Conditions: Heart Failure Respiratory Insufficiency Stroke Acute Infectious Diseases Rheumatic Diseases
Keywords: Heart Failure Respiratory Insufficiency Stroke Acute Infectious Diseases Rheumatic Diseases Medically ill Patient Rivaroxaban Thromboembolism Prophylactic Anti-Coagulation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 12024
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of rivaroxaban compared with placebo in the prevention of symptomatic venous thromboembolism (VTE) events and VTE-related death post-hospital discharge in high-risk, medically ill patients.

Detailed description:
This is a randomized (the study medication is assigned by chance), double-blind (neither physician nor participant knows the identity of the assigned treatment), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect)-controlled, event-driven, multicenter study in patients who are hospitalized for a specific acute medical illness and have other risk factors for venous thromboembolism (VTE). The study is designed to evaluate rivaroxaban in the prevention of symptomatic VTE events and VTE-related deaths for a period of 45 days post-hospital discharge. The study will consist of a screening phase, a 45-day double-blind treatment phase, and a 30-day follow-up phase. Study drug will start at randomization (Day 1), and will continue until Day 45 (inclusive). A total of approximately 12000 patients will be randomly assigned to either rivaroxaban or placebo in a 1:1 ratio. The total duration for a patient who completes the study after randomization is expected to be 75 days.

Arms:
arm 1: Each patient will receive either 10 mg or 7.5 mg rivaroxaban tablet once daily orally (by mouth) for 45 days. The dosing will depend on a creatinine clearance at screening. arm 2: Each patient will receive matching placebo tablet once daily orally (by mouth) for 45 days.

Interventions: intervention 1: Rivaroxaban, 10 mg intervention 2: Rivaroxaban, 7.5 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Patients, randomly allocated to the rivaroxaban arm, with a creatinine clearance at screening greater than or equal to (\>=)50 mL/min will receive 10 mg rivaroxaban tablet with or without food. intervention 2: Patients, randomly allocated to the rivaroxaban arm, with a creatinine clearance at screening from \>=30 to less than (\<)50 mL/min will receive 7.5 mg rivaroxaban tablet with or without food. intervention 3: All patients, randomly allocated to the placebo arm, will receive one placebo tablet with or without food.

Protocol document:
Prot_000.pdf: 
1
Status: Approved, 31 March 2017
Janssen Research & Development *
Clinical Protocol
Medically Ill Patient Assessment of Rivaroxaban Versus Placebo IN Reducing Post-Discharge 
Venous Thrombo-Embolism Risk (MARINER)
Protocol RIVAROXDVT3002; Phase 3 BAY 59-7939/17261
Amendment INT-7
JNJ-39039039; BAY 59-7939 (rivaroxaban) 
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious Diseases BVBA; Janssen 
R&D Ireland; or Janssen Research & Development, LLC. The term “sponsor” is used throughout the 
protocol to represent these various legal entities; the sponsor is identified on the Contact Information page 
that accompanies the protocol. 
This compound is approved for marketing in 6 indications.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER:
2014-000305-13     
Status:
Approved
Date:
31 March 2017
Prepared by:
Janssen Research & Development, LLC 
EDMS No.:
EDMS-ERI-73765690, 8.0
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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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................... 8
TIME AND EVENTS SCHEDULE .............................................................................................................. 17
ABBREVIATIONS ...................................................................................................................................... 18
1.
INTRODUCTION................................................................................................................................ 20
1.1.
Background .................................................................................................................................... 20
1.1.1.
Compound Profile....................................................................................................................... 22
1.1.2.
Medically Ill Patients - Scope of the Problem ............................................................................. 22
1.1.3.
Thromboprophylaxis in Patients with Acute Medical Conditions................................................ 23
1.1.4.
VTE Risk Post Discharge in Patients Hospitalized for Medical Conditions................................ 23
1.1.5.
Studies Examining Extended Thromboprophylaxis in Patients Hospitalized for Acute 
Medical Conditions and MARINER Approach ............................................................................ 25
1.2.
Overall Rationale for the Study...................................................................................................... 27
2.
OBJECTIVES AND HYPOTHESES.................................................................................................. 27
2.1.
Objectives ...................................................................................................................................... 27
2.2.
Hypotheses .................................................................................................................................... 29
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 29
3.1.
Overview of Study Design.............................................................................................................. 29
3.2.
Study Design Rationale.................................................................................................................. 32
3.3.
Committees .................................................................................................................................... 36
3.3.1.
Executive Committee.................................................................................................................. 36
3.3.2.
Independent Data Monitoring Committee................................................................................... 36
3.3.3.
Clinical Events Committee.......................................................................................................... 36
4.
SUBJECT POPULATION.................................................................................................................. 37
4.1.
Inclusion Criteria ............................................................................................................................ 37
4.2.
Exclusion Criteria ........................................................................................................................... 39
4.3.
Prohibitions and Restrictions ......................................................................................................... 43
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 44
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 45
7.
TREATMENT COMPLIANCE............................................................................................................ 47
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 48
9.
STUDY EVALUATIONS .................................................................................................................... 48
9.1.
Study Procedures........................................................................................................................... 48
9.1.1.
Overview..................................................................................................................................... 48
9.1.2.
Screening Phase ........................................................................................................................ 48
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 50
9.1.4.
Post-treatment Phase (Follow-Up) ............................................................................................. 53
9.2.
Efficacy Evaluations and Outcomes .............................................................................................. 54
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Status: Approved, 31 March 2017
9.2.1.
Efficacy Evaluations, Outcomes and Adjudication ..................................................................... 54
9.2.2.
Approach to the Subject with an Efficacy Outcome Event ......................................................... 55
9.3.
Pharmacokinetics........................................................................................................................... 56
9.3.1.
Evaluations ................................................................................................................................. 56
9.3.2.
Analytical Procedures................................................................................................................. 57
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 57
9.4.
Medical Resource Utilization and Health Economics .................................................................... 57
9.5.
Safety Evaluations and Outcomes................................................................................................. 57
9.5.1.
Bleeding Events.......................................................................................................................... 57
9.5.2.
Approach to the Subject with a Bleeding Event ......................................................................... 58
9.5.3.
Other Safety Assessments ......................................................................................................... 59
9.6.
Benefit-Risk Balance...................................................................................................................... 60
9.7.
Sample Collection and Handling.................................................................................................... 60
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 60
10.1.
Completion ..................................................................................................................................... 60
10.2.
Discontinuation of Study Treatment............................................................................................... 60
10.2.1.
Temporary Interruption of Study Treatment ............................................................................... 61
10.2.2.
Approach to Subjects with Temporary Interruption of Study Treatment .................................... 61
10.2.3.
Permanent Discontinuation of Study Treatment......................................................................... 62
10.3.
Withdrawal From the Study............................................................................................................ 63
11.
STATISTICAL METHODS................................................................................................................. 63
11.1.
Analysis Set and Analysis Phase................................................................................................... 64
11.1.1.
Analysis Sets .............................................................................................................................. 64
11.1.2.
Analysis Phases ......................................................................................................................... 64
11.2.
Sample Size Determination ........................................................................................................... 64
11.3.
Efficacy Analyses ........................................................................................................................... 65
11.4.
Pharmacokinetic Analyses............................................................................................................. 68
11.5.
Medical Resource Utilization and Health Economics Analyses..................................................... 68
11.6.
Safety Analyses ............................................................................................................................. 68
11.7.
Interim Analysis.............................................................................................................................. 69
11.8.
Benefit-Risk Analysis ..................................................................................................................... 69
12.
ADVERSE EVENT REPORTING ...................................................................................................... 70
12.1.
Definitions ...................................................................................................................................... 70
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 70
12.1.2.
Attribution Definitions.................................................................................................................. 71
12.1.3.
Severity Criteria .......................................................................................................................... 72
12.2.
Special Reporting Situations.......................................................................................................... 73
12.3.
Procedures..................................................................................................................................... 73
12.3.1.
All Adverse Events...................................................................................................................... 73
12.3.2.
Serious Adverse Events ............................................................................................................. 75
12.3.3.
Pregnancy................................................................................................................................... 76
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 76
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 76
13.1.
Procedures..................................................................................................................................... 76
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 77
14.
STUDY DRUG INFORMATION......................................................................................................... 77
14.1.
Physical Description of Study Drug(s) ........................................................................................... 77
14.2.
Packaging ...................................................................................................................................... 77
14.3.
Labeling.......................................................................................................................................... 77
14.4.
Preparation Handling and Storage................................................................................................. 77
14.5.
Drug Accountability ........................................................................................................................ 77
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 78
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Status: Approved, 31 March 2017
16.
ETHICAL ASPECTS ......................................................................................................................... 78
16.1.
Study-Specific Design Considerations........................................................................................... 78
16.2.
Regulatory Ethics Compliance....................................................................................................... 79
16.2.1.
Investigator Responsibilities ....................................................................................................... 79
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 79
16.2.3.
Informed Consent ....................................................................................................................... 80
16.2.4.
Privacy of Personal Data ............................................................................................................ 81
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 82
17.1.
Protocol Amendments.................................................................................................................... 82
17.2.
Regulatory Documentation ............................................................................................................ 82
17.2.1.
Regulatory Approval/Notification ................................................................................................ 82
17.2.2.
Required Pre-study Documentation ........................................................................................... 83
17.3.
Subject Identification Enrollment and Screening Logs .................................................................. 83
17.4.
Source Documentation................................................................................................................... 84
17.5.
Case Report Form Completion ...................................................................................................... 84
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 85
17.7.
Record Retention ........................................................................................................................... 85
17.8.
Monitoring ...................................................................................................................................... 86
17.9.
Study Completion/Termination....................................................................................................... 86
17.9.1.
Study Completion ....................................................................................................................... 86
17.9.2.
Study Termination....................................................................................................................... 87
17.10.
On-Site Audits ................................................................................................................................ 87
17.11.
Use of Information and Publication................................................................................................ 87
REFERENCES............................................................................................................................................ 89
INVESTIGATOR AGREEMENT ............................................................................................................... 120
LIST OF ATTACHMENTS
ATTACHMENT 1:
EFFICACY OUTCOMES .......................................................................................... 92
ATTACHMENT 2:
SUSPECTED EVENT SUPPORTING DOCUMENTATION..................................... 94
ATTACHMENT 3: 
PHARMACOKINETIC SAMPLE COLLECTION AND HANDLING......................... 96
ATTACHMENT 4: 
SYMPTOM ASSESSMENT...................................................................................... 97
ATTACHMENT 5:
INT-1 TO INT-5 / AMENDMENT CHANGES ........................................................... 98
ATTACHMENT 6:
COMPLETE AMENDMENT HISTORY OF INT-6 INCLUSION AND 
EXCLUSION CRITERIA, AND PROHIBITIONS AND RESTRICTIONS FOR 
DATA COLLECTION PURPOSES ........................................................................ 111
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Status: Approved, 31 March 2017
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Modified IMPROVE VTE Risk Score ........................................................................................ 38
Table 2:
Minimum Number of Heparin Doses Required for Study Eligibility by Duration of Index 
Hospitalization........................................................................................................................... 39
Table 3
Pharmacokinetic Suggested Sampling Schedule..................................................................... 56
Table 4:
Summary of PK Suggested Observations for Rivaroxaban Arm.............................................. 56
Table 5:
Preoperative Interruption of Rivaroxaban: A Suggested Management Approach 
(adapted from Spyropoulos and Douketis 2012) ...................................................................... 61
Table 6:
Postoperative Resumption of Rivaroxaban: A Suggested Management Approach................. 62
Table 7:
Approximate Number of Subjects Needed to Observe 161 Events ......................................... 65
FIGURES
Figure 1:
Kaplan-Meier Curve Showing Cumulative Symptomatic VTE Incidence from Hospital 
Admission to 3 Months of Follow-up......................................................................................... 24
Figure 2:
Cumulative Number of Events Over Time: High-risk Elderly Medical Patients. ....................... 24
Figure 3:
Schematic Overview of the Study (RIVAROXDVT3002).......................................................... 32
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Status: Approved, 31 March 2017
PROTOCOL AMENDMENTS
Amendments are listed beginning with the most recent amendment.
Amendment INT-7 (31 March 2017)
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 that because this is an event-
driven study, additional subjects will need to be enrolled to allow for more primary efficacy outcome events to 
accumulate, due to a lower than expected blinded pooled event rate. 
Applicable Section(s)
Description of Change(s)
Rationale: The upper limit for the number of randomized subjects was increased to allow for the accumulation of 
more primary efficacy outcome events. 
Applicable Section(s)
Description of Change(s)
Synopsis Overview of Study 
Design; Synopsis Sample Size 
Determination; 3.1. Overview 
of Study Design; 11.2.Sample 
Size Determination
The total number of subjects that may be randomized was increased from 
approximately 9,000 to approximately 12,000 subjects.
Rationale: Revisions were made to align the timing of the interim analysis to when approximately 50% of the total 
anticipated subjects with observed blinded pooled primary efficacy outcome events at the end of the study will be 
obtained.  
Applicable Section(s)
Description of Change(s)
Synopsis Overview of Study 
Design; Synopsis Interim 
Analysis; 3.1. Overview of 
Study Design; 11.7. Interim 
Analysis  
The timing of the interim analysis was changed from having observed 
adjudicated primary efficacy outcome events in approximately 80 subjects to 
approximately 50% of subjects based on the expected total number of events. 
Consequently, ‘targeted’ in ‘targeted total number of events’ was changed to 
‘expected total number of events’ based on the actual observed blinded pooled 
event rate because this event rate is lower than the assumed rate.
Protocol Version 
Issue Date
Original Protocol
27 January 2014
Amendment INT-7
31 March 2017
Amendment INT-6
19 June 2015
Amendment INT-5
15 June 2015
Amendment INT-4
19 January 2015
Amendment INT-3
8 December 2014
Amendment INT-2
11 April 2014
Amendment INT-1
14 March 2014
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Rationale: Changes were made to clarify the term of ‘major protocol deviations’ in the per-protocol analysis set.  
11.1.1. Analysis Sets
The term ‘major’ in ‘major protocol deviations’ was changed to ‘key’ protocol 
deviations, because ‘key’ accurately reflects that only a subset of major 
deviations will be excluded from the per-protocol analysis set.
Rationale: Minor errors were noted.
Applicable Section(s)
Description of Change(s)
Throughout the protocol
3.1. Overview of Study Design
Minor grammatical, formatting or spelling changes were made.
For consistency with the rest of the document, the principal safety outcome was 
added.
Amendment INT-6 (19 June 2015)
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 reasons for the amendment are to clarify prescribed 
thromboprophylaxis during index hospitalization and capping during enrollment.  
Applicable Section(s)
Description of Change(s)
Rationale: Prescribed thromboprophylaxis has been clarified.
Applicable Section(s)
Description of Change(s)
4. SUBJECT POPULATION, 
Section 4.1 Inclusion Criteria.
Inclusion Criterion # 4. 
Prescribed maximum daily dose of thromboprophylactic agents allowed was 
clarified.   
Section 5. Treatment Allocation 
and Blinding
Capping for subgroups during enrollment and related communication with sites 
were clarified.
Please note that description of changes for INT-1 to INT-5 can be found in Attachment 5.
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Status: Approved, 31 March 2017
SYNOPSIS
Medically Ill Patient Assessment of Rivaroxaban Versus Placebo IN Reducing Post-Discharge Venous 
Thrombo-Embolism Risk (MARINER)
DESCRIPTION OF THE COMPOUND
Rivaroxaban is an oral, direct acting, Factor Xa (FXa) inhibitor anticoagulant that has been under 
development for the treatment of several thrombosis-mediated conditions. Rivaroxaban is marketed under 
the trade name XARELTO® and has been approved for multiple indications worldwide. The clinical 
development program for rivaroxaban is extensive. Over 70,000 subjects have been studied from Phase 1 
through multiple large Phase 4 studies as of 15 March 2014, covering several indications and potential 
indications in the overall clinical development program. Over 40,000 of these subjects have been exposed 
to rivaroxaban in completed and ongoing company-sponsored interventional clinical trials and 
non-interventional studies, with the total daily doses of rivaroxaban ranging between 5 mg and 60 mg.
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 19.
OBJECTIVE AND HYPOTHESIS
Primary Objective
The primary objective is to assess the efficacy and safety of rivaroxaban compared with placebo in the prevention of 
symptomatic venous thromboembolism (VTE: lower extremity deep vein thrombosis [DVT] and non-fatal 
pulmonary embolism [PE]) and VTE-related death (death due to PE or death in which PE cannot be ruled out as the 
cause) post-hospital discharge in high-risk, medically ill patients.
Secondary Objectives  
The secondary objectives are to compare rivaroxaban with placebo in the following post-hospital 
discharge outcomes in high-risk, medically ill patients:

VTE-related death (death due to PE or death in which PE cannot be ruled out as the cause)

Symptomatic VTE (lower extremity DVT and non-fatal PE)

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE) and all-cause mortality 
(ACM)

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE), myocardial infarction 
(MI), non-hemorrhagic stroke and cardiovascular (CV) death (death due to a known CV cause and 
death in which a CV cause cannot be ruled out; by this definition, a VTE-related death is considered 
a CV death)

ACM 
Exploratory Objectives
The exploratory objectives are to compare rivaroxaban with placebo, in the following post-hospital 
discharge outcomes in high-risk, medically ill patients:
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Status: Approved, 31 March 2017

Symptomatic lower extremity DVT

Symptomatic non-fatal PE

Symptomatic upper extremity DVT

MI  

Non-hemorrhagic stroke

Re-hospitalization for symptomatic VTE (lower extremity DVT and non-fatal PE) within 30 days
after randomization
Pharmacokinetic Objective
The pharmacokinetic (PK) objective is to assess the kinetics of rivaroxaban in high-risk, medically ill 
patients, and to describe drug exposure based on creatinine clearance (CrCl). 
Medical Resource Utilization and Health Economics Objective
The medical resource utilization and health economics objective is to assess the following cost drivers, 
ie, re-hospitalization (including emergency room [ER] visits, intensive care unit and cardiac care unit 
stays), length of stay and subject discharge destination (after re-hospitalization).
Safety Objectives
The safety objectives are to compare rivaroxaban with placebo in the following bleeding outcomes in 
high-risk, medically ill patients:

Major bleeding using validated International Society on Thrombosis and Haemostasis (ISTH)
bleeding criteria.

