drug treatment in order to accommodate those subjects who will be receiving their study drug 
from a centralized drug depot; however, every effort should be made to initiate study drug within 
1 day. Every effort should be made to initiate systemic cancer therapy on the same day as 
administration of the first dose of study drug, or within 72 hours of the first dose of study drug 
when at all possible. However, for pragmatic reasons, subjects may be allowed to initiate 
systemic cancer therapy within a period of ±1 week prior to, or after their first dose of study 
drug, with a preference of this occurring within the first week following study drug 
administration.
Subjects will have study visits, inclusive of visit windows, performed at Week 8 (±7 days), 
Week 16 (±7 days), and Day 180/EOT (±3 days) during the double-blind treatment period, and 
will undergo mandatory CU at these visits. The CU planned for the Day 180/EOT visit must 
occur within this window and before the last dose of study drug. Following a 30-day 
post-treatment follow-up period (Day 210/EOS ±7 days from randomization), all subjects
(or their legally acceptable representative), including those who discontinued the study drug 
prior to the Day 180 visit, will be contacted by telephone for a Day 210/EOS visit follow-up 
assessment and will have their vital status (eg, dead, alive, or lost to follow-up) as well as clinical 
status review for suspected outcome and safety bleeding events completed. Adverse events 
(AEs) and concomitant medications will be collected.
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All study visits may be coordinated with subject’s planned visits that are part of their 
standard-of-care, as long as the planned visits are within the protocol-specified visit windows.
Either the investigator or a qualified subinvestigator will be required to see each subject at every 
study visit for clinical assessment of the subject’s status.
An independent blinded Clinical Endpoint Committee (CEC) will apply the protocol definitions 
to adjudicate and classify efficacy and safety endpoint events. Throughout the double-blind 
treatment and 30-day post-treatment follow-up phases, suspected cases of DVT and PE will be
centrally adjudicated by the CEC. In addition, incidental PE or DVT identified from routine care
imaging (eg, CT scans ordered primarily for staging or restaging of malignancy) during the same 
time period will be adjudicated as asymptomatic PE or DVT events. Lastly, any clinical event 
that suggests the possibility that a major or clinically relevant non-major bleeding event occurred 
will be sent for adjudication. Emergent imaging results at the study site for clinical 
decision-making will be collected for the central adjudication by the CEC. In subjects who died 
during follow up, death certificates and if available, autopsy findings will be reviewed to 
establish a diagnosis of fatal PE.
If a subject permanently discontinues the study drug before the end of the double-blind treatment 
period (Day 180 visit), he/she should be instructed to complete an unscheduled EOT visit as soon 
as possible from the time that the study drug was discontinued, with the CU performed within 
2 days of taking the last dose of study drug. A CU should not be performed at all if it is not 
possible to have it completed within 2 days of the last dose of study drug. In addition, the subject
will be required to complete all remaining study visits and procedures, including what would 
have been their Day 180/EOT and Day 210/EOS visits. If the unscheduled EOT visit falls within 
the window of a remaining study visit, the subject does not need to repeat this required study 
visit.
The investigator should inform subjects of the importance of returning for all study visits 
(regardless of duration of study drug treatment) as it is imperative for the integrity of the study
and results to have vital status and other outcomes ascertained. If the subject is unwilling or 
unable to return for any visits, or is lost-to-follow up, the investigator should collect as much 
follow-up information as possible for each remaining visit, including contacting the subject or 
legally acceptable representative by telephone or by mail to determine vital status and outcome 
ascertainment, as agreed to by the subject during the informed consent process. The site must 
document all attempts to try to contact the subject in the source documents.
An Executive Committee (EC) will be formed that has overall responsibility for the conduct and 
reporting of the study. The independent blinded CEC will apply the protocol definitions and 
adjudicate and classify any clinical event that suggests an efficacy or safety outcome event has 
occurred. The
independent blinded CEC
will also adjudicate
all protocol-specified 
CU examinations. In addition, an unblinded Independent Data Monitoring Committee (IDMC) 
will periodically assess the safety of subjects in this study and evaluate the efficacy data as 
necessary to ensure that the safety of subjects is not compromised. All committees will be 
governed by independent charters.
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Approved, Date: 16 February 2018
The frequency and timing of efficacy, safety, and other measurements are provided in the Time 
and Events Schedule.
SUBJECT POPULATION
The study will include ambulatory adult men and women, 18 years of age and older, with various 
cancer types with an expected survival of >6 months, who are scheduled to initiate systemic 
cancer therapy as a component of their standard-of-care anticancer regimen, have a baseline 
Khorana thromboembolic risk score of ≥2, and are judged by the investigator or qualified 
designee to be an appropriate candidate for treatment with either placebo or rivaroxaban for
thromboprophylaxis based on their clinical status. The duration of the intended continued 
systemic cancer therapy will vary from subject to subject, and it is also understood that treatment 
modalities and drug combinations may change during the double-blind treatment period thereby 
reflecting current standards of clinical care.
DOSAGE AND ADMINISTRATION
Subjects will be randomly assigned in a 1:1 ratio to 1 of 2 treatment groups: rivaroxaban 10 mg 
orally once daily or placebo 10 mg orally once daily for a maximum duration of treatment of 
180 days (±3 days). Every effort should be made to initiate systemic cancer therapy on the same 
day as administration of the first dose of study drug, or within 72 hours of the first dose of study 
drug, when at all possible. However, for pragmatic reasons, subjects may be allowed to initiate 
systemic cancer therapy within a period of ±1 week prior to, or after their first dose of study 
drug, with a preference of this occurring within the first week following study drug 
administration, with the intention that systemic cancer therapy will continue during the 
double-blind treatment period for a duration determined by the treating oncologist according to 
standard protocols of clinical care. The initial dose of study drug should be taken on Day 1 at a 
time that is most convenient for the subject. Subsequent doses of study drug should be taken 
every 24±2 hours thereafter. The study drug can be taken with or without food and should be 
taken at the same time daily. In the event that a dose of study drug is missed, the missed dose 
should be taken as soon as possible. If a dose is missed, advise the subject to take the study drug 
as soon as possible on the same day and continue on the following day with their recommended 
daily dose regimen.
Interruption of study drug
The study drug may be temporarily interrupted; however, these interruptions should be kept to a 
minimum as much as possible. If a subject misses more than 14 consecutive days of study drug, 
he/she will need to permanently discontinue the study drug. It is recommended, when possible, 
that the study drug be discontinued at least 24 hours, and at the discretion of the investigator,
before an invasive procedure (ie, surgical) to reduce the risk of bleeding. In deciding whether a 
procedure should be delayed at least 24 hours after the last dose of study drug, the increased risk 
of bleeding should be weighed against the urgency of intervention. In case of major surgery or 
major bleeding risk procedure, the investigator may consider holding the prior day’s dose of 
study drug (skip both doses of the study drug the day before and the day of surgery), weighing 
the risk of bleeding against that of VTE. Consider bridging with parental anticoagulation, if 
NCT02555878


JNJ39039039/BAY59-7939 (Rivaroxaban)
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Approved, Date: 16 February 2018
necessary. The study drug should be restarted after the surgical or other procedures as soon as 
adequate hemostasis has been established, noting that the time to onset of therapeutic effect is 
short. The investigator may consider resuming the study drug 24 hours after achieving 
hemostasis for low-bleeding risk or minor surgical procedures, and at 48 hours in case of major 
or high-risk bleeding procedures, noting that the time to onset of therapeutic effect is short.
During planned or emergency hospitalization, the study drug should be stopped only if the 
treating clinician determines that thromboprophylaxis or anticoagulation should be administered. 
It might be necessary to interrupt the study drug temporarily (eg, while the contraindicated 
mediation is taken). Subjects should resume the study drug as soon as it is deemed safe by the 
treating clinician, and study drug interruption during the treatment period should not exceed 
14 consecutive days.
EFFICACY EVALUATIONS
Efficacy evaluations include assessment of subjects for VTEs that are part of the primary 
efficacy composite variable. The primary efficacy outcome variable is objectively confirmed 
symptomatic lower extremity proximal DVT, asymptomatic lower extremity proximal DVT, 
symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-
fatal PE, incidental PE, and VTE-related death. Key secondary efficacy outcomes are
symptomatic VTE events (DVT/PE) and VTE-related deaths and all-cause mortality. Other 
secondary outcomes are individual components of the primary composite efficacy variable, 
confirmed fatal/non-fatal ATE events, confirmed fatal/non-fatal visceral VTE events, and 
composites of the primary endpoint. Any clinical event that suggests the possibility that an 
efficacy outcome event has occurred will be sent for adjudication.  
The primary efficacy composite endpoint is the time from randomization to the first occurrence 
of objectively confirmed symptomatic lower extremity proximal DVT, asymptomatic lower 
extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper 
extremity DVT, symptomatic non-fatal PE, incidental PE, or VTE-related death occurring from 
randomization to the Day 180 visit as adjudicated by the independent blinded CEC. The key 
secondary efficacy endpoints include symptomatic VTE events (DVT/PE) and VTE-related 
deaths, and all-cause mortality from the time of randomization to the Day 180 visit. Other 
secondary efficacy endpoints include the time from randomization to the first occurrence for the 
following events during the 180-day, double-blind treatment period, defined as the individual 
components of the primary efficacy composite variable analyzed separately, confirmed fatal/non-
fatal ATE events, and confirmed fatal/non-fatal visceral VTE events. In addition, a composite of 
symptomatic lower extremity proximal DVT, asymptomatic lower extremity proximal DVT, 
symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-
fatal PE, incidental PE, and all-cause mortality, as well as a composite of symptomatic lower 
extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper
extremity DVT, symptomatic non-fatal PE, and VTE-related deaths will be assessed.
If a subject has a suspected efficacy outcome event during the study, the treating physician 
should exercise clinical judgment and follow guidelines to apply the standard-of-care. 
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Unblinding of the study drug should not be necessary, as anticoagulation regimens do not require 
adjustment, regardless of treatment group assigned when the study drug is administered in the 
doses used in this study.
SAFETY EVALUATIONS
Safety will be evaluated by the monitoring of bleeding events, AEs, clinical laboratory tests, 
pregnancy tests, Eastern Cooperative Oncology Group (ECOG) status, central venous catheter 
(CVC) status, concomitant therapies, and vital signs, including weight measurements. 
Additionally, the targeted medical history and physical examination performed at screening 
should be obtained and performed in a manner that facilitates the investigator’s ability to make 
reasonable evidence-based clinical assessments and decisions throughout the study related to the 
safety evaluations or to the assessment of the efficacy evaluations. 
The primary safety objective of this study is the time to a major bleeding event in treated 
subjects in each randomized treatment group as defined by ISTH. Bleeding events will be 
classified using protocol-specified definitions for major, clinically relevant non-major, or minor 
bleeding. 
Secondary 
safety 
endpoints 
include 
proportions
of 
clinically relevant 
non-major bleeding, minor bleeding, and any bleeding (defined as major, clinically relevant 
non-major, and minor bleeding as defined by ISTH). Subjects will be censored for safety 
endpoints events up to 2 days after receiving the last dose of study drug.
Any clinical event that suggests the possibility that a major or clinically relevant non-major 
bleeding event occurred will be sent for adjudication. If a subject has a serious bleeding event 
during study drug treatment, routine measures should be considered. If these measures are 
sufficient to stop bleeding, unblinding of study drug should not be necessary.  
BIOMARKER EVALUATIONS
Blood samples will be collected from subjects at screening, the Weeks 8 and 16 visits, and the 
Day 180/EOT visit to measure levels of circulating D-dimer, P-selectin, and Tissue Factor.
STATISTICAL METHODS
Statistical analysis for this clinical study data will be performed by the sponsor or under the 
authority of the sponsor. A general description of the statistical methods to be used to analyze the 
efficacy and safety data is outlined below. Specific details will be provided in the statistical
analysis plan (SAP).
Data collected on the primary efficacy, safety, as well as the key secondary endpoints will be 
summarized across treatment groups. Specific imputation rules for missing data 
(eg, missing event dates) will be applied, if warranted, and will be specified in the SAP before 
the final database lock. Descriptive statistics such as mean, median, standard deviation, 
interquartile range, minimum, and maximum will be used to summarize continuous variables. 
Counts and proportions will be used to summarize categorical variables. Graphical data displays 
(eg, box plots) may also be used to summarize data. Kaplan-Meier estimates adjusted for 
competing risk over time will be summarized and plotted for time-to-event variables.
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Study Population/Analysis Sets
Following the intent-to-treat (ITT) principle, all randomized subjects will constitute the 
ITT population. The safety population is defined as a subset of the ITT population and consists 
of all randomized subjects who receive at least 1 dose of study drug. The per-protocol (PP) 
population is defined as a subset of the ITT population. Subjects with major protocol deviations 
will be excluded from the PP population. Major protocol deviations will be defined in the SAP. 
The primary efficacy and key secondary endpoint analyses in this study will be based on the 
ITT population. All safety endpoints will be analyzed based on the safety population.
Sample Size Determination
This is a 6-month fixed-duration study to demonstrate the superiority of rivaroxaban compared 
with placebo in ambulatory cancer subjects undergoing systemic cancer therapy. Estimates for 
VTE events in this population vary but in most studies, the data demonstrate a significant benefit 
(or, reduction in events) over placebo when cancer subjects are treated with anticoagulant 
therapy. According to a recent review of the VTE prophylaxis studies in cancer subjects by 
Khorana et al, the majority of RCTs in solid tumors have reported relative risk reductions 
(RRRs) between 50% and 64%. The duration of the earlier primary VTE prophylaxis studies in 
cancer was generally between 3 to 4 months, in conjunction with initiation of systemic 
anticancer therapy. 
The basis for predictive events is derived from the Vienna Cancer and Thrombosis Study 
(CATS) group, which utilized the Khorana thromboembolic risk score, and followed 
819 ambulatory 
cancer 
subjects
for 
symptomatic 
VTE
as 
an 
endpoint.
In 
a 
Kaplan-Meier analysis, the cumulative probability of VTE after 6 months: Khorana 
thromboembolic risk score ≥3, 17.7% (95% confidence interval [CI]: 11.0% - 27.8%, N= 93), 
and 9.6% (95% CI: 6.2% - 14.7%, N=221) in those subjects with a Khorana thromboembolic risk
score of 2. The addition of adjudicated objectively confirmed asymptomatic DVT and PE events 
is expected to contribute an additional 5% to 10% to the primary composite endpoint event rates.
Taken together, these results, along with a number of smaller epidemiologic studies, in general
support a symptomatic VTE rate at 180 days of at least 9.5% in subjects with a Khorana 
thromboembolic risk score of ≥2 and therefore, an overall primary efficacy composite endpoint 
event rate of approximately 14.5% seems reasonable. Furthermore, it is assumed that the use of 
rivaroxaban will reduce this event rate to approximately 6.0%.
Assuming a cumulative incidence rate of 14.5% for the primary efficacy composite endpoint 
events in the placebo group and 6.0% cumulative incidence rate in the rivaroxaban treatment 
group, a total sample of about 700 randomized subjects (350 per treatment group) will be 
required to demonstrate approximately 60% RRR in the primary efficacy composite endpoint 
with a 2-sided Type 1 error rate of 5% and with >90% statistical power (calculation performed 
by EaST 6.3 software), assuming a 20% discontinuation rate. Towards the end of the enrollment 
phase, approximately 800 subjects were planned to be randomized into the study due to the high 
subject discontinuation rate.
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Essentially, the above overall sample size estimate is calculated based on the following 
assumptions:

Effect size: absolute difference in event rates = 8.5%, RRR = 58.6%
o
Primary efficacy composite endpoint event rate in the placebo arm: 14.5%
o
Primary efficacy composite endpoint event rate in the rivaroxaban arm: 6%

Power: >90%  

Overall α level: 5%, 2-sided

Probability of dropping out of the study: 20%

Duration of enrollment period: 12 months

Duration of study: 6 months (fixed for each randomized subject)
Interim Analysis
No interim efficacy analysis is planned in this study. An unblinded IDMC has been established 
for this study to periodically assess the safety of subjects in the study and evaluate the efficacy 
data, as necessary.  
Efficacy and Safety Analyses
The primary efficacy and key secondary endpoint analyses in this study will be based on the 
ITT population. All safety endpoints will be analyzed based on the safety population. Statistical
tests will be based on a 2-sided Type 1 error rate of 5%. Associated 95% CIs will be provided. 
Primary and secondary events will be adjudicated by an independent blinded CEC and analyses 
will be based on these adjudicated events. Investigator-reported events will also be summarized. 
Additional data analyses (including those based on specific subgroups) will be identified in the 
SAP.
Primary Efficacy Composite Endpoint Analysis
This analysis will be performed on a time-to-first-event basis during the observation period up to 
the Day 180 visit, using a stratified Cox proportional hazard model (stratification factor: APC or 
non-APC), including treatment group as a categorical explanatory variable with 2 levels 
(ie, rivaroxaban, placebo) and will be based on the ITT population. This primary efficacy 
analysis will include composite events (ie, objectively confirmed symptomatic lower extremity 
proximal DVT, asymptomatic lower extremity proximal DVT, symptomatic lower extremity 
distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, incidental PE or
VTE-related death) occurring from randomization up to the Day 180 visit for all randomly 
assigned subjects in the study. Subjects who have no primary efficacy outcome during this 
observation period, or subjects who are lost-to-follow up, or subjects who die because of other 
reasons than VTE, or subjects who withdraw informed consent before the end of the predefined 
treatment duration, will be censored at the last day of their complete assessment for study 
outcomes during the treatment period (assuming these types of censorings are independent of the 
primary outcome). Further details will be specified in the SAP.
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To account for competing risks (deaths from causes other than VTE for efficacy, or fatal 
bleeding for safety) in the primary efficacy and safety analyses, a cumulative incidence approach 
will be followed with the use of Gray’s 2-sample test (2-sided Type 1 error rate of 5%). 
Associated hazard ratios (HRs) and 95% CIs will be calculated with the use of the Fine and Gray 
regression model. Cumulative incidence functions will be estimated separately for the 
2 randomized treatment groups. Additional statistical details regarding the specific models and 
inferential procedures to be used will be described in the SAP.
Key secondary efficacy endpoints will be analyzed in a similar fashion as the primary efficacy 
endpoint. 
Safety Endpoints, Laboratory and Vital Signs Data Analysis
The primary safety endpoint includes time to a major bleeding event in treated subjects in each 
randomized treatment group as defined by ISTH. A statistical comparison of the 2 randomized 
treatment groups will be performed using a stratified Cox’s proportional hazards model with 
treatment as a covariate. Additionally, the frequency of bleeding events in each treatment group 
will be summarized. Secondary safety endpoints, defined by proportions of clinically relevant 
non-major bleeding events, will also be summarized. All reported AEs (ie, treatment-emergent 
adverse events [TEAEs], AEs that have worsened since baseline) will be summarized. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an AE, or who experience a severe AE or 
serious adverse event (SAE). Laboratory data will be summarized and descriptive statistics for 
vital signs will be provided.
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TIME AND EVENTS SCHEDULE
Period
Screeninga
Double-Blind Treatment
Post-treatment
(Follow up)
Randomizationa
Every 8-Week Visits
(±7 days)
End of Treatment
(EOT) Visitb
(±3 days)
End of Study
(EOS) Follow Upc
(±7 days)
Month
-
2
4
6
7
Day/Week
Day -14 to -1
Day 1
Wk 8o
Wk 16o
Day 180o
Day 210
Eligibility
Obtain informed consent
X
Apply inclusion/exclusion criteria
X
Demographics
X
Relevant medical history
X
Disease staging (using TNM system [solid tumors] or Ann 
Arbor [lymphoma])
X
Perform physical examination (Record height/weight/BMI)
X
Coagulation Tests (PT, aPTT and INR)
X
Record prestudy drug(s)d
X
X
Record Khorana thromboembolic risk score
X
Randomization 
Xe
Study Drug Administration
Contact IWRS for study drug bottle number to dispensee
X
X
X
Dispense study drug/provide instructions
Xf
X
X
Perform study drug accountability/compliance
X
X
X
Safety Assessments
Urine pregnancy testg
X
X
Record vital signs including weight
X
X
X
X
X
Record ECOG performance statush
X
X
X
X
X
Record CVC status
X
X
X
X
X
Collect laboratory samples (hematology, serum chemistry)i
X
X
X
X
Calculated eGFRj
X
X
X
X
Clinical events relevant to safety endpoints (bleeding events)o
X
X
X
X
Adverse events
X
X
X
X
X
X
Concomitant therapyk
X
X
X
X
X
Efficacy Assessments
Perform CU
X
X
X
Xl
Clinical events relevant to efficacy endpoints (VTE)o
X
X
X
X
Telephone follow up for vital status
X
Exploratory Assessments
Biomarker samplem
X
X
X
X
PK sample
Xn
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a Assess subject’s continuing eligibility by reviewing any changes since screening based upon the scheduled assessments to be performed at this time. Screening and randomization may be performed on the 
same day if historical laboratory results (done per standard-of-care) are already available during the screening period (must have been previously drawn within 2 weeks of randomization), CU results are 
received from the local reader, and all required screening procedures are completed that qualify the subject. See footnote e.
b The Day 180/EOT visit will be performed at the completion of 180 ±3 days of treatment with study drug (regardless of whether a subject is ongoing in a cycle of systemic cancer therapy). If a subject 
permanently discontinues the study drug before the end of the double-blind treatment period (Day 180 visit), he/she should be instructed to complete an unscheduled EOT visit as soon as possible, from the 
time that the study drug was discontinued, and have the CU performed within 2 days of taking the last dose of study drug. At the unscheduled EOT visit, all procedures as outlined will be performed. In 
addition, subjects that permanently discontinue the study drug before the Day 180 visit will be required to complete all remaining study visits, including what would have been their Day 180/ EOT and 
Day 210/EOS visits.  
c
At the end of the post-treatment follow-up period (Day 210 visit), all subjects (or their legally acceptable representative), including those who discontinued the study drug prior to the Day 180 visit, will be 
contacted by telephone for an Day 210/EOS follow-up assessment.
d Prestudy therapies are those administered within 2 weeks before the first dose of study drug (Day 1). All prestudy therapies must be recorded in the eCRF except supplements such as fish oil, herbal 
medicines, and vitamins. The intent is to enroll subjects and begin the first dose of study drug before administration of systemic cancer therapy or radiotherapy, however, if for pragmatic reasons the subject 
begins systemic cancer therapy or radiotherapy prior to the first dose of study drug, the systemic cancer therapy or radiotherapy will be recorded in the appropriate section of the eCRF.
e
An IWRS will be used to randomly assign subjects to treatment. Randomization may be completed once clinical laboratory results and imaging results (CU) from the local reader are available to confirm 
subject eligibility. Note: Historical laboratory results may be used for the screening visit to confirm eligibility; these results must be documented in the subjects’ source documentation. In this case, subjects 
will be randomized on Day 1 based on the historical laboratory results, which must have been previously drawn within 2 weeks of randomization that confirms eligibility; however, screening blood samples 
must still be collected and sent to the central laboratory for analysis. Subsequently, if the screening results from the central laboratory indicate that the subject is not eligible, the historical laboratory results 
will take precedence and should be recorded in the eCRF to document eligibility.
f The initial dose of study drug should be taken on Day 1 at a time that is most convenient for the subject. Subjects will have up to 4 days to complete the Day 1 visit from the point of being randomly 
assigned to the study drug within IWRS (date of randomization) to initiate their study drug treatment in order to accommodate those subjects who will be receiving their study drug from a centralized drug 
depot; however, every effort should be made to initiate their study drug treatment within 1 day. Every effort should be made to initiate systemic cancer therapy on the same day as administration of the first 
dose of study drug, or within 72 hours of the first dose of study drug when at all possible. However, for pragmatic reasons, subjects may be allowed to initiate systemic cancer therapy within a period of 
±1 week prior to or after their first dose of study drug. Subjects that are screened and initiate systemic cancer therapy more than 1 week before the first dose of study drug should not be randomized and will 
be considered a screen failure. However, if a subject does not initiate systemic cancer therapy as planned within +1 week after the first dose of study drug, the subject is allowed to continue taking study drug
and remain in the study. Subsequent doses of study drug should be taken every 24±2 hours, thereafter. The study drug can be taken with or without food and should be taken at the same time daily. The 
maximum duration of study drug administration is 180 days ±3 days.
g To be performed on all women judged to be of childbearing potential. Additional urine pregnancy tests may be performed, as determined necessary by the investigator or required by local regulation, to 
establish the absence of pregnancy before administration of the study drug and throughout the study.
h The ECOG/WHO/Zubrod Performance Status Scale will be used to assess functional status (see Attachment 4).
i
Hematology panel includes hemoglobin, hematocrit, RBC, WBC count with differential, and platelet count. Serum chemistry panel includes sodium, potassium, chloride, bicarbonate, BUN, glucose, uric 
acid, calcium, phosphate, albumin, total protein, creatinine, AST, ALT, total and direct bilirubin, and alkaline phosphatase. 
j
Estimated creatinine clearance will be calculated by the central laboratory using both the Modification of Diet in Renal Disease formula (see Attachment 5) as well as the Cockcroft-Gault formula 
(see Attachment 2). Either formula, as well as the CKD-EPI formula (see Attachment 6) can be used to determine eligibility at screening.
k All concomitant therapies taken throughout the double-blind treatment period for the treatment of AEs/SAEs, prohibited medications, additional medications as listed in Section 8 and systemic cancer 
therapy and radiotherapy must be recorded in the eCRF except supplements such as fish oil, herbal medicines, and vitamins. In addition, concomitant therapies should also be recorded beyond the 
Day 180/EOT visit only in conjunction with SAEs that meet the criteria outlined in Section 12.4.2. Serious Adverse Events.
l
The Day 180/EOT visit will be completed within a window of ±3 days. The CU planned for the Day 180/EOT visit will be conducted preferably on the day of the visit or within the visit window 
(Day 180 3 days) but must be performed before the last dose of study drug. Subjects who discontinue early will have an unscheduled EOT visit as soon as possible from the time that the study drug was 
discontinued, with the CU performed within 2 days of taking the last dose of study drug. A CU should not be performed at all if it is not possible to have it completed within 2 days of the last dose of study 
drug.
m Blood samples will be collected for biomarker assessment (circulating D-dimer, P-selectin, and Tissue Factor ).
n The blood sample for pharmacokinetic sample should be drawn prior to study drug administration at the Week 8 visit.
o Health care resource utilization data will be collected as part of the endpoint assessments, at Weeks 8 and 16, and Day 180/EOT, for all subjects, or until study drug discontinuation. The data collection will 
be specific to the study outcomes of DVT, PE, or bleeding, including visits to health care providers, hospitalization, length of hospitalization, and use of diagnostic procedures.
AE = adverse event; ALT=alanine aminotransferase; aPTT = activated partial thromboplastin time; AST=aspartate aminotransferase; BMI = body mass index; BUN = blood urea nitrogen; 
CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; CU = bilateral lower extremity venous duplex compression ultrasonography; CVC = central venous catheter; DVT = deep venous 
thrombosis; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; eGFR = estimated glomerular filtration rate; EOS = end of study; EOT = end of treatment; 
INR = international normalized ratio; IWRS = Interactive Web Response System; PE = pulmonary embolism; PK=pharmacokinetic(s); PT = prothrombin time; RBC = red blood cell; SAE = serious adverse 
event; TNM = tumor, nodes, metastases; VTE = venous thromboembolism; WBC = white blood cell; WHO = World Health Organization; Wk = week.
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ABBREVIATIONS
ACCP
American College of Chest Physicians
AE
adverse event
AESI
adverse events of special interest
ALT
alanine aminotransferase
APC
advanced pancreatic cancer
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATE
arterial thromboembolism
BMI
body mass index
CEC
Clinical Endpoint Committee
CI
confidence interval
CrCl
creatinine clearance
CT
computed tomography
CU
bilateral lower extremity venous duplex compression ultrasonography
CVC
central venous catheter
CYP
cytochrome P450
DVT
deep vein thrombosis
EC
Executive Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDC
electronic data capture
EINSTEIN
oral direct factor Xa inhibitor rivaroxaban in patients with acute symptomatic deep vein 
thrombosis or pulmonary embolism
EOS
end of study
EOT
end of treatment
ESMO
European Society of Medical Oncology
FRAGEM
Gemcitabine with or without prophylactic weight-adjusted dalteparin in patients with 
advanced or metastatic pancreatic cancer: a multicenter, randomized Phase 3B trial
FXa
activated Factor X
GCP
Good Clinical Practice
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
ISTH
International Society on Thrombosis and Haemostasis
ITT
intent to treat
IWRS
interactive web response system
LFT
liver function test
LMWHl
Low molecular weight heparin
MAGELLAN
The multicenter, randomized, parallel-group efficacy and safety study for the prevention of venous 
thromboembolism in hospitalized acutely ill medical patients comparing rivaroxaban with 
enoxaparin
MedDRA
Medical Dictionary for Regulatory Activities
NCCN
National Comprehensive Cancer Network
PE
pulmonary embolism
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PQC
product quality complaint
PROSPECT-
CONKO-004
A prospective, randomized trial of simultaneous pancreatic cancer treatment with 
enoxaparin and chemotherapy trial
PROTECHT
Prophylaxis of thromboembolism during chemotherapy trial
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PT
prothrombin time
RCT
randomized controlled trial
RECORD
REgulation of coagulation in ORthopedic surgery to prevent DVT and PE
RRR
relative risk reduction
SAE
serious adverse event
SAP
statistical analysis plan
SAVE-ONCO
Evaluation of AVE5026 in the prevention of VTE in cancer patients undergoing 
Chemotherapy
TEAE
treatment-emergent adverse event
ULMWH
ultra-low molecular weight heparin
ULN
upper limit of normal
VKA
vitamin K antagonist
VTE
venous thromboembolism
WHO
World Health Organization
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1.
INTRODUCTION
Rivaroxaban is a potent, orally administered and highly selective direct inhibitor of activated 
factor X (FXa); a protease enzyme that promotes blood coagulation by triggering an amplified 
burst of thrombin generation, ultimately leading to thrombus formation (a blood clot). Activated 
factor X plays a central role in the initiation and propagation of blood coagulation, being 
positioned at the intersection of the Contact Activation and Tissue Factor coagulation pathways 
formerly intrinsic and extrinsic, respectively. Therefore, selective inhibition of FXa by 
rivaroxaban is effective in reducing thrombin generation and clot formation.
Rivaroxaban is an oxazolidinone derivative. The S-configuration-oxazolidinone ring of 
rivaroxaban serves as the central core of the molecule and specifically directs morpholinone 
residue (essential for higher potency) into the S-4 pocket and the chlorothiophene moiety 
(essential for potent FXa inhibition) into the S-1 pocket of FXa.
As of 15 September 2014, more than 84,000 subjects have been enrolled in interventional 
clinical trials (completed and ongoing Phase 1, Phase 2, Phase 3, and Phase 4), including more 
than 47,000 subjects treated with rivaroxaban. Rivaroxaban has been approved for multiple 
thrombosis-mediated conditions worldwide under the trade name XARELTO®.35 For the most 
comprehensive nonclinical and clinical information regarding the efficacy and safety of 
rivaroxaban, refer to the latest version of the Investigator’s Brochure (IB) for rivaroxaban.6 The 
term “sponsor” used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
Nonclinical Studies
Comprehensive toxicologic investigations of rivaroxaban have been performed. No 
clinicopathologic or histopathologic evidence of hepatotoxicity has been observed in any of the 
animal species tested (mice, rats, and dogs). Preclinical pharmacology studies of rivaroxaban31
showed:

Competitive, selective, direct inhibition of human FXa

Inhibition of prothrombinase with resultant anticoagulant activity but no significant 
interaction with platelet function

Species-dependent inhibition of FXa with resultant antithrombotic activity in venous and 
arterial thrombosis models in rats and rabbits

A high degree of correlation between clotting times (eg, prothrombin time [PT]) and plasma 
drug levels

Antithrombotic activity without excessive prolongation of bleeding time in rats and rabbits

Bleeding risk comparable with enoxaparin

Co-administration of rivaroxaban with acetylsalicylic acid (aspirin), naproxen, diclofenac, 
clopidogrel, or warfarin showed additive but not potentiating effects on bleeding time 
prolongation in the tail transection model in rats.
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Toxicologic data indicated no need for follow up in the clinical studies.
Clinical Studies
As of 15 September 2014, more than 84,000 subjects have participated in completed Phase 1, 2, 
3, and 4 studies of rivaroxaban. The Phase 1 program for rivaroxaban included 70 studies with a 
total 1,610 subjects who received rivaroxaban as active treatment. The clinical indication 
program has completed 30 studies; 12 Phase 2 studies, 17 Phase 3 studies, and 1 Phase 4 study 
with in total approximately 49,023 subjects receiving rivaroxaban, 32,293 subjects receiving 
active comparator, and 6,868 subjects receiving placebo treatments. The efficacy and safety of 
rivaroxaban has been studied in several large clinical development programs for the prevention 
and treatment of multiple thrombosis-mediated conditions.
Rivaroxaban has been demonstrated to be highly effective in a number of clinical settings, 
including venous thromboembolism (VTE) prophylaxis in the Regulation of Coagulation in 
Orthopedic Surgery to Prevent Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE) 
(RECORD) 1-3 studies in 9,500 subjects undergoing hip and knee replacement surgery,13,18,23
and in the secondary prevention of VTE in the Oral Direct Factor Xa Inhibitor Rivaroxaban in 
Patients with Acute Symptomatic Deep Vein Thrombosis or Pulmonary Embolism (EINSTEIN)
trials in 8,900 subjects with an acceptable benefit-risk profile.40,41
Clinical experience with rivaroxaban in primary and secondary VTE prophylaxis in active cancer 
subjects
Small subgroups of subjects with active cancer received prophylaxis/treatment with rivaroxaban 
in The Multicenter, Randomized, Parallel-group Efficacy and Safety Study for the Prevention of 
Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban 
with Enoxaparin (MAGELLAN) and EINSTEIN studies.32 In the MAGELLAN study,
8,101 subjects at least 40 years of age or older who were hospitalized for an acute medical illness 
were randomly assigned to receive VTE prophylaxis with subcutaneous enoxaparin, 40 mg once 
daily, for 10±4 days and oral placebo for 35±4 days or to receive subcutaneous placebo for 
10±4 days and oral rivaroxaban, 10 mg once daily, for 35±4 days.11
The MAGELLAN study was a prospective, randomized, double-blind, double-dummy, active 
comparator-controlled, multicenter and multinational study. Acutely ill subjects (admitted to the 
hospital no more than 72 hours prior to randomization) who did not require surgery, were 
completely immobilized for at least 1 day during the hospitalization, were anticipated to have a 
decreased level of mobility for at least 4 days, and met all other inclusion criteria were eligible 
for randomization to receive subcutaneous enoxaparin 40 mg once daily for 10±4 days and oral 
placebo for 35±4 days or to receive subcutaneous placebo for 10±4 days and oral 
rivaroxaban 10 mg once daily for 35±4 days. MAGELLAN enrolled a general medically ill 
subject population, selected based on set criteria for risk factors such as age, immobility, cancer, 
and type of index event but unselected from a validated VTE risk score perspective. This 
population included a high proportion of subjects who were ≥75 years of age (38.3%) or had 
heart failure (38.6 %) at baseline, and were hospitalized for an acute episode of infection (45%) 
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or heart failure (32.3%). The primary objectives of this study were to demonstrate superior 
efficacy at Day 35 in the modified intent-to-treat (ITT) population (Primary Efficacy Endpoint 1) 
and noninferiority at Day 10 in the per-protocol (PP) population.11 The primary endpoint was a 
composite of asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic 
non-fatal PE and VTE-related death.
A total of 592 subjects (7.3%) had active cancer at baseline. Although the subset of cancer 
subjects was too small to merit a meaningful analysis, there were numerical differences
(as measured by the relative risk) between the 2 treatment arms that favored enoxaparin with 
respect to primary efficacy, major bleedings, and clinically relevant bleedings. The primary 
efficacy endpoint showed subjects treated with rivaroxaban 20/202 (9.9%) and enoxaparin 
15/203 (7.4%) relative risk: 1.340; 95% confidence interval [CI]: 0.706 to 2.542. Major bleeding 
occurred in subjects treated with rivaroxaban 7/294 (2.4%) and enoxaparin 0 (data on file).
Subjects with active cancer were also treated with rivaroxaban for secondary prophylaxis of 
recurrent VTE in the EINSTEIN clinical program. In a pooled subgroup analysis, from the 
EINSTEIN-DVT and EINSTEIN-PE trials (2 randomized, open-label, Phase 3 studies) that 
compared rivaroxaban with enoxaparin given with and followed by a Vitamin K antagonist 
(VKA) for the treatment of DVT (EINSTEIN-DVT) or PE (EINSTEIN-PE),655 (8%) subjects
were diagnosed with any active cancer, 462 (6%) presented with the diagnosis at baseline, and 
193 (2%) were diagnosed with cancer during the study.40,41
In subjects with active cancer (diagnosed at baseline or during treatment), recurrent VTE
occurred in 16 (5%) of 354 subjects allocated to rivaroxaban and 20 (7%) of 301 subjects
allocated to enoxaparin and VKA (hazard ratio [HR] 0.67, 95% CI 0.35 to 1.30). Clinically 
relevant bleeding occurred in 48 (14%) of 353 subjects receiving rivaroxaban and in 49 (16%) of 
298 
subjects
receiving 
low 
molecular 
weight 
heparin 
(LMWH)/VKA 
therapy 
(HR 0.80, 95% CI: 0.54 to 1.20). Major bleeding occurred in 8 (2%) of 353 subjects receiving 
rivaroxaban 
and 
in 
15 (5%) 
of 
298 
subjects
receiving 
combination 
therapy 
(HR 0.42, 95% CI: 0.18 to 0.99).
1.2.
Overall Rationale for the Study
Patients with cancer are at 4 to 7 times higher risk of VTE than patients without cancer.8,17 The 
risk for VTE varies according to several factors, including age, obesity, history of thrombosis,
and recent reduced mobility.15 In addition, the VTE risk associated with cancer varies throughout 
the course of the disease. The risk is particularly high in the first few months following diagnosis 
and there is an estimated 4-fold to 13-fold increase in risk for VTE in late-stage metastatic 
disease.8, 9, 10 Cancer treatment also has an important impact on the development of VTE, with 
systemic cancer therapy increasing the VTE risk by up to 6.5-fold. 9, 17
In patients with cancer, VTE is associated with substantial morbidity and complicates the clinical 
management of cancer. Emerging research indicates a detrimental effect of VTE on cancer 
survival.2, 3, 4, 10 Venous thromboembolism is currently recognized as the second leading cause of 
death in patients with cancer.21 The incidence of cancer-associated thrombosis has 
increased,20,21,29,38 probably because of a combination of factors including improved treatment 
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outcomes resulting in longer patient survival, more aggressive and prothrombotic treatment 
regimens, an aging population, and increased detection owing to improvements in imaging 
technology and the increased frequency of imaging. 
A recent real-world retrospective analysis involving 27,479 patients in a health care claims 
database, suggests that the actual rate of VTE may be higher than that reported in clinical trials.24
This analysis assessed the rate of VTE at 3.5 months after the initiation of systemic cancer 
therapy and again at 12 months. In this study, the rate of reported VTE at 3.5 months after the 
initiation of systemic cancer therapy was 7.3% (range, 4.6% to 11.6%), and the cumulative risk 
continued to increase over time to a rate of 13.5% (range, 9.8% to 21.3%) at 12 months. The 
highest VTE risk was observed in those patients receiving systemic cancer therapy for tumors of 
the pancreas, stomach, and lung.9, 10, 21
Current guidelines from the American College of Chest Physicians (ACCP),19 the American 
Society of Clinical Oncology (ASCO),25 the European Society of Medical Oncology (ESMO), 
the National Comprehensive Cancer Network (NCCN)39 have subtle differences, but none 
recommend the routine use of VTE prophylaxis in most ambulatory patients with cancer due to 
limited randomized controlled trial (RCT) data and uncertainty on the benefit/risk in the 
ambulatory cancer population. An exception is made for patients with multiple myeloma who 
require treatment with thalidomide or lenalidomide in combination with systemic cancer therapy
or high-dose dexamethasone; among these patients, rates of VTE of 23% to 75% have been 
reported.14
The low overall risk of studied populations in RCTs (ie, in unselected subjects with low 
VTE risk requiring high numbers needed to treat), high cost for injectables in the United States, 
and logistical issues related to daily patient self-injections have been considered in the current 
guideline recommendations.
Two prospective studies, Gemcitabine with or without Prophylactic Weight-adjusted Dalteparin 
in Patients with Advanced or Metastatic Pancreatic Cancer: A Multicentre, Randomized 
Phase 3b trial (FRAGEM) and A Prospective, Randomized Trial of Simultaneous Pancreatic 
Cancer Treatment with Enoxaparin and Chemotherapy (PROSPECT-CONKO-004) trial, 
evaluated the clinical benefit of the administration of LMWH plus gemcitabine-based systemic 
cancer therapy in advanced pancreatic cancer (APC) subjects.27,34 The FRAGEM trial was a 
Phase 2b RCT of 123 patients. Venous thromboembolism was reduced from 28% to 12%, with a 
relative risk of 0.42 (95% CI: 0.19 to 0.94; p =.039). No differences in rates of major bleeding or 
mortality between study arms were observed. In the PROSPECT-CONKO-004 study, enoxaparin 
decreased the rate of symptomatic VTE after 3 months (control 9.87%; enoxaparin 1.25%) and 
12 months (control 15%; enoxaparin, 5%). 
The largest studies of prophylaxis of VTE, the Prophylaxis of Thromboembolism during 
Chemotherapy Trial (PROTECHT)1 and the Evaluation of AVE5026 in the Prevention of 
Venous 
Thromboembolism 
in 
Cancer 
Patients 
Undergoing 
Chemotherapy 
(SAVE-ONCO study),2 showed decreased rates of events among subjects who were receiving 
systemic cancer therapy. In these clinical trials, the overall rates of VTE among subjects who 
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were receiving placebo were low, ranging from 3% to 4%. The rates of minor bleeding in the 
PROTECHT and SAVE-ONCO studies were similar among the subjects receiving prophylactic 
anticoagulant therapy and those receiving placebo. The PROTECHT study was not powered to 
detect differences in major bleeding. In the SAVE-ONCO study, no increase in major bleeding 
was observed in subjects receiving prophylactic treatment as compared with placebo.
Although RCTs of LMWH or ultra-low molecular weight heparin (ULMWH) prophylaxis have 
shown that anticoagulation therapy in ambulatory subjects with cancer is associated with a 
significant reduction in the relative risk of VTE, the difference in absolute risk was small, 
necessitating a large number of subjects to receive prophylaxis to save one event (eg, number 
needed to treat = 45 in SAVE-ONCO). Suggested reasons for the low VTE rates in these studies, 
as compared with those in real-world observational studies, include possible selection of 
lower-risk subjects combined with relatively short follow-up treatment periods. In addition the 
VTE risk associated with cancer varies throughout the course of the disease. This risk is 
particularly high after the start of the anticancer treatment, during the first months after cancer 
diagnosis, and at the end-stage of disease and may not be fully assessed during a 3-month period 
of observation.
Early detection of asymptomatic PE through computed tomography (CT) imaging procedures 
while restaging after systemic cancer therapy, and treatment of those events with full-dose 
anticoagulation have become routine. Two studies comparing rates of recurrent VTE, bleeding, 
and death between cancer subjects who received anticoagulation for incidentally detected PE and 
those who received anticoagulation therapy for symptomatic PE showed no significant difference 
in outcome between the 2 groups. Both studies confirm that subjects with incidentally detected 
PE benefit from anticoagulation as much as subjects with symptomatic PE.12,24
In summary, VTE results in increased morbidity, mortality, and complexity of care in subjects 
with cancer, and may also lead to delays in surgery and the administration of systemic cancer 
therapy as well as an increased risk of bleeding associated with therapeutic anticoagulation.
Routine thromboprophylaxis is currently not recommended by treatment guidelines, given the 
lack of substantial proven benefit in this population.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objectives
The primary efficacy objective is to demonstrate that rivaroxaban is superior to placebo for 
reducing the risk of the primary composite outcome as defined by objectively confirmed 
symptomatic lower extremity proximal DVT, asymptomatic lower extremity proximal DVT, 
symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-
fatal PE, incidental PE, and VTE-related death in ambulatory adult subjects with various cancer 
types receiving systemic cancer therapy who are at high risk of developing a VTE.
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Secondary Objectives
The key secondary efficacy objectives of this study are to compare the efficacy of rivaroxaban 
with placebo for reducing the risk of symptomatic VTE events and VTE-related deaths, and 
all-cause mortality in ambulatory adult subjects with various cancer types receiving systemic 
cancer therapy who are at high risk of developing a VTE. Other secondary efficacy objectives 
include the evaluation of the individual components of the primary efficacy composite variable, 
confirmed fatal/non-fatal arterial thromboembolism (ATE) events, confirmed fatal/non-fatal 
visceral VTE events, a composite of symptomatic lower extremity proximal DVT, asymptomatic 
lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper 
extremity DVT, symptomatic non-fatal PE, incidental PE, and all-cause mortality, and a 
composite of symptomatic lower extremity proximal DVT, symptomatic lower extremity distal 
DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, and VTE-related deaths.
Safety Objectives
The primary safety objective of this study is to assess the major bleeding events (as defined by 
the International Society on Thrombosis and Hemostasis [ISTH]).37 In addition, clinically 
relevant non-major bleeding, minor bleeding, and any bleeding (defined as major, clinically 
relevant non-major, and minor bleeding) will be assessed as measured by the ISTH definition.  
Exploratory Objectives
The exploratory objectives of this study are: 

To assess inflammation- and hypercoagulability-related biomarkers including D-dimer, 
P-selectin, and Tissue Factor

To analyze the steady state pharmacokinetics (PK) and exposure response of rivaroxaban 

To collect health care resource utilization (HCRU) data that may be used in future economic 
modeling (the construction and reporting of the economic model will be conducted 
separately from this study)
2.2.
Hypothesis
The primary hypothesis of this study is that prophylactic treatment with rivaroxaban 
administered at a dose of 10 mg once daily for up to 6 months will be superior to placebo in 
reducing the risk of objectively confirmed symptomatic lower extremity proximal DVT, 
asymptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, 
symptomatic upper extremity DVT, symptomatic non-fatal PE, incidental PE, and VTE-related 
death in ambulatory adult subjects with various cancer types receiving systemic cancer therapy 
who are at high risk of developing a VTE.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, superiority 
study comparing the efficacy and safety of rivaroxaban with placebo for primary prophylaxis of 
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VTE (defined as DVT and/or PE) in ambulatory adult men and women, 18 years of age and 
older, with various cancer types who are scheduled to initiate systemic cancer therapy as a 
component of their standard-of-care anticancer regimen, who have a baseline Khorana 
thromboembolic risk score of ≥2, and are judged by the investigator or qualified designee to be 
an 
appropriate 
candidate 
for 
treatment 
with 
either 
placebo 
or 
rivaroxaban 
for
thromboprophylaxis based on their clinical status. The duration of the intended continued 
systemic cancer therapy will vary from subject to subject, and it is also understood that treatment 
modalities and drug combinations may change during the double-blind treatment period thereby 
reflecting current standards of clinical care.
Initially, a target of approximately 700 subjects were to be randomly assigned into the study in a 
1:1 ratio to 1 of 2 treatment groups with approximately 350 subjects per treatment group, with an 
assumed rate of discontinuation of approximately 20% from the study as described in Section 6,
Dosage and Administration. Towards the end of the enrollment phase, approximately 800 
subjects were planned to be randomized into the study due to the high subject discontinuation 
rate. In addition, subjects will be stratified at randomization by tumor type (APC or non-APC); it 
is estimated that approximately 25% of the subjects randomly assigned are those with APC.
The study consists of 3 periods: a 2-week screening period, a 180-day double-blind treatment 
period with an end-of-treatment (EOT) visit, and a 30-day post-treatment follow-up period with a
Day 210/end-of-study (EOS) visit. The duration of participation in the study for each subject is 
approximately 32 weeks. 
At the screening visit (Day -14 to -1), designated study personnel will explain the nature of the 
study, including all relevant details, and obtain written informed consent from the subject before 
initiation of any study-related procedures. Once all required screening procedures are completed,
qualifying laboratory results are received, and bilateral lower extremity venous duplex 
compression ultrasonography (CU) results are received from the local reader, subjects will be 
asked to return to the study site as soon as possible, but no more than 14 days after the screening 
visit, for the randomization (Day 1) visit. Subjects found to have baseline DVT on screening CU
or incidental DVT or PE as identified from routine care imaging (eg, spiral CT scans ordered 
primarily for staging or restaging of malignancy) within 30 days prior to randomization will not 
be eligible for randomization. Subjects may be rescreened once, if not randomized after the 
initial screening. All screening procedures must be repeated if rescreening is performed after the 
initial 2-week screening period.
During the double-blind treatment phase, from the time of randomization to the last dose of study 
drug at the Day 180 visit, imaging of suspected cases of DVT and non-fatal PE will be 
adjudicated. In addition, incidental PE or DVT identified from routine care imaging 
(eg, CT scans ordered primarily for staging or restaging of malignancy) during the same time 
period will be adjudicated as asymptomatic PE or DVT events as well.
Eligible subjects will be randomly assigned by an Interactive Web Response System (IWRS), in 
a 1:1 ratio to receive 1 of 2 treatments during the double-blind treatment period: 
rivaroxaban 10 mg orally once daily or placebo 10 mg orally once daily for a maximum of 
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180 days (±3 days). Subjects will be stratified at randomization by tumor type 
(APC or non-APC) and will be instructed to take the study drug for a fixed duration of 180 days
(±3 days). Subjects will have up to 4 days to complete the Day 1 visit from the point of being 
randomly assigned to the study drug within IWRS (date of randomization) to initiate their study 
drug treatment in order to accommodate those subjects who will be receiving their study drug 
from a centralized drug depot; however, every effort should be made to initiate study drug within 
1 day. Every effort should be made to initiate systemic cancer therapy on the same day as 
administration of the first dose of study drug, or within 72 hours of the first dose of study drug 
when at all possible. However, for pragmatic reasons, subjects may be allowed to initiate 
systemic cancer therapy within a period of ±1 week prior to, or after their first dose of study 
drug, with a preference of this occurring within the first week following study drug 
administration.
Subjects will have study visits, inclusive of visit windows, performed at Week 8 (±7 days), 
Week 16 (±7 days), and Day 180/EOT (±3 days) during the double-blind treatment period, and 
will undergo mandatory CU at these visits. The CU planned for the Day 180/EOT visit must 
occur within the specified ±3-day window and before the last dose of study drug. Following a 
30-day post-treatment follow-up period (Day 210 ±7 days from randomization), all subjects
(or their legally acceptable representative), including those who discontinued the study drug
prior to the Day 180 visit, will be contacted by telephone for a Day 210/EOS visit follow-up 
assessment and will have their vital status (eg, dead, alive, or lost-to-follow up) as well as 
clinical status review for suspected outcome and safety bleeding events completed. Adverse 
events (AEs) will be collected as specified in Section 12, Adverse Event Reporting and 
concomitant medications will be collected as specified in Section 8, Prestudy and Concomitant 
Therapy. 
All study visits may be coordinated with subject’s planned visits that are part of their 
standard-of-care, as long as the planned visits are within the protocol-specified visit windows. 
Either the investigator or a qualified subinvestigator will be required to see each subject at every 
study visit for clinical assessment of the subject’s status.
An independent blinded Clinical Endpoint Committee (CEC) will apply the protocol definitions 
to adjudicate and classify efficacy and safety endpoint events. Throughout the double-blind 
treatment and 30-day post-treatment follow-up phases, suspected cases of DVT and PE will be 
centrally adjudicated by the CEC. In addition, incidental PE or DVT identified from routine care
imaging (eg, CT scans ordered primarily for staging or restaging of malignancy) during the same 
time period will be adjudicated as asymptomatic PE or DVT events. Lastly, any clinical event 
that suggests the possibility that a major or clinically relevant non-major bleeding event occurred 
will be sent for adjudication. Emergent imaging results at the study site for clinical 
decision-making will be collected for the central adjudication by the CEC. In subjects who died 
during follow up, death certificates and if available, autopsy findings will be reviewed to 
establish a diagnosis of fatal PE.
If a subject permanently discontinues the study drug before the end of the double-blind treatment 
period (Day 180 visit), he/she should be instructed to complete an unscheduled EOT visit as soon 
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as possible from the time that the study drug was discontinued, with the CU performed within 
2 days of taking the last dose of study drug. A CU should not be performed at all if it is not 
possible to have it completed within 2 days of the last dose of study drug. In addition, the subject
will be required to complete all remaining study visits and procedures, including what would 
have been their Day 180/EOT and Day 210/EOS visits (see TIME AND EVENTS SCHEDULE). 
If the unscheduled EOT visit falls within the window of a remaining study visit, the subject does 
not need to repeat this required study visit.  
The investigator should inform subjects of the importance of returning for all study visits 
(regardless of duration of study drug treatment) as it is imperative for the integrity of the study
and results to have vital status and other outcomes ascertained. If the subject is unwilling or 
unable to return for any visits, or is lost-to-follow up, the investigator should collect as much 
follow-up information as possible for each remaining visit, including contacting the subject or 
legally acceptable representative by telephone or by mail to determine vital status and outcome 
ascertainment, as agreed to by the subject during the informed consent process. The site must 
document all attempts to try to contact the subject in the source documents. 
An Executive Committee (EC) will be formed that has overall responsibility for the conduct and 
reporting of the study. The independent blinded CEC will apply the protocol definitions and 
adjudicate and classify any clinical event that suggests an efficacy or safety outcome event has 
occurred. The independent blinded CEC
will also adjudicate
all protocol-specified 
CU examinations. In addition, an unblinded Independent Data Monitoring Committee (IDMC) 
will periodically assess the safety of subjects in this study and evaluate the efficacy data as 
necessary to ensure that the safety of subjects is not compromised. All committees will be 
governed by independent charters.
The frequency and timing of efficacy, safety, and other measurements are provided in the Time
and Events Schedule.
A diagram of the study design is provided below in Figure 1.
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Figure 1:
Schematic Overview of the Study
3.2.
Study Design Rationale
Choice of Study Population
For the current study, ambulatory men and women, 18 years of age and older with various cancer 
types with an expected survival of >6 months, who are scheduled to initiate systemic cancer 
therapy as a component of their standard-of-care anticancer regimen, have a baseline Khorana 
thromboembolic risk score of ≥2, and in the judgment of the investigator or qualified designee 
are appropriate candidates for being randomized to either placebo or rivaroxaban for 
thromboprophylaxis based on clinical status will be enrolled.
The 2013 ASCO VTE Guidelines Panel recommends against the use of single risk factors or 
biomarkers to identify patients at high risk for VTE.24 The Panel recommends the use of a risk 
score that incorporates multiple variables to identify high-risk patients. A risk assessment score 
for VTE, known as the Khorana thromboembolic risk score, was validated in cancer patients 
treated with chemotherapy and was recently updated to include renal tumors in the high-risk 
category. According to this risk model, 2 points were assigned for a thromboembolic 
“very high-risk” site of cancer (stomach, pancreas, or brain*) and 1 point for a “high-risk” site of 
cancer (lung, lymphoma, gynecologic, bladder, renal, or testicular).22 In addition, 1 point each 
was added for a platelet count of 350 x 109/L or more, hemoglobin less than 10 g/dL and/or use 
of erythropoiesis-stimulating agents, leukocyte count more than 11 x 109/L, and body mass index 
(BMI) of 35 kg/m2 or more. A Khorana thromboembolic risk score of ≥2 is required for 
inclusion into this study. (*Note: subjects with brain tumors are excluded from participation in 
this study). 
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Randomization and Blinding
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. Blinded treatment will be used to reduce 
potential bias during data collection and evaluation of clinical endpoints.
Rationale for Treatment and Dose Selection
Rivaroxaban
Current ASCO, ESMO, and NCCN guidelines do not recommend the routine use of 
VTE prophylaxis in most ambulatory patients with cancer due to the paucity of randomized 
clinical study data,25,28,39 and no agent is currently approved for this indication. Therefore, there 
is clinical equipoise and the proposed study is designed as a randomized, placebo-controlled 
study.  
There is substantial supportive evidence that treatment with rivaroxaban 10 mg daily will be 
effective in the prevention of VTE in cancer patients. The selection of the rivaroxaban dose is 
based primarily on the results of the studies (involving 3,283 subjects) conducted for the 
prophylaxis of VTE in subjects undergoing knee or hip replacement surgery, where 10 mg daily 
of rivaroxaban resulted in a 2.6% to 9.2% reduction in VTE with an acceptable risk profile.13,18,23
Data from the subgroup of subjects with cancer in the MAGELLAN and EINSTEIN studies 
provides some experience with rivaroxaban 10 to20 mg in subjects with cancer, but these studies 
were not specifically designed to evaluate thromboprophylaxis with rivaroxaban in a high-risk 
cohort of subjects with cancer undergoing chemotherapy. The current population with cancer is 
expected to have a lower mean age and fewer comorbidities compared with the hospitalized 
medically ill subjects enrolled in the MAGELLAN study. Clinically relevant bleeding in the 
subjects
with cancer in the pooled analysis of the EINSTEIN studies treated with 
rivaroxaban 15 to 20 mg were similar to the rates in the enoxaparin/VKA antagonist groups and 
there were significantly fewer major bleeding events in the rivaroxaban treatment group with 
cancer. Numerically fewer major bleeding events were also observed when the rivaroxaban 
group was further sub-divided by age, body weight, and creatinine clearance (CrCl).32
Rationale for Duration of Therapy 
The duration of the earlier primary prophylaxis studies was generally between 3 to 4 months, in 
conjunction with initiation of systemic anticancer therapy. However a more recent real-world 
retrospective analysis involving 27,479 patients in a health care claims database, suggests that 
the actual risk of VTEs continues to increase over time from 7.3% (range, 4.6% to 11.6%) at 
3.5 months, to a cumulative risk of 13.5% (range, 9.8% to 21.3%) at 12 months.24 Therefore, 
given the compounding nature of VTE risk in cancer patients on chemotherapy, a 3-month 
period of observation may prove insufficient to properly evaluate the benefit/risk of 
thromboprophylaxis. The proposed study will broaden the window of observation to 6 months 
following initiation of a new regimen of systemic cancer therapy, allowing for better 
categorization of the benefit/risk of thromboprophylaxis in this population.
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The projected duration of 180 days of subject exposure to study drug was selected to ensure 
sufficient primary VTE prevention coverage for cancer subjects who typically undergo several 
cycles of systemic cancer therapy. Thus, the duration of the double-blind treatment period for 
this study was selected to be long enough to more rigorously evaluate the extent to which 
rivaroxaban can safely prevent VTE events in this selected study population. This approach will 
ensure that an adequate number of events will be accrued in order to perform a robust, 
well-powered primary analysis and draw definitive conclusions relating to the primary 
hypothesis.
Rationale for Mandatory Bilateral Lower Extremity Venous Compression 
Ultrasonography
The frequency of VTE in cancer subjects is likely to be substantially underestimated as the rates 
of clinical diagnosis are low compared with rates observed at autopsy.5,16,30 Many factors limit 
the proper diagnosis of VTE in the ambulatory setting. There may be minimal or no symptoms or 
symptoms may be wrongly attributed to issues related to active cancer, eg, shortness of breath to 
lung metastases, or lower extremity edema to pelvic adenopathy. Many cases of PE present 
without symptoms of DVT, and many clinicians’ index of suspicion for VTE is low in 
ambulatory subjects.  
An important feature of this study is the use of screening to detect asymptomatic VTE. Although 
symptomatic disease is most important, many cases of DVT and PE are asymptomatic. 
Asymptomatic DVT identified by screening represents a subclinical manifestation of disease, 
and recommendations for prophylaxis are largely based on studies that used such routine 
screening approaches. Both European regulatory agencies and the United States Food and Drug 
Administration accept this approach in evaluating registration studies. Staging and restaging 
scans conducted in subjects with cancer may identify asymptomatic or incidental PE as well, and 
recent data suggest that such incidentally discovered PE is clinically relevant.
Compression ultrasonography is regarded as the standard method for the diagnosis of 
symptomatic, proximal vein thrombosis because of its low level of invasiveness and high 
sensitivity.26,33 For example, using this approach in non-ambulatory cancer patients without 
DVT symptoms, the rate of asymptomatic DVT was 34% (comprised of asymptomatic proximal 
DVT in 11% and asymptomatic distal DVT in 23% of patients).7 Although rates of isolated distal 
lower extremity DVT are typically much higher than proximal DVT events detected using CU, 
isolated distal DVT events will not be included in the primary efficacy outcome mainly due to 
controversy about its overall clinical significance.42 A prospective cohort study in subjects after 
total hip or knee arthroplasty showed that CU has a positive predictive value of 71% compared 
with 25% for clinical examination, as well as an 83% and 11% sensitivity, respectively.36 The 
Joint American Academy of Family Physicians/American College of Physicians Panel on 
DVT/PE recommend use of CU for patients with at least an intermediate pretest probability of 
lower extremity DVT.42
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Choice of Efficacy Outcome/Endpoint 
The primary efficacy outcome variable is the composite of any symptomatic/asymptomatic DVT, 
symptomatic non-fatal PE, incidental PE, and VTE-related death.
In this study, the primary efficacy composite endpoint is the time from randomization to the first 
occurrence of objectively confirmed symptomatic lower extremity proximal DVT, asymptomatic 
lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper 
extremity DVT, symptomatic non-fatal PE, incidental PE, or VTE-related death occurring from 
randomization to the Day 180 visit as adjudicated by the independent blinded CEC.
Evolution in cancer patient clinical management has resulted in increased frequency of medical 
imaging as part of staging protocols. In fact, incidental thromboembolism is often detected 
during diagnostic imaging, and it has been shown to be clearly associated with higher cancer 
mortality. In a study that analyzed a total of 1,151 radiologic exams of 135 APC subjects, 
incidental events comprised 33.3% of PEs, 21.4% of DVTs and 100% of visceral VTE. In these 
subjects, DVT (HR 25, 95% CI: 10 - 63, p <0.0001), PE (HR 8.9, 95% CI: 2.5 - 31.7, p = 0.007),
and incidental visceral events (HR 2.6, 95% CI: 1.6 - 4.2, p = 0.0001) were all independently 
associated with mortality. There was no significant difference between asymptomatic and 
symptomatic events in terms of conditional survival at 3 or 6 months post diagnosis.
Choice of Safety Measures
The primary safety endpoint of this study is the time to a major bleeding event in treated subjects 
in each randomized treatment group as defined by ISTH.37 Bleeding events will be classified 
using protocol-specified definitions for major, clinically relevant non-major, or minor bleeding. 
Secondary safety endpoints include the proportion of clinically relevant non-major bleeding, 
minor bleeding, and any bleeding (defined as major, clinically relevant non-major, and minor 
bleeding as defined by ISTH; for details on definitions, see Section 9.3, Safety Evaluations).
Subjects will be censored for safety endpoints events up to 2 days after receiving the last dose of 
study drug.
As rivaroxaban has been or is being tested against an active comparator or placebo in studies that 
include over 89,000 subject-participants in the Phase 2/3/4 clinical studies of the rivaroxaban 
clinical development program, the AE profile of rivaroxaban has been well described and 
experience relative to the safe conduct of clinical studies is extensive. For example, over 
12,000 subjects participated in the published Phase 3 RECORD studies of primary VTE 
prevention in subjects undergoing elective total hip/knee replacement alone. Additional 
characterization of the AE profile of rivaroxaban was reported using data from the 
EINSTEIN-DVT, EINSTEIN-PE, EINSTEIN-Extension, ROCKET-AF, ATLAS 2, and 
MAGELLAN Phase 3 clinical studies.
Subjects will have safety assessments conducted at each study visit, including the monitoring of 
bleeding events, AEs, clinical laboratory tests, pregnancy tests, Eastern Cooperative Oncology 
Group (ECOG) status, central venous catheter (CVC) status, concomitant therapies, and vital 
signs, including weight measurements. Hematology panel includes hemoglobin, hematocrit, red 
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blood cell count (RBC), white blood cell (WBC) count with differential, and platelet count. 
Screening serum chemistry panel includes sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen (BUN), glucose, uric acid, calcium, phosphate, albumin, total protein, creatinine, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and direct bilirubin, and 
alkaline phosphatase. 
Biomarker Collection
Biomarker samples will be collected to evaluate objectively measured indicators of pathologic 
and biologic processes associated with inflammation and hypercoagulability in blood, at 
baseline, Week 8, Week 16, and Day 180/EOT.
Medical Resource Utilization
Health care resource utilization (HCRU) data will be collected as part of the endpoint
assessments at Weeks 8 and 16, and Day 180/EOT for all subjects and compared between the 
treatment groups, or until study drug discontinuation.  
4.
SUBJECT POPULATION
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed.
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. Each 
subject must:
1.
Criterion modified per Amendment-3
1.1
Ambulatory men and women, ≥18 years of age;
2.
Have histologically confirmed solid malignancy including but not limited to: 
pancreas, lung, stomach, colon, rectum, bladder, breast, ovary, renal, or 
lymphoma (hematologic), with locally advanced or metastatic disease;
3.
Have an ECOG Performance Status of 0-2 (see Attachment 4, Functional Status 
Assessment Tool);
4.
Have a Khorana thromboembolic risk
Score ≥2
(see Attachment 3, 
Cancer-Associated Venous Thromboembolism Risk Score);
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5.
Criterion modified per Amendment-3
5.1.
Have adequate renal function: CrCl ≥30 mL/min, (calculated using the 
Cockcroft-Gault formula [Attachment 2], the Modification of Diet in 
Renal Disease formula [Attachment 5], or the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation for estimating GFR 
[Attachment 6]).
6.
Criterion modified per Amendment-3
6.1.
Plan to initiate systemic cancer therapy within ±1 week of receiving the 
first dose of study drug with the intention of receiving systemic cancer 
therapy during the double-blind treatment period for an intended duration 
determined by the treating oncologist according to standard protocols of 
clinical care.
Note: Subjects must either be 1) initiating their first systemic cancer 
therapy regimen based on initial diagnosis, 2) initiating their first cycle of 
a new systemic cancer therapy regimen for a recurrence, or 3) starting the 
first cycle of a new regimen of systemic cancer therapy based on 
tolerability or disease progression.
Note: Every effort should be made to initiate systemic cancer therapy on 
the same day as the first dose of study drug or within 72 hours of the first 
dose of study drug when at all possible. However, subjects can continue 
in the study if there is a delay in initiation of systemic cancer therapy 
beyond +7 days after receiving the first dose of study drug.
7.
Be medically stable on the basis of physical examination, medical history, and 
vital signs performed at screening (or within 14 days before randomization on 
Day 1). If there are abnormalities, they must be consistent with the underlying 
illness in the study population.
8.
Criterion modified per Amendment-3
8.1
Contraceptive use by men or women should be consistent with local 
regulations regarding the use of contraceptive methods for subject 
participating in clinical studies.
If a woman, before entry she must be:
postmenopausal (for at least 12 months), or surgically sterile (have had a 
total hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise 
be incapable of pregnancy), or practicing a highly effective method of 
birth control, if sexually active, including hormonal prescription oral 
contraceptives, contraceptive injections, contraceptive patch, intrauterine 
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device, double-barrier method for less effective methods of contraception 
(eg, condoms, diaphragm, cervical cap, or sponge with spermicidal foam, 
cream, or gel), or male partner sterilization, consistent with local 
regulations regarding use of birth control methods for subjects 
participating in clinical trials, for the duration of their participation in the 
study, or not heterosexually active
Note: subjects who are not heterosexually active at screening must agree 
to utilize a highly effective method of birth control if they become 
heterosexually active during their participation in the study.
9.
If a woman of childbearing potential, must have a negative urine -human 
chorionic gonadotropin (-hCG) pregnancy test at screening.
10.
Criterion modified per Amendment-3
10.1
If a man, must agree to use an adequate contraception method as deemed 
appropriate by the investigator (eg, vasectomy, condoms, partner using 
effective contraception).
11.
Be willing and able to adhere to the prohibitions and restrictions specified in this 
protocol.
12.
Be able to provide informed consent and sign an informed consent document 
indicating that he or she understands the purpose of and procedures required for 
the study and is willing to participate in the study.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. The subject will be excluded if he or she has a/an:
1.
Diagnosis of primary brain tumors
2.
Known history of brain metastases
3.
Bleeding diathesis, hemorrhagic lesions, active bleeding, and other conditions 
with a high risk for bleeding
4.
Hematologic malignancies with the exception of lymphoma
5.
Life expectancy of ≤6 months
6.
Significant comorbidities, that in the opinion of the treating physician would 
unnecessarily complicate participation in this clinical study, or provide excessive 
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clinical risk to the subject to participate in this clinical study  
7.
Diagnostically confirmed significant liver disease or dysfunction. Examples of 
significant liver disease include acute clinical hepatitis, chronic active hepatitis, 
or cirrhosis; examples of significant liver dysfunction as defined by liver 
function test (LFT) abnormalities (confirmed by repeat-testing) include:
ALT >5x upper limit of normal (ULN)
ALT >3x ULN plus total bilirubin >2x ULN and a ratio of direct to total 
bilirubin ≥50%.
8.
Evidence of VTE on screening CU or incidental VTE identified on spiral 
CT scans ordered primarily for staging or restaging of malignancy ≤30 days 
prior to randomization 
9.
Platelet count <50,000/mm3
10.
Activated partial thromboplastin time (aPTT) >1.5 ULN or international 
normalized ratio (INR) >1.5
11.
Known allergies, hypersensitivity, or intolerance to rivaroxaban or its excipients 
(refer to IB)
12.
Concomitant use of anticoagulation therapy for prior VTE or other indications 
with either LMWH, warfarin, or direct oral anticoagulants
13.
Criterion modified per Amendment-3
13.1.
P2Y12 receptor antagonist antiplatelet therapy (such as clopidogrel, 
prasugrel, and ticagrelor), daily nonsteroidal anti-inflammatory drugs, or 
other medications known to increase the risk of bleeding (a daily dose of 
≤100 mg of aspirin is permitted)
14.
Any condition (ie, atrial fibrillation) for which, in the opinion of the investigator, 
participation would not be in the best interest of the subject (eg, compromise the 
well-being) or that could prevent, limit, or confound the protocol-specified 
assessments
15.
Combined P-glycoprotein (P-gp) and strong cytochrome P450 (CYP) 3A4 
inhibitors (such as but not limited to ketoconazole, telithromycin or protease 
inhibitors) use within 4 days before randomization, or planned use during the 
study. Itraconazole use within 7 days before randomization or planned use 
during the study.
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16.
Combined P-gp and strong CYP3A4 inducers (such as but not limited to 
rifampin/rifampicin, 
rifabutin, 
rifapentine, 
phenytoin, 
phenobarbital, 
carbamazepine, or St. John's Wort) use within 2 weeks before randomization, or 
planned use during the study.
17.
Inability to take oral medication
18.
Pregnant or breast-feeding or any plan to become pregnant during the study.
19.
Employees of the investigator or study center, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study 
center, as well as family members of the employees or the investigator.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening 
and prior to randomization on Day 1. If a subject's clinical status changes (including any 
available laboratory results or receipt of additional medical records) after screening but before 
the first dose of study drug is given such that he or she no longer meets all eligibility criteria, 
then the subject should be excluded from participation in the study. Section 17.4, Source 
Documentation, describes the required documentation to support meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
All women of childbearing potential must remain on a highly effective method of 
birth control (see inclusion criteria). 
2.
Criterion modified per Amendment-3.
2.1
If a man, must agree to use adequate contraception method as deemed 
appropriate by the investigator (eg, vasectomy, condoms, partner using 
effective contraception).
3.
Criterion modified per Amendment-3
3.1
Subjects must not use mechanical thromboprophylaxis,
such as
pneumatic compression devices, foot pumps, for VTE prevention unless 
in a hospital setting. Compression stockings are permitted regardless of 
the setting.
4.
A subject should not take any prohibited therapy. Refer to Section 8, Prestudy 
and Concomitant Therapy, for the full list of prohibited therapy. If a subject 
requires or takes prohibited medications during the study, they must either 
temporarily interrupt or permanently discontinue the study drug, as appropriate 
for the duration of the therapy with the prohibited medication.
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5.
Modification of an effective pre-existing therapy should not be made for the 
explicit purpose of entering a subject into the study (ie, concomitant medical 
conditions should continue to be treated appropriately).
6.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraception requirements).
5.
TREATMENT ALLOCATION AND BLINDING
Randomization Procedures
A centralized randomization strategy will be implemented in this study. Subjects will be 
randomly assigned in a 1:1 ratio to 1 of 2 treatment groups based on a computer-generated 
subject-randomization schedule prepared by or under the supervision of the sponsor prior to 
initiation of the study. The randomization will be stratified by tumor type (APC or non-APC) 
such that up to approximately 25% of the subjects randomly assigned are those with APC. Using 
the randomization schedule, the IWRS will assign treatment. The IWRS will also provide the 
number of the study drug bottle to be dispensed for each randomly assigned subject on Day 1 
and at each visit (except Day 180/EOT) during the double-blind treatment period. Subjects will 
have up to 4 days to complete Day 1 from the point of being randomly assigned study drug 
within IWRS (date of randomization) to initiate their study drug treatment in order to 
accommodate those subjects who will be receiving their study drug from a centralized drug 
depot; however, every effort should be made to initiate study drug within 1 day. The requestor 
must use his or her own user identification and personal identification number when contacting 
the IWRS, and will then be asked to provide relevant subject details to uniquely identify the 
subject. Based on these randomization codes, the study drug will be packaged and labeled in a 
manner that maintains the double-blinded nature of this study.  
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (ie, events that contribute to the 
primary and secondary outcome or treatment allocation) will be handled with special care to 
ensure that the integrity of the blind is maintained and the potential for bias is minimized. This 
can include making special provisions, such as segregating the data in question from view by the 
investigators, clinical team, or others as appropriate until the time of database lock and 
unblinding.
Unblinding
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the 
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subject. In such cases, the investigator may in an emergency determine the identity of the 
treatment by telephoning the IWRS. It is recommended that the investigator contact the sponsor 
or its designee if possible to discuss the particular situation, before breaking the blind.
Telephone contact with the sponsor or its designee will be available 24 hours per day, 7 days per 
week. In the event the blind is broken, the sponsor must be informed as soon as possible. The 
date and reason for the unblinding must be documented in the appropriate section of the 
electronic case report form (eCRF), and in the source document. The documentation received 
from the IWRS indicating the code break must be retained with the subject’s source documents 
in a secure manner (eg, sealed envelope) so as not to unblind the treatment assignment to the 
study site or sponsor personnel. The investigator is also advised not to reveal the study treatment 
assignment to the study site or sponsor personnel. 
If a subject has a suspected efficacy or bleeding outcome event during the study, the treating 
physician should exercise clinical judgment and follow guidelines to apply the standard-of-care. 
Unblinding of study drug should not be necessary. Anticoagulation regimens do not require 
adjustment regardless of treatment group assigned when the study drug is administered in the 
dose used in this study. If despite this guidance, the investigator believes it is in the best interest 
of the subject to unblind study drug, the investigator may determine the treatment assignment or 
allocation by contacting the IWRS as previously noted.
Subjects who have had their treatment assignment unblinded may continue on study drug and 
will be expected to return for scheduled evaluations unless the subject meets a study drug 
temporary interruption or permanent discontinuation criterion. Investigators should not disclose 
treatment assignment to the subject whenever possible, even in a special situation where the 
treatment assignment has been unblinded to the investigator. In general, randomization codes 
will be disclosed fully only if the study is completed and the clinical database is closed.
An unblinded IDMC will periodically assess the safety date of subjects in the study and evaluate 
the efficacy data, as necessary. The IDMC will not be involved with the study otherwise. 
IDMC responsibilities and procedures are outlined in the IDMC charter.
6.
DOSAGE AND ADMINISTRATION
Subjects will be randomly assigned in a 1:1 ratio to 1 of 2 treatment groups:

Rivaroxaban 10 mg orally once daily for 180 days.

Placebo 10 mg orally once daily for 180 days.
Every effort should be made to initiate systemic cancer therapy on the same day as 
administration of the first dose of study drug, or within 72 hours of the first dose of study drug,
when at all possible. However, for pragmatic reasons, subjects may be allowed to initiate 
systemic cancer therapy within a period of ±1 week prior to, or after their first dose of study 
drug, with a preference of this occurring within the first week following study drug 
administration, with the intention that systemic cancer therapy will continue during the 
double-blind treatment period for a duration determined by the treating oncologist according to 
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standard protocols of clinical care. Subjects that are screened and initiate systemic cancer therapy 
more than 1 week before the first dose of study drug should not be randomized and will be 
considered a screen failure. However, if a subject does not initiate systemic cancer therapy as 
planned within +1 week after the first dose of study drug, the subject is allowed to continue 
taking the study drug and remain in the study. The initial dose of study drug should be taken on 
Day 1 at a time that is most convenient for the subject. Subsequent doses of study drug should be 
taken every 24±2 hours, thereafter. The study drug can be taken with or without food and should 
be taken at the same time daily. For subjects who are unable to swallow whole tablets, tablets 
may be crushed and mixed with applesauce immediately prior to use and administered orally. In 
the event that a dose of study drug is missed, the missed dose should be taken as soon as 
possible. If a dose is missed, advise the subject to take the study drug as soon as possible on the 
same day and continue on the following day with their recommended daily dose regimen.
Throughout the study, study drug will be dispensed at appropriate intervals (see TIME AND 
EVENTS SCHEDULE) to ensure that subjects have adequate quantities of study drug between 
visits. In addition, study staff will instruct subjects on how to store the study drug for at-home 
use as indicated for this protocol. Study staff should also instruct subjects to bring the study drug 
with them to the hospital, if they need to be hospitalized for a reason that would not require 
temporary discontinuation of the study drug.
Refer to Section 9.3, Safety Evaluations, for additional information regarding interruption of 
study drug for bleeding events, Section 10.2.1, Temporary Discontinuation of Study Treatment, 
for circumstances requiring study drug to be temporarily discontinued, and Section 10.2.2, 
Permanent Discontinuation of Study Treatment, for circumstances requiring study drug to be 
discontinued.
7.
TREATMENT COMPLIANCE
The investigator or designated study personnel will maintain a log of all drug dispensed and 
returned. Drug supplies for each subject will be inventoried and accounted for throughout the 
study. Subjects will return empty study drug containers and unused study drug at each visit when 
a new supply of study drug is to be received. 
Subjects should report any unintentional interruptions or missed doses to the study-site personnel 
at each visit. It is understood that subjects may occasionally miss a dose of study drug. 
Additionally, subjects may have study drug temporarily discontinued for bleeding events as 
discussed in Section 9.3, Safety Evaluations, or in Section 10.2, Temporary Discontinuation of 
Study Treatment, for other circumstances. 
8.
PRESTUDY AND CONCOMITANT THERAPY
For prestudy and all concomitant therapies as described below, the identity, indication, dosage, 
and start and stop dates, when applicable, must be recorded in the eCRF.
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Prestudy Therapies
Prestudy therapies are those administered within the 2 weeks before the first dose of study drug 
(Day 1). All prestudy therapies must be recorded in the eCRF except supplements such as fish 
oil, herbal medicines, and vitamins. The intent is to enroll subjects and begin the first dose of 
study drug before administration of systemic cancer therapy or radiotherapy; however, for 
pragmatic reasons subjects can be allowed to initiate systemic cancer therapy within a period of 
±1 week prior to, or after their first dose of study drug, with a preference of this occurring within 
the first week following study drug administration.
Concomitant therapies are those administered after the first dose of study drug (Day 1). 
All concomitant therapies taken throughout the double-blind treatment period for the treatment 
of AEs/serious adverse events (SAEs), prohibited medications, additional medications listed 
below, and systemic cancer therapy and radiotherapy must be recorded in the eCRF except 
supplements such as fish oil, herbal medicines, and vitamins. In addition, concomitant therapies 
should also be recorded beyond the Day 180/EOT visit only in conjunction with SAEs that meet 
the criteria outlined in Section 12.4.2, Serious Adverse Events.
Subjects will receive standard-of-care systemic cancer therapy at the discretion of the 
investigator or qualified designee. 

Use of other agents that may increase the risk of VTE must also be recorded in the eCRF 
(eg, erythropoiesis-stimulating agents).

Nonsteroidal anti-inflammatory drugs (NSAIDs), excluding aspirin (a daily dose of ≤100 mg 
of aspirin is allowed), may be used on a temporary basis (ie, no more than 24 to 48 hours), 
but should be avoided for longer periods during treatment with the study drug, if possible. 

Medicines that reduce gastric acid (eg, H2 antagonists or proton pump inhibitors) may reduce 
the incidence of gastrointestinal bleeding in subjects who are treated with anticoagulants in 
combination with NSAIDs and/or aspirin, and their concomitant use may be considered 
unless contraindicated.

Changes to medications taken prestudy, and if ongoing at study entry, must be recorded in 
the eCRF.

All systemic cancer therapy must be recorded in the eCRF.

All radiotherapy must be recorded in the eCRF.
Prohibited Therapy
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
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The following therapies are prohibited during the study:

Fibrinolytic therapy

Combined P-gp and strong CYP3A4 inhibitors (such as but not limited to 
ketoconazole, telithromycin, or protease inhibitors) use within 4 days before 
randomization, or planned use during the study. Itraconazole use within 
7 days before randomization or planned use during the study.

Antiplatelet therapy

Aspirin >100 mg/day

P2Y12 receptor antagonists (eg, clopidogrel, prasugrel, ticagrelor)

Thrombin receptor antagonists (eg, vorapaxar)

Daily use of NSAIDs, or other medications known to increase the risk of bleeding

Anticoagulant (eg, warfarin sodium or other VKAs, Factor II or Xa inhibitors) is prohibited 
as concomitant therapy during the study. Study drug should be discontinued in subjects who 
develop any condition that requires anticoagulation or thromboprophylaxis. Modification of 
an effective pre-existing therapy should not be made for the explicit purpose of entering a 
subject into the study.
If a subject requires or takes prohibited medications during the study, he/she must either 
temporarily interrupt or permanently discontinue the study drug depending on the duration of the 
prohibited therapy (see Section 10, Subject Completion/Withdrawal), as appropriate for the 
duration of the therapy with the prohibited medication. Study drug may be restarted after the 
prohibited therapy has been discontinued and after completion of a suitable washout period at the 
investigator’s discretion. During the post-treatment period, prohibited therapies may be 
administered, if required in the judgment of the investigator. If administered, these therapies 
must be recorded in the eCRF.  
Thromboprophylaxis with mechanical devices (eg, pneumatic compression devices, foot pumps) 
is prohibited, unless in a hospital setting, because they could potentially interfere with the 
efficacy assessments.
Therapies to be Avoided
The following therapies should be avoided during the study:

Combined P-gp and strong CYP3A4 inducers (such as but not limited to 
rifampin/rifampicin, rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, or 
St. John’s Wort) use within 2 weeks before randomization, or planned use during the study.
Prophylaxis of VTE Following Completion of Study Drug
The subject will be reminded to follow their healthcare provider’s recommendations for their 
ongoing care plan for prophylaxis of VTE at the Day 180/EOT visit. 
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9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, safety, and 
other measurements applicable to this study.
Additional urine pregnancy tests may be performed for female subjects, as determined necessary 
by the investigator or required by local regulation, to establish the absence of pregnancy at any 
time during the subject’s participation in the study.
The estimated total volume of blood to be collected for protocol-specified laboratory evaluations 
in this study is approximately 56.0 mL for each subject. The following table summarizes the 
estimated volume of blood to be drawn during the study.
Type of Sample
Volume per 
Sample
(mL)
Samples per 
Subject
During Study
Maximum 
Total Volume 
of Blooda
(mL)
Clinical laboratory tests

Hematology
2.0
4
8.0

Serum chemistry
2.5
4
10.0

Coagulation
2.0
1
2.0
Biomarkers
8.5
4
34.0
Pharmacokinetic sample
2 mL
1
2
Total
n/a
n/a
56
a Calculated as the number of samples multiplied by the volume of blood per sample.
9.1.2.
Screening Phase
The Time and Events Schedule summarizes the safety and other measurements performed at the 
screening visit.
Subjects with various cancer types who are planned to receive systemic cancer therapy
throughout the double-blind treatment period, and are judged by the investigator or qualified 
designee to be an appropriate candidate for thromboprophylaxis treatment based on their clinical 
status and Khorana thromboembolic risk score ≥2, will be screened for inclusion in the study.
Designated study personnel will explain the nature of the study, including all relevant details, 
and obtain written informed consent from the subject before initiation of any study-related 
procedures. Following the signing of the informed consent form (ICF), screening procedures will 
be completed no more than 14 days before Day 1 of the double-blind treatment period.
Subjects will be screened and randomized using laboratory results (see Note below) and local 
reader results for CU from testing performed within 14 days before randomization (Day 1) for 
the inclusion and exclusion clinical laboratory parameters and imaging requirements. Subjects 
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found to have baseline DVT on screening CU or incidental DVT or PE as identified from routine 
care imaging (eg, spiral CT scans ordered primarily for staging or restaging of malignancy) 
within 30 days prior to randomization will not be eligible for randomization. Subjects may be 
rescreened once, if not randomized after the initial screening. All screening procedures must be 
repeated if rescreening is performed after the initial 2-week screening period.
Note: If historical laboratory results (done per standard-of-care) are already available during the 
screening period (must have been previously drawn within 2 weeks of randomization), they may 
be used to determine eligibility. This will enable subjects to be screened and randomized on the 
same day. These historical laboratory results will be documented in the subject’s source 
documents. In addition, subjects should still have all required safety laboratory tests drawn as per 
the Time and Events Schedule and sent to the central laboratory for analysis. In the event that the 
screening laboratory results from the central laboratory indicates the subject is not eligible then 
the historical laboratory results will take precedence and should be recorded in the eCRF to 
document eligibility.
Adverse events will be recorded from the time a signed and dated ICF is obtained until 
completion of the last study-related procedure. See Section 12, Adverse Event Reporting and 
Attachment 1, Reporting of Efficacy Endpoints, Adverse Events, and Serious Adverse Events.
9.1.3.
Double-Blind Treatment Phase
The Time and Events Schedule summarizes the efficacy, safety, and other measurements
performed at visits during the double-blind treatment period.
Day 1/Day of Randomization
If the subject meets all of the inclusion and none of the exclusion criteria, he or she is eligible to 
be randomly assigned to receive rivaroxaban or placebo. All screening activities must be 
completed before randomization and the results must be available to the investigator to review to 
ensure that no exclusion criteria are present. Subjects will be randomly assigned by an IWRS in a 
1:1 ratio on Day 1 to receive double-blind treatment with either rivaroxaban 10 mg orally once 
daily or placebo 10 mg once daily for 180 days. The IWRS also will provide the number of the 
study drug bottle to be dispensed to subjects based on their randomized treatment. See Section 5, 
Treatment Allocation, for additional information on IWRS. Subjects will have up to 4 days to 
complete Day 1 from the point of being randomly assigned study drug within IWRS 
(date of randomization) to initiate their study drug treatment in order to accommodate those 
subjects who will be receiving their study drug from a centralized drug depot; however, every 
effort should be made to initiate study drug within 1 day.
Once randomly assigned, subjects will have study drug dispensed and will receive instructions 
on study drug dosing, as detailed in Section 6, Dosage and Administration. 
At the randomization visit, before randomization occurs, site staff must review the visit schedule 
and the importance of completing the study with both the subject and any family members 
present. Randomization should not occur if the subject does not have transportation to study 
visits, or does not believe they will have sufficient support to comply with the protocol.
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In addition, the importance of reporting signs and symptoms associated with bleeding, DVT and 
PE will be stressed. Subjects and family members, as appropriate, will be counseled on the signs 
and symptoms associated with DVT, PE, and bleeding.
For bleeding events, subjects and family members as appropriate, will be instructed: 

To seek medical attention if they develop bleeding

To contact the investigative site staff or study investigator before the next dose of study 
medication is due

To inform treating health care providers about study participation
Subjects and family members, as appropriate will also be instructed: 

About the subject’s risk of DVT and PE

About the signs and symptoms of DVT and PE

To seek medical attention if they develop any of these signs or symptoms

To contact the investigative site staff or study investigator as soon as symptoms develop and 
before the next dose of study drug is due