Non-major clinically relevant bleeding

Other bleeding
Overall safety will also be assessed.
Hypotheses  
The primary hypothesis is that rivaroxaban is superior to placebo in the prevention of the composite of 
symptomatic VTE (lower extremity DVT and non-fatal PE) and VTE-related death (death due to PE or 
death in which PE cannot be ruled out as the cause). The secondary hypotheses are that rivaroxaban is 
superior to placebo in the prevention of 1) VTE-related death (death due to PE or death in which PE 
cannot be ruled out as the cause), 2) symptomatic VTE (lower extremity DVT and non-fatal PE), 3) the 
composite of symptomatic VTE (lower extremity DVT and non-fatal PE) and ACM, 4) the composite of 
symptomatic VTE (lower extremity DVT and non-fatal PE), MI, non-hemorrhagic stroke and CV death 
(death due to a known CV cause and death in which a CV cause cannot be ruled out; by this definition, a 
VTE-related death is considered a CV death) and 5) ACM alone.
OVERVIEW OF STUDY DESIGN
This is a multicenter, prospective, randomized, double-blind, placebo-controlled, event-driven study 
designed to evaluate rivaroxaban, compared with placebo, in the prevention of symptomatic VTE 
(lower extremity DVT and non-fatal PE) events and VTE-related deaths (death due to PE or death in 
which PE cannot be ruled out as the cause) for a period of 45 days post-hospital discharge. The study 
consists of a screening phase, a 45-day double-blind treatment phase, and a 30-day safety follow-up 
period. 
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Status: Approved, 31 March 2017
The subject population comprises men and women aged 40 years and older who have completed 
screening no later than 1 day after leaving the hospital and who have been hospitalized for the new onset 
or exacerbation of 1 of the following medical conditions: 

Heart Failure (HF) with a reduced left ventricular ejection fraction (LVEF ≤45%)

Acute respiratory insufficiency or acute exacerbation of chronic obstructive pulmonary disease 
(COPD)

Acute ischemic stroke (including spinal cord infarction if no evidence of intramedullary, subdural or 
epidural hemorrhage) 

Acute infectious disease

Inflammatory disease, including rheumatic disease
The index hospitalization must be at least 3 and no more than 10 consecutive days in duration. In order to 
be eligible, subjects must have an increased VTE risk, as demonstrated by a total modified International 
Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE Risk Score of:

≥4, or 

3 with D-dimer > 2XULN, or

2 with D-dimer > 2XULN  
In addition, subjects must have received treatment during the index hospitalization with LMWH or UFH.
Any patient with a medical condition that will require use of any parenteral or oral anticoagulation 
(eg, atrial fibrillation) during the study is not eligible for participation. In addition, patients at particularly 
increased risk of bleeding and those using medications that might interact with the study drug will be 
excluded. 
Subjects who meet all of the inclusion and none of the exclusion criteria will be randomly assigned to 
receive rivaroxaban or placebo. Randomization should occur on the same day as or the day after the 
subject leaves the hospital, and may occur at the hospital, clinic or other discharge destination. Subjects 
will be randomized by strata including creatinine clearance and country.
After randomization, subjects will receive double-blind treatment with rivaroxaban 10 mg (7.5 mg for 
subjects with a CrCl ≥30 mL/min and <50 mL/min) daily or matching placebo daily. Placebo has been 
chosen as the comparator because of current guidelines which recommend against thromboprophylaxis in 
medically ill patients after hospital discharge. The first dose of study drug should be administered no later 
than the day after the subject leaves the hospital and as soon after randomization as possible. Subjects will 
be instructed to discontinue study drug after they take a dose on Day 45, and complete an end of treatment 
visit within the next 4 days. Regardless of the day on which the Day 45 Visit occurs, no study drug may 
be taken after Day 45. The subject must be assessed 30 days later for safety follow-up.  This will be the 
last contact with the subject unless extended follow-up for safety is required.  
If a subject has a suspected efficacy or bleeding outcome event during the study, the treating physician 
should exercise clinical judgment and follow established 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 study drug is administered in the doses used in this study.  
There is no specific reversal agent for rivaroxaban; management of the subject with a bleeding event 
should not be impacted by knowledge of study drug treatment.
Rivaroxaban will not be provided to subjects after they complete study treatment, unless required by local 
regulations. Randomization in this study is preceded by a hospitalization for an acute illness and the study 
drug treatment phase extends for 45 days after randomization to correspond to the period of greatest risk 
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for VTE.  Chronic therapy with the study drug is not being tested. It will only be after data from the entire 
study is analyzed that the sponsor can determine if the population at risk will benefit from treatment.
The primary efficacy outcome is the composite of all symptomatic VTE events (lower extremity DVT 
and non-fatal PE) and VTE-related death (death due to PE or death in which PE cannot be ruled out as the 
cause), from randomization up to Day 45. The targeted total number of primary efficacy outcomes in this 
event-driven study is 161. It is estimated that a total of approximately 8,000 subjects will need to be 
randomized to either rivaroxaban or placebo in a 1:1 ratio. In the event that the actual observed blinded 
pooled event rate is lower than the assumed rate, more subjects may be enrolled to accumulate additional 
outcome events. Randomization in this study may be stopped at approximately 12,000 subjects for 
administrative considerations even if the targeted 161 events have not been observed by then. An interim 
analysis for futility will be conducted when approximately 50% of subjects with adjudicated primary 
efficacy outcome events have been observed (about 50% of the expected total number of events based on 
the actual observed blinded pooled event rate even if this event rate is lower than the assumed rate). The 
principal safety outcome for this study is ISTH major bleeding.
For population PK analyses, based on the model performance and the high variability of the 
PK parameters observed in the MAGELLaN study, 2 blood samples (at pre-dose and 1-4 hours after study 
drug administration) will be collected at the Day 7 visit  and 2 blood samples (at 3 to 7 and 7 to 12 hours 
after study drug administration) will be collected at the Day 21 visit for each subject for up to 
600 subjects (300 rivaroxaban subjects [200 subjects in the 10 mg daily group and 100 subjects in the 
7.5 mg daily group] and 300 in the placebo group). The sparse blood samples for PK analyses will be 
collected in selected sites only.
An Executive Committee (EC), an Independent Data Monitoring Committee (IDMC) and a Clinical Event 
Committee (CEC) will be commissioned for this study. All committees will be governed by separate 
charters, see Section 3.3.
SUBJECT POPULATION
The subject population comprises men and women age 40 years and older who have completed screening 
no later than 1 day after leaving the hospital and who have been hospitalized for the new onset or 
exacerbation of 1 of the following medical conditions:

HF with a reduced LVEF (LVEF ≤ 45%)

Acute respiratory insufficiency or acute exacerbation of COPD

Acute ischemic stroke (including spinal cord infarction if no evidence of intramedullary, subdural or 
epidural hemorrhage)

Acute infectious disease

Inflammatory disease, including rheumatic disease
The index hospitalization must be at least 3 and no more than 10 consecutive days in duration. In order to 
be eligible, subjects must have an increased VTE risk, as demonstrated by a total modified International 
Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE Risk Score of:

≥4, or 

3 with D-dimer > 2XULN, or

2 with D-dimer > 2XULN  
In addition, subjects must have received treatment during the index hospitalization with low molecular 
weight heparin (LMWH) or unfractionated heparin (UFH).
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Any patient with a medical condition that will require use of any parenteral or oral anticoagulation 
(eg, atrial fibrillation, other medical condition) during the study is not eligible for participation. In 
addition, patients at particularly increased risk of bleeding and those using medications that interact with 
the study drug will be excluded.
DOSAGE AND ADMINISTRATION
Treatment groups in this study are rivaroxaban and placebo. Subjects will be randomly assigned in a 
1:1 ratio to receive rivaroxaban 10 mg daily (or 7.5mg daily in subjects with CrCl ≥30 mL/min and
<50 mL/min) or matching placebo daily. Randomization will be stratified by subjects with 
CrCl ≥30 mL/min and <50 mL/min versus subjects with CrCl ≥50 mL/min and by country.
The first dose of study drug should be administered no later than the day after the subject leaves the 
hospital and as soon after randomization as possible. The date and time of the first dose of study drug and 
the last dose of LMWH or UFH should be recorded as accurately as possible. The first dose of study drug 
should not be delayed to allow administration under supervision. All subjects should take study drug 
(rivaroxaban or placebo) daily with or without food at approximately the same time each day, and 
discontinue study drug after they take a dose on Day 45. Regardless of the day on which the Day 45 Visit 
occurs, no study drug may be taken after Day 45.
A missed dose should be taken as soon as possible (up to 8 hours prior to the next scheduled dose), and 
the next scheduled dose should be taken at the regular time.
Interruption of Study Drug 
Study drug may be interrupted temporarily as necessary for invasive procedures or as medically needed 
(eg, in the setting of a bleeding event or a required prohibited therapy). If a subject is hospitalized for any 
reason other than a VTE-related event or bleeding, study drug should be continued during hospitalization 
unless the treating physician feels that anticoagulation is clinically warranted. Subjects may be placed on 
appropriate anticoagulation at the discretion of the treating physician. In that case, study drug needs to be 
temporarily interrupted and can be restarted upon discharge at the discretion of the investigator. These 
interruptions will be recorded on the electronic case report form (eCRF).
During the study, should the subject develop any condition, which in the investigator’s judgment requires 
long-term anticoagulation thromboprophylaxis, or fibrinolysis, the subject will have study treatment 
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.
EFFICACY EVALUATIONS/OUTCOMES

The primary efficacy outcome is the composite of all symptomatic VTE events (lower extremity 
DVT and non-fatal PE) and VTE-related death (death due to PE or death in which PE cannot be 
ruled out as the cause)

The secondary efficacy outcomes are the following:

VTE-related death (death due to PE or death in which PE cannot be ruled out as the cause)

Symptomatic VTE (lower extremity DVT and non-fatal PE)

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE) and ACM

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE), MI, 
non-hemorrhagic stroke and CV death (death due to a known CV cause and death in which a 
CV cause cannot be ruled out; by this definition, a VTE-related death is considered a CV death)

ACM 
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JNJ-39039039; BAY 59-7939 (rivaroxaban)
Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017

Exploratory efficacy outcomes are:

Symptomatic lower extremity DVT

Symptomatic non-fatal PE

Symptomatic upper extremity DVT

MI

Non-hemorrhagic stroke

Re-hospitalization for symptomatic VTE (lower extremity DVT and non-fatal PE) within 
30 days after randomization
Any clinical event that suggests the possibility that an efficacy outcome event has occurred (including 
acute coronary syndrome (ACS) and transient ischemic attack (TIA) will be sent for adjudication. If a 
subject has a suspected efficacy outcome event during the study, the treating physician should exercise 
clinical judgment and follow established guidelines to apply the standard of care. Unblinding of study 
drug should not be necessary, as anticoagulation regimens do not require adjustment regardless of use of 
placebo vs rivaroxaban when administered in the doses used in this study.
SAFETY EVALUATIONS/ OUTCOMES

The principal safety outcome is major bleeding using validated ISTH bleeding criteria.

Other safety outcomes are non-major clinically relevant bleeding and other bleeding.
Overall safety will also be assessed.
An ISTH major bleeding event is defined as overt bleeding associated with: a fall in hemoglobin of 
2 g/dL or more, or leading to a transfusion of 2 or more units of packed red blood cells or whole blood, or 
bleeding that occurs in a critical site: eg, intracranial, intraspinal, intraocular, pericardial, intra-articular, 
intramuscular with compartment syndrome, retroperitoneal, or a fatal outcome (for details on definitions 
see Section 9.5). 
Non-major clinically relevant 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 associated with discomfort for the subject such as
pain or impairment of activities of daily life.
Other bleeding is defined as any other overt bleeding that does not meet the ISTH criteria for major or 
non-major clinically relevant bleeding. 
Any clinical event that suggests the possibility that a bleeding outcome event has occurred will be sent for 
adjudication. If a subject has a serious bleeding event during study drug treatment, routine measures 
should be considered as described in Section 9.5.2. Unblinding of study drug should not be necessary. As 
there is not a specific reversal agent for rivaroxaban, management of the subject should not be impacted 
by knowledge of study drug treatment.
STATISTICAL METHODS
Key Analysis Set and Analysis Phase

Intention-to-Treat (ITT): This analysis set consists of all randomized subjects who have a signed 
valid informed consent.  

Up-to-Day-45: This analysis phase includes all data from randomization to Day 45 (inclusive).  
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Sample Size Determination
This is an event-driven study. The targeted total number of primary efficacy outcome events is 161, based 
on the ITT analysis set and Up-to-Day-45 analysis phase. If a subject has multiple events, only the first is 
counted towards study size determination.
This targeted total number of events is determined using statistical software East 5.3 based on the primary 
efficacy analysis (defined later) and the following assumptions:

40% relative risk reduction (RRR) in the primary efficacy outcome based on the ITT analysis set and 
Up-to-Day-45 analysis phase (RRR is defined as 1 minus the hazard ratio [HR] of rivaroxaban 
versus placebo).   

Power of 90% assuming the above RRR

Two-sided significance level of 0.05. 
To observe the targeted 161 events, it is estimated that a total of approximately 8,000 subjects will need to 
be randomized to either rivaroxaban or placebo in 1:1 ratio. This estimate is based on an estimated 
placebo incidence rate of the primary efficacy outcome of 2.5%. In the event that the actual observed 
blinded pooled event rate is lower than the assumed rate, more subjects may be enrolled to accumulate 
additional outcome events. Randomization in this study may be stopped at approximately 12,000 subjects 
for administrative considerations even if the targeted 161 events have not been observed by then. The 
total number of VTE-related death events may also be taken into account when deciding to stop 
randomization.
Efficacy Analyses
Primary Efficacy Outcome
The primary efficacy outcome will be analyzed based on time from randomization to the first occurrence 
of symptomatic VTE (lower extremity DVT and non-fatal PE) and VTE-related death (death due to PE or 
death in which PE cannot be ruled out as the cause) in the ITT analysis set and Up-to-Day-45 analysis 
phase. The primary statistical alternative hypothesis is that rivaroxaban is superior to placebo on the 
primary efficacy outcome.
The primary statistical hypothesis will be tested using Cox proportional hazards model, stratified by 
subjects with CrCl ≥30 mL/min and <50 mL/min versus subjects with CrCl ≥50 mL/min, with the 
treatment (as randomized) as the only covariate. This primary efficacy analysis will be based on the ITT
analysis set and Up-to-Day-45 analysis phase. Subjects will be analyzed according to the treatment group 
to which they are randomized, regardless of actual treatment received. As an operational arrangement, the 
2-sided p-value will be reported and if it is less than the 2-sided alpha of 0.05, then superiority of the 
study drug will be declared if the observed survival functions favor rivaroxaban.
The point estimate and corresponding 95% confidence interval (CI) for the HR (rivaroxaban to placebo) 
will be provided based on the Cox proportional hazards model. For the CIs, the plausibility of 
proportional hazards assumption will be assessed by visually comparing the plot of the log of cumulative 
hazard between treatments, and additionally checked by adding a treatment by logarithm-transformed 
time interaction into the Cox model.  
The cumulative event rate derived from Kaplan-Meier estimate will be displayed graphically to evaluate 
the treatment effect over time. 
Homogeneity of treatment effects, both in HR and direction, will be assessed by subgroups and their 
interactions with treatment (for details see Section 11.3). Analysis methods will be detailed in the SAP.
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Secondary Efficacy Outcomes
Each secondary efficacy outcome will be analyzed based on time from randomization to the first 
occurrence in the ITT analysis set and the Up-to-Day 45 analysis phase. The same stratified Cox model as 
that for the primary efficacy outcome will be used.  Details will be provided in the SAP.
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):

VTE-related death (death due to PE or death in which PE cannot be ruled out as the cause)

Symptomatic VTE (lower extremity DVT and non-fatal PE)

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE) and ACM

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE), MI, non-hemorrhagic 
stroke and CV death (death due to a known CV cause and death in which a CV cause cannot be ruled 
out; by this definition, a VTE-related death is considered a CV death)