To inform treating health care providers about study participation and their risk of DVT and 
PE.
The subject’s family should be instructed to have a low threshold to contact the site and if 
necessary, an unscheduled visit can be performed.
Double –Blind Treatment Period (Day 1 -Day 180)
Subjects will have study visits performed at Week 8 (±7 days), Week 16 (±7 days), and at 
Day 180/EOT (±3 days) during the double-blind treatment period as outlined in the Time and 
Events Schedule. All study visits should be coordinated with subject’s planned visits that are part 
of their standard-of-care, as long as the planned visits are within the protocol-specified visit 
windows. Either the PI (or a qualified subinvestigator) will be required to see each subject at 
every study visit for clinical assessment of the subject’s status.
At each visit, the investigator or qualified designee will assess each subject for the occurrence of 
clinical events relevant to efficacy and safety endpoints, and if identified, will ensure that all 
necessary source documentation is collected to be forwarded to the independent blinded CEC as 
described in Section 9.2.1, Efficacy Evaluations and Outcomes. In addition, subject counseling 
on the signs and symptoms associated with DVT, PE, and bleeding provided at the 
randomization visit will be repeated in detail.
Subjects will be instructed to return unused study drug at each visit. The IWRS must be 
contacted at each visit (except Day 180/EOT) to obtain the number of the study drug bottles to 
be dispensed to each subject. Study personnel will reinforce the dosing schedule and procedure 
to follow if a dose is missed. See Section 5, Treatment Allocation, for additional information on 
IWRS.
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Subjects will undergo mandatory CU at Week 8 (±7 days), Week 16 (±7 days) and 
Day 180 (±3 days). The Day 180/ EOT visit will be performed at the completion of 180 ±3 days 
of treatment with study drug (regardless of whether a subject is ongoing in a cycle of systemic 
cancer therapy). The CU planned for the Day 180/EOT visit will be conducted preferably on the 
day of the visit or within the visit window (Day 180 ±3 days) but must be performed before the 
last dose of study drug.
If a subject permanently discontinues the study drug before the end of the double-blind treatment 
period (Day 180 visit), he/she should be instructed to complete an unscheduled EOT visit as soon 
as possible from the time that the study drug was discontinued, and have the CU performed 
within 2 days of taking the last dose of study drug. At the unscheduled EOT visit, all procedures 
as outlined in the Time and Events Schedule will be performed. In addition, subjects that 
permanently discontinue study drug before the Day 180 visit will be required to complete all 
remaining study visits, including what would have been their Day 180/ EOT and Day 210/
EOS visits. If the unscheduled EOT visit falls within the window of a remaining study visit, the 
subject does not need to repeat this next scheduled study visit.
The investigator should inform subjects of the importance of returning for all study visits 
(regardless of duration of study drug treatment) as it is imperative for the integrity of the study
and results to have vital status and other outcomes ascertainment. If the subject is unwilling or 
unable to return for any visits, or is lost to follow up, the investigator should collect as much 
follow-up information as possible for each remaining visit, including contacting the subject or 
legally acceptable representative by telephone or by mail to determine vital status and outcome 
ascertainment, as agreed to by the subject during the informed consent process. The site must 
document all attempts to try to contact the subject in the source documents. If applicable, vital 
status and other outcomes should be obtained by reviewing the subject’s medical or public 
records unless this contact is not allowed by local regulations.
If the subject withdraws consent from the study, this must be documented in the source 
document and the subject will be asked to supplement the withdrawal of consent with a signed 
written statement documenting refusal for all subsequent contact.  
During the double-blind treatment period, study drug dosing may be interrupted as necessary for 
invasive procedures or as medically needed. Recommendations for temporary discontinuation of 
study drug for bleeding can be found in Section 9.3.1.1, Management of Study Drug for 
Bleeding Events. 
Additional guidance on reporting of efficacy endpoints, AEs, and SAEs is presented in 
Section 9.2.1, Efficacy Evaluations and Outcomes, Section 12.4.1, All Adverse Events, 
Section 12.4.2, Serious Adverse Events, and Attachment 1, Reporting of Efficacy Endpoints, 
Adverse Events, and Serious Adverse Events.
9.1.4.
Post-treatment Phase (Follow Up) (Day 181 – Day 210)
The Time and Events Schedule summarizes the efficacy, safety, and other measurements 
performed during the post-treatment period.
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At the end of the post-treatment follow-up period (Day 210 visit), all subjects (or their legally 
acceptable representative), including those who discontinued the study drug prior to the 
Day 180 visit, will be contacted by telephone for a Day 210/EOS follow-up assessment and will 
have their vital status (eg, dead, alive, or lost-to-follow up) as well as any additional information 
available such as AEs, concomitant medications, bleeding events, and clinical events relevant to 
endpoints collected. All subjects will have Day 210/EOS procedures performed at this visit. 
If the subject is lost-to-follow up, the investigator should collect as much follow-up information 
as possible for each remaining visit, including contacting the subject or legally acceptable 
representative by telephone or by mail to determine vital status and outcome ascertainment, as 
agreed to by the subject during the informed consent process. The site must document all 
attempts to try to contact the subject in the source documents. If applicable, vital status and other 
outcomes should be obtained by reviewing the subject’s medical or public records unless this 
contact is not allowed by local regulations.
If the subject withdraws consent from the study, this must be documented in the source 
document and the subject will be asked to supplement the withdrawal of consent with a signed 
written statement documenting refusal for all subsequent contact
Additional guidance on reporting of efficacy endpoints, AEs, and SAEs is presented in 
Section 9.2.1, Efficacy Evaluations and Outcomes, Section 12.4.1, All Adverse Events, 
Section 12.4.2, Serious Adverse Events, and Attachment 1, Reporting of Efficacy Endpoints, 
Adverse Events, and Serious Adverse Events.
9.2.
Efficacy Evaluations and Outcomes
9.2.1.
Efficacy Evaluations and Outcomes
The following efficacy outcomes will be evaluated at the time points listed in the Time and 
Events Schedule:
o
symptomatic lower extremity proximal DVT
o
symptomatic upper extremity DVT
o
asymptomatic lower extremity proximal DVT
o
symptomatic lower extremity distal DVT
o
confirmed fatal/non-fatal ATE events
o
confirmed fatal/non-fatal visceral VTE events
o
symptomatic non-fatal PE
o
incidentally detected PE through restaging imaging
o
VTE-related death
o
all-cause mortality
The primary efficacy outcome variable is objectively confirmed symptomatic lower extremity 
proximal DVT, asymptomatic lower extremity proximal DVT, symptomatic lower extremity 
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distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, incidental PE, and 
VTE-related death. 
The key secondary efficacy outcomes are: 

symptomatic VTE events (DVT/PE) and VTE-related deaths

all-cause mortality.
Other secondary outcomes are:

individual components of the primary efficacy composite variable 

confirmed fatal/non-fatal ATE events

confirmed fatal/non-fatal visceral VTE events

composite of symptomatic lower extremity proximal DVT, asymptomatic lower extremity 
proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity 
DVT, symptomatic non-fatal PE, incidental PE, and all-cause mortality

composite of symptomatic lower extremity proximal DVT, symptomatic lower extremity 
distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, and 
VTE-related death
An independent blinded CEC will apply the protocol definitions and adjudicate and classify 
safety and efficacy endpoint events. 
The investigator will use all available source documents (including hospital records, discharge
summaries, consultant reports, imaging reports, local laboratory results, an autopsy report, and a
death certificate) to determine if an outcome event has occurred for a particular subject. Copies
of these documents must be part of the source documentation for any subject with an outcome
event in order to verify the outcome event.
Investigators will ensure that all necessary source documentation is collected to be forwarded to 
the independent blinded
CEC to enable event adjudication and verification. Source 
documentation should only contain subject number and initials, and care should be taken to 
obscure personal identifiers so that subject privacy is maintained.
Adjudicated results will be used for final analyses. In subjects who died during follow up, death 
certificates, and if available, autopsy findings will be reviewed to establish a diagnosis of fatal 
PE.  
Additional information on reporting of clinical efficacy and safety endpoints is presented in 
Attachment 1, Reporting of Efficacy Endpoints, Adverse Events, and Serious Adverse Events.
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9.2.1.1.
Definitions
The following definitions will be applied by the independent blinded CEC based on objective 
confirmation. 
Lower extremity proximal DVT
The adjudicated presence of a DVT located in the proximal veins of lower extremities
(includes the external iliac vein, common femoral vein, superficial femoral vein, proximal part of 
the deep femoral vein, popliteal vein, and trifurcation area of calf veins), as evidenced by a 
positively diagnosed and adjudicated CU. If the CU is deemed to be of unsatisfactory quality, 
confirmation may be done by venography if ordered by the investigator or qualified designee.
Asymptomatic events will include those subjects who are asymptomatic or otherwise unaware of 
and lack clinical signs for a DVT. Symptomatic events will include those subjects who are 
symptomatic or otherwise aware of and/or have clinical signs for a DVT.
Symptomatic lower extremity distal DVT
The adjudicated presence in subjects who are symptomatic or otherwise aware of and/or have 
clinical signs for a DVT located in the distal veins of the lower extremities, as evidenced by the 
final clinical diagnosis, including a positively adjudicated CU. If the CU is deemed to be of 
unsatisfactory quality, confirmation can be done by venography if ordered by the investigator or 
qualified designee. Asymptomatic lower extremity distal DVTs will not be included in endpoint 
data collection.
Symptomatic upper extremity DVT
The adjudicated presence in subjects who are symptomatic or otherwise aware of and/or have 
clinical signs for a DVT located in the veins of the upper extremities as confirmed by abnormal 
CU (includes but is not limited to the internal jugular vein, subclavian vein, axillary vein, 
brachial vein in the arm, cephalic vein in the arm, basilic vein in the arm, paired ulnar, radial, 
and interosseous veins in the forearm). 
This includes thrombosis of the central line when the subject presents with symptoms 
(eg, swelling, erythema, pain, distal paresthesia, neck swelling, headache, congestion of 
subcutaneous collateral veins)
Symptomatic non-fatal PE
The adjudicated presence in subjects who are symptomatic or otherwise aware of and/or have
clinical signs for a PE objectively confirmed by CT scan.
Incidental PE
Venous thromboembolism in pulmonary arteries identified on scans ordered primarily for 
staging or restaging of malignancy or otherwise conducted for reasons other than the 
identification of PE, with CT scan utilizing 5 mm slice thickness or less.
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VTE-related death 
An adjudicated death attributed, by the investigator, to the occurrence of a fatal VTE event.
Visceral VTE
Thrombi formed in portal, splenic, superior mesenteric, inferior mesenteric, hepatic, gonadal, 
renal veins, or inferior vena cava as evidenced by CT scan.
Any ATE
The adjudicated presence of a final clinical diagnosis of thrombosis/thromboembolism 
diagnostically confirmed, including myocardial infarction, stroke, peripheral arterial disease, and 
involving the following arterial vascular beds: carotid, upper or lower extremity, gastrointestinal 
tract, liver, spleen, or kidney.
All-cause mortality
All-cause mortality includes all deaths.
9.2.2.
Efficacy Endpoints 
The primary efficacy composite endpoint is the time from randomization to the first occurrence 
of objectively confirmed symptomatic lower extremity proximal DVT, asymptomatic lower 
extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper 
extremity DVT, symptomatic non-fatal PE, incidental PE, or VTE-related death occurring from 
randomization to the Day 180 visit as adjudicated by the independent blinded CEC. 
The key secondary efficacy endpoints include the following: 1) symptomatic VTE events
(DVT/PE) and VTE-related deaths and 2) all-cause mortality from the time of randomization to 
the Day 180 visit.
Other secondary efficacy endpoints include the time from randomization to the first occurrence 
for the following events during the 180-day, double-blind treatment period, defined as: 

individual components of the primary efficacy composite variable analyzed separately

confirmed fatal/non-fatal ATE events

confirmed fatal/non-fatal visceral VTE events

composite of symptomatic lower extremity proximal DVT, asymptomatic lower extremity 
proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity 
DVT, symptomatic non-fatal PE, incidental PE and all-cause mortality

composite of symptomatic lower extremity proximal DVT, symptomatic lower extremity 
distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, and VTE-related 
deaths.
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9.2.3.
Approach to the Subject with an Efficacy Outcome Event
If a subject has a suspected efficacy outcome event during the study, the treating physician 
should exercise clinical judgment and follow guidelines to apply the standard-of-care. At the 
treating physician’s discretion, the routine measures described below may be considered.

Temporarily interrupt or permanently discontinue the study drug treatment as clinically 
indicated. Unblinding of the study drug should not be necessary, as anticoagulation 
regimens do not require adjustment, regardless of treatment group assigned, when the study 
drug is administered in the doses used in this study.

Perform necessary diagnostic procedures and consider the usual treatment measures for VTE 
and/or cardiac ischemic events if physical examination and diagnostic testing suggest benefit 
could be obtained.
9.3.
Safety Evaluations
Details regarding the IDMC are provided in Section 11.9.2, Independent Data Monitoring 
Committee.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be managed by the investigator and other treating physicians as a part of standard-of-care. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule:
9.3.1.
Bleeding Events
The primary safety objective of this study is to assess the major bleeding events as defined by 
ISTH from the time of randomization to 2 days after the last dose of study drug. Secondary 
safety endpoints include the proportion of clinically relevant non-major bleeding, minor 
bleeding, any bleeding (defined as major, clinically relevant non-major, and minor bleeding as 
defined by ISTH). Similar to efficacy outcomes, the same independent blinded CEC will
adjudicate and classify bleeding events (major and clinically relevant non-major) according to 
the definitions in the CEC charter. Details of all bleeding events will be captured in the eCRF.
Bleeding events will be classified as major, clinically relevant non-major, or minor bleeding as 
follows: 
Major bleeding
Major bleeding is defined as clinically overt bleeding that is associated with:

A reduction in hemoglobin of 2 g/dL or more, or

A transfusion of 2 or more units of packed RBCs or whole blood, or

Occurrence at a critical site defined as intracranial, intraspinal, intraocular, pericardial, 
intra-articular, intramuscular with compartment syndrome, retroperitoneal, or

Fatal outcome
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Clinically relevant non-major bleeding
Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for 
major bleeding but associated with: 

Medical intervention

Unscheduled contact (visit or telephone call) with a physician

Temporary cessation of study treatment, or

Discomfort such as pain, or impairment of activities of daily life
Examples of clinically relevant non-major bleeding are:

Epistaxis that lasts longer than 5 minutes, is repetitive (2 or more episodes of true bleeding 
[ie, more than isolated drops of blood or simply blood-spotting on a tissue or handkerchief] 
within 24 hours), or that requires an intervention (eg, packing, electrocautery)

Gingival bleeding that occurs spontaneously (ie, unrelated to tooth brushing or eating), or 
lasts longer than 5 minutes

Hematuria that is macroscopic, and either spontaneous or lasts longer than 24 hours after 
instrumentation (eg, catheter placement or surgery) of the urogenital tract

Macroscopic gastrointestinal hemorrhage: at least 1 episode of melena or hematemesis, if 
clinically apparent

Rectal blood loss, if more than a few drops of blood

Hemoptysis, if more than a few streaks or specks of blood in the sputum

Intramuscular hematoma without compartment syndrome

Subcutaneous hematoma if larger than 25 cm2 in general or 100 cm2 if provoked

Multiple-source non-major bleeding
Minor bleeding
All other overt bleeding episodes not meeting the criteria for major or clinically relevant 
non-major bleeding will be classified as minor bleeding.
9.3.1.1.
Management of Study Drug for Bleeding Events
For clinically significant (major and relevant non-major) bleeding events, the study drug should 
be stopped or the subject managed according to the guidelines below. The decision to restart or 
permanently withdraw study drug after resolution of a bleeding event will be made by the 
investigator and must be documented.
If a subject has a clinically significant bleeding event during study treatment, the following 
routine measures could be considered:

Delay the next study drug administration, or discontinue treatment if appropriate. 
Rivaroxaban has a half-life of approximately 5 to 13 hours; depending on factors, including 
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age, etc. Therefore, temporary cessation of study drug may be sufficient to establish control 
of bleeding.  

Appropriate examinations and symptomatic treatment, (eg, mechanical compression 
[eg, for severe epistaxis], surgical interventions, as appropriate, fluid replacement and 
hemodynamic support, blood product or component transfusion) should be considered.

Also consider that other causes besides antithrombotic medication can be contributory to the 
seriousness of the bleeding event (eg, rule out disseminated intravascular coagulation, 
thrombocytopenia, other coagulopathies, kidney and liver dysfunction, concomitant 
medications), and treat accordingly.
If bleeding cannot be controlled by the above measures, consider administration of one of the 
following procoagulants according to the dosages advised in the package insert:

activated prothrombin complex concentrate

prothrombin complex concentrate

recombinant factor VIIa 
However, there is currently no experience with the use of these products in individuals receiving 
rivaroxaban. Any products administered to control bleeding should be entered in the eCRF.  
Note: Protamine sulfate and Vitamin K are not expected to affect the anticoagulant activity of 
rivaroxaban. There is currently no scientific rationale for benefit or experience with systemic 
hemostatics (eg, desmopressin, aprotinin, tranexamic acid, aminocaproic acid) in individuals 
receiving rivaroxaban.
9.3.2.
Other Safety Assessments
9.3.2.1.
Adverse Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures. Adverse events will be reported by the subject (or, when 
appropriate, by a caregiver, surrogate, or the subject's legally acceptable representative) for the 
duration of the study. Adverse events will be followed by the investigator as specified in 
Section 12, Adverse Event Reporting.
9.3.2.2.
Clinical Laboratory Tests 
Subjects will be screened and randomized using central laboratory results from testing performed 
within 14 days before randomization (Day 1) for the inclusion and exclusion clinical laboratory 
parameters. If historical laboratory results (done as per standard-of-care) are already available 
during the screening period (must be previously drawn within 2 weeks of randomization), they 
may be used to determine eligibility. This will enable subjects to be screened and randomized on 
the same day. These historical laboratory results will be documented in the source 
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documentation. In addition, subjects should still have all required screening labs drawn as per the 
Time and Events Schedule and sent to the central laboratory for analysis. In the event that the 
screening laboratory results returned from the central laboratory indicates the subject is not 
eligible, then the historical laboratory results will take precedence and should be entered into the 
eCRF to document subject eligibility.
Blood samples for hematology and serum chemistry will be collected. The investigator must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the eCRF. 
The following tests will be performed:

Hematology Panel: hemoglobin, hematocrit, RBC, WBC count with differential, and platelet 
count

Serum Chemistry Panel: sodium, potassium, chloride, bicarbonate, BUN, glucose, uric acid, 
calcium, phosphate, albumin, total protein, creatinine (for calculation of CrCl), AST, ALT, 
total and direct bilirubin, and alkaline phosphatase

Urine Pregnancy Testing will be performed at the screening and at the Day 180/EOT visit 
for women judged by the investigator to be of childbearing potential only. The 
protocol-specified sample for urine
pregnancy testing must be collected before 
randomization. If, subsequently, the results are positive for pregnancy, the subject should be 
discontinued from the study drug as soon as possible and should enter the post-treatment
follow-up period. See Section 12.4.3, Pregnancy, for information on reporting pregnancy to 
the sponsor. Additional urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy before 
administration of the study drug and throughout the study.
9.3.2.3.
Vital Signs
Vital Signs (oral or tympanic temperature, automated pulse, manual respiratory rate, automated 
blood pressure)
Blood pressure and pulse rate will be measured after subjects have been semi-recumbent for 
5 minutes. Blood pressure and pulse rate measurements will be assessed with a completely 
automated device consisting of an inflatable cuff and an oscillatory detection system. All values 
will be registered on a built-in recorder so that measurements are observer-independent. 
9.3.2.4.
Medical History and Physical Examination
The targeted medical history and physical examination (including weight, height, and BMI)
performed at screening should be obtained and performed in a manner that facilitates the 
investigator’s ability to make reasonable evidence-based clinical assessments and decisions 
throughout the study related to the following circumstances and/or conditions that are related to 
the safety evaluations described in this section or to the assessment of the efficacy evaluations 
described in Section 9.2.1, Efficacy Evaluations:
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
Vital signs 

Functional performance status 

Risk or presence of thromboembolism

Risk or presence of bleeding including hematology status

Liver function status and changes thereof

Renal function status and changes thereof

Status of study endpoints, including safety

Potential presence of thrombophilia, if suspected

Acute changes in the subject’s clinical status
9.4.
Biomarkers
9.4.1.
Evaluations
Biomarkers related to inflammation and hypercoagulability will be assessed. Biomarker samples 
will be collected at the time points indicated in the Time and Events Schedule. The data will be 
used to quantitate circulating levels of D-dimer, P-selectin, and Tissue Factor.
9.5.
Pharmacokinetics
9.5.1.
Pharmacokinetic Sample Collection and Handling
At Week 8, blood samples will be taken to determine study drug concentrations. Subjects will 
attend the clinic for their regularly scheduled visit, before taking their study drug. Only 1 PK 
sample will be drawn immediately before study drug intake. Exact times of blood sampling and 
last 2 intakes of study drug will be recorded in the eCRF. All samples will be collected and 
processed according to the central laboratory’s instruction manual. Handling and shipment of the 
samples and the materials will also be described in the manual. 
9.5.2.
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of rivaroxaban using a validated,
specific, and sensitive liquid chromatography coupled to tandem mass spectrometry
(LC-MS/MS) method under the supervision of the sponsor’s Bioanalytical Laboratory
Department of Bioanalysis.
9.5.3.
Pharmacokinetic Parameters
Rivaroxaban predose concentration at Week 8 will be summarized by descriptive statistics. 
Rivaroxaban PK parameters including AUC0-24, Cmax after single dose and AUC0-24, Cmax, and 
minimum plasma concentration (Cmin) at steady state may be derived through model-based 
methods. When appropriate, PK data collected in this study may be pooled with data from other 
studies to reduce the uncertainty in the analysis. Relationship of efficacy and safety endpoints 
versus rivaroxaban exposure will be explored by graphical analysis and, if a trend is suggested 
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by graphical analysis, followed by quantitative analysis. Results from PK modeling and 
exposure-endpoint analyses will be reported separately from the clinical study report. 
9.6.
Health Care Resource Utilization 
Health care resource utilization (HCRU) data, associated with medical encounters, will be 
collected in the eCRF by the investigator and study-site personnel for all subjects throughout the 
study. 
Health care resource utilization data will be collected as part of the endpoint assessments, at 
Weeks 8 and 16, and Day 180/EOT, for all subjects and compared between the treatment groups, 
or until study drug discontinuation. The data collection will be specific to the study outcomes of 
DVT, PE, or bleeding, including visits to health care providers, hospitalization, length of 
hospitalization, and use of diagnostic procedures.
9.7.
Other Evaluations
Functional Status
The functional status of the subjects will be assessed using the ECOG performance status scale 
(see Attachment 4, Functional Status Assessment Tool). 
9.8.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. 
For those blood samples collected for exploratory biomarker evaluation, instructions on sample 
collection, labeling, handling, and shipment will be provided in the laboratory manual.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY 
TREATMENT/WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the double-blind treatment period if the subject 
continues taking the double-blind study drug until the Day 180 visit as well as has completed all 
study-related assessments.
A subject will be considered to have completed the study if the subject (regardless of whether 
he/she continues on study drug) is followed according to the visit schedule until the 
Day 210/EOS visit.
A subject will be considered to have not completed the study if the subject does not complete all 
study visits according the visit schedule until the Day 210/EOS visit.
All feasible efforts and measures will be made to collect complete vital status and other outcome 
data from randomization to the Day 180 visit for each subject randomized in this study, 
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regardless of compliance with study drug or visits. For subjects who are lost-to-follow up or 
withdraw consent from the study, efforts will be made to obtain their vital status and other 
outcomes from permitted sources.  
It is important to note that withdrawal of consent does not withdraw permission to collect vital 
status and other outcomes. Withdrawal of permission to collect vital status and other outcomes 
must be made separately. In cases where subjects indicate they do not want to “continue”, 
investigators must determine whether this refers to discontinuation of study treatment 
(the most common expected scenario), unwillingness to attend follow-up visits, unwillingness to 
have telephone contact, unwillingness to have any contact with study personnel, or unwillingness 
to allow contact with a third party (eg, family member, doctor). In all cases, every effort must be 
made to continue to follow the subject, and vital status and other outcomes must be determined 
for all randomized subjects. 
10.2.
Discontinuation of Study Treatment 
If a subject’s study treatment must be discontinued before the end of the double-blind treatment 
period, this will not result in automatic withdrawal of the subject from the study and the subject 
should continue to be followed for efficacy and safety outcome events.  
During the study, should the subject develop any condition, which in the investigator’s judgment 
requires 
treatment 
with 
an 
agent 
that 
precludes 
double-blind 
treatment 
(long-term anticoagulation thromboprophylaxis, or fibrinolysis, LMWH, alteplase), the subject 
will have the study drug either temporarily interrupted or permanently discontinued and will be 
managed as deemed appropriate by the treating physician. The subject will be asked to continue 
in the study to be followed for efficacy and safety outcomes. 
10.2.1.
Temporary Interruption of Study Treatment
The study drug may be temporarily interrupted; however, these interruptions should be kept to a 
minimum as much as possible. If the subject misses more than 14 consecutive days of study 
drug, he/she will need to permanently discontinue the study drug. It is recommended, when 
possible, that the study drug be discontinued at least 24 hours, and at the discretion of the 
investigator, before an invasive procedure (ie, surgical) to reduce the risk of bleeding. In 
deciding whether a procedure should be delayed at least 24 hours after the last dose of study 
drug, the increased risk of bleeding should be weighed against the urgency of intervention. In 
case of major surgery or major bleeding risk procedure, the investigator may consider holding 
the prior day’s dose of study drug (skip both doses of the study drug the day before and the day 
of surgery), weighing the risk of bleeding against that of VTE. Consider bridging with parental 
anticoagulation, if necessary. The study drug should be restarted after the surgical or other 
procedures as soon as adequate hemostasis has been established, noting that the time to onset of 
therapeutic effect is short. The investigator may consider resuming the study drug 24 hours after
achieving hemostasis for low-bleeding risk or minor surgical procedures, and at 48 hours in case 
of major or high-risk bleeding procedures, noting that the time to onset of therapeutic effect is 
short.
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During planned or emergency hospitalization, the study drug should be stopped only if the 
treating clinician determines that thromboprophylaxis or anticoagulation should be administered. 
It might be necessary to interrupt the study drug temporarily (eg, while a contraindicated 
mediation is taken). Subjects should resume the study drug as soon as it is deemed safe by the 
treating clinician, and study drug interruption during the treatment period should not exceed 
14 consecutive days.
Study drug should be temporarily discontinued if the subject: 

Develops a new neurologic deficit or significant alteration in mental status.

If the platelet count decreases to <25 x 109/L for more than 1 week, the subject will be 
temporarily discontinued until the platelet count returns to ≥25 x 109/L. Subjects should 
have their platelet count monitored carefully if the platelet count decreases to <50 x 109/L
and investigator discretion should be used.

Has a SAE that is considered by the investigator to be possibly related to, or exacerbated by, 
study drug administration.

Requires any of the following prohibited therapies on a temporary basis:

Fibrinolytic therapy

Combined P-gp and strong CYP3A4 inhibitors (such as but no limited to ketoconazole, 
telithromycin, or protease inhibitors)

Antiplatelet therapy
o
Aspirin>100 mg per day, P2Y12 receptor antagonists (eg, clopidogrel, prasugrel, 
ticagrelor)
o
Thrombin receptor antagonists (eg, vorapaxar)

Daily use of NSAIDs, or other medications known to increase the risk of bleeding

Anticoagulants (eg, warfarin sodium or other VKAs, Factor II or Xa inhibitors)

Experiences a major bleeding event. For less severe bleeding events, investigator discretion 
is allowed. If possible, the study drug should be resumed when the bleeding event has 
resolved and the cause has been identified and corrected (see Section 9.3.1.1, Management of 
Study Drug for Bleeding Events).

Subjects should have their renal function monitored when CrCl drops below <30 mL/min and 
investigator discretion should be used with regard to study drug administration. If the 
subject’s CrCl decreases to <15 mL/min, the subject should be discontinued from study drug 
treatment.
The study drug can be resumed when the investigator considers it safe to do so. If more than 
14 consecutive days of study drug are missed, the subject will permanently discontinue the study 
drug and have an unscheduled EOT visit performed.
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Subjects who have the study drug discontinued will be reminded to follow their healthcare 
provider’s recommendations for their ongoing care plan for prophylaxis of VTE at the 
unscheduled EOT visit (see Section 8, Prestudy and Concomitant Therapy).
10.2.2.
Permanent Discontinuation of Study Treatment
If a subject must be permanently discontinued from the study drug before the end of the 
double-blind treatment period, this will not result in automatic withdrawal of the subject from the 
study, and the subject should continue to be followed for efficacy and safety outcome events.  
A subject’s study drug treatment will be permanently discontinued if:

At their own request, or at the request of their legally acceptable representative, without 
giving reasons (even though providing a reason is encouraged).

If, in the investigator’s opinion, continuation in the study would be detrimental to the 
subject’s well-being.

At the specific request of the sponsor (exceptional circumstances).

The subject develops a condition that requires anticoagulation or thromboprophylaxis 
extending beyond 14 consecutive days (see Section 10.2.1, Temporary Interruption of Study 
Treatment).

The subject’s calculated CrCl is <15 mL/min.

The subject misses more than 14 consecutive days of study drug.

The subject becomes pregnant.

If the subject experiences an endpoint event, including a clinically significant bleeding 
event, at the treating physician’s discretion, the routine measures described below may be 
considered.

Temporarily interrupt (not more than 14 consecutive days) or permanently discontinue 
study drug treatment as clinically indicated. If a subject experiences a VTE event, 
unblinding of study drug should not be necessary, as anticoagulation regimens do not 
require adjustment regardless of treatment group assigned when study drug is 
administered in the doses used in this study. If a subject has a serious bleeding event 
during study drug treatment, routine measures should be considered as described in 
Section 9.3.1.1, Management of Study Drug for Bleeding Events. If these measures are 
sufficient to stop bleeding, unblinding of study drug should not be necessary. If despite 
this guidance, the investigator believes it is in the best interest of the subject to unblind 
the study drug, the investigator may determine the treatment assignment or allocation 
by contacting the IWRS as previously noted.

Perform necessary diagnostic procedures and consider the usual treatment measures for 
VTE and/or arterial ischemic events if physical examination and diagnostic testing 
suggest benefit could be obtained.

After clinical evaluation of the suspected efficacy outcome event is completed,
restarting the study drug may be considered if none of the conditions requiring 
permanent discontinuation noted above are present.
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Early permanent discontinuation of study drug is discouraged wherever possible. The single 
most important reason for premature discontinuation should be marked on the appropriate eCRF 
and in the subject source documents. Subjects missing more than 14 consecutive days of taking 
the study drug will be discontinued from further study drug treatment and will not be restricted 
from seeking appropriate medical care available outside the protocol, but will be encouraged to 
make every effort to continue with their scheduled study visits until the planned end of their 
study duration. Discontinued subjects will not be replaced. Subjects who permanently 
discontinue the study for any reason will not be re-enrolled into the study.
If a subject permanently discontinues the study drug before the end of the double-blind treatment 
period (Day 180 visit), he/she should be instructed to complete an unscheduled EOT visit as soon 
as possible from the time that the study drug was discontinued, with the CU performed within 
2 days of taking the last dose of study drug. In addition, the subject will be required to complete 
all remaining study visits and procedures including what would have been their Day 180/EOT 
and Day 210/EOS visits (see TIME AND EVENTS SCHEDULE). If the unscheduled EOT visit 
falls within the window of a remaining study visit, the subject does not need to repeat this 
required study visit.  
The subject is required to return for all subsequent site visits and procedures until the 
Day 210/EOS visit. The investigator should inform the subject of the importance of returning for 
all study visits as it is imperative for the integrity of the study and results to have ongoing 
ascertainment of outcome event and vital status. If the subject is unwilling or unable to return for 
any visits, or is lost-to-follow up, the investigator should collect as much follow-up information 
as possible for each remaining visit, including contacting the subject or legally acceptable 
representative by telephone or by mail to determine vital status and outcome ascertainment, as 
agreed to by the subject during the informed consent process. In that respect, the investigator 
should ask the subject at the study start for the contact details of a relative or a friend who can be 
contacted in case the subject cannot be reached. The site must document all attempts to try to 
contact the subject in the source documents. In the event a subject withdraws consent and does 
not agree to any kind of follow up and specifically refuses any further contact with the 
investigator, this must be documented in the source document and the subject will be asked to 
supplement the withdrawn consent with a signed written statement documenting refusal for all 
subsequent contact. If applicable, the vital status and other outcomes will be obtained at study 
end through public information (death registries or other registries) according to local guidelines 
and as allowed by local regulations.
A decision to stop recruitment and/or study treatment can be taken by the EC following advice
on safety aspects of study by the IDMC. The Independent Ethics Committee/Institutional Review 
Board (IEC/IRB) will be informed of the decision. Stopping guidelines will be defined prior to 
the start of the study. The sponsor has the right to close this study, and the investigator/the 
sponsor has the right to close a center, at any time, although this should occur after consultation 
between involved parties and the EC. The IEC/IRB must be informed. Should the study/center be 
closed prematurely, all study materials (except documentation that has to remain stored at the
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site) must be returned to the sponsor. The investigator will retain all other documents until 
notification given by the sponsor for destruction. 
10.2.3.
Medication Transition Management
Subjects who experience a primary or secondary study endpoint of objectively confirmed 
symptomatic lower extremity DVT, upper extremity DVT, non-fatal PE, asymptomatic proximal 
DVT of the lower extremity, incidental PE, and VTE-related death, confirmed non-fatal ATE 
events, and confirmed non-fatal visceral VTE events or any other thrombotic event that in the 
judgment of the treating physician will require antithrombotic treatment during the double-blind 
treatment period will have study drug discontinued and receive treatment per physician 
discretion.

Switching study therapy with other anticoagulants 

If switching blinded therapy to an anticoagulant with a rapid onset, discontinue study
therapy and give the first dose of the other anticoagulant (oral or parenteral) at the 
time that the blinded treatment dose would have been taken.

When switching back from a rapid onset anticoagulant (eg, LMWH or non-warfarin 
oral anticoagulant) after a temporary discontinuation, start blinded study therapy 
0 to 2 hours prior to the next scheduled administration of the drug and omit 
administration of the other anticoagulant. 