ACM 
Exploratory Efficacy Outcomes
Each exploratory outcome will be summarized by treatment groups based on the ITT analysis set and 
Up-to-Day-45 analysis phase.
Pharmacokinetic Analyses 
The population PK model will characterize and predict the overall exposure to rivaroxaban and determine 
different PK parameters.
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics will be descriptively summarized by treatment group.   
Safety Analyses
Bleeding Outcomes
The principal safety outcome will be analyzed based on time from randomization to the first occurrence 
of ISTH major bleeding.  Treatments will be compared using the same Cox proportional hazards model as 
that for the primary efficacy outcome described earlier.  The analysis will be based on the safety analysis 
set and on-treatment analysis phase. Subjects will be analyzed according to study drug received. If a 
subject inadvertently receives both drugs, the subject will be analyzed as randomized. Non-major 
clinically relevant bleeding will be analyzed based on time from randomization to the first occurrence. 
The same analysis as that for the principal safety outcome will be used.
Interim Analysis
An interim analysis for futility will be conducted when approximately 50% of subjects with adjudicated 
primary efficacy outcome events have been observed (about 50% of the expected total number of events
based on the actual observed blinded pooled event rate even if this event rate is lower than the assumed 
rate) and there will be no alpha adjustment to the final analysis (for details see Section 11.7).
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Benefit-Risk Analysis
The benefit-risk of rivaroxaban vs placebo will be evaluated based on the excess number of events 
between treatments for events intended to be prevented (benefits) and events that may be caused (risks)
(for details see Section 11.8).
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
TIME AND EVENTS SCHEDULE
Protocol Activity
Screena
Randomizeb
Treatment
30 Day F/U
Screening
Day 1
Day 7
Day 21
Day 45
EOTc
Day 75
EOS
Hospital/
Clinic/
Discharge 
Destination
Hospital/
Clinic/
Discharge 
Destination
Clinic/
Discharge 
Destination/
Telephone
Clinic/
Discharge 
Destination
Clinic/
Discharge 
Destination
Clinic/
Discharge 
Destination/
Telephone
Window
-2/+5d
-3/+7d
-0/+4d
-5/+5d
Informed Consentd
X
Inclusion / Exclusione
X
X
VTE Riske
X
X
Physical Exam and Vitalsf
X
Demographics
X
Medical History
X
Hemoglobin/ Platelet countg
X
Serum Creatinineg
X
Serum/Urine Pregnancyh
X
D-dimer (local)i
X
Computed tomography/MRI of the 
headj
X
IWRS Registration
X
Dispense Study Drug
X
Xc
Index Hospitalization 
X
LMWH/UFH Use
X
Clinical Assessmentf
X
X
X
Symptom Assessment
X
X
X
X
Subject Counselingk
X
X
X
X
Study Drug Accountability
X
X
Clinical Status/Suspected Outcomes
X
X
X
X
Adverse Events
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
Medical Resource HECON
X
X
X
X
PK Sampling l
X
X
Key: EOS=end of study; EOT=end of treatment; F/U=follow up; HECON= health economics; LMWH=low molecular weight heparin; 
MRI=magnetic resonance imaging; PK=pharmacokinetics; VTE=venous thromboembolism; IWRS= interactive web response system; 
UFH=unfractionated heparin.
a)
Screening may begin any time, after the admission for the index hospitalization and once the informed consent is obtained.  The index 
hospitalization must be at least 3 and no more than 10 consecutive days in duration.
b) Randomization should occur on the same day as or the day after the subject leaves the hospital.
c) The subject will be instructed to discontinue study drug after taking a dose on Day 45. Regardless of the day on which the Day 45 Visit 
occurs, no study drug may be taken after Day 45.
d) A limited informed consent may be used for a screening local D-dimer or head computed tomography (CT) if permitted locally. Full 
informed consent must still be obtained before other study procedures are performed.
e)
Screening inclusion / exclusion criteria and VTE risk score should be assessed and verified at randomization. 
f)
Vital signs include pulse and blood pressure. Physical exam will be performed at Screening or Randomization. Clinical Assessment is a 
focused evaluation of heart, lungs, lower extremities, and neurological status.  If the physical examination is conducted at Day 1, then 
the Clinical assessment is not required on that day.
g) Hemoglobin, platelet count and serum creatinine must be obtained at least as recently as 2 days before the subject leaves the hospital or 
later, but before randomization.
h) Pregnancy test must be performed for women of child-bearing potential and may be repeated as indicated or required locally.
i) D-dimer may be obtained any time from the beginning of the index hospitalization up until randomization; the value obtained closest to 
the beginning of the index hospitalization should be used.  A value >2xULN is required if the VTE risk score is 2 or 3.
j) Head CT/MRI performed only for subjects with ischemic stroke who received fibrinolytic agents; obtain at least 24 hours after 
fibrinolysis.
k) Includes training on the signs and symptoms associated with DVT, PE and bleeding and the appropriate response if symptoms develop.
l) Non-fasting PK samples will be obtained for subjects consented to participate at selected sites. For subjects participating in the PK assessment, the 
telephone visit option will not be applicable. For these subjects, visits at Day 7 and Day 21 must be conducted at the clinic.
At Day 7, 2 samples will be obtained: 1) pre-dose and 2) 1-4 hours post dose. 
At Day 21, 2 samples at least 3 hours apart will be obtained: 1) 3-7 hours post-dose and 2) 7-12 hours post-dose.
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JNJ-39039039; BAY 59-7939 (rivaroxaban)
Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
ABBREVIATIONS
ACCP
American College of Chest Physicians 
ACM
all-cause mortality
ACS
acute coronary syndrome
ASA
acetylsalicylic acid
AUC
area under the plasma concentration curve
AV
arteriovenous
BP
blood pressure
CCU
cardiac care unit
CEC
CHF
Clinical Event Committee
congestive heart failure
CI
confidence interval
CL/F
clearance
Cmax
maximum serum concentration
Cmin
minimum serum concentration
COPD
chronic obstructive pulmonary disease
CrCl
creatinine clearance
CT
computed tomography
CV
cardiovascular
CYP3A4
Cytochrome P450 3A4
DVT
deep vein thrombosis
eCRF
electronic case report form
eDC
electronic data capture
EC
Executive Committee
EF
ejection fraction
EOS
end of study
EOT
end of treatment
ER
emergency room
EU
European Union
FDA
Food and Drug Administration
FXa
factor Xa
GCP
Good Clinical Practice
HF
heart failure
HR
hazard ratio
ICF
informed consent form
ICH
International Conference on Harmonisation
ICU
intensive care unit
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IMPROVE
International Medical Prevention Registry on Venous Thromboembolism (IMPROVE)
IRB
Institutional Review Board
ISTH
International Society on Thrombosis and Haemostasis
ITT
intention-to-treat
IWRS
interactive web response system
Ka
first-order absorption rate constant
LC-MS/MS
liquid chromatography coupled to tandem mass spectrometry
LDUH
low-dose unfractionated heparin 
LOS
length of stay
LMWH
low molecular weight heparin 
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MRI
Magnetic resonance imaging 
NT-proBNP
N-terminal pro-brain natriuretic peptide
P2Y12 
G protein-coupled purinergic receptor P2Y 
PE
pulmonary embolism
PK
pharmacokinetic
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Status: Approved, 31 March 2017
PP
per protocol
PPI
proton pump inhibitor
PQC
product quality complaint
RRR
relative risk reduction
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
tmax
time to reach maximum concentration in plasma
TIA
transient ischemic attack
UFH
unfractionated heparin 
ULN
upper limit of normal
US
United States
V/F
volume of distribution
VTE
venous thromboembolism
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Status: Approved, 31 March 2017
1.
INTRODUCTION
Rivaroxaban is an oral, direct acting, Factor Xa (FXa) inhibitor anticoagulant that has been under 
development for the treatment of several thrombosis-mediated conditions. Rivaroxaban is 
marketed under the trade name XARELTO® and has been approved for multiple indications 
worldwide. The clinical development program for rivaroxaban is extensive. Over 70,000 subjects 
have been studied from Phase 1 through multiple large Phase 4 studies as of 15 March 2014, 
covering several indications and potential indications in the overall clinical development 
program. Over 40,000 of these subjects have been exposed to rivaroxaban in completed and 
ongoing company-sponsored interventional clinical trials and non-interventional studies, with the 
total daily doses of rivaroxaban ranging between 5 mg and 60 mg. In addition, rivaroxaban 
(10 mg daily) was evaluated for thromboprophylaxis in medically ill patients in the MAGELLaN 
trial10. 
For the most comprehensive nonclinical and clinical information regarding the efficacy and 
safety of rivaroxaban, refer to the latest version of the Investigator's Brochure19.
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
Hemostasis is a normal physiological process following damage of the vascular system.  In 
various diseases, however, the hemostatic mechanisms are inappropriately activated with 
pathological consequences known as thrombosis. Venous thromboembolism (VTE) including 
deep vein thrombosis (DVT) and pulmonary embolism (PE) represents one of the most common 
health problems. More than 2 million Americans suffer from acute VTE each year. In the 
European Union (EU), incidence rates of DVT and PE are assumed to be slightly higher, but are 
generally consistent with those in the United States (US)9,39. Deep vein thrombosis and PE are a 
burden for healthcare systems as they are associated with high mortality and considerable 
morbidity in terms of recurrent events, the post-thrombotic syndrome, and chronic 
thromboembolic pulmonary hypertension 14,22,30,43.  Treatment of DVT and PE aims at 
prevention of worsening of the existing thrombus, as well as prevention of recurrent VTE41.
Medically ill patients, ie, patients that are hospitalized for the treatment of acute medical 
illnesses, are at high risk for the development of VTE during their hospital stay and immediately 
after their hospital discharge. The American College of Chest Physicians (ACCP) 
Evidence-Based 
Clinical 
Practice
Guidelines 
currently 
recommend 
anticoagulant 
thromboprophylaxis for acutely ill hospitalized medical patients with increased risk of 
thrombosis for 6 to 21 days, until full mobility is restored or until discharge from hospital, 
whichever comes first20. In the US and in many other countries including those in Europe, there 
is a growing trend for shorter hospital stays for patients hospitalized for medical conditions1,29. 
While continued thromboprophylaxis with parenteral agents post discharge could potentially 
reduce the overall risk of VTE, this approach has not yet been widely used, likely due to the 
challenges in administering a parenteral medication by the patient or caregivers and the lack of 
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Status: Approved, 31 March 2017
compelling benefit-risk data with existing anticoagulants. The duration of thromboprophylaxis is 
largely determined by the duration of hospitalization and currently post-hospital
thromboprophylaxis with parenteral agents is infrequently used, despite the fact that the risk of 
VTE persists after hospital discharge. Since the documented increase in risk of VTE persists well 
beyond hospital discharge, studies of extended thromboprophylaxis with oral anticoagulants in 
post-discharge patients hospitalized for medical conditions at risk for VTE are warranted36. 
Recently, 3 studies with extended treatment duration of enoxaparin (EXCLAIM), apixaban 
(ADOPT) and rivaroxaban (MAGELLaN) failed to demonstrate a positive benefit-risk profile for 
extended-duration thromboprophylaxis in patients hospitalized for medical conditions primarily 
due to increased bleeding with the anticoagulants10,13,15,17.
The previous trial in medically ill patients (the MAGELLaN study) showed positive efficacy 
results of rivaroxaban but a bleeding risk that outweighed the benefit. Compared with this and 
the other trials, the MARINER trial was therefore modified to improve the overall safety of the 
subjects by addressing the bleeding risk observed in previous extended duration therapy studies 
while maintaining the efficacy that was observed. Several study design elements were modified 
to reduce the risk of major bleeding observed in the MAGELLaN study. Subjects with a baseline 
creatinine clearance (CrCl) of 30 to 49 mL/min have a higher risk for bleeding. Given that a 
relatively high number of medically ill patients with this lower CrCl will be enrolled, there will 
be a rivaroxaban dose adjustment for this subgroup. In addition, other high bleeding 
risk-subjects, eg, with active cancer or with clinically significant bleeding during index 
hospitalization, subjects who use 2 or more antiplatelet agents or acetylsalicylic acid (ASA)
alone at a dose >162 mg/day or clopidogrel alone at a dose >75 mg/day will be excluded. None 
of the proposed measures, ie, dose alteration and exclusion of specific subgroups, is expected to 
reduce the efficacy of the overall study, but they are expected to reduce the risk of major 
bleeding in this population. Furthermore, in the present study, only hard efficacy outcomes 
(eg, symptomatic VTE [lower extremity DVT and non-fatal PE] events, VTE-related deaths
[death due to PE or death in which PE cannot be ruled out as the cause]) will be assessed, 
compared with MAGELLaN, EXCLAIM, and ADOPT, where inclusion of asymptomatic 
proximal DVT as part of the primary efficacy outcome may have resulted in a less clinically 
meaningful evaluation (Section 3.2, Study Design Rationale). This Phase 3 clinical study with 
rivaroxaban is warranted to evaluate extended thromboprophylaxis up to 45 days after hospital 
discharge in medically ill subjects. 
The proposed Phase 3 multicenter, prospective, randomized, double-blind, placebo-controlled, 
event-driven study is designed to evaluate rivaroxaban, compared with placebo, in the prevention 
of symptomatic VTE (lower extremity DVT and non-fatal PE) events and VTE-related deaths
(death due to PE or death in which PE cannot be ruled out as the cause) for a period of 45 days 
post-hospital discharge in subjects ≥40 years of age who have been hospitalized for a specific 
acute medical illness and who have other risk factors for VTE. Prior to randomization, all 
subjects must have been prescribed thromboprophylaxis with low molecular weight heparin 
(LMWH) or unfractionated heparin (UFH) during the index hospitalization. If the treating 
physician believes that additional post-hospital discharge therapy with any anticoagulant is 
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Status: Approved, 31 March 2017
clinically indicated, the patient will not be eligible for participation in the study. A dose 
adjustment to 7.5 mg daily will be implemented in high-risk medically ill subjects with 
CrCl ≥30 mL/min and <50 mL/min. The double-blind treatment duration will be 45 days 
followed by a 30-day follow-up period.
1.1.1.
Compound Profile
As part of the prothrombinase complex, FXa directly converts prothrombin to thrombin. 
Thrombin converts fibrinogen to fibrin and activates platelets leading to clot formation. FXa 
occupies a critical place in the coagulation cascade since it is at the confluence of both the 
intrinsic and extrinsic clotting pathways, and is the key amplification point for the generation of 
thrombin. One molecule of FXa is able to generate more than 1,000 molecules of thrombin due 
to the amplification nature of the coagulation cascade. Selective inhibitors of FXa can terminate 
the amplified burst of thrombin generation and prevent clot formation. 
Rivaroxaban is an oral, direct, FXa inhibitor anticoagulant. Rivaroxaban is rapidly absorbed after 
oral administration, with peak plasma concentrations occurring approximately 2 to 4 hours post 
dose. The elimination pathways of rivaroxaban include both hepatic and renal routes. The 
terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy young subjects and from 
11 to 13 hours in healthy elderly subjects (aged 65 to 83 years). Due to the multiple elimination 
pathways of rivaroxaban, there are few clinically relevant drug-drug interactions.
Rivaroxaban has been under development and approved for the treatment of several 
thrombosis-mediated conditions. The clinical development program for rivaroxaban is extensive 
with over 70,000 subjects having been studied and includes data from clinical trials and post-
marketing surveillance.  Rivaroxaban is marketed under trade name XARELTO®.
1.1.2.
Medically Ill Patients - Scope of the Problem
Medically ill patients, ie, patients that are hospitalized for the treatment of acute medical 
illnesses, are at high risk for the development of VTE during their hospital stay and immediately
after their hospital stay. The rationale for the use of thromboprophylaxis is based on solid 
principles and scientific evidence 20. Almost all hospitalized patients have at least one risk factor 
for VTE, and a high proportion have 3 or more risk factors. Without thromboprophylaxis, the 
incidence of objectively-confirmed, hospital-acquired DVT ranges from 10% to 40% among 
medical or general surgical patients and 40% to 60% following major orthopedic surgery. 
Thromboprophylaxis for the prevention of VTE in hospitalized medically ill patients is routinely 
prescribed and is recommended by internationally recognized guidelines20. Medically ill patients 
are generally defined as patients who are acutely hospitalized for 1 of the following diseases, 
including but not limited to, heart failure (HF) with reduced ejection fraction, respiratory 
conditions, acute infectious diseases, neurologic diseases, inflammatory and hematologic 
diseases, and cancer. Parenteral anticoagulation, including enoxaparin and UFH, are 
recommended 
for 
thromboprophylaxis 
in 
hospitalized 
medically 
ill 
patients, 
but 
thromboprophylaxis is not recommended after discharge 20.
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1.1.3.
Thromboprophylaxis in Patients with Acute Medical Conditions 
Studies of short-term (10 to 12 days) thromboprophylaxis in medically ill patients showed a 
benefit for the LMWH enoxaparin administered during hospitalization (MEDENOX study), for 
the LMWH dalteparin administered for 14 days during and after hospital discharge 
(PREVENT study), and for the indirect Factor-Xa inhibitor fondaparinux administered during 
hospitalization (ARTEMIS study) over placebo7,24,34.
A meta-analysis of 4 studies of short-term enoxaparin treatment (treatment phase, 7 to 10 days) 
compared with UFH showed similarly a substantial reduction in VTE for enoxaparin compared 
with UFH in populations of hospitalized medically ill patients with acute respiratory disease, 
acute cardiovascular (CV) disease and acute ischemic stroke23. The combined incidence of VTE 
at Day 15 in this meta-analysis was 2.6% in the enoxaparin group and 5.2% in the UFH group;
both rates are much lower than in untreated subjects. The combined major bleeding rate at 
Day 15 reported in the studies included in this meta-analysis was 0.65% for the enoxaparin-
treated patients and 0.56% for the UFH-treated patients. Based on the clinical information 
available for acutely ill hospitalized medical patients at increased risk of thrombosis, the ACCP
recommends anticoagulant thromboprophylaxis for 6-21 days, until full mobility is restored or 
until discharge from the hospital, whichever comes first20. Guidelines for post-hospital discharge 
specifically recommend against thromboprophylaxis.
1.1.4.
VTE Risk Post Discharge in Patients Hospitalized for Medical 
Conditions
The risk of VTE persists after hospital discharge. More symptomatic VTEs have been diagnosed 
in the first 3 months following hospitalization than during the hospitalization phase36. It has been 
reported that in patients hospitalized for medical conditions, the cumulative symptomatic VTE 
incidence from admission to 3 months was 1% and stabilizes around 50 days (Figure 1)37. In this 
study, the median length of the hospitalization stay was 7 days.
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Figure 1:
Kaplan-Meier Curve Showing Cumulative Symptomatic VTE Incidence from Hospital 
Admission to 3 Months of Follow-up 
(n=15,156; n = 143 Patients with symptomatic VTE)
Source: From Spyropoulos et al., 201137
Hull et al. (2013) demonstrated that in high risk patients 80% of the confirmed symptomatic 
VTE events (ie, DVT, PE) occurred within 57 days after hospital discharge and a VTE event rate 
of 2.7% was observed at 45 days post discharge18. Patients were classified as having VTE if the 
events were subsequently confirmed by diagnostic testing. High risk patients were defined as 
>60 years of age and having at least 1 of the following risk factors: history of malignancy, 
respiratory illness, neurological illness, inflammatory bowel disease, previous VTE, acute 
infection, or heart failure. Over the 100 day follow-up, 3.8% of the 989 patients had a confirmed 
VTE event (Figure 2) 18. 
Figure 2:
Cumulative Number of Events Over Time: High-risk Elderly Medical Patients. 
Source: Hull et al., 201318
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1.1.5.
Studies Examining Extended Thromboprophylaxis in Patients 
Hospitalized for Acute Medical Conditions and MARINER Approach
While extended-duration (4-week) thromboprophylaxis has been shown to significantly reduce 
the incidence of VTE compared with a standard (1-week) regimen in high-risk surgical patients, 
extended duration thromboprophylaxis has not been shown to be of value in patients hospitalized 
for medical conditions. Medical patients represent most hospitalized patients and at least 75% of 
fatal pulmonary emboli occur in this group5,8,12,16,31.
In the MAGELLaN study, the primary efficacy endpoint was a composite of events of: 
1) asymptomatic proximal DVT in a lower extremity detected by mandatory bilateral lower 
extremity venous ultrasonography, 2) symptomatic DVT in a lower extremity, proximal or distal, 
3) symptomatic, non-fatal PE, and 4) VTE-related death. VTE-related death was defined as 
either a well-documented fatal PE, or sudden death with no other plausible explanation. The 
study compared VTE prophylaxis with oral rivaroxaban 10 mg once daily for 35 days with 
enoxaparin 40 mg daily for 10 days in subjects who were hospitalized for a medical illness. The 
MAGELLaN study met both of its protocol-specified primary efficacy outcomes for rivaroxaban 
versus enoxaparin/placebo at both Day 10 (non-inferiority) and Day 35 (superiority). At Day 35, 
at the end of the rivaroxaban-enoxaparin/placebo phase (treatment phase), rivaroxaban was 
statistically significantly superior to enoxaparin in the mITT Day 35 population (two-sided 
p=0.0211). The RR was 0.77 with the 95% confidence interval (CI) ranging from 0.62 to 0.96. 
The incidence rate of the primary efficacy composite outcome events at Day 35 was higher in the 
enoxaparin group (5.7% [175/3057]) than in the rivaroxaban group (4.4% [131/2967]) 
(mITT Day 35 population). At Day 10, at the end of the rivaroxaban-enoxaparin phase (active 
control treatment phase), rivaroxaban was demonstrated to be non-inferior to enoxaparin in the 
per protocol (PP) population (statistically significant with a one-sided p=0.0025). The RR was 
0.97 with a 95% CI ranging from 0.71 to 1.31. The incidence rate of the primary efficacy 
composite outcome events at Day 10 was identical in both treatment groups in the PP Day 10 
population (rivaroxaban, 2.7% [78/2938]); enoxaparin, 2.7% [82/2993]). However, rivaroxaban 
also increased major bleeding events. 
The CIs and p-values for the weighted relative risks of bleeding events in the 3 treatment phases 
were statistically significant in favor of enoxaparin. By phase, the major bleeding events in the 
rivaroxaban-enoxaparin/placebo phase (Day 1 to Day 35) were reported in 43 (1.1%) vs 
15 (0.4%) subjects, in the rivaroxaban-enoxaparin phase (Day 1 to Day 10) in 24 (0.6%) vs 
11 (0.3%) subjects, in the rivaroxaban-placebo phase (Day 10 to 35) in 19 (0.5%) and 4 (< 0.1%) 
subjects in the rivaroxaban and enoxaparin groups, respectively. 
The EXCLAIM study (Extended prophylaxis for VTE in acutely ill medical patients with 
prolonged immobilization), compared an extended duration (28 days) enoxaparin with placebo in 
patients recently hospitalized for acute medical illnesses who received enoxaparin during their 
initial hospital stay17. The extended-duration enoxaparin treatment was found to reduce the 
incidence of VTE compared with placebo (2.5% vs. 4%; absolute risk difference favoring 
enoxaparin, -1.53% [95.8% CI, -2.54% to -0.52%]). However, enoxaparin also increased major 
bleeding events (0.8% vs. 0.3%; absolute risk difference favoring placebo, 0.51% [95% CI, 
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0.12% to 0.89%]). As such, the benefit-risk balance of VTE thromboprophylaxis was not 
positive for the patients studied and enoxaparin is not approved for extended use in this 
population.
The ADOPT study (Apixaban versus enoxaparin for thromboprophylaxis in medically ill 
patients) compared an extended duration (30 days) of 2.5 mg twice daily oral apixaban with 
enoxaparin, administered subcutaneously at a dose of 40 mg daily for 6 to 14 days 15.  Based on 
the results of the primary efficacy endpoint (the composite of death related to VTE, PE, 
symptomatic DVT or asymptomatic proximal-leg DVT at Day 30) extended duration 
thromboprophylaxis with apixaban was not superior to a shorter duration of thromboprophylaxis 
with enoxaparin (2.71% vs. 3.06%; relative risk [RR] 0.87; 95% CI, 0.62 to 1.23).  Major 
bleeding events during the 30 day treatment period occurred in 0.47% of the patients in the 
apixaban group and in 0.19% of the patients in the enoxaparin group (RR 2.58; 95% CI, 1.02 to 
7.24). The primary efficacy endpoint was not positive in this study and apixaban is not approved
for this indication. 
The increased bleeding associated with extended duration of therapy was seen in all 3 studies, 
MAGELLaN, EXCLAIM and ADOPT. Any new clinical study purporting to evaluate extended 
duration of antithrombotic therapy must address this observed hazard. One potential means to 
diminish the excess bleeding rates would be to identify those patients with a more positive 
benefit/risk profile. Post-hoc analysis of the MAGELLaN study indicated that those who 
experienced a bleeding event while hospitalized or patients with active cancer were at higher risk 
of bleeding and are therefore excluded from MARINER. 
The selection of a high VTE-risk population is also important for the demonstration of a positive 
benefit/risk with anticoagulant therapy. Since the completion of the pivotal Phase 3 studies of 
extended thromboprophylaxis in hospitalized medical patients, there has been extensive research 
in the use of clinical VTE-risk assessment models as well as biomarkers in helping to define a 
high VTE-risk group in this patient population.3,10,26,33 In this regard, the MARINER study is 
relying on an evidence-derived, weighted, and scored clinical VTE-risk score, the IMPROVE 
VTE-risk score, alone or in combination with an elevated D-dimer to enroll a sufficiently high 
VTE-risk cohort when compared to previous studies that would benefit from extended 
thromboprophylaxis. The IMPROVE VTE-risk score has been extensively validated in 2 large 
external validation studies and a D-dimer >2X the upper limit of normal (ULN) was shown to be 
a powerful predictor of VTE in the general patient population of the MAGELLaN study as well 
as the subgroup with CHF.11, 31, 25,26
As MARINER will be assessing only symptomatic events it will be critical to study conduct to 
ensure all efficacy events are appropriately captured. Pulmonary embolism (PE) has been 
reported as the most common missed or delayed diagnosis by physicians.35,41 Misdiagnosis of PE 
has been shown in the literature to occur in up to 50% of patients with PE.2 Reports show that PE 
can be misdiagnosed as pneumonia, bronchitis, heart failure, cardiorespiratory failure, 
exacerbation of chronic obstructive pulmonary disease (COPD) and other diagnoses.2,32,12 A 
meta-analysis of the prevalence of PE in acute exacerbations of COPD concluded that 25% of 
COPD patients who require hospitalization for acute exacerbation and 9% of patients 
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hospitalized with severely decompensated heart failure may have a PE.32, 12 Both study staff and 
subjects will be educated on signs and symptoms associated with PE.
1.2.
Overall Rationale for the Study
The primary objective is to assess the efficacy and safety of rivaroxaban, compared with placebo
in the prevention of symptomatic VTE (lower extremity DVT and non-fatal PE) and VTE-related
death (death due to PE or death in which PE cannot be ruled out as the cause) post-hospital 
discharge in high-risk medically ill subjects.   
Three extended duration studies with enoxaparin (EXCLAIM), apixaban (ADOPT) and 
rivaroxaban (MAGELLaN) failed to demonstrate a positive benefit/risk profile for extended-
duration thromboprophylaxis in patients hospitalized for medical conditions primarily due to 
excessive bleeding with the anticoagulants10,15,17. 
Therefore, the proposed MARINER study was designed to improve the overall safety of 
medically ill patients with rivaroxaban (10 mg daily in subjects with CrCl ≥50 mL/min or 7.5 mg 
daily in subjects with CrCl of ≥30 to <50 mL/min) treatment for 45 days post-hospital discharge 
by addressing the bleeding risk observed in the MAGELLaN study while also enrolling a higher 
VTE-risk population to enhance the overall expected benefit/risk assessment. The proposed 
study is a multicenter, prospective, randomized, double-blind, event-driven, placebo-controlled 
study in subjects who are hospitalized for a specific acute medical illness and have other risk 
factors for VTE.  In the proposed study, a specific population of medically ill patients at high 
risk who could benefit most from extended thromboprophylaxis has been identified.
The MARINER study is designed as a pivotal Phase 3 study, to determine if the use of the FXa 
inhibitor rivaroxaban can prevent symptomatic VTE (lower extremity DVT and non-fatal PE)
and VTE-related death post-hospital discharge in high-risk, medically ill patients.
2.
OBJECTIVES AND HYPOTHESES
2.1.
Objectives
Primary Objective

The primary objective is to assess the efficacy and safety of rivaroxaban, compared with
placebo in the prevention of symptomatic VTE (lower extremity DVT and non-fatal PE) and 
VTE-related death (death due to PE or death in which PE cannot be ruled out as the cause) 
post-hospital discharge in high-risk, medically ill patients.
Secondary Objectives
The secondary objectives are to compare rivaroxaban with placebo in the following post-hospital 
discharge outcomes in high-risk, medically ill patients:
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
VTE-related death (death due to PE or death in which PE cannot be ruled out as the cause)

Symptomatic VTE (lower extremity DVT and non-fatal PE)

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE) and all-cause 
mortality (ACM)

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE), MI, 
non-hemorrhagic stroke and CV death (death due to a known CV cause and death in which a 
CV cause cannot be ruled out; by this definition, a VTE-related death is considered a 
CV death)

ACM
Exploratory Objectives
The exploratory objectives are to compare rivaroxaban with placebo, in the following 
post-hospital discharge outcomes in high-risk, medically ill patients:

Symptomatic lower extremity DVT

Symptomatic non-fatal PE

Symptomatic upper extremity DVT

MI

Non-hemorrhagic stroke

Re-hospitalization for symptomatic VTE (lower extremity DVT and non-fatal PE) within 
30 days after randomization
Pharmacokinetic Objective
The pharmacokinetic objective (PK) is to assess the kinetics of rivaroxaban in high-risk, 
medically ill patients, and to describe drug exposure based on CrCl. 
Medical Resource Utilization and Health Economics Objective  
The medical resource utilization and health economics objective is to assess the following cost 
drivers, ie, re-hospitalization (including ER visits, intensive care unit and cardiac care unit stays), 
length of stay and subject discharge destination (after re-hospitalization).
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Safety Objectives
The safety objectives are to compare rivaroxaban with placebo in the following bleeding 
outcomes in high-risk, medically ill patients:

Major bleeding using validated International Society on Thrombosis and Haemostasis 
(ISTH) bleeding criteria.

Non-major clinically relevant bleeding

Other bleeding
Overall safety will also be assessed.
2.2.
Hypotheses
The primary hypothesis is that rivaroxaban is superior to placebo in the prevention of the 
composite of symptomatic VTE (lower extremity DVT and non-fatal PE) and VTE-related death
(death due to PE or death in which PE cannot be ruled out as the cause). The secondary 
hypotheses are that rivaroxaban is superior to placebo in the prevention of 1) VTE-related death
(death due to PE or death in which PE cannot be ruled out as the cause), 2) symptomatic VTE 
(lower extremity DVT and non-fatal PE), 3) the composite of symptomatic VTE (lower 
extremity DVT and non-fatal PE) and ACM, 4) the composite of symptomatic VTE (lower 
extremity DVT and non-fatal PE), MI, non-hemorrhagic stroke and CV death (death due to a 
known CV cause and death in which a CV cause cannot be ruled out; by this definition, a 
VTE-related death is considered a CV death)  and 5) ACM alone.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a multicenter, prospective, randomized, double-blind, placebo-controlled, event-driven 
study designed to evaluate rivaroxaban, compared with placebo, in the prevention of 
symptomatic VTE (lower extremity DVT and non-fatal PE) events and VTE-related deaths 
(death due to PE or death in which PE cannot be ruled out as the cause) for a period of 45 days 
post-hospital discharge. The study consists of a screening phase, a 45-day double-blind treatment 
phase, and a 30-day safety follow-up period. 
The subject population comprises men and women age 40 years and older who have completed 
screening no later than 1 day after leaving the hospital and who have been hospitalized for the 
new onset or exacerbation of 1 of the following medical conditions: 

Heart Failure (HF) with a reduced left ventricular ejection fraction (LVEF ≤45%)

Acute respiratory insufficiency or acute exacerbation of COPD

Acute ischemic stroke (including spinal cord infarction if no evidence of intramedullary, 
subdural or epidural hemorrhage) 

Acute infectious disease

Inflammatory disease, including rheumatic disease
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The index hospitalization must be at least 3 and no more than 10 consecutive days in duration. In 
order to be eligible, subjects must have an increased VTE risk, as demonstrated by a total 
modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) 
VTE Risk Score of:

≥ 4, or 

3 with D-dimer > 2XULN, or

2 with D-dimer > 2XULN  
In addition, subjects must have received treatment during the index hospitalization with LMWH 
or UFH.
Any patient with a medical condition that will require use of any parenteral or oral 
anticoagulation (eg, atrial fibrillation) during the study is not eligible for participation. In 
addition, patients at particularly increased risk of bleeding and those using medications that 
might interact with the study drug will be excluded. 
Subjects who meet all of the inclusion and none of the exclusion criteria will be randomly 
assigned to receive rivaroxaban or placebo. Randomization should occur on the same day as or 
the day after the subject leaves the hospital, and may occur at the hospital, clinic or other 
discharge destination. Subjects will be randomized by strata including creatinine clearance and 
country.
After randomization, subjects will receive double-blind treatment with rivaroxaban 10 mg 
(7.5 mg for subjects with a CrCl ≥30 mL/min and <50 mL/min) daily or matching placebo daily. 
Placebo has been chosen as the comparator because of current guidelines which recommend 
against thromboprophylaxis in medically ill patients after hospital discharge.  The first dose of 
study drug should be administered no later than the day after the subject leaves the hospital and 
as soon after randomization as possible. Subjects will be instructed to discontinue study drug 
after they take a dose on Day 45, and complete an end of treatment visit within the next 4 days. 
Regardless of the day on which the Day 45 Visit occurs, no study drug may be taken after 
Day 45. The subject must be assessed 30 days later for safety follow-up.  This will be the last 
contact with the subject unless extended follow up for safety is required.  
If a subject has a suspected efficacy or bleeding outcome event during the study, the treating 
physician should exercise clinical judgment and follow established 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 study drug is placebo vs 
rivaroxaban when administered in the doses used in this study.  There is no specific reversal 
agent for rivaroxaban; management of the subject with a bleeding event should not be impacted 
by knowledge of study drug treatment.
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Rivaroxaban will not be provided to subjects after they complete study treatment unless required 
by local regulations. Randomization in this study is preceded by a hospitalization for an acute 
illness and the study drug treatment phase extends for 45 days after randomization to correspond 
to the period of greatest risk for VTE.  Chronic therapy with the study drug is not being tested. It 
will only be after data from the entire study is analyzed that it will be determined if the 
population at risk will benefit from treatment.
The primary efficacy outcome is the composite of all symptomatic VTE events (lower extremity 
DVT and non-fatal PE) and VTE-related death (death due to PE or death in which PE cannot be 
ruled out as the cause), from randomization up to Day 45. The targeted total number of primary 
efficacy outcomes in this event-driven study is 161. It is estimated that a total of approximately 
8,000 subjects will need to be randomized to either rivaroxaban or placebo in a 1:1 ratio. In the 
event that the actual observed blinded pooled event rate is lower than the assumed rate, more 
subjects may be enrolled to accumulate additional outcome events. Randomization in this study 
may be stopped at approximately 12,000 subjects for administrative considerations even if the 
targeted 161 events have not been observed by then. An interim analysis for futility will be 
conducted when approximately 50% of subjects with adjudicated primary efficacy outcome 
events have been observed (about 50% of the expected total number of events based on the 
actual observed blinded pooled event rate even if this event rate is lower than the assumed rate).
The principal safety outcome for this study is ISTH major bleeding.
For population PK analyses, based on the model performance and the high variability of the 
PK parameters observed in the MAGELLaN study, 2 blood samples (at pre-dose and 1-4 hours 
after study drug administration) will be collected at the Day 7 visit  and 2 blood samples (at 3 to 
7 and 7 to 12 hours after study drug administration) will be collected at the Day 21 visit  for each 
subject for up to 600 subjects (300 rivaroxaban subjects [200 subjects in the 10 mg daily group 
and 100 subjects in the 7.5 mg daily group] and 300 in the placebo group). The sparse blood 
samples for PK analyses will be collected in selected sites only.
An Executive Committee (EC), an Independent Data Monitoring Committee (IDMC) and a 
Clinical Event Committee (CEC) will be commissioned for this study. All committees will be 
governed by separate charters, see Section 3.3.
A diagram of the study design is provided below in Figure 3:
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Figure 3:
Schematic Overview of the Study (RIVAROXDVT3002) 
Note: Subjects will be randomized by strata including creatinine clearance and country.  
3.2.
Study Design Rationale
Study Population 
Medically ill patients, ie, patients who have been hospitalized for the treatment of acute medical 
illnesses, are at high risk for the development of VTE during their hospital stay and immediately
after hospital discharge. These are important clinical events that profoundly impact medically ill 
patients, and constitute a large burden in terms of health care provision. High-risk medically ill 
subjects have been chosen for this study because post-hospital discharge thromboprophylaxis is a 
useful therapeutic approach to reduce the risk of increased VTE events, morbidity and mortality 
in these patients and would meet an unmet medical need. The pharmacology, mechanism of 
action, and previous clinical studies of rivaroxaban suggest that rivaroxaban will reduce the risk 
of VTE events and VTE-related death (death due to PE or death in which PE cannot be ruled out 
as the cause). The timing of enrollment, randomization and treatment phase for these subjects has 
been chosen because there is a high rate of VTEs and VTE-related mortality during this 
post-hospitalization phase, particularly during the first 2 months after discharge18,37. Compared 
with previous studies, there are several differences in the choice of study populations to reduce 
the bleeding risk (Section 1.1).
Blinding Control Study Phase/Periods Treatment Groups
This randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven 
design, is a scientifically rigorous approach for evaluating the efficacy and safety of rivaroxaban 
in high-risk, medically ill patients and meets the registration requirements for a superiority study. 
Randomization and stratification will be used to minimize bias in the assignment of subjects to 
treatment groups, to increase the likelihood that known and unknown subject attributes 
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(eg, demographic and baseline characteristics) are evenly balanced across treatment groups, and 
to enhance the validity of statistical comparisons across treatment groups. Subjects will be 
randomized by strata (by subjects with CrCl ≥30 mL/min and <50 mL/min versus subjects with 
CrCl ≥50 mL/min, and by country). Double-blinded treatment will be implemented to reduce 
potential bias during data collection and evaluation of clinical outcomes. 
There has been no well-controlled study to date that demonstrates any anticoagulant with a 
favorable benefit/risk profile (reduction of symptomatic VTE events and VTE-related mortality 
vs increase in major bleeding) in post-discharge high-risk medically ill patients.  
Comparator Selection
The control group in the MARINER study will receive placebo, a decision that was made based 
on careful consideration of the literature and existing guidelines for the standard of care practice.
Medically ill patients are at risk for the development of VTE both when hospitalized and 
immediately after their hospital discharge. These 2 periods of risk have been studied, are 
reported in the literature, and the ACCP has published thromboprophylaxis guidelines. 
Guidelines have been published for the inpatient period, and also for the post-hospital discharge 
period.  
For inpatients, the ACCP recommends:
“For acutely ill hospitalized medical patients at increased risk of thrombosis, we 
recommend anticoagulant thromboprophylaxis with LMWH, low-dose unfractionated 
heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B).” 
For post-hospital discharge, the ACCP recommends (emphasis added):
“In acutely ill hospitalized medical patients who receive an initial course of 
thromboprophylaxis, we suggest against extending the duration of thromboprophylaxis
beyond the period of patient immobilization or acute hospital stay.”
The ACCP Evidence-Based Clinical Practice Guidelines further recommend that during 
hospitalization, anticoagulant thromboprophylaxis for acutely ill hospitalized medical patients 
with increased risk of thrombosis should be administered for 6 to 21 days (an evidence-based 
duration derived from the range of the durations of therapies studied and reported in the 
literature). However, if full mobility is restored while hospitalized or the patient is discharged 
from the hospital, the recommendation is that thromboprophylaxis be discontinued. As such, the 
guidelines recommend that patients not receive thromboprophylaxis after discharge.  
As described in Section 1.1.5, 3 studies have been conducted testing an extended period of 
thromboprophylaxis. For each of these studies, a post-hospital discharge placebo comparator was 
used, and none provided evidence of a benefit/risk balance better than placebo. The MARINER 
study will enroll a population at greater risk of VTE and lower risk of bleeding than previously 
studied, and will use the placebo comparator as the standard of care, as recommended by the 
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ACCP. Given the ACCP guidelines, the duration of thromboprophylaxis in these patients is 
usually determined by the duration of hospitalization, as it is unusual for patients to receive 
thromboprophylaxis after discharge. In fact, in the MARINER study, patients for whom 
thromboprophylaxis is prescribed after discharge are specifically excluded.
Based on the above, placebo has been chosen as the appropriate comparator to allow for the 
evaluation of benefit/risk of rivaroxaban as thromboprophylactic agent in post-hospital discharge 
high-risk, medically ill patients.
Any patient with a medical condition that will require chronic use of any parenteral or oral 
anticoagulation (eg, atrial fibrillation) during the study is not eligible for participation. During 
the study, should the subject develop any condition, which in the investigator’s judgment 
requires long-term anticoagulation, thromboprophylaxis, or fibrinolysis, the subject will have 
study treatment 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. 
Dose Selection
The selection of a dose of 10 mg daily of rivaroxaban is based primarily on the results of the 
studies conducted for prophylaxis of VTEs in patients undergoing knee or hip replacement 
surgery, where 10 mg daily of rivaroxaban resulted in benefit with an acceptable risk profile.
Subjects with CrCl ≥50 mL/min will be randomly assigned to receive rivaroxaban 10 mg daily or 
placebo. In order to reduce the risk of bleeding in subjects with a baseline CrCl ≥30 mL/min and
<50 mL/min (estimated to be approximately 20% of study population), a dose adjustment of 
rivaroxaban from 10 mg daily to 7.5 mg daily will be implemented (Section 3.1)
In the ROCKET AF study, a 25% dose reduction of rivaroxaban (15 mg daily) was implemented 
in subjects with CrCl 30 to 49 mL/min (approximately 20% of the study population), which 
provided comparable exposure, efficacy and safety to that of rivaroxaban 20 mg daily
administered to subjects with CrCl ≥50 mL/min29. Since the age and comorbidities of the 
subjects in the proposed MARINER study are similar to the population studied in the 
ROCKET AF study and based on the population PK simulations of a virtual medically ill 
population, a similar 25% dose reduction of rivaroxaban (from 10 mg to 7.5 mg daily) in the 
subjects with CrCl ≥30 mL/min and <50 mL/min is a reasonable strategy. This rivaroxaban dose 
reduction in medically ill subjects with CrCl ≥30 mL/min and <50 mL/min is predicted to yield 
similar rivaroxaban plasma exposures to those in subjects with CrCl ≥50 mL/min at a 10 mg 
dose. Based on the achievement of similar plasma exposures, comparable efficacy and safety 
would be expected in these 2 population subgroups.
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Choice of Efficacy Measure
The choice of the primary efficacy outcome is based on prior rivaroxaban trials for primary and 
secondary prevention of VTE events (such as DVT, PE) and VTE-related deaths. In addition, 
these outcomes are considered acceptable and verifiable for the evaluation of prevention of VTE 
events in medically ill patients10,15,18. 
Asymptomatic proximal DVT, as detected on compression ultrasonography, was included as part 
of the primary efficacy outcome in the 3 extended-duration studies (EXCLAIM, ADOPT and 
MAGELLaN). Compression ultrasonography is not performed routinely in medical patients and 
the use of this test might influence the symptomatic VTE component of the primary efficacy 
composite outcomes15. Specifically, the performance of compression ultrasound during 
double-blind treatment likely influences the subsequent natural history of the disease by 
prompting investigators to treat asymptomatic clots. Therefore, without asymptomatic clot 
detection there will be a higher symptomatic event rate and assessment of only symptomatic 
events may provide a more clinically meaningful evaluation of a therapeutic intervention. Thus, 
in the present study only hard efficacy outcomes (symptomatic VTE events, VTE-related deaths, 
etc.) will be measured.
Choice of Safety Measures
The principal safety outcome is major bleeding using validated ISTH bleeding criteria.
In addition, data will be collected to ascertain non-major clinically relevant 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 associated with discomfort for the subject such as pain or 
impairment of activities of daily life, and other bleeding, defined as any other overt bleeding that 
does not meet the ISTH criteria for major or non-major clinically relevant bleeding (Section 9.5).
All serious adverse events except the study outcomes (VTE-related death, MI, acute coronary 
syndrome [ACS], stroke, transient ischemic attack [TIA], symptomatic VTE [lower or upper 
extremity DVT and PE], bleeding events) will be collected. Refer to Section 12.3.1, All Adverse 
Events for more details.
Interim Analysis
The primary reason for the prespecified interim analysis is to assess for futility.   
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Pharmacokinetics Analysis
The PK analysis will be done:

To predict the overall exposure of rivaroxaban and estimate the PK model parameters for 
medically ill patients.

To describe the effect of dosing modification on exposure for subjects with 
CrCl ≥30 mL/min and <50 mL/min.
Medical Resource Utilization and Health Economics
The medical resource utilization and health economics will assess cost drivers and details on 
medical resource utilization and health economics can be found in Section 9.4.
3.3.
Committees
3.3.1.
Executive Committee
The EC consists of members of the academic leadership of the study and 1 member from the 
sponsor. Ad hoc members may be appointed as necessary. The EC has overall responsibility for 
the design, conduct and reporting of the study. The EC will monitor overall safety during the 
study and will receive any recommendations from the IDMC regarding possible additional 
analyses or modifications to the study and decide whether to accept them. The EC will oversee 
the implementation of any modifications to the study and publication of the results.
3.3.2.
Independent Data Monitoring Committee
An IDMC will be established to monitor the progress of the study and ensure that the safety of 
subjects enrolled in the study is not compromised. The IDMC will include, but is not limited to, a 
clinical chairman, physician(s) experienced in clinical trials, but not participating in this study, 
and at least 1 statistician. Details of the composition, roles, responsibilities, and processes of the 
IDMC will be documented in its charter. The IDMC will review results of the planned interim 
analysis and make a recommendation whether the study should be continued as planned, 
modified, or terminated prematurely due to futility or safety (Section 11.7).
3.3.3.
Clinical Events Committee
The Clinical Events Committee (CEC) is comprised of board-eligible or board-certified 
specialist physicians as appropriate and necessary. Committee members do not directly enroll 
subjects in the study, are not involved in the MARINER study monitoring, and do not have direct 
operational responsibilities for the conduct of the study. Members will review all suspected 
outcome events as described below that occurred post-randomization as they become available 
and adjudicate and classify in a consistent and unbiased manner according to definitions in the 
CEC charter while blinded to treatment assignment:

Death 

Symptomatic DVT

Symptomatic non-fatal PE
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
Non-fatal MI

Non-fatal stroke

Bleeding
4.
SUBJECT POPULATION
Screening may begin any time after the admission for the index hospitalization, and once the 
informed consent is obtained. If a subject’s status changes (including laboratory results or receipt 
of additional medical records) after screening but before randomization such that he or she no 
longer meets all eligibility criteria, then the subject should not be randomized.
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 should consult with the appropriate sponsor representative before enrolling a subject 
in the study. Waivers for study participation will not be granted.
For Sections 4.1, Inclusion Criteria, 4.2, Exclusion Criteria, and 4.3, Prohibitions and 
Restrictions, numbered criteria in brackets are for data collection purposes and are intentionally 
non-sequential (for complete amendment history, see Attachment 6). 
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
[1.2]  
a. Subject must be a man or woman, ≥40 years of age.
b. The duration of the index hospitalization must have been at least 3 and no more than 
10 consecutive days. 
The index hospitalization is defined as a hospitalization that ended on the day of or 
the day before randomization and is a continuous period of time at an acute care 
facility (including hospital, observation unit, ER and/or transferring facility; 
collectively referred to as "hospital"). The first day that the subject spends any part of 
the day in the hospital will be counted when determining the duration of the index 
hospitalization, but the day the patient leaves the hospital will not be counted.
c. The reason for the index hospitalization must have been a new diagnosis or 
exacerbation of 1 of the following medical conditions:

Heart Failure (HF) 
Subject must have a documented LVEF ≤45% within 1 year before 
randomization or during the index hospitalization. The ejection fraction may 
be determined by one of the following methods: echocardiogram, nuclear 
multi-gated acquisition (MUGA) scan, cardiac magnetic resonance imaging 
(MRI), cardiac computed tomography (CT) scan, or left ventriculography). If 
more than 1 value for LVEF is available, the most recent one should be used.