For those subjects taking VKA for a temporary discontinuation who will be switched
back to study therapy discontinue warfarin and start blinded study therapy as soon as 
the INR is below 3.0 to avoid overlapping anticoagulation and increased bleeding 
risk.

When switching from study therapy to VKA discontinue blinded therapy and begin 
both a parenteral anticoagulant and warfarin at the time the next dose of study drug
would have been taken.
10.2.4.
Withdrawal from the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost-to-follow up (only after all means of all subsequent contact, where permitted by law, 
up until the Day 210/EOS visit, will lost-to-follow up be declared)

Withdrawal of consent (unless specifically refused by the subject, subject contact will be 
made to obtain vital status at the Day 210/EOS visit)

Death
If a subject is lost-to-follow up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented. Outcome events and vital status data are crucial to the 
statistical analysis and must be collected until the end of the study even if subjects are no longer 
taking the study drug. Every effort will be made to contact any subject who is lost-to-follow up 
or withdraws consent and collect information on the occurrence of efficacy and safety endpoint 
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events and vital status, including a review of the subject’s medical or public records unless this 
contact is not allowable by local regulations. 
11.
STATISTICAL METHODS
Statistical analysis will be performed by the sponsor or under the authority of the sponsor. A 
general description of the statistical methods to be used to analyze the efficacy and safety data is 
outlined below. Specific details will be provided in the statistical analysis plan (SAP).
The primary study objective will be addressed by comparing the distribution of time to the first
occurrence of a primary efficacy composite endpoint between treatment groups. Specifically, the 
following primary statistical hypothesis will be tested:

Null hypothesis H0: there is no difference between treatments in distribution of time from 
randomization to the first occurrence of the primary efficacy composite endpoint event.

Alternative hypothesis HA: The distributions of time from randomization to the first 
occurrence of the primary efficacy composite endpoint event are different between the 
2 treatment groups.
In this study, data collected on the primary efficacy, safety, as well as the key secondary 
endpoints will be summarized across treatment groups. Specific imputation rules for missing 
data (eg, missing event dates) will be applied, if warranted, and will be specified in the SAP 
before final database lock. Descriptive statistics such as mean, median, standard deviation, 
interquartile range, minimum, and maximum will be used to summarize continuous variables. 
Counts and proportions will be used to summarize categorical variables. Graphical data displays 
(eg, box plots) may also be used to summarize data. Kaplan-Meier estimates adjusted for 
competing risk over time will be summarized and plotted for time-to-event variables.
11.1.
Analysis Populations and Observation Periods
Definition of an analysis data set contains these 2 elements: 1) subject population, which 
specifies which subjects will be included in an analysis; and 2) observation period, which 
specifies the time window within which data will be included in an analysis. Key subject 
populations and observation periods are defined below.
Subject Population
Intent-to-treat (ITT) population: This subject population consists of all randomized subjects.
Per-protocol (PP) population: this population is a subset of the ITT population. Subjects with
major protocol deviations will be excluded from PP population. Major protocol deviations will
be defined in the SAP.
Safety population: this population is a subset of the ITT population, consisting of all randomized
subjects who receive at least 1 dose of study drug.
Observation Periods
Up to Day 180-visit: this observation period includes all data from randomization to the 
Day 180 visit, inclusive. For time-to-event analyses, subjects who do not experience endpoint 
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events during this period will be censored at the Day 180 visit or at the last day of their 
completed unscheduled EOT assessments for study outcomes during the treatment period,
whichever occurs first.
On-treatment: this observation period includes data from the first dose of study drug to 2 days 
after the last dose of the study drug, inclusive. For time-to-event analyses, subjects who do not 
experience endpoint events during this period will be censored on the last dose date +2 days or at
the last day of their completed unscheduled EOT assessments for study outcomes during the 
treatment period, whichever occurs first.
Post-randomization: this observation period includes all data from randomization to the last
contact (ie, up to Day 210-/EOS visit).
Post-first dose of study drug: this observation period includes all data from the first dose of study 
drug to the last contact (ie, Day 210-/EOS visit).
11.2.
Sample Size Determination
This is a 6-month, fixed-duration study to demonstrate the superiority of rivaroxaban compared 
with placebo in ambulatory cancer subjects undergoing systemic cancer therapy. 
Estimates for VTE events in this population vary but in most studies, the data demonstrate a 
significant benefit (or, reduction in events) over placebo when cancer subjects are treated with 
anticoagulant therapy. According to a recent review of the VTE prophylaxis studies in cancer 
subjects by Khorana et al, the majority of RCTs on solid tumors have reported relative risk 
reductions (RRRs) anywhere between 50% and 64%. The duration of the earlier primary VTE 
prophylaxis studies in cancer was generally between 3 to 4 months, in conjunction with initiation 
of systemic anticancer therapy. The basis for predictive events is derived from the Vienna CATS 
group,4 which utilized the Khorana thromboembolic risk score, and followed 819 ambulatory 
cancer subjects for symptomatic VTE as an endpoint. In a Kaplan-Meier analysis, the cumulative 
probability 
of 
VTE 
after 
6 
months: 
Khorana 
thromboembolic 
risk 
score 
≥3, 
17.7% (95% CI: 11.0%-27.8%, N= 93), and 9.6% (95% CI: 6.2%-14.7%, N=221) in those 
subjects with a Khorana thromboembolic risk score of 2. Taken together, these results, along 
with a number of smaller epidemiologic studies, in general support a symptomatic VTE rate at 
180 days of at least 9.5% in subjects with a Khorana thromboembolic risk score of >2. The 
adjudication of objectively confirmed asymptomatic DVT and PE is estimated to add an 
additional 5% to 10% to the primary efficacy composite endpoint; therefore, an overall primary 
efficacy composite endpoint event rate of approximately 14.5% seems reasonable. Furthermore, 
it is assumed that the use of rivaroxaban will reduce this event rate to approximately 6.0%.
An independent blinded CEC, as described in Section 11.9.3, Clinical Endpoint Committee will 
apply the protocol definitions and adjudicate and classify safety and efficacy endpoint events, 
including major bleeding and clinically relevant non-major bleeding.
Based on the above information and recommendations from the Cancer-Associated Thrombosis 
Advisory Council, the sponsor planned the duration of the thromboprophylaxis treatment in the 
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multiple malignancy study up to 6 months. Therefore, the estimates of assumed events rates are 
relatively conservative given that the period of treatment follow up is longer than earlier RCTs.
In this study, with a 6-month planned treatment with rivaroxaban, the primary efficacy outcome 
variable is a composite of any symptomatic DVT, proximal asymptomatic DVT, any PE, and
VTE-related death. The study design allows for a fixed treatment duration of 6 months on each 
successfully randomized subject. Assuming a cumulative incidence rate of 14.5% for the primary 
efficacy composite events in the placebo group and 6.0% cumulative incidence rate in the 
rivaroxaban treatment group, a total sample of about 700 randomized subjects (350 per treatment 
group) will be required to demonstrate approximately 60% RRR in the primary efficacy 
composite endpoint with a 2-sided Type 1 error rate of 5% and >90% statistical power 
(calculation performed by EaST 6.3 software), assuming a 20% discontinuation rate. Towards 
the end of the enrollment phase, approximately 800 subjects were planned to be randomized into 
the study due to the high subject discontinuation rate. In addition, this sample size will allow for 
80% statistical power in each stratum (APC or non-APC) for slightly larger differences in 
incidence rates between the 2 randomized treatment groups to be statistically significant.
Essentially, the above overall sample size estimate is calculated based on the following 
assumptions:

Effect size: absolute difference in event rates = 8.5%, RRR = 58.6%

Primary efficacy composite endpoint event rate in the placebo arm: 14.5%

Primary efficacy composite endpoint event rate in the rivaroxaban arm: 6%

Power: >90%

Overall α level: 5%, 2-sided

Probability of dropping out of the study: 20%

Duration of enrollment period: 12 months

Duration of study: 6 months (fixed for each randomized subject)
11.3.
Handling of Missing Data
For both the efficacy and safety endpoints, extensive efforts will be made to collect complete 
event and vital status data for all subjects randomized in this study. The number of subjects with 
missing follow up and the percentages of missing follow-up times will be summarized. Specific 
imputation rules will be applied to the missing data (eg, missing event dates). Sensitivity 
analyses will be conducted to assess impact of missing data on study results. Details will be 
provided in the SAP.
11.4.
Interim Analysis
No interim efficacy analysis is planned in this study. An unblinded IDMC has been established
for this study to periodically assess the safety of subjects in the study and evaluate the efficacy 
data, as necessary. For lower than expected numbers of primary events and/or significantly 
higher numbers of dropouts from the study, a blinded sample size re-estimation will be specified 
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in the SAP. Details of the IDMC roles, responsibilities, and key activities/timelines are provided 
in the IDMC charter.  
11.5.
Efficacy and Safety Analyses
The primary efficacy and key secondary endpoint analyses in this study will be based on the 
ITT population. All safety endpoints will be analyzed based on the safety population. Statistical 
tests will be based on a 2-sided Type 1 error rate of 5%. No adjustment in p-values for 
multiplicity of testing will be made unless otherwise specified. Associated 95% CIs will be 
provided. Primary and secondary events will be adjudicated by the independent blinded CEC and 
analyses will be based on these adjudicated events. Investigator-reported events will also be 
summarized. Additional data analyses (including those based on specific subgroups) will be 
identified in the SAP. 
Primary efficacy composite endpoint analysis
The primary efficacy composite endpoint is the time from randomization to the first occurrence 
of objectively confirmed symptomatic lower extremity proximal DVT, asymptomatic lower 
extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper 
extremity DVT, symptomatic non-fatal PE, incidental PE, or VTE-related death during the 
observation period up to the Day 180 visit. The associated statistical null hypothesis is that there 
is no difference between treatment groups in distribution of the time to primary efficacy 
composite event, and the alternative hypothesis is that there is a difference between treatment 
groups. The primary statistical hypothesis will be tested using a log-rank test, stratified by tumor 
type (ie, APC vs. non-APC).
The primary efficacy composite endpoint analysis will be performed using a stratified Cox 
proportional hazard model (stratification factor: APC or non-APC), including treatment group as 
a categorical explanatory variable with 2 levels (ie, rivaroxaban, placebo) and will be based on 
the ITT population. Subjects who have no primary efficacy outcome during this observation 
period, or subjects who are lost to follow-up, or subjects who die because of other reasons than
VTE, or subjects who withdraw informed consent before the end of the predefined treatment 
duration, will be censored at the last day of their complete assessment for study outcomes during
the treatment period (assuming these types of censorings are independent of the primary 
outcome). Further details will be specified in the SAP. Subjects will be analyzed according to the 
treatment group to which they are randomized, regardless of actual treatment received.
To control the family-wise Type I error rate at alpha of 0.05 (2-sided) in testing for efficacy 
outcomes, if superiority of rivaroxaban over placebo on the primary efficacy outcome is 
established, superiority of rivaroxaban over placebo on secondary outcomes will be tested 
sequentially using a closed testing procedure in the following hierarchical order, each at alpha of 
0.05 (2-sided):

symptomatic VTE events + VTE-related deaths;

all-cause mortality.
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For each of these key secondary endpoint analyses, a Cox proportional hazard model with 
treatment and stratification factor as covariates will be employed. A point estimate along with 
2-sided 95% CI for the treatment effect of RRR (RRR=100 x [1-HR] %) will be provided. The 
proportional hazards assumption will be assessed by visually comparing the plot of the log of 
cumulative hazard between treatments, and, if required, will be tested by appropriately including 
a treatment by log-transformed time interaction term in the Cox’ model. Other secondary 
endpoints will be analyzed in similar fashion. The cumulative event rate derived from 
Kaplan-Meier estimate will be displayed graphically to evaluate the timing of event occurrence 
and the consistency of the treatment effect over time. 
A number of sensitivity analyses will be conducted to assess the robustness of the primary 
efficacy analysis by subgroups. These will include summarizing the incidence of symptomatic 
events and asymptomatic events by treatment group. An unstratified log-rank test will be used by
repeating analyses mentioned above for different analysis sets and analysis observational 
periods. Additional post-hoc analyses may be conducted to investigate unexpected results. 
Relative risk reductions on components of the primary efficacy endpoint will be evaluated using 
a Cox proportional hazards model as described above.
Homogeneity of treatment effects will be evaluated using the statistical model described above 
with treatment only as a covariate for the key subgroups listed below:

Age (18 to <65 vs ≥ 65 years)

Gender (men vs women)

Tumor type (APC vs non-APC)

Stage of disease (I-II vs III-IV)

Khorana Score (<2, 2, and >2)

ECOG score (0-1 vs 2 and above)

Race (White or Caucasian, Black or African American, Asian, Other)

Weight (<50 kg, >50 kg)

Cancer types (eg, stomach, lung, lymphoma, renal, bladder, gynecologic, testicular)

Geographic region (North America, Western Europe, Other)

CrCl (30 to <50, 50 to <80, 80 mL/min)
To account for competing risks (deaths from causes other than VTE for efficacy, or fatal 
bleeding for safety) in the primary efficacy and safety analyses, a cumulative incidence approach 
will be followed with the use of Gray’s 2-sample test (2-sided Type 1 error rate of 5%). 
Associated HRs and 95% CIs will be calculated with the use of the Fine and Gray regression 
model. Cumulative incidence functions will be estimated separately for the 2 randomized 
treatment groups. Additional statistical details of the specific models and inferential procedures 
to be used will be described in the SAP.
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Key secondary efficacy endpoints will be analyzed in a similar fashion as the primary efficacy 
endpoint.
11.5.1.
Safety Endpoints, Laboratory, and Vital Signs Data Analysis
The primary safety endpoint includes time to a major bleeding event in treated subjects in each 
randomized treatment group as defined by ISTH. A statistical comparison of the 2 randomized 
treatment groups will be performed using a stratified Cox’s proportional hazards model with 
treatment as a covariate. Additionally, the frequency of bleeding events in each treatment group 
will be summarized. Secondary safety endpoints defined by percentages of clinically relevant 
non-major bleeding events will also be summarized. All reported AEs (ie, treatment-emergent 
adverse events [TEAEs], AEs that have worsened since baseline) will be summarized. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an AE, or who experience a severe AE or 
SAE. Laboratory data will be summarized and descriptive statistics for vital signs will be 
provided.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events 
are AEs with onset during the treatment phase or that are a consequence of a pre-existing 
condition that has worsened since baseline. All reported AEs will be included in the analysis. For 
each AE, the percentage of subjects who experience at least 1 occurrence of the given event will 
be summarized by treatment group. In addition, comparisons between treatment groups will be 
provided if appropriate.
11.6.
Biomarker Analyses
Biomarker data will be summarized by treatment group and time point.
11.7.
Pharmacokinetic Analysis
Descriptive statistics will be calculated for the plasma concentrations of the study drug at 
Week 8 and the derived PK parameters. Statistics include sample size (n), mean, standard 
deviation, coefficient of variation, geometric mean, median, minimum, and maximum.
11.8.
Health Care Resource Utilization
The statistical analytic methods for the HCRU data will be further specified in the SAP. The 
HCRU data will be analyzed by treatment group with non-parametric methods for categorical 
variables, and log-transformation for continuous variables.
11.9.
Committees
The EC, CEC, and IDMC responsibilities, authorities, and procedures will be documented in 
their respective charters.
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11.9.1.
Executive Committee
An EC will be formed that has overall responsibility for the conduct and reporting of the study. 
In addition, the EC will receive recommendations from the IDMC regarding safety analyses or 
modifications to the study. The EC will ultimately decide whether to accept the 
recommendations and will oversee the implementation of any modifications. Details of the 
composition, roles, and responsibilities will be documented in its charter. The members of the
EC will be sponsor representatives identified by the study team and will include at least 2 clinical 
experts and an independent internal statistical expert.
11.9.2.
Independent Data Monitoring Committee
An IDMC will be established to monitor unblinded data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in this study. Members of the IDMC will be appointed 
by the study team. The IDMC will consist of at least 1 medical expert in the relevant therapeutic 
area(s) and at least 1 statistician. As required, the IDMC will make recommendations to the EC 
based on its ongoing review of study data. General details on the membership and 
responsibilities of the IDMC, and its communication with the EC will be provided in an
IDMC charter, while technical details will appear in the SAP for this study.
11.9.3.
Clinical Endpoint Committee
An independent blinded CEC will apply the protocol definitions and adjudicate and classify the 
following endpoints: symptomatic lower extremity DVT, symptomatic upper extremity DVT, 
non-fatal PE, asymptomatic proximal DVT of the lower extremity, incidental PE, VTE-related 
death, confirmed fatal/non-fatal ATE events, confirmed fatal/non-fatal VTE events, major 
bleeding, clinically relevant non-major bleeding events, and all-cause mortality. The independent 
blinded CEC will include leading scientific investigators with VTE, coagulation, diagnostics, and 
statistical expertise.
12.
ADVERSE EVENT REPORTING
Refer to Section 9.2.1, Efficacy Evaluations and Outcomes, 9.2.2 Efficacy Endpoints, 9.3, Safety 
Evaluations, and Attachment 1, Reporting of Efficacy Endpoints, Adverse Events, and Serious 
Adverse Events for details on the AEs to be collected during this study.
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with these procedures.
As of 15 September 2014, more than 84,000 subjects have been enrolled in interventional 
clinical trials (completed and ongoing Phase 1, Phase 2, Phase 3, and Phase 4) including more 
than 47,000 subjects treated with rivaroxaban and its overall safety profile has been well 
characterized. Appropriate information concerning AEs were systematically collected and 
submitted to regulatory authorities in the past. For the purposes of this study, certain nonserious
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AEs will not be collected, while certain events will be collected as endpoints and therefore not 
reported as SAEs. All data on safety and efficacy outcomes will be reviewed regularly by an 
unblinded IDMC. 
Section 12.2.1, Adverse Events Definitions and Classifications, describes the usual definitions of 
AEs and SAEs.
12.1.
Warnings/Precautions
For rivaroxaban, Phase 1, 2, and 3 data are available (refer to Section 1, Introduction, and the IB) 
(Rivaroxaban IB 2014).6 The known side effect profile for rivaroxaban can be found in the 
current IB. The IB is updated on a regular basis. Any new relevant information about side effects 
of rivaroxaban will be given to the subject and investigator. 
In addition, the possibility of unforeseen side effects and allergic reactions to the drug, which can 
result in severe damage and even death, must always be considered.
12.2.
Definitions
12.2.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International Council
on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.4.1, All 
Adverse Events, for time of last AE recording).
Serious Adverse Event
A SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization
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
Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
* Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as, important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
For the purposes of this study, efficacy and safety outcomes will not be considered as AEs or 
SAEs (see Section 12.4.1 All Adverse Events).  
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For rivaroxaban, the expectedness of an AE will be 
determined by whether or not it is listed in the IB. For a non-sponsor investigational medicinal 
product (eg, a comparator product) with a marketing authorization, the expectedness of an AE
will be determined by whether or not it is listed in the package insert.
Adverse Event Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 12.2.2, Attribution Definitions.
12.2.2.
Attribution Definitions
Not Related
An AE that is not related to the use of the drug.
Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the drug. An alternative explanation, eg, concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
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Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in time 
is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.2.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
Life-threatening: extreme limitation in activity, significant assistance required, significant 
medical intervention/therapy required, hospitalization or hospice care probable.
Death: the event results in death.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.3.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational exposure to a sponsor study drug

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study drug

Unexpected therapeutic or clinical benefit from use of a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor medicinal product, eg, name confusion)

Exposure to a sponsor study drug from breast-feeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a SAE should be recorded on the SAE page of the eCRF.
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12.4.
Procedures
12.4.1.
All Adverse Events
In this study, recording of only a subset of AEs is necessary. However, any AE of particular 
concern to the investigator may be recorded in the eCRF to alert the sponsor.  
Suspected outcome events are excluded from AE/SAE collection and reporting, regardless of 
seriousness or severity. These suspected events will be captured on the eCRF as outcome events
and will be waived from SAE collection and unblinding and exempted from expedited reporting. 
These events include:

Symptomatic lower extremity proximal DVT

Asymptomatic lower extremity proximal DVT

Symptomatic lower extremity distal DVT

Symptomatic upper extremity DVT

Symptomatic non-fatal PE

Incidental PE

VTE-related death

All-cause mortality

ATE events (eg, MI, stroke)

Visceral VTE

All bleeding events
If the independent blinded CEC determines that a suspected event does not meet the criteria for 
an outcome event as defined in the CEC charter, it will still be excluded from AE collection and 
reporting even if serious criteria were met.
The following AEs or SAEs will be collected and entered into the eCRF, unless they are 
considered outcome events as specified in the list above. The SAEs need to be reported to the 
sponsor within the appropriate timeline as described in Section 12.2.1, Serious Adverse Events.

Adverse events leading to permanent study drug discontinuation

All SAEs that are not considered endpoint events as listed above
In addition, certain AEs are considered to be Adverse Events of Special Interest (AESI) and 
should be reported as SAEs. These include:

Suspected severe hypersensitivity reaction (eg, anaphylaxis, angioedema, severe urticaria, 
bronchospasm) 

Severe skin reactions such as Stevens-Johnson Syndrome 

Suspected severe liver injury
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All AEs and special reporting situations, as discussed in this section and in Section 12.3, Special 
Reporting Situations whether serious or nonserious, will be reported from the time a signed and 
dated ICF is obtained until completion of the subject’s last study-related procedure,
(which may include contact for follow up of safety). Refer to Attachment 1, Reporting of 
Efficacy Endpoints, Adverse Events, and Serious Adverse Events for additional information on 
reporting of events in this study.
All outcome events will be monitored by the IDMC during the study and analyzed in the clinical 
study report after study termination. The IDMC will periodically review and assess all safety 
data for imbalances in safety endpoints. It is believed that in this way subject safety can continue 
to be monitored throughout the duration of the study, along with study integrity. If unexpected 
safety issues are identified, specific amendments will be implemented.  
For all studies with an outpatient phase, including open-label studies, the subject 
(or their designees, if appropriate) must be provided with a “wallet (study) card” and instructed 
to carry this card with them for the duration of the study indicating the following: 

Subject’s name

Subject number

Subject’s date of birth

Study site number

Investigator’s name and 24-hour contact information

Local sponsor’s name and 24-hour contact information (for medical staff only)

Statement, in the local language(s), that the subject is participating in a clinical study

Any other information that is required to do an emergency breaking of the blind
12.4.2.
Serious Adverse Events
All SAEs that are not outcome events as listed above occurring during the study must be reported 
to the appropriate sponsor contact person by study-site personnel within 24 hours of their 
knowledge of the event.  
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form, which must be completed and signed by a physician from the study site, and transmitted to 
the sponsor within 24 hours. The initial and follow-up reports of a SAE should be made by 
facsimile (fax).
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes
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
The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject's participation in a study must be reported as a SAE, except hospitalizations 
for the following:

Hospitalization not intended to treat an acute illness or AE (eg, social reasons such as 
pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the eCRF) 
12.4.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, and congenital anomalies, ectopic pregnancy) are considered 
SAEs and must be reported using the SAE Form. Any subject who becomes pregnant during the 
study must discontinue further study treatment. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
subjects included in the study will be reported by the study-site personnel within 24 hours of 
their knowledge of the event using the appropriate pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 
12.5.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may 
have an impact on the safety and efficacy of the product. Timely, accurate, and complete 
reporting and analysis of PQC information from studies are crucial for the protection of subjects,
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
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appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.4.2, Serious Adverse 
Events). A sample of the suspected product should be maintained for further investigation if 
requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
The study drug supplied for this study is rivaroxaban 10 mg and matching placebo, provided as 
round, white to yellow-white tablets, without markings. It will be manufactured and provided 
under the responsibility of the sponsor. Refer to the IB for a list of excipients.
14.2.
Packaging
The study drug, rivaroxaban and matching placebo will be packaged in bottles and will be 
dispensed in child-resistant packaging.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage 
For rivaroxaban tablets and the placebo, no storage restrictions (temperature, humidity, light) 
apply. The storage recommendation for rivaroxaban is room temperature (approximately 15°C to 
30°C).
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects must be instructed to return all original containers, whether empty 
or containing study drug. Study drug returned by study subjects will be stored and disposed of 
according to the sponsor’s instructions. Study-site personnel must not combine contents of the 
study drug containers.
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Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor’s site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the drug return form. When the study site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
Study drug should be dispensed under the supervision of the investigator, a qualified member of 
the investigational staff, or by a hospital/clinic pharmacist. Study drug will be supplied only to 
subjects participating in the study. Returned study drug must not be dispensed again, even to the 
same subject. Whenever a subject brings his or her study drug to the site for pill count, this is not 
seen as a return of supplies. Study drug may not be relabeled or reassigned for use by other 
subjects. The investigator agrees neither to dispense the study drug from, nor store it at, any site 
other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Central clinical laboratory manual

Central clinical laboratory supplies

IWRS manual

Imaging materials
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
All subjects enrolled in this study will be scheduled to undergo systemic cancer therapy. This 
study will assess whether the administration of a novel, oral anticoagulant medication can safely 
be given for the primary prevention of VTE and provide important benefits to the subjects in the 
reduction of mortality or major morbid events. In accordance with the current NCCN and 
ASCO guidelines, the existing evidence base for optimal primary VTE prevention is in need of 
additional data from a robustly designed RCT such as this study. The specific form of 
thromboprophylaxis recommended for a given subject ultimately should be based on the treating 
physician’s best clinical judgment.
It is unknown at the present time whether a direct, orally available inhibitor of FXa can or should 
be given for a prolonged period to prevent VTE primary events in cancer subjects. To minimize 
potential safety risks, subject safety will be closely monitored by the IDMC throughout the 
study. Given the extensive AE data currently available for rivaroxaban, a streamlined approach to 
collection of AE data is being utilized in this study, as described in Section 3.2, Study Design 
Rationale. 
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Women of childbearing potential who are enrolled in the study must agree to use an adequate 
birth control method or remain abstinent throughout the study, and pregnancy testing will be 
done on all women of childbearing potential before study entry and at the end of treatment.
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential AEs of the study, and provide their consent voluntarily will be enrolled. 
Investigators should inform the subject of the importance to complete all study visits if their study 
drug is discontinued prematurely due to an AE, or other reasons, in order to assess the vital status 
and determine if outcome events may have occurred. If these subjects refuse office visits, the 
investigator should remind the subject about the importance of allowing regular contact until study 
end, according to the Time and Events Schedule, either with them, or with a legally acceptable 
representative, or their primary care physician to determine vital status and if an efficacy or safety 
outcome event has occurred.
The total blood volume to be collected is considered to be an acceptable volume for a subject 
with cancer. 
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects.
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials
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
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB 
(at least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s). 
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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required. The reapproval should be documented in writing (excluding the ones that are purely 
administrative, with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any 
study-related activity. The ICF(s) that is/are used must be approved by both the sponsor and by 
the reviewing IEC/IRB and be in a language that the subject can read and understand. The 
informed consent should be in accordance with principles that originated in the Declaration of 
Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and sponsor 
policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her disease. Subjects will be 
told that alternative treatments are available if they refuse to take part and that such refusal will 
not prejudice future treatment. Finally, they will be told that the investigator will maintain a 
subject identification register for the purposes of long-term follow up if needed and that their 
records may be accessed by health authorities and authorized sponsor personnel without 
violating the confidentiality of the subject, to the extent permitted by the applicable law(s) or 
regulations. By signing the ICF the subject is authorizing such access, including permission to 
obtain information about his or her survival status, and agrees to allow his or her study physician 
to recontact the subject for the purpose of obtaining consent for additional safety evaluations, if 
needed, and subsequent disease-related treatments, or to obtain information about his or her 
survival status.  
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy 
of the ICF must be given to the subject.
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the subject is obtained.
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16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory biomarker research is not conducted under standards appropriate for the return of 
data to subjects. In addition, the sponsor cannot make decisions as to the significance of any 
findings resulting from exploratory research. Therefore, exploratory research data will not be 
returned to subjects or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 5 years (or according to local regulations) 
for additional research and will not include molecular, biologic, or genetic studies. Samples will 
only be used to understand rivaroxaban, thromboprophylaxis in ambulatory cancer subjects, 
differential drug responders, and to develop tests/assays related to rivaroxaban. The research may 
begin at any time during the study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.2.4, Withdrawal From the Study).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
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addressed as a specific ethical consideration in Section 16.1, Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the 
investigator. 
Protocol 
amendments 
must 
not 
be 
implemented 
without 
prior 
IEC/IRB approval, or when the relevant competent authority has raised any grounds for 
non-acceptance, except when necessary to eliminate immediate hazards to the subjects, in which 
case the amendment must be promptly submitted to the IEC/IRB and relevant competent 
authority. Documentation of amendment approval by the investigator and IEC/IRB must be 
provided to the sponsor. When the change(s) involves only logistic or administrative aspects of 
the study, the IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate 
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator.

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
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applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable.

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable.

Documentation of investigator qualifications (eg, curriculum vitae).

Completed investigator financial disclosure form from the principal investigator, where 
required.

Signed and dated clinical trial agreement, which includes the financial agreement.