Acute respiratory insufficiency or acute exacerbation of COPD
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
Acute ischemic stroke (including spinal cord infarction if no evidence of 
intramedullary, subdural or epidural hemorrhage)
If the subject received fibrinolysis as part of the initial treatment for stroke, 
fibrinolysis must have been administered at least 3 full days before the 
subject is randomized. These subjects must have had a CT/MRI scan at 
presentation and a repeat scan performed at least 24 hours after 
administration of fibrinolysis that documents the absence of hemorrhage. 
Subjects with hemorrhagic transformation of an ischemic infarct prior to 
randomization are not excluded unless there is evidence of parenchymal 
hemorrhage (types PH-1 and PH-2). All planned diagnostic tests for stroke 
evaluation must be completed before randomization. Brain imaging and 
24-hour cardiac monitoring must have been repeated if new symptoms of 
stroke/TIA occurred after the initial stroke evaluation, as does 24-hour 
cardiac monitoring if symptoms suggestive of AF occur.  

Acute infectious disease

Inflammatory disease, including rheumatic disease
[2.2] The subject must be at increased risk for VTE by the total modified IMPROVE 
VTE Risk Score (Table 1; modified from Spyropoulos37) assessed at screening and 
verified at randomization.
a. If the total modified IMPROVE VTE Risk Score is ≥4, the subject meets this 
inclusion criterion.
b. If the total modified IMPROVE VTE Risk Score is 2 or 3, a D-dimer >2X ULN must 
have been obtained after the beginning of the index hospitalization and before 
randomization 
Table 1:
Modified IMPROVE VTE Risk Score
VTE Risk Factor
VTE Risk Score
Previous VTE
3
Known thrombophiliaa
2
Current lower limb paralysis or paresisb
2
History of cancerc
2
ICU/CCU stay
1
Complete immobilizationd ≥1 day
1
Age ≥60 years
1
CCU= cardiac care unit; ICU= intensive care unit; VTE= venous 
thromboembolism.
a: A congenital or acquired condition leading to excess risk of thrombosis 
(eg, factor V Leiden, lupus anticoagulant, factor C or factor S deficiency).
b: Leg falls to bed by 5 seconds, but has some effort against gravity (taken 
from NIH stroke scale28).  
c: Cancer (excluding non-melanoma skin cancer) present at any time in the 
last 5 years (cancer must be in remission to meet eligibility criteria)
d: Immobilization is being confined to bed or chair with or without bath-
room privileges.
[3.1] Life expectancy of at least 3 months.
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[4.3] Prescribed thromboprophylaxis (according to ACCP guidelines)20 with UFH or 
LMWH (eg, dalteparin and enoxaparin) not exceeding 15,000 U on any given day for 
UFH and not exceeding 5,000 U on any given day for LMWH.
Table 2 below provides the minimum number of doses of thromboprophylaxis required by 
index hospitalization duration. For ischemic stroke with thrombolysis, do not use the index 
hospital duration to determine the number of doses required. Instead, use the number of days 
the patient was in the hospital after the first day the patient was prescribed 
thromboprophylaxis.
Table 2:
Minimum Number of Heparin Doses Required for 
Study Eligibility by Duration of Index Hospitalization
Index Hospitalization 
Duration (days)
LMWH doses 
required
UFH doses 
required
3
2
3
4
2
4
5
3
6
6
4
7
7
4
8
8
5
10
9
6
11
10
6
12
LMWH= low molecular weight heparin, UFH= unfractionated heparin.
Note: In the event that both LMWH and UFH are used during the index 
hospitalization, the number of doses of LMWH received should be 
doubled and added to the number of UFH doses received, and the UFH 
doses required column should be used to determine whether the 
requirement was met.
[6.1] Each subject must sign an informed consent form (ICF) indicating that he or she 
understands the purpose of and procedures required for the study and is willing to 
participate in the study.  
Note: Numbered criteria in brackets are for data collection purposes and are intentionally 
non-sequential.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
Bleeding Risk-Related Criteria
[1.1] Any bleeding (defined as bleeding requiring hospitalization, transfusion, surgical 
intervention, invasive procedures, occurring in a critical anatomical site, or causing 
disability) within 3 months prior to randomization or occurring during index 
hospitalization.
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[2.3] Major surgery, biopsy of a parenchymal organ, ophthalmic surgery (excluding 
cataract surgery), or serious trauma (including head trauma) within 4 weeks before 
randomization.
Investigator discretion should be applied, but the following guidance may be considered 
for the purpose of this study.
Major surgery often involves opening 1 of the major body cavities the abdomen, the 
chest, or the skull and can stress vital organs. Major surgery usually is done using 
general anesthesia in a hospital operating room by a surgeon(s) and usually requires a 
stay of at least 1 night in the hospital after surgery.
In contrast, with minor surgery, major body cavities are not opened. Minor surgery can 
involve the use of local, regional, or general anesthesia and may be done in an 
emergency department, an ambulatory surgical center, or a doctor's office. Vital organs 
usually are not stressed, and surgery can be done by a single doctor, who may or may 
not be a surgeon. Usually, the person can return home on the same day that minor 
surgery is done.
Investigator discretion should be applied, but fracture or concussion would be 
considered serious head trauma, while external trauma without fracture or concussion 
could be considered for inclusion.
[3.3] Any planned major surgery (see exclusion criterion #2.3) or major invasive 
diagnostic procedure intended during the duration of the trial.  
[4.1] Subjects with any known coagulopathy or bleeding diathesis, or an INR >1.5 during 
the index hospitalization without a subsequent value (the last value before randomization) 
that is ≤1.5. 
[5.2] A history of hemorrhagic stroke or any intracranial bleeding at any time in the past, 
evidence of primary intracranial hemorrhage on CT or magnetic resonance imaging scan 
of the brain, or clinical presentation consistent with intracranial hemorrhage. This applies 
as well to subjects hospitalized for ischemic stroke upon randomization.
Subjects with hemorrhagic transformation of an ischemic infarct prior to randomization 
are not excluded unless there is evidence of parenchymal hemorrhage (types PH-1 and 
PH-2):
Hemorrhagic infarction type 1 (HI-1) is defined as small petechiae along the margins of 
the infarct, and HI type 2 (HI-2) is defined as more confluent petechiae within the 
infarcted area but without space-occupying effect. PH type 1 (PH-1) is defined as 
hematoma in ≤30% of the infarcted area with some slight space-occupying effect; 
PH type 2 (PH-2) is defined as dense hematoma >30% of the infarcted area with 
substantial space-occupying effect or as any hemorrhagic lesion outside the infarcted 
area (Berger, 20012).
Hemorrhagic infarction type 1 and HI-2 subjects are NOT excluded from this study, but 
PH-1 and PH-2 subjects ARE excluded from this study. 
[7.1] Subject has a history of or current intracranial neoplasm (benign or malignant), 
cerebral metastases, arteriovenous (AV) malformation, or aneurysm.
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[8] Active gastroduodenal ulcer, defined as diagnosed within 3 months or currently 
symptomatic or known AV malformations of the gastrointestinal tract.
[9.1] Screening platelet count <75 x 109 cells/L.
Concomitant Conditions or Diseases
[10.2] Active cancer (excluding non-melanoma skin cancer) defined as cancer not in 
remission or requiring active chemotherapy or adjunctive therapies
such as 
immunotherapy or radiotherapy. Chronic hormonal therapy (eg, tamoxifen, anastrazole, 
leuprolide acetate) for cancer in remission is allowed.
[11.1] Any medical condition (eg, atrial fibrillation) that requires use of any parenteral or 
oral anticoagulant(s) (eg, warfarin sodium or vitamin K antagonists, Factor II or Xa 
inhibitors, fibrinolytics) concomitantly with study medication.
[12.1] Bilateral and unilateral above-knee lower extremity amputation.
[13] Subject has known allergies, hypersensitivity, or intolerance to rivaroxaban or any of 
its excipients.
[14.1] Severe renal insufficiency (baseline CrCl <30 mL/min calculated using the 
Cockcroft-Gault 6 formula provided in Section 9.1.2).
[15.1] Known significant liver disease (eg, acute hepatitis, chronic active hepatitis, 
cirrhosis) which is associated with coagulopathy or moderate or severe hepatic 
impairment.
[16] Known HIV infection.
[17] Sustained uncontrolled systolic blood pressure (BP) of ≥180 mmHg or diastolic BP 
of ≥100 mmHg at randomization despite treatment.
[18.1] Current drug or alcohol abuse, based on investigator’s assessment.
[19.1] Cardiogenic or septic shock with the need for vasopressor(s) or devices for blood 
pressure support during index hospitalization.
[20] Presence of inferior vena caval filter
[21] Severe bronchiectasis or cavitary tuberculosis or any other pulmonary condition 
(eg, vasculitis) at risk for major hemoptysis 
Drugs or Procedures 
[22.2]
a. 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 is prohibited within 
7 days before randomization and during the study.
b. 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. 
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[23.2] Received fibrinolysis during index hospitalization, unless received for ischemic 
stroke at least 3 full days before randomization.
[24.2] Use of antiplatelet therapy during the index hospitalization, including:
a. ASA >162 mg/day 
b. Clopidogrel >75 mg/day or ticlopidine >250 mg twice daily
c. Clopidogrel at any dose in combination with omeprazole or esomeprazole
d. Dipyridamole >400 mg/day
e. Cilostazol >200 mg/day
f. Dual therapy with 2 or more antiplatelet agents (dipyridamole with ASA is permitted) 
g. Other G protein-coupled purinergic receptor P2Y (P2Y12) antagonists (eg, prasugrel,
ticagrelor)
h. Thrombin-receptor antagonists (eg, vorapaxar)
[25.1] Childbearing potential without proper contraceptive measures, pregnancy or breast 
feeding.
a. Before randomization, a woman must be either:

Not of childbearing potential: premenarchal; postmenopausal (>45 years 
of age with amenorrhea for at least 12 months or any age with amenorrhea for at 
least 6 months and a serum follicle stimulating hormone (FSH) level >40 IU/L]); 
permanently 
sterilized 
(eg, 
tubal 
occlusion, 
hysterectomy, 
bilateral 
salpingectomy); or otherwise be incapable of pregnancy,

Of childbearing potential and practicing a highly effective method of birth 
control consistent with local regulations regarding the use of birth control 
methods for subjects participating in clinical studies: eg, established use of oral, 
injected or implanted hormonal methods of contraception; placement of an 
intrauterine device or intrauterine system; barrier methods: condom with 
spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male 
partner sterilization (the vasectomized partner should be the sole partner for that 
subject); true abstinence (when this is in line with the preferred and usual lifestyle 
of the subject). 
Note: If the childbearing potential changes after start of the study (eg, woman 
who is not heterosexually active becomes active, premenarchal woman 
experiences menarche) a woman must begin a highly effective method of birth 
control, as described above. The initiation of hormonal contraception for the 
purpose of the study is not recommended.
A woman of childbearing potential must have a negative serum (β human 
chorionic gonadotropin [β hCG]) or urine pregnancy test at screening.  
b. A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a double-barrier method of birth control eg, either 
condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive 
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cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository, and all men must also not donate sperm during the 
study, from the time of the first dose to the last dose of study drug.
[26] Participation in another pharmacotherapeutic study or experimental medical device 
within 30 days before the start of study treatment.
[28.2] Prescribed daily use of nonsteroidal anti-inflammatory agents (NSAIDs) during 
the index hospitalization 
[29] Subject is unwilling or unable to complete all study visits as well as follow-up visit.
[30] Subject is an employee of the investigator or study site, with direct involvement in 
the proposed study or other studies under the direction of that investigator or study site, 
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. 
If a subject's status changes (including laboratory results or receipt of additional medical records) 
after screening but before randomization such that he or she no longer meets all eligibility 
criteria, the subject should not be randomized. But if the subject has been randomized, he/she 
should not be excluded from participation in the study and must be followed until the Day 75 
(±5d) visit. 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. If subjects require or 
take prohibited medications during the study as outlined below, they must either temporarily 
interrupt or permanently discontinue the study drug, as appropriate for the duration of the 
therapy with the prohibited medication:
Note: Numbered criteria in brackets are for data collection purposes and are intentionally non-
sequential.
[2.2] 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 is prohibited within 
7 days before randomization and during the study. 
[3.2] 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. 
[4.1] Anticoagulant (eg, warfarin sodium or other vitamin K antagonists, Factor II or Xa 
inhibitors) is prohibited as concomitant therapy during the study. Study drug should be 
discontinued in subjects who develop any condition which requires anticoagulation or 
thromboprophylaxis (eg, atrial fibrillation, VTE) that will extend beyond the end of the 
study treatment phase. 
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[6.1] Fibrinolytic therapy (see Section 10.2.1 for guidance)
[7.1] Use of antiplatelet therapy, including:
a. ASA >162 mg/day 
b. Clopidogrel > 75 mg/day or ticlopidine > 250 mg twice daily
c. Clopidogrel at any dose in combination with omeprazole or esomeprazole
d. Dipyridamole >400 mg/day
e. Cilostazol >200 mg/day
f. Dual therapy with 2 or more antiplatelet agents (dipyridamole with ASA is 
permitted) 
g. Other P2Y12 receptor antagonists (eg, prasugrel, ticagrelor)
h. Thrombin-receptor antagonists (eg, vorapaxar)
i. Prescribed daily non-steroidal anti-inflammatory drugs (temporary use as needed is 
allowed).
[9] Modification of an effective pre-existing therapy should not be made for the explicit 
purpose of entering a subject into the study.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups based on a computer-generated randomization schedule prepared before 
the study under the supervision of the sponsor. The randomization will be balanced by using 
randomly permuted blocks and will be stratified by subjects with CrCl ≥30 and <50 mL/min 
versus subjects with CrCl ≥50 mL/min and by country. Enrollment may be capped for subgroups 
with certain baseline characteristics (eg, index hospitalization duration, reason for index 
hospitalization, risk score, and index hospitalization thromboprophylaxis) or by country or 
region. If a decision is made to institute capping, the site will receive a written communication 
with instructions for implementation and a request for confirmation of receipt.
The IWRS will assign a unique treatment code, which will dictate the treatment assignment and 
matching study drug kits for the subject. The requestor must use his or her own user
identification and personal identification number when contacting the IWRS, and will then give 
the relevant subject details to uniquely identify the subject.
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.
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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 governed by knowledge of the treatment 
assignment of the subject. In such cases, the investigator may determine the treatment 
assignment or allocation by contacting 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, time, and reason for the unblinding must be documented by the IWRS 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.
Subjects who have had their treatment assignment unblinded may continue on study drug unless 
the subject meets a study drug temporary interruption or permanent discontinuation criterion.
Investigators should not disclose treatment assignment to the subject whenever possible.  
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. However, if an interim analysis is specified, the randomization codes 
and, if required, the translation of randomization codes into treatment and control groups will be 
disclosed to those authorized and only for those subjects included in the interim analysis.
If a subject has a suspected efficacy or bleeding outcome event during the study, the treating 
physician should exercise clinical judgment and follow established 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 study drug is administered in 
the doses used in this study. There is no specific reversal agent for rivaroxaban; management of 
the subject with a bleeding event should not be impacted by knowledge of study drug treatment.
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.
6.
DOSAGE AND ADMINISTRATION
Treatment groups in this study are rivaroxaban and placebo. Subjects will be randomly assigned 
in a 1:1 ratio to receive rivaroxaban 10 mg daily (7.5mg daily in subjects with CrCl of ≥30 and
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<50 mL/min) or matching placebo daily. Randomization will be stratified by subjects with 
CrCl ≥30 and <50 mL/min versus subjects with CrCl ≥50 mL/min and by country. The dose of 
study drug will not be adjusted in the event of change in CrCl between the 2 strata during the 
course of the study.
The first dose of study drug should be administered no later than the day after the subject leaves 
the hospital and as soon after randomization as possible. The date and time of the first dose of 
study drug and the last dose of LMWH or UFH should be recorded as accurately as possible. The 
first dose of study drug should not be delayed to allow administration under supervision. All 
subjects should take study drug (rivaroxaban or placebo) daily with or without food at 
approximately the same time each day, and discontinue study drug after they take a dose on 
Day 45. Regardless of the day on which the Day 45 Visit occurs, no study drug may be taken 
after Day 45.
A missed dose should be taken as soon as possible (up to 8 hours prior to the next scheduled 
dose), and the next scheduled dose should be taken at the regular time.
After the subject takes a dose of study drug on Day 45, the subject should discontinue study drug 
and complete the Day 45 (+4d) visit (refer to TIME AND EVENTS SCHEDULE). Regardless 
of the day on which the Day 45 Visit occurs, no study drug may be taken after Day 45.
Throughout 
the 
study, 
study 
drug 
will 
be 
dispensed 
at 
appropriate 
intervals 
(see the TIME AND EVENTS SCHEDULE) to ensure that subjects have adequate quantities of 
study drug between study visits. In addition, study site personnel will instruct subjects on how to 
store study drug for at-home use as indicated for this protocol. The storage recommendation for 
rivaroxaban or placebo is at room temperature (approximately 15to 30C).
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Randomization in this study is preceded by a hospitalization for an acute illness and the study 
drug treatment phase extends for 45 days after randomization to correspond to the period of 
greatest risk for VTE.  Chronic therapy with the study drug is not being tested. For these reasons, 
rivaroxaban will not be provided to the subject after the subject completes the Day 75 (±5d) visit, 
unless required by local regulations. It will only be after data from the entire study is analyzed 
that it will be determined if the population at risk will benefit from treatment.
Interruption of Study Drug
Study drug may be interrupted temporarily (see Section 10.2.1, Temporary Interruption of Study 
Treatment) as necessary for invasive procedures or as medically needed (eg, in the setting of a 
bleeding event or a required prohibited therapy). If a subject is hospitalized for any reason other 
than a VTE-related event or bleeding, study drug should be continued during hospitalization 
unless the treating physician feels that anticoagulation, temporary interruption or permanent
discontinuation of study drug is clinically warranted. Subjects may be placed on appropriate 
anticoagulation at the discretion of the treating physician. In that case, study drug may be 
restarted upon discharge at the discretion of the investigator. These interruptions will be recorded 
on the electronic case report form (eCRF). For guidance on study drug temporary interruption, 
see Section 10.2.1.
Intentional stopping of study drug by the subject, unintentional stopping of study drug, or 
direction to temporarily interrupt study drug by the investigator or other physician will be 
documented. Study drug interruption will be recorded in the eCRF. 
7.
TREATMENT COMPLIANCE
The IWRS will keep track of study drug dispensed to the subjects. Subjects will return empty 
study drug containers and unused study drug at the Day 21 visit when a new supply of study drug 
is to be received. The last dose of study drug should be taken on Day 45. Regardless of the day 
on which the Day 45 Visit occurs, no study drug may be taken after Day 45. Subjects will also 
return empty study drug containers and unused study drug at the Day 45 (+4d) visit.
Study drug accountability will be performed at the Day 21 and Day 45 visits. Subjects should 
report any unintentional interruption or missed doses to the study-site personnel at each visit. It is 
understood that subjects may occasionally miss a dose or that a subject may be placed on 
temporary interruption (see Section 10.2.1, Temporary Interruption of Study Treatment). 
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8.
PRESTUDY AND CONCOMITANT THERAPY
For each subject, the drug identity and dose of the following relevant medications taken during 
the index hospitalization through the end of the study will be recorded on the appropriate page of 
the eCRF: antiplatelet (including NSAIDs) and anticoagulant medications, statins, and 
medications relevant to SAEs. Only the drug identity should be recorded for proton pump 
inhibitors, glucocorticoids, hormonal therapies including but not limited to estrogens, 
progesterones, androgens, anti-androgens and any analogues. In the event a prohibited 
medication other than NSAIDs is received, only the identity of the medication will be recorded.
Prophylactic treatment with LMWH or UFH during the index hospitalization must be reported as 
accurately as possible at screening.  
Allowed Therapy
All decisions regarding concomitant medications are left to the treating physician unless 
otherwise required by the protocol.
Refer to Section 4.3 for prohibited therapies.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The TIME AND EVENTS SCHEDULE in the synopsis summarizes the frequency and timing of 
procedures applicable to this study.
Additional serum or urine pregnancy tests may be performed, 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.  
9.1.2.
Screening Phase
Screening may begin any time after the admission for the index hospitalization, and once the 
informed consent is obtained. 
Subjects with a modified IMPROVE VTE Risk Score of 2 or 3 must have had a local D-dimer 
value >2X ULN before randomization to be eligible for the study.  For those subjects, if the 
D-dimer was not ordered as part of the standard of care by the treating physician during the 
index hospitalization, a screening sample may be obtained by site staff after obtaining informed 
consent. The informed consent may be a limited informed consent to allow for this screening 
activity. No other screening procedures must be performed until the full informed consent is 
obtained. Alternatively, the full study informed consent may be obtained if selected by site staff 
and necessary to be in compliance with local and IRB/Ethics Committee requirements. 
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For subjects enrolled with ischemic stroke as the reason for hospital admission and who received 
fibrinolysis agents as treatment for the stroke, a head CT or MRI must be obtained at least 
24 hours after fibrinolysis. Results of the head CT/MRI must meet Inclusion Criterion [1.2] for 
the subject to be randomized.
Eligibility based on laboratory results will be determined using local laboratory results for the 
inclusion and exclusion clinical laboratory parameters, and the latest one will also serve as 
baseline if there are multiple laboratory values. Laboratory screening assessments that are part of 
the standard care performed by the investigator do not need to be repeated if performed within 
the time frame required by the protocol. A local D-dimer value should be obtained on all 
subjects; if available, a screening D-dimer value can be used if available. If more than 1 D-dimer 
value is available, the value obtained closest to the beginning of the index hospitalization should 
be used. Hemoglobin, platelet count and the serum creatinine utilized to determine 
randomization CrCL (calculated by IWRS using the Cockcroft-Gault formula) must be obtained 
at least as recently as 2 days before the subject leaves the hospital or later, but before 
randomization.
The creatinine clearance will be calculated by IWRS using the Cockcroft-Gault formula, which 
relates serum creatinine with age (in years) and body weight (in kg)4,6. If one measures creatinine 
concentration 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)]
If one measures creatinine concentration 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)]
All screening activities must be completed before randomization and the results must be 
available to the investigator for review to ensure that eligibility criteria are met.
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9.1.3.
Double-Blind Treatment Phase
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 at the Day 1 visit. 
Randomization should occur on the day the subject leaves the hospital; randomization will also 
be permitted the day after the subject leaves the hospital. Randomization may occur at the 
hospital, clinic or other discharge destination.
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

does not believe they will have sufficient support to comply with the protocol

is being discharged to a destination other than home and acceptability of study 
participation has not been confirmed with the accepting physician

post-discharge anticoagulation or thromboprophylaxis is planned
Also, before randomization occurs, site staff should review eligibility criteria, including 
concomitant medications administered during the index hospitalization and planned at discharge.  
Particular attention should be paid to ensure that acceptable types and doses of 
thromboprophylaxis were used during the index hospitalization, and that prohibited medications 
were not administered and are not planned.
After randomization, the first dose of study drug should be administered as soon as possible and 
no later than the day after the subject leaves the hospital. The time of the first dose should be 
recorded as accurately as possible. The first dose also should not be delayed to allow 
administration under supervision. The first dose does not need to be delayed because of the 
recent administration of LMWH or UFH. The administration date and time of the first dose of 
study drug will be recorded in the source document and eCRF. The subject will be instructed to 
take study drug daily through Day 45. Regardless of the day on which the Day 45 Visit occurs, 
no study drug may be taken after Day 45.
Also, at the randomization visit, 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 and given educational material on the signs and symptoms associated with DVT, PE 
and bleeding. 
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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 medication 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.
Treatment Visits
Subjects will be instructed to adhere to the visit schedule in the TIME AND EVENTS 
SCHEDULE. Treatment visits should be conducted at the site, but to allow for as complete 
follow up as possible, they may be conducted at home or at another discharge destination, if 
allowed by local regulatory and IRB/Ethics Committee requirements. Day 7 and Day 75 visits 
may be conducted as a telephone visit. Visits conducted at home may only be performed by 
medically qualified personnel (eg, training and education) as delegated by the Principal 
Investigator and as documented in the Delegation Log.  If a visit in the subject’s presence cannot 
be achieved, telephone contact with the subject should be attempted. If telephone contact with 
the subject cannot be achieved, the site should attempt to contact others who have knowledge of 
the subject as allowed by local and IRB/Ethics Committee requirements.
Day 7 Visit
The Day 7 Visit may be conducted at the clinic or other discharge destination including a home 
visit if allowed by local requirements or as a telephone visit. Visits conducted at home may only 
be performed by medically qualified personnel as delegated by the Principal Investigator and as 
documented in the Delegation Log.If the information is obtained via telephone contact, written 
documentation of the communication must be available for review in the source documents. The 
visit window is -2 days/+5 days. Study personnel will confirm sufficient drug supply to allow for 
daily dosing through the Day 21 Visit, and will reinforce the dosing schedule and procedure to
follow if a dose is missed. The clinical status review for suspected outcome events will be 
completed, as will the symptom assessment, consisting of a set of scripted questions 
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(Attachment 4). Adverse events will be collected as specified in Section 12, and concomitant 
medication will be collected as specified in Section 8.
Subject counseling provided at the randomization visit will be repeated in detail.
Day 21 Visit
The Day 21 Visit may be conducted at the clinic or other discharge destination including a home 
visit if allowed by local requirements.  Visits conducted at home may only be performed by 
medically qualified personnel (eg, training and education) as delegated by the Principal 
Investigator and as documented in the Delegation Log. The Day 21 Visit should not be 
conducted as a telephone visit. Attendance in person is required to allow study drug dispensing. 
The visit window is -3 days/+7 days to ensure compliance. Study drug accountability will be 
performed and a supply of 30 tablets dispensed. Site staff will reinforce the dosing schedule and 
procedure to follow if a dose is missed. The clinical status review for suspected outcome events 
will be completed, as will the symptom assessment, consisting of a set of scripted questions 
(Attachment 4) and a clinical assessment. Adverse events will be collected as specified in 
Section 12, and concomitant medication will be collected as specified in Section 8.
Subject counseling provided at the randomization and Day 7 Visits will be again repeated in 
detail.
Day 45 Visit
The Day 45 Visit may be conducted at the clinic or other discharge destination including a home 
visit if allowed by local requirements.  Visits conducted at home may only be performed by 
medically qualified personnel (eg, training and education) as delegated by the Principal 
Investigator and as documented in the Delegation Log. The Day 45 Visit should not be 
conducted as a telephone visit. The visit window is -0 days/+4 days to ensure all events through 
the end of treatment are captured. The last dose of study drug will be administered on Day 45 
regardless of the day of the Day 45 visit. Regardless of the day on which the Day 45 Visit 
occurs, no study drug may be taken after Day 45. Study drug accountability will be performed. 
The clinical status review for suspected outcome events will be completed, as will the symptom 
assessment, consisting of a set of scripted questions (Attachment 4) and a clinical assessment. 
Adverse events will be collected as specified in Section 12, and concomitant medication will be 
collected as specified in Section 8.
Subject counseling provided at the randomization, Day 7, and Day 21 Visits will be again 
repeated in detail.
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Unscheduled Visit
Subjects may be seen by the investigator between scheduled visits for any reason such as:

Suspected efficacy or bleeding outcome event

Early study drug permanent discontinuation

Adverse event, based upon the severity and clinical judgment of the investigator

Lost medication requiring replacement
Early Study Drug Permanent Discontinuation/Early Withdrawal from Study
If the subject permanently discontinues study drug before Day 45, he/she should be instructed to 
complete an unscheduled visit and the remaining scheduled visits, including the Day 7 (-2d/+5 d) 
and Day 21 (-3d/+7d) visits and the Day 45 (+4d) and Day 75 (±5d) visits (see TIME AND 
EVENTS SCHEDULE). Because the primary efficacy analysis of the study is based upon the 
intention-to-treat (ITT) principle, the investigator should inform the subject of the importance of 
returning for all study visits. It is imperative for the integrity of the trial and results to have vital 
status and other outcomes ascertainment. If the subject is unwilling or unable to return for any
visits, the site should collect as much follow-up information as possible, including contacting the 
subject or legally acceptable representative by telephone or by mail to determine vital status and 
if an outcome has occurred, as agreed to by the subject during the initial informed consent 
process. 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.
9.1.4.
Post-treatment Phase (Follow-Up)
Day 75 Visit
The Day 75 Visit may be conducted at the clinic or other discharge destination including a home 
visit if allowed by local and IRB/Ethics Committee requirements or by a telephone visit.  Visits 
conducted at home may only be performed by medically qualified personnel (eg, training and 
education) as delegated by the Principal Investigator and as documented in the Delegation Log. 
The visit window is -5 days/+5 days. The clinical status review for suspected outcome events 
will be completed, as will the symptom assessment, consisting of a set of scripted questions 
(Attachment 4). Adverse events will be collected as specified in Section 12, and concomitant 
medication will be collected as specified in Section 8.
If the information
is obtained via telephone contact, written documentation of the 
communication must be available for review in the source documents. 
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Randomization in this study is preceded by a hospitalization for an acute illness and the study 
drug treatment phase extends for 45 days after randomization to correspond to the period of 
greatest risk for VTE. Chronic therapy with the study drug is not being tested. For these reasons, 
rivaroxaban will not be provided to the subject after the subject completes the Day 75 (±5d) visit
unless required by local regulations. It will only be after data from the entire study is analyzed 
that the sponsor will determine if the population at risk will benefit from treatment.
9.2.
Efficacy Evaluations and Outcomes
As described in Section 1.1.5, PE is reported by physicians to be the most commonly missed or 
delayed diagnosis. As MARINER is a symptomatic event-driven trial it is critical all efficacy 
outcome events, including symptomatic PE are appropriately diagnosed. Any suspected event 
that includes symptoms or signs suggestive of a PE must be sent for adjudication. Investigators 
are encouraged to give careful consideration of the diagnosis of PE for subjects admitted under 
their care with symptoms of or exacerbations of conditions such as (pneumonia, bronchitis, heart 
failure, cardiorespiratory failure and exacerbation of COPD). Investigators are also strongly 
encouraged to expeditiously contact the treating physician for any subject hospitalized with any 
of these conditions.2,32,12
9.2.1.
Efficacy Evaluations, Outcomes and Adjudication
This is a clinical outcomes study. The primary efficacy outcome is the composite of all 
symptomatic VTE events (lower extremity DVT and non-fatal PE) and VTE-related death (death 
due to PE or death in which PE cannot be ruled out as the cause). 
Secondary efficacy outcomes are:

VTE-related death (death due to PE or death in which PE cannot be ruled out as the cause)

Symptomatic VTE (lower extremity DVT and non-fatal PE)

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE) and ACM

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE), MI, 
non-hemorrhagic stroke and CV death (death due to a known CV cause and death in which a 
CV cause cannot be ruled out; by this definition, a VTE-related death is considered a CV 
death)

ACM 
Exploratory efficacy outcomes are:

Symptomatic lower extremity DVT 

Symptomatic non-fatal PE

Symptomatic upper extremity DVT

MI

Non-hemorrhagic stroke
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
Re-hospitalization for symptomatic VTE (lower extremity DVT and non-fatal PE) within 
30 days after randomization
Submission of a suspected event for adjudication will be required for:

All deaths

Suspected events that include symptoms or signs suggestive of PE or DVT.

Performance of any imaging or other diagnostic study that could yield an incidental 
diagnosis of PE or DVT.  

Suspected events that include acute coronary syndrome or MI. Chest pain determined not to 
be cardiac in origin does not need to be sent for adjudication.

Suspected events that include symptoms compatible with a TIA or stroke. Events 
determined not to be a TIA or stroke (eg, seizure, hypoglycemia) do not need to be sent for 
adjudication.
Any clinical event that suggests the possibility that an efficacy outcome event has occurred 
(including ACS and TIA) should be indicated on the Clinical Status page of the eCRF and will 
be sent for adjudication. Examples of objective testing diagnostic procedures that may have been
performed as part of the standard of care are listed in Attachment 2. For imaging studies, a copy 
of the original study should be sent with the adjudication package. For other tests, a report of the 
results will suffice. All clinical data must be sent to CEC for adjudication. The CEC may request 
additional imaging in order to ensure appropriate adjudication. The CEC will apply the 
definitions (see Attachment 1) contained in the CEC charter to adjudicate and classify the events 
while blinded to treatment assignment. Adjudicated results will be used for final analyses.
9.2.2.
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 established 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 study drug treatment as clinically 
indicated. 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.

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.
After clinical evaluation of the suspected efficacy outcome event is completed restarting study 
drug may be considered if none of the conditions requiring permanent discontinuation are 
present (Section 10.2.3, Permanent Discontinuation of Study Treatment), and after consultation 
with the medical monitor.
In the event that a decision is made to restart study drug 
(Section 10.2.1, Temporary Interruption of Study Treatment), guidelines for restarting study drug 
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(Section 10.2.2, Approach to Subjects with Temporary Interruption of Study Treatment) may be 
followed if applicable based on the clinical judgment of the investigator.
9.3.
Pharmacokinetics 
9.3.1.
Evaluations
Pharmacokinetic samples will be collected at selected countries and sites that can provide the 
logistical requirements necessary for the PK sampling. Fasting is not required to validate the
population PK model. Four sparse blood samples will be collected at 2 visits for about 
600 subjects (300 subjects in rivaroxaban subjects [200 subjects in the 10 mg daily and 100 in 
the 7.5 mg daily group] and 300 in the placebo group) (Table 3 and Table 4). These data will be 
used to describe drug exposure. Blood samples (2.0 mL each) for determination of rivaroxaban 
plasma concentrations will be collected at the time points indicated in the TIME AND EVENTS 
SCHEDULE. The exact date and time of the administration of the current dose (plus the 2 
preceding doses) and the precise actual time of blood sample collection must be accurately 
documented in the eCRF or laboratory requisition form, as appropriate. The PK sub-study will 
only be conducted at specific sites (ie, those that have the capability to draw, process, and store 
the PK samples), where all subjects screened will be given the choice to participate. For the PK
sample population, drug should always be taken in the morning. At the Day 7 visit, the study 
drug must be administered under supervision following the collection of the trough sample. At 
the Day 21 visit, subjects will take the study medication at home in the morning and visit the 
clinic for PK sampling. At the Day 21 visit, the date and time of the dose administration must be 
recorded and there needs to be a minimum of 3 hours between sample collections. Subjects may 
be confined to the study site during PK sampling, if considered appropriate. Samples will be 
used to evaluate the PKs of rivaroxaban (Attachment 3). 
Table 3
Pharmacokinetic Suggested Sampling Schedule
PK Blood sampling 
(selected sites 
and subjects)
Day 7
Day 21
Pre-dose
Hours
Post-dose
Hours
Post-dose
1-4
Hours
3-7
Hours
7-12
Hours
X
X
X
X
Table 4:
Summary of PK Suggested Observations for Rivaroxaban Arm
Active doses
(mg/day)
Total number of subjects with 
measured samples on 
Rivaroxaban
Number of  
Measurements
Plasma
Concentrations
7.5
100
400
10
200
800
Total
300
1,200
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9.3.2.
Analytical Procedures
Pharmacokinetics
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.
9.3.3.
Pharmacokinetic Parameters
Based on the individual plasma concentration-time data, using the actual dose taken and the 
actual sampling times, PK parameters and exposure information of rivaroxaban will be derived 
using population PK modelling. Baseline covariates (eg, lean body mass, age, serum creatinine) 
will be included in the model.
9.4.
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data collection will include re-hospitalization 
(including ER visits, intensive care unit and cardiac care unit stays), length of stay and subject 
discharge destination (after re-hospitalization). 
9.5.
Safety Evaluations and Outcomes  
9.5.1.
Bleeding Events
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the TIME AND EVENTS SCHEDULE: ISTH major bleeding, non-major 
clinically relevant bleeding, other bleeding, adverse events, and clinical laboratory tests.  
The study will use the ISTH Bleeding Event Classification Scale to assess bleeding events as 
major, non-major clinically relevant bleeding, or other bleeding. Similar to efficacy outcomes, 
the same independent CEC will adjudicate and classify bleeding events according to definitions 
in the CEC charter. The CEC will also classify bleeding events using the Bleeding Academic 
Research Consortium scale as a supportive approach.27
The principal safety outcome for this study is major bleeding using validated ISTH bleeding 
criteria. Other safety outcomes are non-major clinically relevant bleeding and other bleeding.
An ISTH major bleeding event is defined as overt bleeding that is associated with:

A fall 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

A critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, 
intramuscular with compartment syndrome, retroperitoneal, or 

A fatal outcome
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Non-major clinically relevant 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 associated with discomfort 
for the subject such as pain or impairment of activities of daily life.
Examples of non-major clinically relevant bleeding are:

Epistaxis if it lasts for more than 5 minutes, if it is repetitive (ie, 2 or more episodes of true 
bleeding, ie, not spots on a handkerchief, within 24 hours), or leads to an intervention 
(packing, electrocautery, etc.)

Gingival bleeding if it occurs spontaneously (ie, unrelated to tooth brushing or eating), or if 
it lasts for more than 5 minutes

Hematuria if it is macroscopic, and either spontaneous or lasts for more 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 spots

Hemoptysis, if more than a few speckles in the sputum, or

Intramuscular hematoma

Subcutaneous hematoma if the size is larger than 25 cm2 or larger than 100 cm2 if provoked

Multiple source bleeding
Other bleeding is defined as any other overt bleeding episodes that do not meet the ISTH criteria 
for major or non-major clinically relevant bleeding.
Details of all bleeding events will be captured in the eCRF.
All suspected bleeding events will be submitted for adjudication.
9.5.2.
Approach to the Subject with a Bleeding Event
If a subject has a serious bleeding event during study drug treatment, the following routine 
measures should be considered: 

Delay the next study drug administration, or discontinue treatment if indicated. Rivaroxaban 
has a plasma half-life of approximately 5 to 9 hours, and in some subjects up to 13 hours. 
Therefore, temporary cessation of study drug may allow control of bleeding. Unblinding of 
study drug should not be necessary. As there is not a specific reversal agent for rivaroxaban, 
management of the subject should not be impacted by knowledge of study drug treatment.

Consider the usual treatment measures for bleeding events, including fluid replacement and 
hemodynamic support, blood transfusion, and fresh frozen plasma, if physical examination 
and laboratory testing suggest benefit could be obtained.