Any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of signed informed consent; dates of visits; results of safety and efficacy 
parameters as required by the protocol; record of all AEs and follow up of AEs; concomitant 
medication; drug receipt/dispensing/return records; study drug administration information; and 
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date of study completion and reason for early discontinuation of the study drug or withdrawal 
from the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
The minimum source documentation requirements for Section 4.1, Inclusion Criteria, and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the case report form in the protocol include the electronic source system but information 
collected through the electronic source system may not be limited to that found in the CRF. Data 
in this system may be considered source documentation.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. 
Electronic data capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an eCRF, and transmitted in a secure 
manner to the sponsor within the timeframe agreed upon between the sponsor and the study site. 
The electronic file will be considered to be the eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Study-site personnel must complete the eCRF as soon as possible after a subject visit, 
and the forms should be available for review at the next scheduled monitoring visit.
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All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the eDC tool. The 
investigator or study-site personnel must adjust the eCRF (if applicable) and complete the query. 
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
3 different ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Study-site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review eCRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources. 
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
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accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study-site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare data entered into the eCRFs with the hospital or clinic records (source 
documents); a sample may be reviewed. The nature and location of all source documents will be 
identified to ensure that all sources of original data required to complete the eCRF are known to 
the sponsor and study-site personnel and are accessible for verification by the sponsor study-site 
contact. If electronic records are maintained at the study site, the method of verification must be 
discussed with the study-site personnel. 
Remote data surveillance will be performed to monitor the study. Key subject demographic data, 
site performance data, and other key variable data will be monitored remotely as part of routine 
data surveillance on a monthly basis for all sites and be compared to the results seen overall for 
that country and region. Sites identified as having subjects with data that deviates substantially 
from the norm may also be subject to additional in-person monitoring visits.
Direct access to source documentation must be allowed for the purpose of verifying that the data 
recorded in the eCRF are consistent with the original source data. Findings from this review of 
CRFs and source documents will be discussed with the study-site personnel. The sponsor expects 
that, during monitoring visits, the relevant study-site personnel will be available, the source 
documentation will be accessible, and a suitable environment will be provided for review of 
study-related documents. The monitor will meet with the investigator on a regular basis during 
the study to provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts will occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last visit for the last subject participating in the 
study. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final subject visit at that study site, in the time frame specified in the Clinical Trial 
Agreement.
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17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding rivaroxaban or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including exploratory biomarker research data, generated as 
a result of this study, are considered confidential and remain the sole property of the sponsor. 
The investigator agrees to maintain this information in confidence and use this information only 
to accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of rivaroxaban, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information 
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derived from the clinical studies to be used, the investigator is obligated to provide the sponsor 
with all data obtained in the study.
The results of the study will be reported in a clinical study report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of exploratory biomarker
analyses performed after the clinical study report has been issued will be reported in a separate 
report and will not require a revision of the clinical study report. Study subject identifiers will 
not be used in publication of results. Any work created in connection with performance of the 
study and contained in the data that can benefit from copyright protection (except any 
publication by the investigator as provided for below) shall be the property of the sponsor as 
author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study-site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 12 months of the availability of the final data 
(tables, listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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BAY 59-7939 (Rivaroxaban) Investigator Brochure, version no.: 22. Bayer HealthCare 
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Cohen AT, Spiro TE, Buller HR, et al. Rivaroxaban thromboprophylaxis in acutely ill medical 
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Eriksson BI, Borris LC, Friedman RJ, et al., on behalf of the RECORD 1 Study Group. 
Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med.
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Falanga A, Marchetti M. Venous thromboembolism in the hematologic malignancies. J Clin 
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Geerts WH, Bergqvist D, Pineo GF et al. Prevention of venous thromboembolism: American 
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Gomes M MP, Deitcher SR. Diagnosis of venous thromboembolic disease in cancer patients. 
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Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ III. Risk factors 
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Kakkar Ak, Brenner B, Dahl QE, et al for the RECORD2 Investigators. Extended duration 
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Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic 
therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians 
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Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM, Lyman GH. Thromboembolism 
in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24:484-490.
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Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a 
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2007;5:632-634.
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Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation 
of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111:4902-4907.
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Lassen MR, Ageno W, borris LC, et al for the RECORD3 Investigators. Rivaroxaban versus 
enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med.
2008;358:2776-2786.
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Lyman GH, Eckert L, Wang Y, Wang H, Cohen A. Venous thromboembolism risk in patients 
with cancer receiving chemotherapy: a real-world analysis. Oncologist. 2013;18:1321-1329.
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Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and 
treatment in patients with cancer: Clinical Oncology Practice Guideline Update. J Clin Oncol. 
2013;31:2189-2204.
26.
Mack WJ, Ducruet AF, Hickman ZL, et al. Doppler ultrasonography screening of poor-grade 
subarachnoid hemorrhage patients increases the diagnosis of deep venous thrombosis. 
Neurol Res. 2008;9:889-892.
27.
Maraveyas A, Waters J, Roy R, et al. Gemcitabine versus gemcitabine plus dalteparin 
thromboprophylaxis in pancreatic cancer. Eur J Cancer. 2012;48:1283-1292.
28.
Menapace LA, Peterson DR, Berry A, Sousou T, Khorana AA. Symptomatic and incidental 
thromboembolism are both associated with mortality in pancreatic cancer. Thromb Haemost. 
2011;106:371-378.
29.
O’Connell CL, Boswell WD, Duddalwar V, et al. Unsuspected pulmonary emboli in cancer 
patients: clinical correlates and relevance. J Clin Oncol. 2006;24:4928-4932.
30.
Ottinger H, Belka C, Kozole G, et al. Deep venous thromboembosis and pulmonary artery 
embolism in high-grade non-Hodgkin’s lymphoma. Incidence, causes and prognostic relevance. 
Eur J Haematol. 1995;54: 186-194.
31.
Perzborn E, Strassburger J, Wilmen A, et al. In vitro and in vivo studies of the novel 
antithrombotic agent BAY 59-7939-an oral, direct factor Xa inhibitor. J Thromb Haemost. 
2005;3:514-521.
32.
Prins MH, Lensing AW, Brighton TA, et al. Oral Rivaroxaban versus enoxaparin with vitamin K 
antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer 
(EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of 2 randomized controlled 
trials. Lancet Haematol. 2014;1(1):e37-e46.
33.
Qaseem A, Snow V, Barry P, et al; Joint American Academy of Family Physicians/American 
College of Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism. Current 
diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the 
American Academy of Family Physicians and the American College of Physicians. Ann Intern 
Med. 2007;146(6):454-458.
34.
Riess H, Pelzer U, Deutschinoff G, et al. A prospective, randomized trial of chemotherapy with 
or without the low molecular weight heparin (LMWH) enoxaparin in patients (pts) with 
advanced pancreatic cancer (APC): results of the CONKO 004 trial (abstract LBA4506). J Clin 
Oncol. 2009;27:Suppl:18S. abstract.
35.
Rivaroxaban [package insert]. Titusville, NJ. Janssen Pharmaceuticals, Inc; 2015.
36.
Robinson KS, Anderson DR, Gross M, et al. Accuracy of screening compression 
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ultrasonography and clinical examination for the diagnosis of deep vein thrombosis after total 
hip or knee arthroplasty. Can J Surg 1998;41(5):368-373.
37.
Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and 
Standardization Committee of the International Society on Thrombosis and Haemostasis. 
Definition of major bleeding in clinical investigations of antihemostatic medicinal products in 
non-surgical patients. J Thromb Haemost. 2005;3(4):692-694.
38.
Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE. Incidence of venous 
thromboembolism in patients hospitalized with cancer. Am J Med. 2006;119:60-68.
39.
Streiff MB, Bockenstedt PL, Cataland SR, et al. Venous thromboembolic disease.J Natl Compr 
Canc Netw. 2013;11:1402-1429.
40.
The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. 
N Engl J Med. 2010;363; 2499-2510.
41.
The EINSTEIN-PE Investigators. Oral Rivaroxaban for the treatment of symptomatic pulmonary 
embolism. N Engl J Med. 2012;366:1287-1297.
42.
Wang CJ, Wang JW, Weng LH, Hsu CC, Lo CF. Outcome of calf deep vein thrombosis after 
total knee arthroplasty. J Bone Joint Surg Br. 2003;85(6):841-844.
.
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Attachment 1:
Reporting of Efficacy Endpoints, Adverse Events, and Serious Adverse Events
Event category
Collected in the CRF 
(reviewed by IDMC)
Reported to Sponsor by 
Investigator
(within 24 h)
Primary efficacy composite endpointa including VTE/ATE related deaths
Yes (endpoint page)
No
Secondary efficacy endpointb including all-cause mortality
Yes (endpoint page)
No
All bleeding events
Yes (endpoint page)
No
All other SAEs, and AESI
Yes
Yes
Nonserious AEs leading to permanent discontinuation from study drug treatment 
and AEs of particular concern to the investigator
Yes (AE page)
No
Other nonserious AEs
No
No
Pregnancy and pregnancy outcome
Yes (AE page)
Yes
AE=adverse event; AESI=adverse events of special interest; ATE=arterial thromboembolism; CRF=case report form; h=hour; IDMC=Independent Data Monitor 
Committee; SAE=serious adverse event; VTE=venous thromboembolism
a
The primary efficacy composite endpoint is the composite of objectively confirmed symptomatic lower extremity proximal deep vein thrombosis (DVT), 
asymptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, 
incidental PE, or VTE-related death.
b
The secondary efficacy endpoint includes: individual components of the primary efficacy composite variable, confirmed fatal/non-fatal ATE events, confirmed 
fatal/non-fatal visceral VTE events, composite of symptomatic lower extremity proximal DVT, asymptomatic lower extremity proximal DVT, symptomatic 
lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, incidental PE, and all-cause mortality, and the composite of 
symptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, and 
VTE-related deaths.
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Attachment 2:
Calculation of Creatinine Clearance 
The CrCl (expressed as mL/min), is yielded by the Cockcroft and Gault formulas, relating serum creatinine, with 
age (in years) and body weight (in Kg).a
If creatinine concentration is measured in µmol/L, then the following 2 equations are used for men and women:
Men:
[(140 – age [yr]) weight (kg)]
[0.814 creatinine (µmol/L)]
Women:
[(140 – age [yr]) weight (kg)]
0.85
[0.814 creatinine (µmol/L)]
If creatinine concentration is measured in mg/dL, then the following 2 equations are used for men and women:
Men:
[(140 – age [yr]) weight (kg)]
[72 creatinine (mg/dL)]
Women:
[(140 – age [yr]) weight (kg)]
0.85
[72 creatinine (mg/dL)]
a Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.
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Attachment 3:
Cancer-Associated Venous Thromboembolism Risk Score
A Modified Risk Stratification Model for Cancer-Associated Venous Thromboembolism
Patient Characteristic
Score
Cancer

Very high risk: stomach, pancreasa
2

High risk: bladder, gynecologic, lymphoma, lung, renalb or testicular
1
Body mass index ≥35 kg/m2
1
Platelet count ≥350,000/mm3
1
Hemoglobin <10 g/dL 
1
Leukocyte count >11,000/mm3
1
a
In the very high-risk category, primary brain tumors were removed since subjects with known brain tumors are 
excluded from study inclusion.
b
Updated guidelines (inclusion of renal tumors): Lyman GH, Khorana AA, Kuderer NM, et al. Venous 
thromboembolism prophylaxis and treatment in patients with cancer: Clinical Oncology Practice Guideline 
Update. J Clin Oncol 2013; 31:2189-2204.
Adapted from Sud R, Khorana AA. Cancer-associated thrombosis: risk factors, candidate biomarkers and a risk 
model. Thromb Res 2009;123(Suppl 4):S18-S21.
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Attachment 4:
Functional Status Assessment Tool
ECOG/WHO/Zubrod Performance Status Scale
0
Asymptomatic (fully active; able to carry on all predisease activities without restriction)
1
Symptomatic but completely ambulatory (restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or sedentary nature; eg, light housework, office 
work)
2
Symptomatic, <50% in bed during the day (ambulatory and capable of all self-care but unable to 
carry out any work activities; up and about more than 50% of waking hours)
3
Symptomatic, >50% in bed, but not bedbound (capable of only limited self-care; confined to bed 
or chair 50% or more of waking hours)
4
Bedbound (completely disabled; cannot carry on any self-care; totally confined to bed or chair)
5
Death
WHO=World Health Organization
Oken MM, Creech RH, Tormey DC, et al. Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol. 1982;5:649-655. 
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Attachment 5: 
The MDRD Formula for Calculation of GFR
The Modification of Diet in Renal Disease (MDRD) study was a multicenter, controlled trial that evaluated the 
effect of dietary protein restriction and strict blood pressure control on the progression of renal disease. During the 
baseline period, serum creatinine and several variables were measured in 1,628 subjects with chronic renal disease. 
The objective was to develop an equation that would predict GFR.
From this study, it was determined that older age and female sex were independent predictors of GFR, reflecting the 
well-known relation of age and sex to muscle mass. GFR was further adjusted for body surface area so that neither 
height nor weight was an independent predictor of adjusted GFR. African American ethnicity was an independent 
predictor of higher GFR as on average, black persons have greater muscle mass than whites.
The final MDRD Study prediction equation for GFR is as follows with Pcr being serum or plasma creatinine in in 
mg/dL:
GFR (mL/min1.73 m2) = 186 x (Pcr)-1.154 x (age)-0.203 x (0.742 if female) x (1.210 if African American)
The GFR is expressed in mL/min/1.73m2
Levey AS, Bosch JP, Lewis JB et al. A more accurate method to estimate glomerular filtration rate from serum 
creatinine: a new prediction equation. Ann Intern Med. 1999;130:461-470.
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Attachment 6: 
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Equation for 
Estimating GFR
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black]
where:

Scr is serum creatinine in mg/dL,

κ is 0.7 for females and 0.9 for males,

α is -0.329 for females and -0.411 for males,

min indicates the minimum of Scr /κ or 1, and

max indicates the maximum of Scr /κ or 1.
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. 
Ann Intern Med. 2009;150(9):604-612.
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INVESTIGATOR AGREEMENT
NCT02555878

SAP_000.pdf: 
1
Approved, Date: 5 September 2018
Janssen Scientific Affairs *
Statistical Analysis Plan
Efficacy and Safety of Rivaroxaban Prophylaxis Compared with Placebo in Ambulatory 
Cancer Patients Initiating Systemic Cancer Therapy and at High Risk for Venous 
Thromboembolism
Protocol STM4001; Phase [3b]
BAY59-7939/JNJ39039039STM4001 (Rivaroxaban)
Status:
Approved
Date:
5 September 2018
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-120534500; 6.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 7
1.
INTRODUCTION.................................................................................................................................. 8
1.1.
Study Objectives .............................................................................................................................. 8
1.2.
Study Design.................................................................................................................................... 9
1.2.1.
Study Drug Discontinuation and Early Withdrawal from Double-Blind Period ........................... 10
1.3.
Statistical Hypotheses for Study Objectives .................................................................................. 10
1.4.
Sample Size Justification ............................................................................................................... 10
1.5.
Randomization and Blinding .......................................................................................................... 12
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 13
2.1.
Visit Windows................................................................................................................................. 13
2.2.
Baseline ......................................................................................................................................... 13
2.3.
Pooling Algorithm for Analysis Centers.......................................................................................... 13
2.4.
Analysis Populations...................................................................................................................... 13
2.4.1.
Intent-to-Treat (ITT) Population .................................................................................................. 13
2.4.2.
Per-Protocol (PP) Population ..................................................................................................... 13
2.4.3.
Safety Population:....................................................................................................................... 14
2.5.
Definition of Study Dates and Observation Period End Dates ...................................................... 15
2.6.
Observation Periods....................................................................................................................... 16
2.6.1.
Up-to-Day-180 Observation Period ............................................................................................ 17
2.6.2.
On-Treatment Observation Period ............................................................................................. 17
2.6.3.
Post-Randomization Observation Period ................................................................................... 18
2.6.4.
Post-First Dose Observation Period ........................................................................................... 19
2.7.
Definition of Subgroups.................................................................................................................. 20
3.
INTERIM ANALYSIS AND INDEPENDENT DATA MONITORING COMMITTEE (IDMC) .............. 20
4.
SUBJECT INFORMATION................................................................................................................ 21
4.1.
Demographics and Baseline Characteristics ................................................................................. 21
4.2.
Disposition Information................................................................................................................... 21
4.3.
Treatment Compliance Based on Exposure .................................................................................. 21
4.4.
Extent of Exposure......................................................................................................................... 22
4.5.
Systemic Cancer Therapies and Concomitant Medications .......................................................... 22
4.6.
Study Drug Discontinuation and Early Withdrawal from Double-Blind Period............................... 22
5.
EFFICACY ......................................................................................................................................... 24
5.1.
Analysis Specifications................................................................................................................... 24
5.1.1.
Level of Significance................................................................................................................... 24
5.1.2.
Data Handling Rules................................................................................................................... 24
5.2.
Primary Efficacy Composite Endpoint............................................................................................ 24
5.2.1.
Definition..................................................................................................................................... 25
5.2.2.
Analysis Methods........................................................................................................................ 25
5.2.2.1.
Assessment of Proportional Hazards Assumption .................................................................. 25
5.2.3.
Supportive Analyses for Primary Efficacy Composite Endpoint................................................. 25
5.2.4.
Subgroup Analyses for the Primary Efficacy Composite Endpoint............................................. 26
5.2.5.
Sensitivity Analyses.................................................................................................................... 27
5.2.5.1.
Additional Primary Efficacy Composite Endpoint – Include Asymptomatic Distal DVT .......... 27
5.2.5.2.
Sensitivity Analysis for Primary Efficacy Composite Endpoint ................................................ 27
5.3.
Competing Risk Analysis ............................................................................................................... 28
5.4.
Key Secondary Endpoints.............................................................................................................. 29
5.4.1.
Definition..................................................................................................................................... 29
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5.4.2.
Analysis Methods........................................................................................................................ 29
5.5.
Adjustment for Multiplicity .............................................................................................................. 30
5.6.
Additional Secondary Efficacy Variable(s)..................................................................................... 30
5.6.1.
Definition..................................................................................................................................... 31
5.6.2.
Analysis Methods........................................................................................................................ 32
5.7.
End-of-Study Vital Status Summary .............................................................................................. 32
6.
SAFETY............................................................................................................................................. 33
6.1.
Bleeding ......................................................................................................................................... 33
6.1.1.
Bleeding Events Classification ................................................................................................... 33
6.1.2.
Primary Safety Endpoint of Bleeding.......................................................................................... 34
6.1.2.1.
Definition.................................................................................................................................. 34
6.1.2.2.
Analysis Methods .................................................................................................................... 34
6.1.3.
Supportive Analysis of the Primary Safety Endpoint of Bleeding............................................... 35
6.1.4.
Secondary Safety Endpoints of Bleeding ................................................................................... 35
6.1.4.1.
Definition.................................................................................................................................. 35
6.1.4.2.
Analysis Methods .................................................................................................................... 35
6.2.
Adverse Events .............................................................................................................................. 36
6.2.1.
Imputation Rules for Missing AE Dates...................................................................................... 37
6.2.2.
Adverse Events Resulting in Withdrawal from the Study and Discontinuation of 
Treatment: .................................................................................................................................. 37
6.2.3.
Serious Adverse Events (SAE) and Deaths during the Study:................................................... 38
6.2.4.
Adverse Events of Special Interest............................................................................................. 38
6.3.
Clinical Laboratory Tests................................................................................................................ 39
6.4.
Vital Signs and Physical Examination Findings ............................................................................. 39
6.5.
Electrocardiogram.......................................................................................................................... 39
6.6.
Other Safety Parameters ............................................................................................................... 39
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 39
7.1.
Pharmacokinetics........................................................................................................................... 39
7.2.
Pharmacodynamics........................................................................................................................ 39
8.
BIOMARKER..................................................................................................................................... 40
9.
HEALTH CARE RESOURCE UTILIZATION .................................................................................... 40
REFERENCES............................................................................................................................................ 41
ATTACHMENT: EXAMPLES OBSERVATION PERIOD AND EVENT/CENSORING TIME .................... 42
ATTACHMENT: IDMC DATA PRESENTATION SPECIFICATION .......................................................... 46
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AMENDMENT HISTORY
All changes and clarifications of planned analyses in the SAP are listed below:
Topic or Section
Description of Changes and Clarifications of Planned Analyses
Changes from v5.0 to v6.0
2.5
Definition of Study Dates
Imputation rule for partial exposure end dates was added to the rule of 
missing end dates.
Changes from v4.0 to v5.0
2.5
Definition of Study Dates and
Observation Period End Dates
Up-to-Day 180 observation period end date for subjects who withdrew 
early is maximum of withdrawal date and randomization date+180 days.
2.6
Subgroups 
Subgroup criteria for the Khorana score is update to 2, 3, 4, and ≥5.
4.3
Treatment Compliance 
Treatment compliance definition is updated.  This is based on exposure 
data for subjects and based on the duration the subjects were in the trial.
4.5
Systemic Cancer Therapies and 
Concomitant Medications
Systemic cancer therapies taken at randomization and during the double-
blind period as well as concomitant medications taken during double-blind 
period is defined.
5.2.4
Subgroup Analysis for Primary 
Efficacy Composite Endpoint
Subgroup analysis will be performed if there are at least 30 total 
randomized subjects in each subgroup category
5.6, 5.6.1
Additional Secondary Efficacy 
Variables
Definition
A 3rd composite endpoint is added to the secondary efficacy endpoints.  
This is a composite of events in the primary efficacy composite endpoint, 
fatal/non-fatal ATE, and visceral VTE.
A 4th composite endpoint is added to the secondary efficacy endpoints.  
This is a composite of symptomatic VTE events and major bleeding
9
Health Care Resource Utilization
Section heading relabeled and only descriptive statistics (frequency counts, 
mean, median, SD) will be presented.
Attachment
Added IDMC Data Preparation Specification.
Version 3.0 to 4.0
Document resaved with no changes made to v3.0
Changes from v2.0 to 3.0
1.0
Introduction
Updated the version of the protocol to Amendment INT-4 finalized on 
February 16, 2018. 
1.1
Study Objectives/Primary Objective
The occurrence of symptomatic lower extremity distal DVT event is 
included in the primary objective based on the amended protocol (v4.0).
1.3
Statistical Hypothesis for Study 
Objective
The occurrence of symptomatic lower extremity distal DVT event is 
included in the composite.
1.4 
Sample Size Justification
Section updated based on the amended protocol (v 4.0). The following text 
is added – Towards the end of the enrollment phase, approximately 800 
subjects were planned to be randomized into the study due to the high 
subject discontinuation rate.
2.4 
Definition of End-of-Study date
The End-of-Study date updated to include the last assessment date during 
the study, including the Day 210/Post-Treatment Follow-Up visit.
5.2 
Primary Efficacy Composite Endpoint
5.2.1 
Definition
The occurrence of symptomatic lower extremity distal DVT event is 
included in the primary efficacy composite endpoint.
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5.2.4
Subgroup Analyses for the Primary 
Endpoint
Subgroup analysis will be performed if there are enough subjects in each 
subgroup (at least 5% of total randomized subjects).  In addition, the Gail-
Simon test is specified to assess interactions if found to be significant.
5.3
Competing Risk Analysis
The occurrence of symptomatic lower extremity distal DVT event is 
included in the primary efficacy composite endpoint for the analysis.
5.4
Key Secondary Endpoints
The occurrence of symptomatic lower extremity distal DVT event is 
included in the key secondary efficacy composite endpoint of symptomatic 
VTE events and VTE-related deaths
5.4.2 
Analysis Methods
Additional supportive analysis of the key secondary endpoints based on the 
post-randomization observation period is included.
5.6
Additional Secondary Efficacy 
Endpoints
Definition of an ATE event is clarified. The occurrence of symptomatic 
lower extremity distal DVT event is included in the additional efficacy 
composite endpoint 1.
Additional composite endpoint of symptomatic events and major bleeding 
event s added.
5.6.1
Definition
The time to first occurrence of fatal/non-fatal ATE is defined.
Additional composite endpoint of symptomatic events and major bleeding 
event is added.
6.1.1
Bleeding Events Classification
Imputation rules for partial bleeding start dates is added.
Changes from v1.0 to v2.0
1.2.1
Study Drug Discontinuation and Early 
Withdrawal from Double-Blind Period
Section added describing the details as per the protocol with regards to 
subject permanently discontinuing study drug.
2.3.1
Intent-to-Treat (ITT) Population
2.3.3 Per-Protocol (PP) Population
Section numbering corrected.
2.3.3
Safety Population
Section added with the definition of safety population.
2.4
Definition of Study Dates and 
Observation Period End Dates
Definitions of study dates and observation period end dates is further 
clarified.
2.5
Observation Periods
Table describing the efficacy and safety endpoints and analysis added. 
2.5.1 
Up-to-Day 180 Observation Period
Section renumbered to be 2.5.1.
Censoring rule for subjects who did not experience an event during this 
observation period updated to be defined as censored at the last day of their 
complete assessment for study outcomes.
2.5.2
On-Treatment Observation Period
Imputation rule using a conservative approach for randomized subjects but 
never dosed is added.
2.5.3
Post-Randomization
Censoring rule for subjects who did not experience an event during this 
observation period updated to be defined as censored at the last contact date 
is clarified.
2.5.4
Post-First Dose Observation Period
Imputation rule using a conservative approach for randomized subjects but 
never dosed is added.
2.6
Definition of Subgroups
Tumor type subgroup is clarified.
4.3
Treatment Compliance
Imputation rule in the event of missing information on the returned number 
of tables added.
4.6
Study Discontinuation and Early 
Withdrawal from Double-Blind Period
Section updated to include two scenarios with regards to discontinuation 
from study treatment and withdrawal from double-blind period.
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5.1.2
Data Handling Rules
Imputation rule for partial dates is added.
5.2.2
Analysis Methods
The primary composite endpoint analysis will be based on the Up-to-Day 
180 observation period for the ITT population
5.2.2.1
Assessment of Proportional Hazards 
Assumption
In event of non-proportional hazards, alternative approaches were included.
5.2.3 
Supportive Analyses for Primary 
Efficacy Composite Endpoint
Section updated to include supportive analysis based on the on-treatment 
observation period.
5.2.5.1
Additional Primary Efficacy 
Composite Endpoint – Include Distal 
DVT
Additional composite efficacy endpoint defined to include the occurrences 
of symptomatic lower extremity distal DVT and asymptomatic lower 
extremity distal DVT.
5.2.5.2
Sensitivity Analysis for Primary 
Efficacy Endpoint
Clarification for analysis is added. 
5.3
Competing Risk Analysis
Section moved from 5.6. 
5.4.2
Analysis Methods
Analysis of key secondary efficacy endpoints will be based on the up-to-
day 180 observation period.
6.1.3
Supportive Analysis of the Primary 
Safety Endpoint of Bleeding
Additional supportive analysis of time to multiple bleeding event using 
recurrent event analysis is added.
Attachments
Illustrations with examples depicting the different observation periods 
including occurrences of events and censoring rules is added
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BAY59-7939/JNJ39039039STM4001  (Rivaroxaban)                                             Statistical Analysis Plan STM4001
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ABBREVIATIONS
AE
adverse event
ATE
arterial thrombosis event
AESI
adverse event of special interest
APC
advanced pancreatic cancer
CEC
Clinical Endpoint Committee
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
eCRF
electronic case report form
CSR
Clinical Study Report
CU
compression ultrasonography
DPS
Data Presentation Specification
DVT
deep vein thrombosis
ECOG
European Cooperative Oncology Group
EODB
end-of-double-blind period
EOS
end-of-study
EOT
end-of-treatment
HR
Hazard ratio
IDMC
Independent Data Monitoring Committee
ISTH
International Society on Thrombosis & Haemostasis
ITT
Intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamic
PE
pulmonary embolism
PK
pharmacokinetic(s)
PP
per-protocol
RRR
relative risk reduction
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
T&E
Time and Events
TEAE
treatment-emergent adverse event
VTE
venous thromboembolism
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1.
INTRODUCTION
This statistical analysis plan (SAP) specifies definitions of analysis populations, derived variables, 
and statistical methods for analysis of efficacy and safety for the Phase 3b study BAY59-
7939/JNJ39039039STM4001. This SAP is based on the Clinical Protocol BAY59-
7939/JNJ39039039STM4001 Amendment INT-4 finalized on February 16, 2018. 
Titles, mock-ups and programming instructions for all statistical outputs (tables, figures, and 
listings) will be provided in a separate document entitled Data Presentation Specifications (DPS).
This study SAP will be finalized prior to database lock.  
This study SAP is also used for the Independent Data Monitoring Committee (IDMC) pre-
specified safety reviews.  For the IDMC however the definitions and imputation rules are defined 
based on the data cutoffs and accumulating data at the time of each DMC meetings.  
1.1.
Study Objectives
Primary Objective
The primary efficacy objective is to demonstrate that rivaroxaban is superior to placebo for 
reducing the risk of the primary composite outcome as defined by objectively confirmed 
symptomatic lower extremity proximal DVT, asymptomatic lower extremity proximal DVT, 
symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-
fatal PE, incidental PE, and VTE-related deaths in ambulatory adult subjects with various cancer 
types receiving systemic cancer therapy who are at high risk of developing a VTE.
Secondary Objectives
The key secondary efficacy objectives of this study are to compare the efficacy of rivaroxaban 
with placebo for reducing the risk of symptomatic VTE events and VTE related deaths and all-
cause mortality in ambulatory adult subjects with various cancer types receiving systemic cancer 
therapy who are at high risk of developing a VTE.
Other secondary efficacy objectives include the evaluation of the individual components of the 
primary efficacy composite outcome variable, confirmed fatal/non-fatal arterial thromboembolism 
(ATE) events, confirmed fatal/non-fatal visceral VTE events, symptomatic lower extremity distal 
DVT, a composite of symptomatic lower extremity proximal DVT, asymptomatic lower extremity 
proximal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, incidental PE, and 
all-cause mortality, and a composite of symptomatic lower extremity proximal DVT, 
symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-
fatal PE, and VTE-related deaths.  
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1.2.
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, superiority 
study comparing the efficacy and safety of rivaroxaban with placebo for primary prophylaxis of 
VTE (defined as DVT and/or PE) in ambulatory adult men and women, 18 years of age and older, 
with various cancer types who are scheduled to initiate systemic cancer therapy as a component of 
their standard of care anticancer regimen, who have a baseline Khorana thromboembolic risk 
score of ≥2, and are judged by the investigator or qualified designee to be an appropriate 
candidate for treatment with either placebo (10 mg orally once daily for 180 days) or rivaroxaban 
(10 mg orally once daily for 180 days) for thrombo-prophylaxis based on their clinical status.
The study consists of 3 periods: a 2-week screening period, a 180-day double-blind treatment 
period with an End-of-Treatment (EOT) visit [for subjects who permanently stop study drug], and 
a 30-day post-treatment follow-up period with a Day 210/End-of-Study (EOS) visit. The duration 
of participation in the study for each subject is approximately 32 weeks.
A target of approximately 700 subjects will be randomly assigned into the study in a 1:1 ratio to 1 
of 2 treatment groups (rivaroxaban 10 mg qd and placebo) with approximately 350 subjects per 
treatment group. Towards the end of the enrollment phase, the planned total of subjects to be 
randomized into the study was revised to approximately 800 subjects due to a higher than 
originally anticipated subject discontinuation rate. In addition, subjects will be stratified at 
randomization by tumor type (APC or non-APC) such that approximately 25% of the subjects 
randomly assigned are those with APC. 
Randomized subjects will continue with their recommended systemic cancer therapy (SCT) 
during the study period and will be examined by compression ultrasonography (CU) at every 
8-week intervals. Subjects permanently discontinuing the study drug will be required to have a 
CU performed within 2 days of receiving their last dose of study drug. 
Figure 1: Schematic Overview of the Study
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1.2.1.
Study Drug Discontinuation and Early Withdrawal from Double-Blind 
Period 
As per the protocol (Section 10.2.2), if a subject permanently discontinued study drug before the 
Day 180 visit/End of double-blind (EODB) period, this would not result in automatic permanent 
withdrawal of the subject from the study. Subjects are encouraged to make every effort to 
continue participation in the study and complete the schedule subsequent study visits until the 
planned end of their study double-blind duration (Day 180/EODB). All outcomes/events data 
(VTE, vital status (alive/dead), MI, stroke, and other thrombosis events) and safety data 
(including bleeding events) are collected. If a subject permanently discontinued study drug prior 
to Day 180 but continued in the study and completed all study visits up to Day 180, then this 
subject is considered as having ‘completed the double-blind period’ (that is, participated in the 
study up to the Day 180 visit).  
All subjects including those who discontinued prior to Day 180 visit are contacted by telephone 
for a Day 210/EOS follow-up assessment.  Any outcome/event data (including vital status) 
reported during this telephone visit is collected at this Day 210/EOS visit as agreed upon by the 
subject informed consent.  In the event a subject withdrew consent or is lost-to-follow up, the 
vital status data are obtained through public information (death and other registries) per local 
guidelines and as allowed by local registration. 
1.3.
Statistical Hypotheses for Study Objectives
The primary hypothesis of this study is that prophylactic treatment with rivaroxaban administered 
at a dose of 10 mg once daily for up to 6 months will be superior to placebo in reducing the risk 
of objectively confirmed symptomatic lower extremity proximal DVT, asymptomatic lower
extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity 
DVT, symptomatic non-fatal PE, incidental PE, or VTE-related death in ambulatory adult 
subjects with various cancer types receiving systemic cancer therapy who are at high risk of 
developing a VTE.
1.4.
Sample Size Justification
This is a 6-month fixed duration study to demonstrate the superiority of rivaroxaban compared 
with placebo in the ambulatory cancer subjects undergoing systemic cancer therapy.  Sample size 
determination is provided in the protocol Section 11.2 and described below:
Estimates for VTE events in this population vary but point out to a significant benefit (or, 
reduction in events) over placebo when treated with anticoagulant therapy. Per a recent review of 
the VTE prophylaxis studies in cancer subjects by Khorana et al (protocol ref 20-22), most RCTs 
on solid tumors have reported relative risk reductions (RRRs) anywhere between 50% and 64%. 
The duration of the earlier primary prophylaxis studies was generally between 3 to 4 months, in 
conjunction with initiation of systemic anticancer therapy. The basis for predictive events is 
derived from the Vienna CATS group, which utilized the Khorana thromboembolic risk score, 
and followed 819 ambulatory cancer subjects for symptomatic VTE as an endpoint. In a Kaplan-
Meier analysis, the cumulative probability of VTE after 6 months: Khorana thromboembolic risk 
score ≥ 3, 17.7% (95% CI: 11.0%-27.8%, N= 93), and 9.6% (95% CI: 6.2%-14.7%, N=221) in 
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those subjects with a Khorana thromboembolic risk score of 2. Taken together, these results show 
a symptomatic VTE rate at 180 days of at least 12% in subjects with a Khorana thromboembolic 
risk score of >2 is reasonable. The adjudication of objectively confirmed asymptomatic DVT and 
PE is estimated to add an additional 5%-10 % to the primary efficacy composite endpoint. 
Based on the above information and recommendations from the Cancer Associated Thrombosis 
Advisory Council, the sponsor planned the duration of the thromboprophylaxis treatment in the 
multiple malignancy study up to 6 months. Therefore, our estimates of assumed events rates are 
relatively conservative given that the period of treatment follow up is longer than earlier RCTs.
In this study with a six-month planned treatment with rivaroxaban, the primary efficacy outcome 
variable is a composite of any symptomatic DVT, proximal asymptomatic DVT, any PE, and 
VTE-related death. The study design allows fixed treatment duration of 6 months on each 
successfully randomized subject. Assuming a cumulative incidence rate of 14.5% for the primary 
composite events in the placebo group and 6.0% cumulative incidence rate in the rivaroxaban 
treatment group, a total sample of about 700 randomized subjects (350 per treatment group) will 
be required to demonstrate approximately 60% relative risk reduction (RRR) in the primary 
efficacy composite endpoint with a 2-sided Type 1 error rate of 5% and >90% statistical power 
(calculation performed by EAST 6.3 software) assuming a 20% discontinuation rate. Towards the 
end of the enrollment phase, approximately 800 subjects were planned to be randomized into the 
study due to the high subject discontinuation rate. In addition, this sample size will allow for 80% 
statistical power in each stratum (APC or non-APC) for slightly larger differences in incidence 
rates between the two randomized treatment groups to be statistically significant.
Essentially, the above overall sample size estimate is calculated based on the following 
assumptions:

Effect size: absolute difference in event rates = 8.5%, RRR = 58.6%
o
Primary efficacy composite endpoint event rate in the placebo arm: 14.5%
o
Primary efficacy composite endpoint event rate in the rivaroxaban arm: 6%

Power: >90%

Overall α level: 5%, 2-sided

Probability of dropping out of the study: 20%

Duration of enrollment period: 12 months

Duration of study: 6 months (fixed for each randomized subject)
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1.5.
Randomization and Blinding
A centralized randomization strategy will be implemented in this study. Subjects will be 
randomly assigned in a 1:1 ratio to 1 of 2 treatment groups based on a computer-generated 
subject-randomization schedule prepared by or under the supervision of the sponsor prior to 
initiation of the study. The randomization will be stratified by tumor type (Advanced Pancreatic 
Cancer [APC] or non-APC) such that up to approximately 25% of the subjects randomly assigned 
are those with APC. Using the randomization schedule, the IWRS will assign treatment. The 
IWRS will also provide the number of the study drug bottle to be dispensed for each randomly 
assigned subject on Day 1 and at each visit (except Day 180/End-of-Treatment) during the 
double-blind treatment period. The requestor must use his or her own user identification (ID) and 
personal identification number (PIN) when contacting the IWRS and will then be asked to 
provide relevant subject details to uniquely identify the subject. Based on these randomization 
codes, the study drug will be packaged and labeled in a manner that maintains the double-blinded 
nature of this study.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (ie, events that contribute to the 
primary and secondary outcome or treatment allocation) will be handled with special care to 
ensure that the integrity of the blind is maintained and the potential for bias is minimized. This 
can include making special provisions, such as segregating the data in question from view by the 
investigators, clinical team, or others as appropriate until the time of database lock and 
unblinding.
Pancreatic cancer subjects are at a higher risk to develop VTE (VTE Khorana risk score ≥2).  
These subjects are also more likely to discontinue early from the study. Therefore, higher than 
planned (25%) number of pancreatic subjects were allowed for enrollment into this study.
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2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
Data collected in the study from randomization through End-of-Double-Blind (EODB) will be re-
assigned to visit windows based on the actual date of assessment (only for the ECOG 
performance status evaluation, laboratory and vital signs data). 
The reference day is Study Day1 which will correspond to the randomization day.  The relative 
day will be determined relative to Study Day 1.
The visit windows are based on the scheduled clinic visits (see Time & Events Schedule in 
protocol) and are defined below:
Period
Visit Window
Time Intervalsa
for
Visit Window
Target Daya for
Visit Window
Screening/Randomization
Baseline
≤1
1
Double-Blind Period
Week 8
>1 to 84
56
Week 16
85 to 146
112
          Day 180/EODBb
≥147
180
a Based on actual study day of assessment; b = End of Double-Blind Period.  No lab or vital signs data 
were collected at the Day 210 Follow-Up/End-of-Study visit
If more than one assessment falls in the same visit window, the one closest to the target date will 
be used in summary tables.  In case of a tie (2 or more assessment which are equidistant), the 
latter assessment will be used.
2.2.
Baseline
Baseline value is defined as the last observation prior to and including Day 1.
2.3.
Pooling Algorithm for Analysis Centers
No pooling of centers (with varying number of randomized subjects) will be done.
2.4.
Analysis Populations 
2.4.1.
Intent-to-Treat (ITT) Population
This analysis population consists of all randomized subjects.  
2.4.2.
Per-Protocol (PP) Population
This population is a subset of the ITT population. Subjects with predefined major protocol 
deviations will be excluded from the ITT population. 
The predefined protocol deviations (based on major deviations) employed to define the PP 
population are:
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
Randomized without informed consent (entered study but inclusion criterion #12 not met)

Received wrong treatment (deviation recorded to be received wrong treatment or incorrect 
dose)

Randomized but not treated  

Randomized but did not satisfy the key study entry criteria (inclusion criteria not 
met/exclusion criteria met) 
o
Inclusion Criteria

#1 Ambulatory men and women ≥18 years of age

#4 Subject must have a Khorana thromboembolic risk score ≥2
o
Exclusion Criteria

#1 Subject has diagnosis of primary brain tumors

#2 Subject has known history of brain metastases

#3 Subject has bleeding diathesis, hemorrhagic lesions, active bleeding and 
other conditions with a high risk for bleeding

#4 Subject has hematologic malignancies with the exception of lymphoma

#8 Subject has evidence of VTE on screening Compression Ultrasound or 
incidental VTE identified on spiral computed tomography scans ordered 
primarily for staging or restaging of malignancy ≤30 days prior to 
randomization
All protocol deviations, including the deviations listed above will be examined and reviewed from 
a medical perspective prior to End-of-Study/database lock in a blinded fashion and subjects will 
be flagged accordingly in the final analysis database.
2.4.3.
Safety Population: 
This population is a subset of the ITT population, consisting of all randomized subjects who 
receive at least one dose of study drug.
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2.5.
Definition of Study Dates and Observation Period End Dates
The study dates and period end dates will be used to define the time period for data included in 
the analysis of efficacy and safety endpoints for the different observation periods (defined in 
Section 2.6).  
Study Day 1 date: the date of randomization of the subject.
End-of-Study (EOS): the date of the last study-related procedure for the subject (EOS is defined 
as last assessment day during the study, including the Day 210/Post-Treatment Follow Up visit) 
and is defined as the minimum (last assessment day during the study, death date).
Double-Blind period start date will be the date of randomization.  
Double-Blind period end date will be defined as the completion/early withdrawal date (date of 
completion or early withdrawal [any reason including death] from the double-blind period).
Up-to-Day 180 observation period end date will be defined as follows;
o
Day 180/EODB completion date (for subjects who completed the double-blind period) or
o
Death date (subjects who died during the double-blind period [DB reason=death] or 
during any time from randomization through Day 180 [died post withdrawal from DB but 
before Day 180/EODB visit) or
o
Maximum (double-blind withdrawal date, randomization date + 180 days) for subjects 
who withdrew early from the double-blind period [any reason other than death] and had 
not died during the time from randomization through Day 180
First dose date: the date on which the first dose of study drug is taken by the subject. If missing 
or partial for a subject who takes study drug, the first dose date is set to the randomization date. 
Last dose date: the date on which the last dose of study drug is taken by the subject (dose end 
date). If the dose end date is missing or partial for a subject who takes study drug, the last dose 
date is set as follows 

Maximum (Minimum (discontinuation date in the double-blind period [including death 
date during double-blind period], last visit date when drug is dispensed + number of pills 
dispensed - number of pills returned at following visit), imputed partial last dose date, 
exposure start date of last record))
o
Imputation rule for partial dates:  If only the day is missing, then day imputed to 
the last day of that month.  If day and month are missing, the date will be imputed 
to the start date if year is the same, else imputed to January 1st.
The last dose date will not be later than the double-blind period end date.  The last dose date will 
not be before the first dose date and if a subject has not taken any study drug, the last study drug 
date will be set to missing.
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2.6.
Observation Periods
In this study, four observation periods will be defined.  These are Up-to-Day 180, On-Treatment, 
Post-Randomization and Post-First Dose observation periods.  An observation period refers to a 
time window.  Analyses of primary and secondary efficacy as well as safety endpoints will 
include data within a specified observation period.  The primary efficacy endpoint analysis will be 
performed for more than one observation period as shown in the table below.
Up-to-Day 180 observation period: Primary efficacy composite endpoint analyses (including 
supportive and sensitivity analyses described in Sections 5.2.3 and 5.2.5 respectively) and
secondary efficacy endpoints analyses.
On-Treatment observation period:  Primary efficacy composite endpoint supportive analysis. 
Primary and secondary safety analyses.
Post-Randomization and Post-First Dose observation periods: Primary efficacy composite 
endpoint supportive analyses.
Analysis of Efficacy Endpoints (Refer to Sections 5.2, 0 for details) 
Analysis Population: ITT
Endpoint
Observation 
Period(s)
Endpoint
Observation Period
Primary Efficacy Composite 
Endpoint
Time to the first occurrence of 
objectively confirmed 
symptomatic lower extremity 
proximal DVT, asymptomatic 
lower extremity proximal 
DVT, symptomatic lower 
extremity distal DVT, 
symptomatic upper extremity 
DVT, symptomatic non-fatal 
PE, incidental PE, or VTE-
related death
Primary
Up-to-Day 180
Sensitivity 
Up-to-Day 180
Supportive
On-Treatment
Post-Randomization
Post-First Dose
Key Secondary Endpoints
1.
Time to first occurrence of 
objectively confirmed 
symptomatic VTE events 
(symptomatic lower 
extremity proximal DVT, 
symptomatic lower extremity 
distal DVT, symptomatic 
upper extremity DVT, or 
symptomatic non-fatal PE) or 
VTE-related deaths
2.
Time to all-cause mortality
Additional Secondary
Endpoints
Key Secondary & 
Additional 
Secondary
Up-to-Day 180
Safety Endpoints (Refer to Section 6.0 for details)
Analysis Population: Safety
Primary Endpoint
Time to the first occurrence of 
objectively confirmed ISTH 
major bleeding event
Primary
On-Treatment
Secondary Safety Endpoints
On-Treatment
Time to first occurrence of:
1.
Clinically relevant non-major 
bleeding
2.
Minor bleeding
3.
Composite bleeding (major, 
clinically non-major and 
minor)
Secondary
On-Treatment
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2.6.1.
Up-to-Day-180 Observation Period
This observation period includes data from randomization to Up-to-Day 180 end date (defined in 
Section 2.5).
Event: All efficacy events (with respect to deaths, VTE-related deaths are counted as events for 
primary efficacy endpoint.  For the secondary efficacy endpoints, all-cause deaths are counted as 
events) that occurred from randomization through the Up-to-Day 180 end date (Section 2.5) will 
be included in the analysis of this observation period. 

Event time - The time to event is defined as the time from randomization to the time of the
first event during this observation period. 
Censoring: Subjects who did not experience an event during this observation period will be 
censored at the last day of their complete assessment for study outcomes.
Subjects who died during this observation period will be censored as of their death date for 
endpoint analyses not related to death. 

Censoring time - The time to censoring is defined as the time from randomization to the
minimum of (last day of their complete assessment for study outcomes during the double-
blind period [double-blind completion/withdrawal], death date [non VTE-related deaths 
for primary efficacy composite endpoint]).
2.6.2.
On-Treatment Observation Period
This observation period includes data from the day of the first dose of study drug to 2 days 
after the last dose of the study drug, inclusively (dose dates defined in Section 2.5).  
All randomized subjects will be included in the On-Treatment observation period.  A conservative 
approach will be used for subjects who were randomized but never dosed to include any event 
that may occur even if the subject did not take study drug.  This is defined to include VTE-related 
events that occur during the study even if the subject had not taken study drug. Only those events 
that occur prior to the double-blind period end date will be included in the on-treatment 
observation period.
Event: All efficacy and safety events (with respect to deaths, VTE-related deaths are counted as 
events for primary efficacy composite endpoint.  For Bleeding related deaths, major bleeding is
counted as events for the primary safety endpoint) that occurred from the date of first dose of 
study drug up to the last dose of study drug+2 days will be included in the analysis of the On-
Treatment observation period.

Event time - The time to event is defined as the time from first dose date to the time of the 
first event during this observation period.
o
For randomized subjects but never dosed: The time to event will be defined as the 
time from randomization to the time of the event during the time in study. This 
imputation rule will be applied only for the ITT population.
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Censoring: Subjects who do not experience an event during this observation period will be 
censored.  
Subjects who died during this observation period will be censored as of their death date for 
endpoint analysis not related to death.

Censoring time - The time to censoring is defined as the time from first dose date to the 
minimum (earliest) of (last dose date+2 days, death date).
o
For randomized subjects but never dosed the time to censoring will be defined as 
the time from randomization to the minimum of (last day of their complete 
assessment for study outcomes during the double-blind period [double-blind 
completion/withdrawal], death date [non VTE-related deaths for primary efficacy 
composite endpoint]).
2.6.3.
Post-Randomization Observation Period
This observation period includes all data from randomization to Day 210/EOS.
Specifically, this observation period will include all events that have occurred after randomization 
through Day 210/EOS inclusive of all events after completion of double-blind period/Day 180
through Day 210 as well as all events that occurred after subject had withdrew early from the 
double-blind period through Day 210.
Event: All efficacy events (with respect to deaths, VTE-related deaths are counted as events for 
primary efficacy composite endpoint) that occurred from the date of randomization up to the Day 
210/End-of-Study [EOS] (defined in Section 2.5) will be included in the analysis of the Post-
Randomization observation period. 

Event time - The time to event is defined as the time from randomization to the time of the 
first event during this observation period.  
Censoring: Subjects who do not experience an event during this observation period will be 
censored.  
Subjects who died during this observation period will be censored as of their death date for 
endpoint analysis not related to death.

Censoring time - The time to censoring will be time from randomization to the minimum 
of (last contact date [up to and including the Day 210 = EOS date defined in Section 2.5], 
death date [non VTE-related deaths]).
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BAY59-7939/JNJ39039039STM4001  (Rivaroxaban)                                             Statistical Analysis Plan STM4001
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2.6.4.
Post-First Dose Observation Period
This observation period includes all data from the first dose of study drug to Day 210/EOS.
Specifically, this observation period will include all events that have occurred after first dose 
through Day 210 inclusive of all events after double-blind period completion/Day 180 through 
Day 210 as well as all events that occurred after subject had withdrew early from the double-blind 
period through Day 210.
All randomized subjects will be included and the imputation rule for event times for randomized 
subjects but never dosed described in Section 2.6.2 will also be applied for the analysis of data for 
this observation period. All events that occur prior to the End-of-Study date will be included in 
the post-first dose observation period.
Event: All efficacy events (with respect to deaths, VTE-related deaths are counted as events for 
primary efficacy composite endpoint) that occurred from the date of first dose up to the Day 
210/End-of-Study[EOS] (Section 2.5) will be included in the analysis of the Post-First Dose 
observation period. 

Event time - The time to event is defined as the time from first dose date to the time of the 
first event during this observation period.
o
For randomized subjects but never dosed: The time to event will be defined as the 
time from randomization to the time of the event during the time in study. This 
imputation rule will be applied only for the ITT population.
Censoring: Subjects who do not experience an event during this observation period will be 
censored.  
Subjects who died during this observation period will be censored as of their death date for 
endpoint analysis not related to death.

Censoring time - The time to censoring is defined as the time from first dose date to the 
minimum (earliest) of (last contact date [up to and including Day 210 visit date = EOS 
date defined in Section 2.5], death date [non VTE-related deaths]) 
o
For randomized subjects but never dosed: The time to censoring will be defined as 
the time from randomization to the minimum of (last contact date [up to and 
including Day 210=EOS date, death date [non VTE-related deaths]).
Examples are illustrated in Figures in the Appendix. 
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2.7.
Definition of Subgroups
Homogeneity of treatment safety and effects, both in hazard ratio (HR) and direction, will be 
assessed in the following subgroups classified at baseline:

Stratification factor: Pancreatic (APC) or Non-Pancreatic (Non-APC)

Age (18 - <65, 65- <75, ≥75 years)

Sex (Male, Female)

Race (White, Black, Asian, Other, Unknown, Not Reported)

Ethnicity (Hispanic or Latino, not Hispanic or Latino, Unknown, Not Reported)

BMI (<25, 25-<30, 30-<35, ≥35 kg/m2)

Tumor type (Gastric/GE Junction, Lung, Lymphoma, Ovarian, and Other [which will 
include all the remaining non-pancreatic cancer types])

Stage of Disease (I, II, III, IV) based on the TNM classification

Baseline Khorana Score (2, 3, 4, and ≥5)

Baseline ECOG score (0-1, ≥2)

Geographic region (North America, Western Europe, Eastern Europe)
o
North America (USA, Canada), Western Europe (Belgium, France, Germany, 
Italy, UK), Eastern Europe (Bulgaria, Czech Republic, Russia), South America
(Brazil)

Baseline Creatinine Clearance (30 to < 50, 50 to <80, ≥80 mL/min)
Race and ethnicity for subjects from France will be denoted as ‘Not Reported’ in the subgroup 
analysis as this information is not collected from France due to local regulations.
3.
INTERIM ANALYSIS AND INDEPENDENT DATA MONITORING COMMITTEE 
(IDMC)
No interim efficacy analysis is planned in this study and there are no pre-specified stopping rules 
planned in this study. However, an IDMC has been set up for this study to periodically assess the 
safety of subjects in this study and to evaluate the efficacy data as necessary to ensure that the safety 
of subjects is not compromised. Details of the IDMC roles, responsibilities, and key 
activities/timelines are provided in the IDMC charter.
The programming rules for deriving the analysis variables and the data tables for the IDMC 
meetings are specified in the data presentation specification document (DPS). Brief description is
included in the Attachment.
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4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Summaries of demographic and baseline characteristics, risk factors and medical history will also 
be provided by treatment group. 
Descriptive statistics (such as mean, standard deviation, median, minimum and maximum) will be 
provided for continuous variables such as age (at baseline visit), weight, and height. Counts and 
(appropriate) percentages will be provided for categorical variables such as sex and race.
4.2.
Disposition Information
The number of subjects included in the analysis populations (ITT, PP and safety) and number of 
subjects who completed or withdrew from the double-blind period will be summarized by 
treatment group and stratification factor: APC or non-APC.
Summaries of reasons for withdrawal from the double-blind period and permanent 
discontinuation of treatment will be provided by treatment group. 
Time to study drug discontinuation will be summarized by treatment group using the Kaplan-
Meier method.
Time to early study discontinuation will also be summarized by treatment group using the 
Kaplan-Meier method.
4.3.
Treatment Compliance Based on Exposure
The following rules will be implemented to determine the compliance based on exposure 
information.
For subjects who died during the double-blind period and for those subjects who permanently 
discontinued their treatment early the compliance will be determined as:
Days on drug= [(last dose date-first dose date+1) – days of drug interruption]
Total exposure duration = last dose date-first dose date+1
Compliance (%) = [Days on drug/Total exposure duration]x100 
For all other subjects who completed or withdrew (but had not ended treatment early) from 
double-blind period the compliance will be determined as:
Days on drug= [(last dose date-first dose date+1) – days of drug interruption]
Total exposure duration = double-blind end date-first dose date+1
Compliance (%) = [Days on drug/Total exposure duration]x100 
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BAY59-7939/JNJ39039039STM4001  (Rivaroxaban)                                             Statistical Analysis Plan STM4001
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4.4.
Extent of Exposure
Duration of double-blind treatment is defined as the duration between the first dose date and last 
dose date, inclusive.  Duration of treatment exposure will be summarized by treatment group.  
Total treatment duration = last dose date - first dose date + 1.
The total number of temporary drug interruptions (>3 days) and reasons for interruptions will also 
be summarized by treatment group.
Duration of double-blind period will also be summarized. The duration of double-blind period is 
defined as the duration from randomization up to the double-blind period end date.
Duration of Double-Blind period = Double-blind period end date (completers or withdrew
subjects) – randomization date + 1.
4.5.
Systemic Cancer Therapies and Concomitant Medications
Systemic cancer therapies at randomization and during the double-blind period (those that started 
after randomization and those started before randomization by continued during the double-blind 
period) will be summarized by treatment group. The number and percentage of randomized 
subjects, who received systemic cancer therapies will be presented.
Concomitant medications include all medications received at or after the randomization date. 
These will be summarized by treatment group, for all randomized subjects, using the Anatomical 
Therapeutic Chemical (ATC) dictionary.
4.6.
Study Drug Discontinuation and Early Withdrawal from Double-Blind 
Period 
If a subject’s study treatment must be permanently discontinued before the end of the double-
blind treatment period, this will not result in automatic withdrawal of the subject from the study 
and they are encouraged to continue to be followed for efficacy and safety outcome until the end 
of the double-blind period/Day 180. Data from remaining scheduled visits are collected until the 
subject either completes the double-blind period/Day 180 visit or withdraws early from the study.
Outcome data for all subjects, those who completed the double-blind period as well as those who 
withdrew early from the double-blind period is also collected at the Day 210/EOS visit as agreed 
during the informed consent.  Every effort will be made to follow-up the subject and collect the 
data including vital status. In the event a subject withdrew consent or is lost-to-follow up, the vital 
status data (dead/alive) will be obtained through public information (death and other registries) 
per local guidelines and as allowed by local registration.
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BAY59-7939/JNJ39039039STM4001  (Rivaroxaban)                                             Statistical Analysis Plan STM4001
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Thus, there are two scenarios as described below:
1. Subject permanently discontinues study treatment but completes the double-blind period 
(i.e. completed the study/end of double-blind period)
a.
If subject experiences an efficacy (primary or secondary) endpoint event at any time 
during the study (from randomization through double-blind period completion), then 
the event and corresponding time to the occurrence of the event will be included in 
the analysis of primary efficacy composite endpoint
b. If a subject has no efficacy composite endpoint event (primary or secondary) during 
the time in study, then this subject will be censored with the time to censoring 
defined as the time from randomization to last day of their complete assessment for 
study outcomes during the double-blind period [double-blind completion].
2. Subject permanently discontinues study treatment and withdraws early prior to the end of 
the double-blind period (i.e. withdrew from the study altogether) or dies during the double-
blind period
a.
If subject experiences an efficacy composite endpoint event (primary or secondary, 
including VTE-related deaths) after withdrawing from the study and the time to the 
occurrence of the event is prior to Day 180, then this event and corresponding time 
to the occurrence of the event will be included in the analysis of primary efficacy 
composite endpoint.  If subject dies (all causes other than VTE-related) after 
withdrawing from the study and reported on Day 210 but event time is prior to Day 
180, then this event and corresponding time to death will be included in the all-cause 
mortality endpoint analysis
b. If a subject does not experience any efficacy composite endpoint event (primary or 
secondary) in the study, then this subject will be censored.  The time to censoring is 
defined as the time from randomization to the minimum of (last day of their 
complete assessment for study outcomes during the double-blind period/Day 180 
[double-blind withdrawal date for those who withdrew], or death date [censored at 
death date for analysis not related to the specific death endpoint]). 
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5.
EFFICACY
5.1.
Analysis Specifications
5.1.1.
Level of Significance
All statistical tests will be 2-sided and conducted at 5% significance level unless specified 
otherwise. 
The fixed-sequence step down procedure with a priori ordered hypotheses will be used to control 
the type I error for multiple testing (Section 5.5). If the result of a test in the sequence is not 
significant, the tests in lower hierarchical order will be interpreted as not significant regardless of 
the actual p-value.  All confidence intervals will be estimated at the 95% level.
5.1.2.
Data Handling Rules
The primary efficacy and key secondary endpoint analyses in this study will be based on the ITT 
analysis population (which includes all randomized subjects). All safety endpoints will be 
analyzed based on the safety analysis population (which includes all randomized subjects who 
receive at least one dose of study drug). 
Time to event analyses will use censoring rules that apply to subjects with no primary efficacy 
outcomes during the specified observation periods, or, to subjects who withdrew from the study, 
or to subjects who die because of reasons other than VTE-related or bleeding, or withdrew 
informed consent before the end of the predefined treatment duration (Section 2.6 describes in 
detail all the censoring rules for the different observation periods).  
All efforts will be made to collect complete data for all subjects randomized in this study to avoid
missing or partial event dates.  If the event date is not known, the investigators will provide their
best estimate as to when the event occurred based on all the data available for that subject. In the 
extreme scenario where the event date is partial (missing day and month and year available), the 
day will be imputed as the first of the month.
5.2.
Primary Efficacy Composite Endpoint
The primary efficacy outcome variables (objectively confirmed – CEC Adjudicated) that will be 
used to define the primary efficacy composite endpoint are:  

symptomatic lower extremity proximal DVT

asymptomatic lower extremity proximal DVT 

symptomatic lower extremity distal DVT

symptomatic upper extremity DVT 

symptomatic non-fatal PE 

incidental PE and 

VTE-related death
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5.2.1.
Definition
The primary efficacy composite endpoint is defined as the time to the first occurrence of 
objectively confirmed symptomatic lower extremity proximal DVT, asymptomatic lower 
extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity 
DVT, symptomatic non-fatal PE, incidental PE or VTE-related death as adjudicated by the 
independent Clinical Endpoint Committee (CEC).
5.2.2.
Analysis Methods
The primary efficacy composite endpoint analysis will be based on the ‘Up-to-Day 180’ 
observation period for the ITT population with censoring as defined in Section 2.6.  
The cumulative distribution function of the time to first occurrence of the primary efficacy 
composite endpoint will be estimated by the Kaplan-Meier method.  The primary statistical 
hypothesis will be tested using a log-rank test, stratified by tumor type (APC or non-APC).
The estimate of the hazard ratio (HR), RRR (RRR=100*[1-HR] %) and the 95% confidence 
intervals for the treatment effect will be provided based on a stratified Cox proportional hazard 
model (stratification factor: APC or non-APC) and including treatment group as a binary 
covariate (i.e., rivaroxaban, placebo).
The cumulative event rate derived from Kaplan-Meier estimate will also be displayed graphically 
to evaluate the timing of event occurrence and the consistency of the treatment effect over time.
5.2.2.1.
Assessment of Proportional Hazards Assumption
The proportional hazards assumption in the primary efficacy time-to-event endpoint analysis 
based on the Cox-proportional hazard model will be assessed graphically using 

-log(-log) plots

The goodness of fit testing approach as proposed by Harrell and Lee (1986)1,2, a variation 
of a test originally proposed by Schoenfeld (1982)3
(Kleinbaum and Klein (2012)4 provide details on the implementation of this approach).
In the event of non-proportional hazards, alternative approaches will be used that include the 
Peto-Prentice test (Peto and Peto, 19725; Prentice, 19786) and Fleming-Harrington (19847) test
(with parameters for this test defined at p=1 and q=0).  All tests will be performed with the use of
SAS version 9.4 or higher (SAS Institute). Additional data explorations will be carried out to 
assess the non-proportionality of hazards between groups.
5.2.3.
Supportive Analyses for Primary Efficacy Composite Endpoint
To assess the robustness of the conclusion of the primary analysis, supporting analyses of the 
primary efficacy composite endpoint will be performed based on different observation periods 
and analysis populations as described below with censoring rules defined in Section 2.6:
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
Based on the ‘On-Treatment’ observation period for the ITT population 