Consider that other causes besides antithrombotic medication can be contributory to the 
seriousness of the bleeding event (i.e., rule out disseminated intravascular coagulation, 
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thrombocytopenia, and other coagulopathies; kidney and liver dysfunction; concomitant 
medications, etc.), and treat accordingly.
If bleeding cannot be controlled by these measures, consider administration of 1 of the following 
procoagulants (according to the dosages advised in their respective package inserts).43

Activated prothrombin complex concentrate 

Prothrombin complex concentrate 

Recombinant factor VIIa (NovoSeven®)
Any products administered to control bleeding should be entered in the CRF.
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, and epsilon aminocaproic acid).
After resolution of the bleeding event, restarting study drug may be considered based on the 
clinical judgment of the investigator.  
9.5.3.
Other Safety Assessments
Adverse Events
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.
Clinical Laboratory Tests
Separate laboratory screening tests are not expected to be performed by the investigator as these 
will likely be part of the subjects’ hospital evaluation. No pre-specified laboratory tests will be 
performed for the duration of the study. However, these subjects are likely to have local 
laboratory tests performed during their index hospitalization. Any laboratory test along with 
reference ranges relevant to a serious adverse event or an outcome event should be recorded on 
the appropriate eCRF page.
The following tests results with reference ranges will be obtained from the hospital 
laboratory/local laboratory at the time of the index hospitalization:

hematology 

hemoglobin

platelet count

serum creatinine (CrCl to be calculated by IWRS using Cockcroft-Gault formula6)

D-dimer

serum or urine pregnancy testing for women of childbearing potential only
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9.6.
Benefit-Risk Balance
Benefit-risk balance of rivaroxaban will be explored. Refer to Section 11.8, Benefit-Risk 
Analysis for details.
9.7.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. If blood samples are collected via an indwelling cannula, an appropriate 
amount (1 mL) of fluid slightly greater than the dead space volume of the lock will be removed 
from the cannula and discarded before each blood sample is taken. After blood sample 
collection, the cannula should be managed per local practice.
Refer to the TIME AND EVENTS SCHEDULE for the timing and frequency of all sample 
collections.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
The total duration for a subject who completes the study after randomization is expected to be 
75 days.
All feasible efforts and measures will be made to collect complete vital status and other outcome 
data from randomization to the Day 75 (±5d) visit for each subject randomized in this study, 
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 
phase, the subject must continue to be followed for efficacy and safety outcomes.
During the study, should the subject develop any condition, which in the investigator’s judgment 
requires long-term anticoagulation thromboprophylaxis, or fibrinolysis, the subject will have 
study treatment 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.
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10.2.1.
Temporary Interruption of Study Treatment
If the subject requires re-hospitalization (re-hospitalization is defined as a combined total of 
inpatient and/or ER stay ≥24 hours) during the study drug treatment for reasons other than the 
primary efficacy outcome or bleeding, the subject should be maintained on the study drug at the 
discretion of the investigator. If the treating physician feels that the subject requires any 
anticoagulation during the re-hospitalization, study drug needs to be temporarily interrupted, and 
can be resumed upon hospital discharge. Mechanical methods of prophylaxis may be used during 
hospitalization. If this method is chosen, study drug may be continued.
In addition, the study drug should be temporarily interrupted if the subject: 

Develops any medical condition that may require use of anticoagulant therapy, 
thromboprophylaxis, fibrinolysis or poses an increased bleeding risk.

Undergoes percutaneous coronary intervention, coronary artery bypass graft, any other 
interventional 
procedure, 
that 
may 
require 
use 
of 
anticoagulant 
therapy, 
thromboprophylaxis, or poses an increased bleeding risk. For temporary interruption of 
study drug for an elective procedure or surgery, it is suggested that investigators follow 
measures in Table 4 and Table 5 (Section 10.2.2 Approach to Subjects with Temporary 
Interruption of Study Treatment).

Experiences a major bleeding event other than intracranial bleeding. For less severe bleeding 
events, investigator discretion is allowed. If possible, study drug should be resumed when 
the bleeding event has resolved and the cause has been identified and corrected.

If a subject develops a new neurologic deficit or significant alteration in mental status
suggesting a cerebral vascular accident. Once a diagnosis is definitively made and 
appropriate treatment is provided, the study drug may be restarted at the discretion of the 
investigator.

Develops a platelet count less than 50,000/µL. If a repeat platelet count is obtained, and the 
result indicates that the abnormal platelet count was spurious, study drug may be restarted.  
If the finding was not spurious, study drug may be restarted after 2 consecutive values 
greater than 75,000/µL at least 1 week apart have been obtained.

Has a serious adverse event that is considered by the investigator to be possibly related to, or 
exacerbated by, study drug administration.

Requires a prohibited therapy on a temporary basis (see Section 8, Prestudy and 
Concomitant Therapy).
10.2.2.
Approach to Subjects with Temporary Interruption of Study 
Treatment
If study drug is temporarily interrupted to allow a procedure to be performed, the routine 
measures described in Table 5 and Table 6 should be considered: 
Table 5:
Preoperative Interruption of Rivaroxaban: A Suggested Management Approach (adapted from 
Spyropoulos and Douketis 2012)
Patient Renal 
Function
Low Bleeding Risk Surgerya
(2-3 drug half-lives between last 
High Bleeding Risk Surgeryb
(4-5 drug half-lives between last 
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dose and surgery)
dose and surgery)
Normal or mild 
impairment 
(CrCl ≥50 mL/min), or 
moderate (CrCl ≥30 
and <50 mL/min)
impairment
Last dose: 2 days before surgery 
(skip 1 dose)
Last dose: 3 days before surgery 
(skip 2 doses)
CrCl, creatinine clearance. 
a aiming for mild-to-moderate residual anticoagulant effect at surgery (<12-25%).
b aiming for no or minimal residual anticoagulant effect (<3-6%) at surgery.
Table 6:
Postoperative Resumption of Rivaroxaban: A Suggested Management Approach
Low Bleeding Risk Surgery
High Bleeding Risk Surgery
resume on evening of or day after surgery (within 
24 hours postoperative)
resume 2 to 3 days after surgery (within 48 to 
72 hours postoperative)
Spyropoulos, 201238.
10.2.3.
Permanent Discontinuation of Study Treatment
If a subject must be permanently discontinued from study drug before the end of the 
double-blind treatment phase, 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 outcomes (for 
details see Section 3.1).
A subject should be permanently discontinued from study drug if:

The investigator believes that for safety reasons (ie, adverse event) it is in the best interest of 
the subject to stop study drug.

The subject develops any condition which requires anticoagulation or thromboprophylaxis 
extending beyond the treatment phase of the study (eg, atrial fibrillation, VTE).

The subject becomes pregnant.

The subject has a fall in CrCl to below 20 mL/min or 2 consecutive measurements less than 
30 mL/min at least 1 week apart (as calculated by Cockcroft-Gault formula, see 
Section 9.1.2) during the study. 

The subject requires hemofiltration or dialysis on a permanent basis

The subject requests to discontinue study drug permanently

The subject has a hemorrhagic stroke, or intracranial bleeding
If the subject permanently discontinues study drug before Day 45, he/she should be instructed to 
complete an unscheduled visit and the remaining scheduled visits, including the Day 7 and 
Day 21 visits (if not yet completed), and Day 45 (+4d) and Day 75 (±5d) visits (Section 9.1.3). 
The Day 45 visit should be a clinic visit; the Day 75 visit may be a telephone visit. 
The eCRF is to be completed to identify the reason for permanent discontinuation of study drug. 
The investigator will provide a narrative to describe any adverse events that occur up to the 
Day 75 (±5d) visit. The appropriate adverse event or serious adverse event sections of the eCRF 
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are to be completed. If study drug is terminated for a serious adverse event, expedited reporting 
(within 24 hours) is also required as outlined in Section 12.3.2, Serious Adverse Events.  
10.3.
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, including locator services 
where permitted by law, up until the Day 75 (±5d) visit, have been exhausted, lost to 
follow-up will be declared). 

Withdrawal of consent (unless specifically refused by the subject, subject contact will be 
made to obtain vital status and other outcomes at the Day 75 (±5d) visit).
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. 
Study drug assigned to the withdrawn subject may not be assigned to another subject. Subjects 
who withdraw will not be replaced.
If a subject withdraws consent from study or is lost to follow-up, his or her vital status and other 
outcomes will be collected at the Day 75 (±5d) visit either by telephone or in person, or if 
applicable, by a review of the subject’s medical or public records unless this contact is not 
allowed by local regulations.
11.
STATISTICAL METHODS
Statistical analysis will be done 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 of 
the study drug is outlined below. A more detailed SAP, including detailed censoring rules for 
time to event analyses and imputation rules for missing or partially missing dates, will be 
provided in a separate document that will be finalized before the first subject is randomized.  
Summaries by treatment group using appropriate descriptive statistics will be provided for all 
study variables including demographic and baseline characteristics. No imputation will be 
applied, unless specified otherwise in the SAP. Descriptive statistics such as mean, median, 
standard deviation, minimum, and maximum will be used to summarize continuous variables. 
Counts and percentages will be used to summarize categorical variables. Kaplan-Meier method 
will be used to summarize time-to-event variables. Graphical data displays may also be used to 
summarize the data.
Unless stated otherwise, all statistical tests will be interpreted at a nominal (that is, without 
adjustment for multiplicity) 2-sided significance level of 0.05 and all CIs at a nominal 2-sided 
level of 95%.
Adjudicated results on efficacy and safety outcomes will be used for the interim and final 
analyses.
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11.1.
Analysis Set and Analysis Phase
Each analysis involves the following 2 aspects: 1) analysis set, specifying the subjects to be 
included; and 2) analysis phase, specifying the time window within which data will be included.  
Key analysis sets and analysis phases are defined below.
11.1.1.
Analysis Sets 

Intention-to-Treat (ITT) (as in the International Conference on Harmonisation [ICH] E9 
guideline): This analysis set consists of all randomized subjects who have a signed valid 
informed consent.  

Per-Protocol (PP): This analysis set is a subset of the ITT analysis set. Subjects with key
protocol deviations will be excluded from the PP analysis set. Key protocol deviations will 
be defined in the SAP.

Safety: This analysis set is a subset of the ITT analysis set, consisting of subjects who 
receive at least 1 dose of study drug.
11.1.2.
Analysis Phases

Up-to-Day-45: This analysis phase includes all data from randomization to Day 45 
(inclusive).  

On-Treatment: This analysis phase includes all data from randomization to 2 days after the 
last dose of the study drug (inclusive).  
11.2.
Sample Size Determination
This is an event-driven study. The targeted total number of primary efficacy outcome is 161, 
based on the ITT analysis set and Up-to-Day-45 analysis phase. If a subject has multiple events, 
only the first is counted towards study size determination.
This targeted total number of events is determined using statistical software East 5.3 based on the 
primary efficacy analysis (defined later) and the following assumptions:

40% relative risk reduction (RRR) in the primary efficacy outcome based on the 
ITT analysis set and Up-to-Day-45 analysis phase (RRR is defined as 1 minus the hazard 
ratio (HR) of rivaroxaban versus placebo.) 

Power of 90% assuming the above RRR

Two-sided significance level of 0.05. 
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To observe the targeted 161 events, it is estimated that a total of approximately 8,000 subjects 
will need to be randomized to either rivaroxaban or placebo in 1:1 ratio. This estimate is based 
on an estimated placebo incidence rate of the primary efficacy outcome of 2.5%. In the event that 
the actual observed blinded pooled event rate is lower than the assumed rate, more subjects may 
be enrolled to accumulate additional outcome events. Randomization in this study may be 
stopped at approximately 12,000 subjects for administrative considerations even if the targeted 
161 events have not been observed by then. The total number of VTE-related death events may 
also be taken into account when deciding to stop randomization.
The above assumptions are based on observations from the MAGELLaN study and the 
IMPROVE VTE risk score published data.10, 11, 31, 25, 26, 37
Table 7 below additionally shows the approximate numbers of randomized subjects needed to 
observe 161 events based on several other placebo incidence rates.
Table 7:
Approximate Number of Subjects Needed to Observe 161 Events
Placebo Incidence Rate
Number of Subjects
3.0%
6,700
2.75%
7,300
2.5%
8,000
2.25%
9,000
2.0%
10,100
11.3.
Efficacy Analyses
Primary Efficacy Outcome
The primary efficacy outcome will be analyzed based on the time from randomization to the first 
occurrence of symptomatic VTE (lower extremity DVT and non-fatal PE) and VTE-related death
(death due to PE or death in which PE cannot be ruled out as the cause) in the ITT analysis set
and Up-to-Day-45 analysis phase. The primary statistical alternative hypothesis is that 
rivaroxaban is superior to placebo on the primary efficacy outcome, that is, time to event for the 
rivaroxaban group is stochastically later than that for the placebo group from randomization up 
to Day 45. More specifically, the survival function for the placebo group is lower than that for 
the rivaroxaban group. The null hypothesis is the negation of the alternative hypothesis, that is, 
the survival function for the placebo group is not lower than that for the rivaroxaban group.  As a 
further illustration of the hypotheses, for the case where hazard functions are proportional, the 
above alternative hypothesis can be expressed as that the HR of rivaroxaban versus placebo is 
less than 1, and the null hypothesis is that the HR is at least 1.  
The primary statistical hypothesis will be tested using Cox proportional hazards model, stratified 
by subjects with CrCl ≥30 mL/min and <50 mL/min versus subjects with CrCl ≥50 mL/min, with 
the treatment (as randomized) as the only covariate. This primary efficacy analysis will be based 
on the ITT analysis set and Up-to-Day 45 analysis phase. Subjects will be analyzed according to 
the treatment group to which they are randomized, regardless of actual treatment received.  As an 
operational arrangement, the 2-sided p-value will be reported, and if it is less than the 2-sided 
alpha of 0.05, then superiority of the study drug will be declared when the observed survival 
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functions favor rivaroxaban. Note that the above testing procedure is equivalent to stratified 
logrank test40. The use of the Cox model format facilitates a consistent presentation of tests and 
CIs from analyses of efficacy and safety outcomes and from subgroup and sensitivity analyses. 
The point estimate and corresponding 95% CI for the HR (rivaroxaban to placebo) will be 
provided based on the Cox proportional hazards model. For the CIs, the plausibility of 
proportional hazards assumption will be assessed by visually comparing the plot of the log of
cumulative hazard between treatments, and additionally checked by adding a treatment by 
logarithm-transformed time interaction into the Cox model.  If there is strong indication that the 
proportional hazards assumption is not valid, the 95% CI for relative risk of rivaroxaban versus 
placebo based on the incidence of the primary efficacy outcome from randomization up to 
Day 45 will be additionally provided, using the Cochran–Mantel–Haenszel (CMH) statistic with 
stratification by CrCl groups.
The cumulative event rate derived from the Kaplan-Meier method will be displayed graphically 
to evaluate the treatment effect over time. 
The following sensitivity analyses of the primary efficacy outcome will be conducted to assess 
the robustness of the conclusion from primary efficacy analysis: a) stratified Cox model as in the 
primary efficacy analysis but additionally stratified by region, b) stratified Cox model as in the 
primary efficacy analysis but based on the per-protocol analysis set and on-treatment analysis 
phase. Additional post-hoc analyses may be conducted to investigate unexpected results. 
Off-treatment primary efficacy outcome events will be summarized by treatment groups.
As described in Sections 9 and 10, extensive efforts will be made to collect complete vital status 
and other outcome data for all subjects randomized in this study. The amount of unavoidable 
missing follow-up in this study with relatively short treatment duration of 45 days is not 
expected to influence the conclusion from the efficacy analyses. To illustrate the extent of 
missingness, the numbers of subjects with missing follow-up and the percentages of missing 
follow-up time out of supposed follow-up time will be summarized.  Sensitivity analyses will be 
conducted to estimate any additional events from the rivaroxaban and placebo group during the 
missing follow-up time that are needed to overturn a superiority conclusion from the primary 
efficacy analysis.  Additional details will be provided in the SAP. 
Homogeneity of treatment effects, both in HR and direction in the following subgroups will be 
assessed by subgroup analysis. Analysis methods and any changes to these subgroups will be 
detailed in the SAP.

Age (< 65 vs ≥65; <75 vs ≥75 years)

Sex (men vs women)

Race (White vs others)

Geographic region (North America, South America, Western Europe, Eastern Europe, other)

CrCl (≥30 to <50, ≥50 to <80, ≥80 mL/min)
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
Body Mass Index (<25, ≥25 to <35, ≥35 kg/m2)

Admitting diagnosis (HF with reduced ejection fraction, acute respiratory insufficiency or 
acute exacerbation of COPD, acute ischemic stroke, acute infectious disease, and 
inflammatory diseases)

History of diabetes (yes vs no)

History of cancer (yes vs no)

Baseline D-dimer level

Baseline aspirin use (yes vs no)

Baseline thienopyridine use (yes vs no)

Baseline proton pump inhibitor use (yes vs no)

Duration of index hospitalization (3 to 6, 7 to 10 days)

Duration of anticoagulation during index hospitalization (3 to 6, 7 to 10 days)

LMWH or UFH during index hospitalization (LMWH vs UFH)

Total modified IMPROVE VTE risk factor score (2, 3, ≥4)
Secondary Efficacy Outcomes
Each secondary outcome will be analyzed based on time from randomization to the first 
occurrence in the ITT analysis set, and the Up-to-Day-45 analysis phase. The same stratified Cox 
model as that for the primary efficacy outcome will be used.  Details will be provided in the 
SAP.
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):

VTE-related death (death due to PE or death in which PE cannot be ruled out as the cause)

Symptomatic VTE (lower extremity DVT and non-fatal PE)

The composite of symptomatic VTE and ACM

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE), MI, 
non-hemorrhagic stroke and CV death (death due to a known CV cause and death in which a 
CV cause cannot be ruled out; by this definition, a VTE-related death is considered a CV 
death)  

ACM 
Exploratory Efficacy Outcomes
Each exploratory outcome will be summarized by treatment groups based on the ITT analysis set
and Up-to-Day-45 analysis phase.  
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11.4.
Pharmacokinetic Analyses
The population PK model will characterize and predict the overall exposure to rivaroxaban and 
determine different PK parameters, such as, clearance (CL/F), volume of distribution (V/F), 
first-order absorption rate constant (Ka), area under the plasma concentration curve (AUC), 
maximum serum concentration (Cmax), minimum serum concentration (Cmin), time to reach 
maximum concentration in plasma (tmax), and half-life (t1/2).
A previously developed population PK model will be used in an attempt to externally validate it 
using data from the current study
(ODIXa-DVT, 2006;
EINSTEIN-DVT, 2006; 
BAY 59-7939 /12143, 2008). The model will be utilized to predict the PK parameters for the 
current medically ill population and to generate empirical Bayesian (individual) predictions for 
all concentrations in the current data set. Predictive performance check of the model will be
analyzed. Changes to the structural components of the model will be performed to address any 
observed model misspecifications.
11.5.
Medical Resource Utilization and Health Economics Analyses
Medical resource utilization and health economics will be descriptively summarized by treatment 
group.
11.6.
Safety Analyses
Bleeding Outcomes
The principal safety outcome will be analyzed based on time from randomization to the first 
occurrence of ISTH major bleeding.  Treatments will be compared using the same Cox 
proportional hazards model as that for the primary efficacy outcome described earlier.  The 
analysis will be based on the safety analysis set and on-treatment analysis phase. Subjects will be 
analyzed according to study drug received. If a subject inadvertently receives both drugs, the 
subject will be analyzed as randomized.
Non-major clinically relevant bleeding and the composite of major plus non-major clinically 
relevant bleeding will be analyzed based on time from randomization to the first occurrence. The 
same analysis as that for the principal safety outcome will be used. Bleeding Academic Research 
Consortium bleeding event classification categories will be analyzed similarly. 
All bleeding, other bleeding, as well as sub-categories of major bleeding, including critical sites,
will be also summarized by treatment groups.
Adverse Events
For adverse events that are collected as specified in Section 12, ADVERSE EVENT 
REPORTING, the verbatim terms reported in the eCRF by investigators to identify adverse
events will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA). For each MedDRA preferred term, the percentage of subjects who report 
at least 1 occurrence of the given event will be summarized by treatment group. Additional 
summaries, listings, or subject narratives may be provided, as appropriate.
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Clinical Laboratory Tests
Because this study will not collect laboratory data routinely, laboratory data will not be 
summarized. Local lab data may be discussed in subject narratives.     
Vital Signs
Descriptive statistics of pulse and blood pressure will be provided.
Physical Examination
Descriptive statistics of physical examination findings will be provided.
11.7.
Interim Analysis
An interim analysis for futility will be conducted when approximately 50% of subjects with 
adjudicated primary efficacy outcome events have been observed (about 50% of the expected 
total number of events based on the actual observed blinded pooled event rate even if this event 
rate is lower than the assumed rate) and there will be no alpha adjustment to the final analysis.
The IDMC will review results of the planned interim analysis and make a recommendation 
whether the study should be continued as planned, modified, or terminated prematurely due to 
futility or safety.
The study may be stopped early for futility when it would be unlikely to establish superiority on 
the primary efficacy outcome and/or a positive benefit over risk of rivaroxaban compared with
placebo, if the study were to run to completion.  Detailed characteristics of non-binding futility 
criteria will be specified in the SAP.
11.8.
Benefit-Risk Analysis
The benefit-risk of rivaroxaban vs placebo will be evaluated based on the excess number of 
events between treatments for events intended to be prevented (benefits) and events that may be 
caused (risks). Excess number of events is defined as the difference in event rate times a 
hypothetical population size (eg, 10,000 patients). To have a comprehensive benefit-risk 
evaluation, several comparisons will be considered. One analysis will be based on a comparison 
between the primary efficacy outcome (the composite of symptomatic VTE (lower extremity 
DVT and non-fatal PE) and VTE-related death (death due to PE and death in which PE cannot be 
ruled out as the cause) up to Day 45 post-hospital discharge) and the principal safety outcome 
(the ISTH major bleeding). This analysis phase includes all data from randomization to Day 45 
(inclusive), which is the period of treatment. In addition, benefit-risk balance may be further 
assessed for secondary efficacy outcomes in relation to major bleeding, while potentially taking 
into consideration the clinical importance of those events, eg, in the context of irreversible harm. 
The Kaplan-Meier method will be used to display and evaluate the benefits and risks over time. 
Also a bivariate approach to benefit-risk assessment will be explored.21 Additional details for 
benefit-risk analysis will be specified in the SAP.
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12.
ADVERSE EVENT REPORTING
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.
Rivaroxaban has been extensively studied in Phase 1 through Phase 4 clinical studies involving 
more than 70,000 patients and its overall adverse event profile has been well described. 
Appropriate information concerning adverse events were systematically collected and submitted 
to regulatory authorities. For the purposes of this study (and after discussion with appropriate 
regulatory agencies) a value-driven approach to safety data collection will be utilized. Certain
non-serious adverse events will not be collected, while certain events will be collected as 
suspected outcome events and therefore not reported as serious adverse events. All data on safety 
and outcomes will be reviewed regularly by an unblinded IDMC.
Section 12.1.1 describes the usual definitions of adverse events and serious adverse events.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event 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 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 adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
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Serious Adverse Event
A serious adverse event 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