Based on the ‘Up-to-Day 180’ observation period for the PP population

Based on the ‘On-Treatment’ observation period for the PP population 

Based on the ‘Post-Randomization’ observation period for the ITT population

Based on the ‘Post-First Dose’ observation period for the ITT population 
In all cases, the 2-sided 95% confidence interval (CI) for the hazard ratio (rivaroxaban vs placebo) 
will be provided using the stratified Cox proportional hazards model (stratification factor: APC or 
non-APC) and including treatment group as a binary covariate (i.e., rivaroxaban, placebo).
The cumulative event rate derived from Kaplan-Meier estimate will also be displayed graphically 
to evaluate the timing of event occurrence and the consistency of the treatment effect over time 
and tested using a log-rank test, stratified by tumor type (APC or non-APC).
Summary of Primary Efficacy Composite Endpoint Analysis Methods
Endpoint
Observation Period
Analysis 
Population
Method 
Primary Efficacy 
Composite Endpoint
(CEC Adjudicated 
Events)  
Primary
Up-to-Day 180
Supportive
On-Treatment
Up-to-Day 180
On-Treatment
Post-Randomization
Post-First Dose
Up-to-Day 180
Up-to-Day 180
ITT
ITT
PP
PP
ITT
ITT
ITT
ITT
Primary Analysis
Kaplan-Meier Estimates 
(Cumulative event rates and
stratified log-rank test)
Cox-model (HR, 95% CI)
Sensitivity Analysis
1.Include asymptomatic distal DVT
2.Dropout with no follow up – treating
time to discontinuation as being time to 
an event.
Competing Risk Analysis
Deaths due to causes other than VTE-
related will be a competing risk event
Gray’s 2-sampel test 
(Cumulative Incidence Function)
Fine and Gray regression model
5.2.4.
Subgroup Analyses for the Primary Efficacy Composite Endpoint
Analyses of the primary efficacy composite endpoint will also be performed to examine the 
consistency of treatment effect across subgroups listed in Section 2.7.  Homogeneity of treatment 
effect will be evaluated using the same model as described in Section 5.2.2 (stratified Cox 
proportional hazard model with treatment as a covariate). Subgroup analysis will be performed if 
there are at least 30 total randomized subjects in each subgroup category. Only descriptive 
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BAY59-7939/JNJ39039039STM4001  (Rivaroxaban)                                             Statistical Analysis Plan STM4001
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summaries will be presented for subgroups with fewer subjects. The subgroup analysis by race 
and ethnicity will be denoted as ‘Not Reported’ for subjects from France as this information is 
not collected from the sites due to local regulation.
The interaction of treatment with each of the subgroups will be analyzed based a stratified Cox 
proportional hazard model with stratification factor and treatment group with additional terms for 
subgroup and subgroup-by-treatment interaction.  Further evaluations will be performed to assess 
and explain the nature of the interaction (qualitative or quantitative) if a significant (p value 
<0.10) interaction is observed.  Significant interactions will be examined using a two-sided Gail-
Simon8 test.  Descriptive statistics (n, mean, standard deviation, median, and range) will be 
presented by treatment groups for each subgroup.
The subgroup analyses of the primary efficacy composite endpoint will be based on the ‘Up-to-
Day 180’ observation period for the ITT population with censoring as defined in Section 2.6.
5.2.5.
Sensitivity Analyses 
5.2.5.1.
Additional Primary Efficacy Composite Endpoint – Include 
Asymptomatic Distal DVT
An additional composite efficacy endpoint will also be defined to include the occurrences of 
‘asymptomatic lower extremity distal DVT’.  
Sensitivity analysis will be performed on the time to the first occurrence of objectively confirmed 
symptomatic lower extremity proximal DVT, asymptomatic lower extremity proximal DVT, 
symptomatic lower extremity distal DVT, asymptomatic lower extremity distal DVT,
symptomatic upper extremity DVT, symptomatic non-fatal PE, incidental PE or VTE-related 
death as adjudicated by the independent Clinical Endpoint Committee (CEC). This analysis will 
be based on the ITT analysis population for the ‘Up-to-Day 180’ observation period.
Cumulative distribution function of the time to first occurrence will be estimated by the Kaplan-
Meier method and tested using a log-rank test, stratified by tumor type (APC or non-APC).
The estimate of the hazard ratio (HR), RRR (RRR=100*[1-HR] %) and the 95% confidence 
intervals for the treatment effect will be provided based on a stratified Cox proportional hazard 
model (stratification factor: APC or non-APC) and including treatment group as a binary 
covariate (i.e., rivaroxaban, placebo).
5.2.5.2.
Sensitivity Analysis for Primary Efficacy Composite Endpoint
In this study, all data regarding occurrence of DVT, PE events and vital status (alive/dead) events 
will be collected for all subjects (completers and early withdrawal) at the Day 210/follow-up visit.  
Data for the primary efficacy composite endpoint will be missing for subjects for whom the Day 
210/follow-up visit is not performed or if the visit was performed but the occurrence of an event 
was reported as unknown. A conservative approach will be used for subjects who withdrew from 
the double-blind period and did not have an event during the double-blind period.
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In this approach, subjects who withdrew from the double-blind period for any reason other than 
death and were censored (i.e. had not experienced any VTE-related primary efficacy event during 
the double-blind period) and have missing or unknown Day210/follow up status will be 
considered as having a VTE-related event (i.e. not censored). The time from randomization to 
time of withdrawal will be assumed to be the time to an occurrence of a VTE-related primary 
efficacy composite event (no specific individual component will be assigned as the worst case).
The sensitivity analysis for the primary efficacy composite endpoint will be based on the ‘Up-to-
Day 180’ observation period for the ITT analysis population. For the above sensitivity analyses, 
the cumulative distribution function of the time to first occurrence will be estimated by the 
Kaplan-Meier method and tested using a log-rank test, stratified by tumor type (APC or non-
APC).
The estimate of the hazard ratio (HR), RRR (RRR=100*[1-HR] %) and the 95% confidence 
intervals for the treatment effect will be provided based on a stratified Cox proportional hazard 
model (stratification factor: APC or non-APC) and including treatment group as a binary 
covariate (i.e., rivaroxaban, placebo).
5.3.
Competing Risk Analysis
Competing risks arise when subjects are at risk of experiencing more than one cause of failure 
(event) and failure due to other causes precludes observing the main cause of interest (i.e. 
censored for primary efficacy composite endpoint). 
The primary efficacy composite endpoint is defined as a composite of objectively confirmed 
symptomatic lower extremity proximal DVT, asymptomatic lower extremity proximal DVT, 
symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-
fatal PE, incidental PE or VTE-related death (adjudicated by CEC). For this type of outcome (the 
primary endpoint), a death due to causes other than VTE-related is a competing risk event and, as 
such, a patient is no longer at risk of having any of the events of interest.
To account for competing risks (deaths from causes other than venous thromboembolism related; 
VTE-related deaths are included in the primary efficacy composite endpoint) in the primary 
efficacy analysis, a cumulative incidence approach will be followed with the use of Gray’s 
(1988)9 two-sample test (two-sided alpha level, 0.05). Hazard ratios and 95% confidence intervals 
will be calculated with the use of the Fine and Gray (1999)10 regression model (with treatment 
group as a factor). Cumulative incidence functions (defined as the cumulative probability of 
failure from a specific cause over time) will be estimated separately for the two study groups. 
These analyses will be based on the ‘Up-to-Day 180’ observation period for the ITT population 
with censoring as defined above in Section 2.6.
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5.4.
Key Secondary Endpoints
The key secondary efficacy outcomes (objectively confirmed – CEC Adjudicated) are:

symptomatic VTE events (symptomatic lower extremity proximal DVT, symptomatic 
lower extremity distal DVT, symptomatic upper extremity DVT and symptomatic non-
fatal PE) or VTE-related deaths 

All-cause mortality
5.4.1.
Definition
The key secondary efficacy endpoints defined based on the key secondary efficacy outcomes 
above are as follows:

Time to first occurrence of objectively confirmed symptomatic VTE events (symptomatic 
lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic 
upper extremity DVT, or symptomatic non-fatal PE) and VTE-related deaths 

Time to all-cause mortality
5.4.2.
Analysis Methods
Analysis of the key secondary efficacy endpoints will follow the same approach as in the analysis 
of the primary efficacy composite endpoint analysis. The analysis will be based on the ‘Up-to-
Day 180’ observation period for ITT population with censoring as defined above (Section 2.6).
Each of the key secondary endpoints will be tested using a log-rank test, stratified by tumor type.
For each of these two key secondary endpoint analyses, a Cox proportional hazard model with 
treatment and stratification factor as covariates will be fitted. A point estimate along with 2-sided 
95% CI for the treatment effect of RRR (RRR=100 x [1-HR] %) will be provided.
The cumulative event rate derived from Kaplan-Meier estimate will also be displayed graphically 
to evaluate the timing of event occurrence and the consistency of the treatment effect over time.
Summary of Key Secondary Efficacy Endpoints Analysis Methods
Endpoint
Observation 
Period
Analysis 
Population
Method 
Key Secondary Endpoints 
1. Composite of symptomatic 
VTE events or VTE-related death
2. All-cause mortality
(CEC Adjudicated Events)
Up-to-Day 180
ITT
Kaplan-Meier Estimates 
(Cumulative event rates and 
stratified log-rank test)
Cox-model (HR, 95% CI)
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5.5.
Adjustment for Multiplicity
Superiority of rivaroxaban over placebo on the primary efficacy composite endpoint will be first 
established. If this is established, then a sequential approach using a closed testing hierarchical 
procedure (to control the family-wise type I error rate at alpha at 5%, 2-sided) will be used to test 
the following two secondary hypotheses:

symptomatic VTE events + VTE-related deaths

all-cause mortality
Overall Hierarchy of Testing Multiple Hypothesis
Primary Efficacy Composite Endpoint (ITT/Up-to-Day 180)

Time to first occurrence of symptomatic lower extremity proximal DVT, 
asymptomatic lower extremity proximal DVT, symptomatic lower extremity 
distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, 
incidental PE or VTE-related death
α=0.05

Secondary Efficacy Endpoints (ITT/Up-to-Day 180)

Time to first occurrence of symptomatic VTE events and VTE-related death  
α=0.05


All-cause mortality                                                                            
α=0.05
5.6.
Additional Secondary Efficacy Variable(s)
Additional secondary outcomes (objectively confirmed – CEC Adjudicated) are:  

Individual components of the primary efficacy composite variable

Confirmed fatal/non-fatal arterial thrombosis event (ATE) (e.g. MI and stroke) events
(these will include the following events: occurrence of a stroke, MI or any arterial 
thrombosis event)

Confirmed fatal/non-fatal visceral VTE events

Composite of symptomatic lower extremity proximal DVT, asymptomatic lower extremity 
proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity 
DVT, symptomatic non-fatal PE, incidental PE and all-cause mortality

Composite of symptomatic lower extremity proximal DVT, symptomatic lower extremity 
distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE and VTE-
related deaths

Composite of events in the primary efficacy composite endpoint, fatal/non-fatal ATE, 
visceral VTE

Composite of symptomatic lower extremity proximal DVT, symptomatic lower extremity 
distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE and VTE-
related deaths and major bleeding events
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5.6.1.
Definition
Secondary efficacy endpoints defined based on the other secondary outcomes above are as 
follows:

Individual components of the primary efficacy composite variable
o
Time to first occurrence of symptomatic lower extremity proximal DVT
o
Time to first occurrence of asymptomatic lower extremity proximal DVT
o
Time to first occurrence of symptomatic lower extremity distal DVT
o
Time to first occurrence of symptomatic upper extremity DVT
o
Time to first occurrence of symptomatic non-fatal PE
o
Time to first occurrence of incidental PE 
o
Time to VTE-related death
In addition to the analysis of the individual components, concordance between the investigator 
reported events and the CEC adjudicated events will also be presented.

Time to first occurrence of fatal/non-fatal ATE (a composite of occurrence of MI, stroke
[ischemic infarction with or without hemorrhagic conversion or primary hemorrhagic 
events – intraparenchymal hemorrhage, subdural hematoma or epidural hematoma] or any 
other ATE recorded on eCRF) event.

Time to first occurrence of fatal/non-fatal visceral VTE event (include only visceral 
(venous) events recorded on the eCRF).

Composite endpoint #1: Time to first occurrence of the composite endpoint of 
symptomatic lower extremity proximal DVT, asymptomatic lower extremity proximal 
DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, 
symptomatic non-fatal PE, incidental PE and all-cause mortality (composite: primary
efficacy composite endpoint event components but including all-cause mortality).

Composite endpoint #2: Time to first occurrence of the composite of symptomatic lower 
extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper 
extremity DVT, symptomatic non-fatal PE and VTE-related deaths
(composite: 
symptomatic events only and VTE-related deaths).

Composite endpoint #3: Time to first occurrence of the primary efficacy composite 
endpoint (symptomatic lower extremity proximal DVT, asymptomatic lower extremity 
proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity 
DVT, symptomatic non-fatal PE, incidental PE and VTE-related deaths), fatal/non-fatal 
ATE (composite of MI, stroke or any ATE), and fatal/non-fatal visceral VTE event
(composite: primary efficacy composite endpoint event components, ATE events, and 
visceral VTE events).

Composite endpoint #4: Time to first occurrence of the composite of symptomatic lower 
extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper 
extremity DVT, symptomatic non-fatal PE, VTE-related deaths, and major bleeding event
(composite: symptomatic events and include major bleeding events for the ITT population 
and up-to-Day 180 observation period).
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5.6.2.
Analysis Methods
Analysis of the other secondary efficacy endpoints will follow the same approach as in the 
analysis of the primary efficacy endpoint analysis. These analyses will be based on the ‘Up-to-
Day 180’ observation period for the ITT population with censoring as defined above 
(Section 2.6).
In addition to be above endpoints, the key secondary endpoints (time to symptomatic VTE events 
or VTE-related deaths, all-cause mortality) will also be analyzed based on the ‘Up-to-Day 180’
observation period for the ITT population.
The cumulative distribution function of the time to first occurrence of each of these endpoints will 
be estimated by the Kaplan-Meier method and tested using a log-rank test, stratified by tumor 
type. In addition, a Cox proportional hazard model with treatment and stratification factor as 
covariates will be fitted. A point estimate along with 2-sided 95% CI for the treatment effect of 
RRR (RRR=100 x [1-HR] %) will be provided.
The cumulative event rate derived from Kaplan-Meier estimate will also be displayed graphically 
to evaluate the timing of event occurrence and the consistency of the treatment effect over time.   
No multiplicity adjustment will be performed for the analysis of these endpoints.
Frequency summary (N, %) of the total number of deaths and the primary cause of death, total 
number of subjects with myocardial infarction (MI), stroke, and other arterial thrombosis (ATE) 
events will also be presented for the Up-to-Day 180 observation period.
5.7.
End-of-Study Vital Status Summary
In this study, vital status data (alive/dead) was collected at the Day 210 follow up visit for all 
randomized subjects, except for those who had died during the double-blind period. The Cochran-
Mantel-Haenszel (CMH) test, adjusting for the stratification factor (APC/non-APC), for the 
association between the treatment group and each of these endpoints will be performed provided 
there are non-zero entries in each cell of the 2x2 treatment-by-endpoint table.  
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6.
SAFETY
6.1.
Bleeding
The primary safety objective of this study is to assess the major bleeding events as defined by 
International Society on Thrombosis and Haemostatis (ISTH) based on the CEC classification 
from the time of first dose to two days after the last dose of study drug. 
6.1.1.
Bleeding Events Classification
Like efficacy outcomes, the same independent CEC will adjudicate and classify bleeding events 
per the definitions in the CEC Charter.
Bleeding events will be classified as major, clinically relevant non-major, or minor bleeding using 
the ISTH classification as follows:
Major Bleeding
Major bleeding is defined as clinically overt bleeding that is associated with:

A reduction in hemoglobin of 2 g/dL or more, or

A transfusion of 2 or more units of packed red blood cells or whole blood, or

Occurrence at a critical site defined as intracranial, intra-spinal, intraocular, pericardial, 
intra-articular, intra-muscular with compartment syndrome, retroperitoneal, or

Fatal outcome
Clinically Relevant Non-Major Bleeding
Clinically relevant non-major bleeding defined as overt bleeding not meeting the criteria for 
major bleeding but associated with:

Medical intervention

Unscheduled contact (visit or telephone call) with a physician

Temporary cessation of study treatment, or

Discomfort such as pain, or impairment of activities of daily life
Minor Bleeding
All other overt bleeding episodes not meeting the criteria for major or clinically relevant non-
major bleeding will be classified as minor bleeding (corresponds to minimal bleeding event
captured on the case record form).
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Imputation Rules for Partial Bleeding Start Dates
If the bleeding start date is a partial date (only unknown day)

If only the day is missing, and the month and year are known, the month and year of the 
AE will be compared with the month and year of double-blind medication start date. 
o
If the both the month and year of the bleeding event is equal to the month and year 
of double-blind medication start date, then the imputed day will be the start day of 
medication.
o
If the month or the year of the bleeding event is different, then the imputed day 
will be the 1st day of the month.
6.1.2.
Primary Safety Endpoint of Bleeding
The primary safety endpoint is ISTH major bleeding as adjudicated by the CEC.
6.1.2.1.
Definition
The primary safety endpoint is defined as the time from the first study drug to first occurrence of 
ISTH major bleeding events in Section 6.1.1 during the ‘On-Treatment’ observation period
(observation periods defined in Section 2.6).
Censoring - subjects who do not experience endpoint events during the ‘On-Treatment’
observation period will be censored at the minimum of (last dose date + 2, death date).
6.1.2.2.
Analysis Methods
The primary safety endpoint will be analyzed using the same approach as in the primary efficacy 
endpoint but based on the ‘On-Treatment’ observation period for the Safety population
(randomized and taken at least one dose of the study drug) with censoring as defined above.
The cumulative distribution function of the time to first occurrence of the primary safety endpoint 
will be estimated by the Kaplan-Meier method and tested using a log-rank test, stratified by tumor 
type.
The estimate of the hazard ratio (HR), RRR (RRR=100*[1-HR] %) and the 95% confidence 
intervals for the treatment effect will be provided based on a stratified Cox proportional hazard 
model (stratification factor: APC or non-APC) and including treatment group as a binary 
covariate (i.e., rivaroxaban, placebo).
Incidence of major bleeding events and primary location of bleeding will also be summarized for 
each treatment group.
The primary safety endpoint will also be summarized for the subgroups defined in Section 2.7.
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6.1.3.
Supportive Analysis of the Primary Safety Endpoint of Bleeding
In addition to the primary safety analysis for major bleeding safety endpoint, supportive analysis 
will be performed to account for multiple major bleeding event times experienced by the same 
subject. Multiple major bleeding events will be analyzed using the recurrent event analysis by 
Anderson-Gill (1982)11 method.  The supportive analyses will be performed for the ISTH major 
bleeding endpoint and the clinically relevant non-major bleeding endpoint and will be based on 
the ‘On-Treatment’ observation period for the safety analysis population. All tests will be 
performed with the use of SAS version 9.4 or higher (SAS® Institute).
6.1.4.
Secondary Safety Endpoints of Bleeding
6.1.4.1.
Definition
Secondary safety endpoints of bleeding include time to:

Clinically relevant non-major bleeding  

Minor bleeding (corresponds to minimal bleeding)

Any bleeding event (defined as a composite of ISTH major, clinically relevant non-major 
and minor bleeding) 
6.1.4.2.
Analysis Methods
The secondary safety endpoints of bleeding will be analyzed using the same approach as in the 
primary safety endpoint.  The analysis will be based on the Safety population in the ‘On-
Treatment’ observation period with censoring as defined above (Section 2.6).
Each of the secondary endpoints will be tested using a log-rank test, stratified by tumor type 
(APC or non-APC). In addition, a Cox proportional hazard model with treatment and stratification 
factor as covariates will be fitted. A point estimate for hazard ratio (rivaroxaban/placebo) along 
with 2-sided 95% CI for the treatment effect of RRR (RRR=100 x [1-HR] %) will be provided.
The cumulative event rate derived from Kaplan-Meier estimate will also be displayed graphically to 
evaluate the timing of event occurrence and the consistency of the treatment effect over time.
Summary of Safety Endpoints Analysis Methods
Endpoint
Observation Period
Analysis 
Population
Method 
Primary Endpoint 
ISTH Major bleeding event
Secondary Endpoints
1. Clinically relevant non-major 
bleeding
2. Minor bleeding
3.Composite bleeding event (major, 
clinically non-major and minor)
(CEC Adjudicated Events)
On-Treatment
Safety
Kaplan-Meier Estimates 
(Cumulative event rates
and log-rank test)
Cox-model (HR, 95% CI)
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6.2.
Adverse Events
The original terms used in the CRFs by investigators to identify AE will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 or higher. 
A treatment-emergent adverse event (TEAE) is defined as any adverse event that starts between 
the first study medication administration and the last study medication administration + 2 days.
Only the AEs with start dates between the first dose date and the last dose date+2 days will be 
included in all TEAE summaries, including study (double-blind period) withdrawal and treatment 
discontinuation.  
As per the protocol (Section 12.4), in this study suspected outcome events are excluded from 
AE/SAE collection and reporting, regardless of seriousness or severity. These suspected events 
will be captured on the eCRF as outcome events and will be waived from SAE collection and 
unblinding and exempted from expedited reporting. These events include: symptomatic lower 
extremity proximal DVT, asymptomatic lower extremity proximal DVT, symptomatic lower 
extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, incidental 
PE, VTE-related death, all-cause mortality, ATE events (e.g., MI, stroke), visceral VTE, and all 
bleeding events.
The number (%) of subjects who had treatment-emergent adverse events will be summarized by 
System Organ Class (SOC) and preferred term (PT) for the Safety analysis population.
The number and percentage of subjects experiencing TEAEs will be summarized by treatment 
group for the Safety analysis population, and stratification factor: APC or non-APC.  
In addition, overall summaries of all AEs (all AEs that are reported from start of study through 
the Day 210/End-of-Study) for the safety population will also be presented.  Summary table of 
AE by body system and preferred term will also be presented for all AEs.
Adverse events will also be summarized by treatment group, severity, relationship to study 
medication, combined severity and relationship to study medication, action taken during 
treatment, and subject outcome. They will also be presented by treatment group, SOC, and PT.
Differences in the percentages of AEs between the two groups will be summarized and the 95% 
CI for the difference using the normal approximation to binomial distribution will be provided.
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6.2.1.
Imputation Rules for Missing AE Dates
A conservative approach will be used to handle the missing dates for adverse events. The rules for 
handling the incomplete AE onset dates will be as follows:

If only the day is missing, and the month and year are known, the month and year of the 
AE will be compared with the month and year of double-blind medication start date. 
o
If the both the month and year of the AE is equal to the month and year of double-
blind medication start date, then the imputed day will be the start day of 
medication.
o
If the month or the year of the AE are different, then the imputed day will be the 1st
day of the month.

If only the month is missing, and day and year are known, the year of the AE will be 
compared with the year of the double-blind medication start date.
o
If the year of the AE is equal to the year of the double-blind medication start date, 
then the imputed month will be the same as the month of the double-blind 
medication. 
o
If the year is different, then the month will be as January.

If both the day and month are missing but year is known, compare the year with the year 
of the double-blind medication start date. 
o
If the year is the same, then impute the AE start date as the same as the first dose 
date.  
o
If the year is different, then impute the AE start date to be January 1.

If the day, month and year are all missing, then the imputed date for the AE will be the 
date of the first dose of study medication.
After imputation if the AE start date is greater than the AE end date, then the AE start date will be 
set equal to the AE end date.

No imputation will be done for AE end date.
6.2.2.
Adverse Events Resulting in Withdrawal from the Study and 
Discontinuation of Treatment:
The number and percentage of subjects who withdrew from the double-blind period due to an 
TEAE (TEAE led to withdrawal from the study) will be summarized by treatment group and 
listed by subject. In addition, TEAEs that led to discontinuation of study drug (drug withdrawal)
will also be summarized by treatment group.
In addition, overall summaries of all AEs (all AEs that are reported from start of study through 
the Day 210/End-of-Study) with action taken of drug withdrawal will also be presented
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6.2.3.
Serious Adverse Events (SAE) and Deaths during the Study:
The number and percentage of serious TEAE and deaths will be summarized by treatment group 
and listed by subject.  
Serious TEAE that led to study drug discontinuation will be summarized by treatment group and 
listed by subject. 
In addition, all serious AEs and deaths (all AEs that are reported from start of study through the 
Day 210/End-of-Study) will also be summarized.  
6.2.4.
Adverse Events of Special Interest 
In addition to the overall AEs summaries, certain AEs that are considered to be Adverse Events of 
Special Interest (AESI) will be summarized.  The special interest TEAEs for the following groups 
will be summarized:

Suspected severe hypersensitivity reaction 

SMQ preferred terms included are: anaphylaxis, angioedema, severe urticaria, 
bronchospasm, idiopathic urticaria, anaphylactic reaction, anaphylactic shock, 
anaphylactoid reaction, and anaphylactic shock.

Severe skin reactions  

SMQ preferred terms included are: Stevens-Johnson Syndrome.

Suspected severe liver injury

SMQ preferred terms included are: drug-induced liver injury, acute hepatic failure, 
hepatic failure, hepatocellular injury, liver injury, mixed liver injury, alanine 
aminotransferase 
abnormal, 
alanine 
aminotransferase 
increase, 
aspartate 
aminotransferase abnormal, aspartate aminotransferase increased, blood bilirubin 
increased, blood bilirubin unconjugated increased, hyperbilirubinaemia, and liver 
function test abnormal.
Summaries of the special interest TEAEs will be based on the safety population.
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6.3.
Clinical Laboratory Tests
Descriptive statistics for each clinical laboratory analyte (collected at baseline and at Week 8, 
Week 16, and EODB will be provided. Changes from baseline at each post-baseline visit will be 
calculated by treatment group and will be based on the safety population in the ‘Up-to-Day 180’
observation period. The number of shifts from baseline in the categories of test results (low, 
normal, high) will be summarized by treatment group. A clinical laboratory test value is 
considered abnormal if it is outside the reference range (provided by the laboratory). Incidences 
of abnormal laboratory values will be summarized by treatment group based on subjects who 
have non-missing baseline and non-missing post-baseline values.
All laboratory test summaries will be based on the safety population (data from first dose through 
Day 180).  Laboratory data from the central lab Covance will only be included in the summaries.
6.4.
Vital Signs and Physical Examination Findings
Vital Signs
Descriptive statistics (mean, median, standard deviation, range, and number of observations) for 
blood pressure (systolic and diastolic) and pulse will be provided by treatment group for the 
safety analysis population. The changes from baseline for vital signs will also be summarized by 
treatment group at each visit.  
Physical Examinations
Listings of physical examination results will be provided.
All vital signs and physical examination summaries will be based on the safety population (data 
from first dose through Day 210).
6.5.
Electrocardiogram
N/A
6.6.
Other Safety Parameters
N/A
7.
PHARMACOKINETICS/PHARMACODYNAMICS
7.1.
Pharmacokinetics
Pharmacokinetics samples collected at Month 2 (Week 8) will be analyzed and descriptive 
statistics (n, mean, standard deviation, median, and rage) for plasma concentrations will be 
provided.  
7.2.
Pharmacodynamics
N/A
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8.
BIOMARKER 
In this study, biomarker samples are collected at screening, month 2 (Week 8), month 4 (Week 
16) and month 6 (EODB).  Biomarker assessments which include D-dimer, soluble P-selectin, 
and Tissue Factor (Factor III) will be summarized as part of the laboratory data summary.
9.
HEALTH CARE RESOURCE UTILIZATION
The Health Care Resource Utilization (HCRU) data will be collected as part of the endpoint 
assessments for all patients. The HCRU data will be specific to the study outcomes of DVT, PE, 
or bleeding, including outpatient visits to health care providers (including all specialties), 
hospitalizations (including admittance to intensive care unit), time to first hospitalization (DVT, 
PE, bleeding or an AE), length of hospitalization (defined as the sum of the duration of days over 
all the hospitalizations), and use of diagnostic procedures (type of imaging or diagnostic tests 
performed). Descriptive summaries (frequency counts and mean, median, SD) will be provided 
for the HCRU. All summaries will be presented by treatment group for the ITT analysis 
population.  
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Harrell F. and Lee K. (1986) Verifying Assumptions of the Cox Proportional Hazards Model.  Proceeding of the 
Eleventh Annual SAS User’s Group International conference, Cary, NC, SAS Institute, Inc.  
3.
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BAY59-7939/JNJ39039039STM4001  (Rivaroxaban)                                             Statistical Analysis Plan STM4001
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Approved, Date: 5 September 2018
ATTACHMENT: EXAMPLES OBSERVATION PERIOD AND EVENT/CENSORING TIME 
The different observation periods and the time intervals within which study data will be included are shown in the figures below.
Figure 1: Up-to-Day 180 observation period
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BAY59-7939/JNJ39039039STM4001  (Rivaroxaban)                                             Statistical Analysis Plan STM4001
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Approved, Date: 5 September 2018
Figure 2: On-Treatment observation period
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BAY59-7939/JNJ39039039STM4001  (Rivaroxaban)                                             Statistical Analysis Plan STM4001
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Approved, Date: 5 September 2018
Figure 3: Post-Randomization observation period
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BAY59-7939/JNJ39039039STM4001  (Rivaroxaban)                                             Statistical Analysis Plan STM4001
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Approved, Date: 5 September 2018
Figure 4: Post-Randomization observation period
NCT02555878


BAY59-7939/JNJ39039039STM4001  (Rivaroxaban)                                             Statistical Analysis Plan STM4001
46
Approved, Date: 5 September 2018
ATTACHMENT: IDMC DATA PRESENTATION SPECIFICATION
The study SAP is used as the IDMC SAP however some of the rules for imputation times and 
missing dates due to data cutoffs were applied to generate the tables for the DMC meetings.
As per the IDMC Charter, three meetings were planned to be conducted for safety data and key 
efficacy data reviews. The IDMC meetings are scheduled at the availability of 25 % data (that is, 
when 25% of total planned subjects are randomized into the study and complete at least 30 days 
on study).  Each of subsequent 2 meetings coincide with the enrollment of 50% and 75% of the 
planned subjects respectively who have been randomized and completed at least 30 days of study 
follow-up.  An addition ad hoc review (fourth IDMC safety review meeting) was planned at the 
end of enrollment when 100% subjects are randomized.  
Appropriate database was provided to IDMC statistical support group in accordance with the DMC 
Charter and established timeframes for each meeting.
For the fourth DMC meeting, symptomatic distal DVT was included in the primary efficacy 
composite endpoint in accordance with the amended protocol.  
Rules
Analysis phase end date: min (death date, rand date+183, cutoff date)
Treatment end date imputed as: min (rand date+183, cutoff date, analysis phase end date) for 
ongoing subjects.
CNSR: the censor flag = 0 if event and censor flag = 1 if censor (no event)
Event date:
ADT: the date of event up to the time subject was in the study.  That is, up to the subject’s 
completion/withdrawal date (the Day 180 end date not defined for DMC).
Censor date:
Up-to-Day 180 observation period:  
ADT for censored subjects = min (death date, rand date+183, cutoff date) 
On-Treatment observation period:
ADT for censored subjects = min (death date, last dose+2), using the imputed TRTEDT
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