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 adverse 
events or serious adverse events (See Section 12.3.1, All Adverse Events). 
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For rivaroxaban, the expectedness of an adverse 
event will be determined by whether or not it is listed in the Investigator's Brochure19.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event 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.
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Possible
An adverse event 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 adverse event 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).
Very Likely
An adverse event 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).
12.1.3.
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.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
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12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
In this study, recording of only a subset of adverse events is necessary. However, any adverse 
event of particular concern to the investigator may be recorded in the eCRF to alert the sponsor.  
The following are excluded from adverse event collection and reporting, regardless of 
seriousness or severity. Exempted events will be captured on the eCRF as suspected outcome 
events only and will be waived from unblinding and exempted from expedited reporting and 
include:

VTE-related death (death due to PE or death in which PE cannot be ruled out as the cause)

MI

ACS

Stroke

TIA

Symptomatic VTE (lower or upper extremity DVT and PE)

Bleeding events
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If the 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 adverse event collection and reporting 
even if serious criteria were met.
Serious Adverse Events
All serious adverse events that are not outcome events as listed above should be reported to the 
sponsor as described in Section 12.3.2. While one of the efficacy outcome measures is ACM, 
any non-VTE-related death will be reported to the sponsor as a serious adverse event.
Certain adverse events are considered to be Adverse Events of Special Interest and should be 
reported as serious adverse events. These include: 

Suspected severe toxic effect on the bone marrow, such as severe thrombocytopenia (platelet 
count less than 50,000/µL), severe neutropenia (white blood cell count less than 500/µL), 
pancytopenia, aplastic anemia

Suspected severe hypersensitivity reaction (eg, anaphylaxis, angioedema, severe urticaria, 
bronchospasm, etc.)

Severe skin reactions such as Stevens-Johnson Syndrome

Suspected severe liver injury
Non-Serious Adverse Events
The following should be reported:

Non-serious adverse events leading to permanent study drug discontinuation

All severe non-serious adverse events (regardless of relation to study drug) including severe 
laboratory abnormalities will be collected except the study outcomes.   
Any other non-serious adverse events do not require reporting. However, any adverse event of 
particular concern to the investigator may be recorded in the eCRF to alert the sponsor.  
Reporting Timelines and Processes
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time any 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). Serious adverse 
events, including those spontaneously reported to the investigator up to the Day 75 (±5d) visit, 
must be reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection"). Investigators must record their opinion concerning the relationship of the adverse 
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event to study therapy. All measures required for adverse event management must be recorded in 
the source document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. A SUSAR will be reported to regulatory 
authorities unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR 
summary, unless otherwise specified. 
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all serious adverse events that are unlisted (unexpected) and associated 
with the use of the study drug. The investigator (or sponsor where required) must report these 
events to the appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
that approved the protocol unless otherwise required and documented by the IEC/IRB. 
12.3.2.
Serious Adverse Events
All serious adverse events 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 serious adverse events 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 serious 
adverse event should be made by facsimile (fax, e-mail).
All serious adverse events 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

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)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject's participation in a clinical study must be reported as a serious adverse event, 
except hospitalizations for the following:
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
Social reasons in the absence of an adverse event

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF).
12.3.3.
Pregnancy
All initial reports of pregnancy 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, stillbirth, and congenital 
anomaly) are considered serious adverse events and must be reported using the Serious Adverse 
Event 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. 
12.4.
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 
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 serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
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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, rivaroxaban 7.5 mg and matching 
placebo.  All study drugs will be provided as round white tablets. The crushed 10 mg tablet has 
been studied for bioequivalence and approved for administration as a crushed tablet; the crushed 
7.5 mg tablet has not been tested.
Refer to the Investigator's Brochure for a list of excipients 19. 
14.2.
Packaging
The study drug will be supplied in bottles and 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
The storage recommendation for rivaroxaban is at room temperature (approximately 15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 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 must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study 
drug 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 or a qualified member 
of the study-site personnel, 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. Study drug may not be relabeled or reassigned for use by other subjects. The 
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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:

Investigator Brochure

Pharmacy manual/study site investigational product manual

IWRS Manual

electronic data capture (eDC) Manual
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
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 adverse events of the study, and provide their consent voluntarily will be enrolled.  
This study was designed to closely mimic current clinical practice of discontinuing anticoagulation 
at hospital discharge. Over 90% of post-discharge patients do not continue thromboprophylaxis 
with anticoagulants. Furthermore, thromboprophylactic treatment is limited by the growing trend 
for shorter hospital stays (see Section 1.1). As VTE events still occur post-hospital discharge, there 
is a need to evaluate the current standard of care. A placebo comparator group is therefore justified 
to evaluate this post-discharge treatment paradigm. The bleeding risk will be reduced in this high 
risk medically ill population through dose adjustment and exclusion of patient subgroups with a 
comparatively higher bleeding risk, eg, active cancer (see Exclusion Criteria Section 4.2). 
Any subject with a medical condition that requires use of any parenteral or oral anticoagulation 
(eg, atrial fibrillation) during the study is not eligible for participation. During the study, should the 
subject develop any condition which in the investigator’s judgment requires anticoagulation, 
fibrinolysis, or thromboprophylaxis, the subject will have study treatment 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.
Rivaroxaban has been studied in over 70,000 patients for treating or preventing thrombotic 
associated diseases. Because the safety profile of rivaroxaban and the risk of bleeding with its use 
are well known, blood draws were kept to a minimum in this fragile group of subjects. Subjects 
will undergo all other treatments and diagnostic tests according to the standard of care in their 
locality, thus making this study minimally intrusive in their regular routine health care. 
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Investigators should inform the subject of the importance to complete all study visits if their study 
drug is discontinued prematurely due to an adverse event, 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, a close friend or relative, or their primary care physician to 
determine vital status and if an efficacy or safety outcome event has occurred.
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

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), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
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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 Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events 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).
At least once a year, the IEC/IRB will be asked to review and reapprove this study. 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 
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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 if they choose 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.
If a subject is unwilling or unable to return for a Day 45 (+4d) and/or follow-up Day 75 (±5d)
visit, sites should collect as much information as possible, including contacting the subject or 
legally acceptable representative by telephone or by mail to determine vital status and if an 
outcome event has occurred, as agreed to by the subject during the initial informed consent 
process.
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.
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 
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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.
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 (see Contact Information page(s) provided separately). 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.
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17.2.2.
Required Pre-study 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 
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 
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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 adverse events and follow-up of adverse 
events; 
concomitant 
medication; 
drug 
receipt/dispensing/return 
records; 
study 
drug
administration information; and date of study completion and reason for early discontinuation of 
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 will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
The following data will be recorded directly into the eCRF and will be considered source data: 

History of smoking

Blood pressure and pulse 

Height and weight 
17.5.
Case Report Form Completion
Case report forms are provided for each subject in printed or 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 CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. 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 CRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.
The investigator must verify that all data entries in the CRFs are accurate and correct.
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All CRF 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 
an authorized member of the study-site personnel must adjust the CRF (if applicable) and 
complete the query.
The investigator or study-site personnel must adjust the CRF (if applicable) and complete the 
query.
If corrections to a CRF are needed after the initial entry into the CRF, this can be done in 
3 different ways:

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, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
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 CRFs for accuracy and completeness during on-
site monitoring visits and after their return to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. The data will be entered into the study database 
and 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.
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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 
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.  At these visits, 
the monitor will compare a sample of the data entered into the CRFs with the hospital or clinic 
records (source documents).  The nature and location of all source documents will be identified 
to ensure that all sources of original data required to complete the CRF 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 (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data.  Findings 
from this review of eCRFs 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 can 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 study assessment 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 assessment 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 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 CRF data from all study sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the sponsor's database. 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 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 outcomes 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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Attachment 1:
Efficacy Outcomes
All efficacy evaluations and outcomes described in Section 9.2 will be evaluated and adjudicated by the 
CEC (defined below). Safety outcomes are defined in Section 9.5.
1.
Death will be assigned to 1 of the following:
a.
CV death 
i)
VTE-related 
(1) VTE-related death – death due to confirmed PE documented by objective testing or 
autopsy,
(2) VTE-related, PE cannot be ruled out – death, which cannot be attributed to a documented 
cause and for which pulmonary embolism cannot be ruled out (unexplained death)
ii) Other CV death
b.
Non-CV death – death not included in 1 of the above categories 
2.
Symptomatic DVT – displaying signs or symptoms of proximal or distal lower extremity DVT, upper 
extremity DVT, or other DVT and confirmed by adjudication, based on 1 or more of the following 
diagnostic criteria:
a.
a non-compressible venous segment on compression ultrasonography, or in patients with a history 
of previous DVT, either a new non-compressible venous segment or a substantial increase (4 mm 
or more) in the diameter of the vein during full compression in a previously abnormal segment on 
ultrasonography, or 
b.
the presence of an intraluminal filling defect on venography, or
c.
DVT documented at autopsy.  
If in patients with history of previous DVT or incomplete documentation of the previous episode is 
available, additional criteria may be integrated into the adjudication of the current event, such as: 
ultrasonography appearance of the thrombus, or D-dimer at presentation. Soleal or muscular branch 
DVTs, lower extremity superficial DVT will not be included. The totality of available clinical, 
imaging and laboratory findings should be considered 
3.
Symptomatic PE – displaying signs or symptoms suggestive of PE  and confirmed by adjudication 
based on 1 or more of the following diagnostic criteria: 
a.
an intraluminal filling defect on computed tomography (CT) angiography or spiral CT, or 
b.
an intraluminal filling defect on pulmonary angiography or cutoff of a vessel more than 2.5 mm 
in diameter, or 
c.
a perfusion lung scan defect of at least 75% of a segment with corresponding normal ventilation 
(high probability ventilation-perfusion (V-Q) scan), or 
d.
a non-high probability V-Q scan abnormality associated with DVT documented by 
ultrasonography or venography, or 
e.
in the absence of imaging test in a hemodynamically unstable patient, evidence of right 
ventricular dysfunction by transthoracic or trans esophageal echocardiogram (ESC criteria), or 
f.
PE documented at autopsy.  
The anatomic extent of PE will be classified by the adjudication committee as either segmental or 
greater, or sub-segmental.  The totality of available clinical, imaging and laboratory findings should 
be considered.
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4.
Myocardial infarction
Requires combination of evidence of myocardial necrosis (either changes in cardiac biomarkers or 
post-mortem pathological findings), and supporting information from clinical presentation, ECG 
changes or the results of myocardial imaging or coronary artery imaging.  The totality of available 
clinical, ECG and cardiac biomarker should be considered:
1.
Clinical Presentation consistent with the diagnosis of myocardial ischemia and infarction, 
taking into account differential conditions associated with elevations in cardiac biomarkers
2.
Biomarker elevations
a.
Elevations relative to URL in CK, CK-MB or troponin
3.
ECG changes 
a.
ECG manifestations of acute myocardial ischemia (in absence of left ventricular 
hypertrophy and left bundle branch block); abnormalities may be lesser in patients 
with abnormal biomarkers
i.
New ST elevation at the J point in 2 contiguous leads with the cut-points: 
≥0.1 mV in all leads other than leads V2-V3 where the following cut-points 
apply: ≥0.2 mV in men ≥40 years (≥0.25 mV in men <40 years) or ≥0.15 mV in 
women
ii.
New horizontal or down-sloping ST depression ≥0.05 mV in 2 contiguous leads 
and/or new T inversion ≥0.1 mV in 2 contiguous leads with prominent R wave or 
R/S ratio>1
b.
Criteria for pathological Q-wave
i.
Any Q-wave in leads V2-V3 (abnormalities may be lesser in patients with 
abnormal biomarkers) 0.02 seconds or QS complex in leads V2 and V3
ii.
Q-wave ≥0.03 seconds and ≥0.1mV deep or QS complex n leads I, II, aVL, aVF, 
or V4-V6 in any 2 leads of a contiguous lead grouping (I, aVL, V1-V6, II, III, 
and aVF; the same criteria are used for supplemental leads V7-V9 and for the 
Cabrera frontal plane lead grouping)
c.
ECG changes with prior myocardial infarction
i.
Pathological Q-waves, as defined above
ii.
R-wave ≥0.04 seconds in V1-V2 and R/S≥1 with a concordant positive T-wave 
in the absence of a conduction defect
d.
Criteria for prior myocardial infarction
i.
Pathological Q waves with or without symptoms in the absence of non-ischemic 
causes
ii.
Imaging evidence of a region of loss viable myocardium that is thinned and fails 
to contract, in the absence of a non-ischemic change
iii.
Pathological findings of a prior myocardial infarction
5. Stroke – an acute episode of focal or global neurological dysfunction caused by non-traumatic brain or
spinal cord injury as a result of hemorrhage or infarction
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Status: Approved, 31 March 2017
Attachment 2:
Suspected Event Supporting Documentation
The following supporting material, if available, will be requested to be submitted for each suspected event 
by the investigative site. The totality of available clinical, imaging and laboratory findings should be 
considered. Supporting materials to be completed/collected, not limited to:
1.
Death with cause 
1.
Complete Death eCRF data 
2.
Hospital admission history and physical/death summary
3.
Autopsy reports 
2.
Suspected Symptomatic deep venous thrombosis (DVT) 
1.
Complete Symptomatic Deep Vein Thrombosis eCRF data
2.
Imaging 
3.
Hospital admission history and physical
4.
Hospital discharge summary
5.
Duplex ultrasound 
6.
Venography  
7.
Computed tomography (CT) scan or MRI
8.
D-Dimer 
9.
Autopsy reports 
3.
Suspected Symptomatic PE
1.
Complete Symptomatic Pulmonary Embolism eCRF data 
2.
Hospital admission history and physical
3.
Hospital discharge summary
4.
D-Dimer 
5.
High resolution CT pulmonary angiogram or helical chest CT scan
6.
Ventilation/perfusion scan
7.
Transthoracic or transesophageal echocardiogram in hemodynamically unstable 
patient
8.
MRI
9.
Chest X-Ray 
10. Duplex Ultrasound or venography 
11. Electrocardiogram
12. Autopsy reports 
4.
Suspected Myocardial infarction / acute coronary syndrome
1.
Complete Myocardial Infarction eCRF data 
2.
Hospital admission history and physical
3.
Hospital discharge summary
4.
Electrocardiogram
5.
Cardiac Biomarkers
6.
Autopsy reports 
5.
Suspected Stroke / transient ischemic attack
1.
Complete Stroke eCRF data 
2.
Hospital admission history and physical
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
3.
Hospital discharge summary
4.
Computed tomography (CT) scan 
5.
Magnetic resonance imaging (MRI)
6.
Suspected Major bleeding (MB)
1.
Complete Bleeding Event eCRF data 
2.
Hospital admission history and physical
3.
Hospital discharge summary
4.
Procedure notes
5.
CBC laboratory test
7.
Suspected Non-major clinically relevant bleeding (NMCR) 
1.
Complete Bleeding Event eCRF data
2.
Hospital admission history and physical
3.
Hospital discharge summary
4.
Procedure notes
5.
CBC laboratory test
8.
Suspected Other Bleeding
1.
Complete Bleeding Event eCRF data
2.
Hospital admission history and physical
3.
Hospital discharge summary
4.
Procedure notes
5.
CBC laboratory test
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Attachment 3: Pharmacokinetic Sample Collection and Handling
Materials and Labeling
Blood must be collected in glass or plastic blood collection tubes (eg, Vacutainer®) containing appropriate 
anticoagulants. Resulting plasma samples must be stored in polypropylene storage tubes. No tubes with 
separation gel should be used.
Use of alternative materials will not result in a protocol amendment if preapproved by the Bio-analysis 
Scientist.
All tubes and containers will be labeled with preprinted labels. The preprinted information will include 
the study number, CRF identification number (CRF I.D.  #), treatment arm or treatment period, scheduled 
sampling day and time as stipulated in the flow chart, and the analyte name if applicable. No other 
information will be written on the labels. Labels should be attached to the storage tubes at least 12 hours 
before being frozen to ensure proper adherence.
Labels should be applied to the sample tubes as follows:

Apply labels to the sample tubes so that they do not overlap and obscure any information. 
If possible, expose an area between the 2 ends of the label to allow viewing of the 
contents of the tube.

Do not alter the orientation of the label on the sample tube.

Apply labels to all tubes in the same manner.
Preparation of Plasma Pharmacokinetic Samples for Rivaroxaban

Collect 2 mL of blood into the appropriate K2EDTA -containing collection tube (eg,
Vacutainer) at each time point.

Record the exact date and time of sampling in the CRF.

Gently invert the tubes 8 to 10 times to afford mixing, before processing.

Centrifuge blood samples at room temperature within 1 hour of collection in a clinical 
centrifuge at 1,300 g for 15 minutes or centrifuge for 10 minutes at 1,500 - 1,600 g, 
unless otherwise specified by the supplier, to yield approximately 1 mL of plasma from 
each 2 mL whole blood sample.

Transfer all separated plasma immediately with a clean, disposable glass or polyethylene 
pipette (use 1 new pipette per sample) to a pre-labeled storage tube (1.8 mL NUNC 
tubes).

Store plasma samples in an upright position in a freezer, at a set temperature of -20°C 
until transfer to the bio-analytical facility.

The time between blood collection and freezing the plasma will not exceed 2 hours.

Ship specimens according to the instructions provided.

Ship specimens to the bio-analytical facility, sorted by subject, by sample collection date 
and time.

Questions regarding handling the plasma PK specimens should be addressed to the 
contact person for the sponsor.

Alternative procedures will not result in a protocol amendment if approved by the 
Bioanalysis Scientist.
Please refer to the Study Lab Manual for proper shipping instructions.
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JNJ-39039039; BAY 59-7939 (rivaroxaban)
Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Attachment 4: Symptom Assessment
During all contacts, the treatment and clinical course of the subject is to be evaluated using a 
standard list of questions. Please ask the subject systematically the following questions -
1.
Since the last contact did you experience new or increased?
Shortness of Breath
Yes 
    No 
Chest Pain especially while breathing
Yes 
    No 
Cough
Yes 
    No 
Blood in Sputum
Yes 
    No 
Dizziness or Fainting
Yes 
    No 
Rapid Breathing
Yes 
    No 
Rapid Heart Rate
Yes 
    No 
Blue Lips or Fingers
Yes 
    No 
Weakness on one side of face/body
Yes 
    No 
Fever
Yes 
    No 
If PE is clinically suspected, perform objective testing and complete the adjudication package as 
described in Attachment 2 (Suspected Event Supporting Documentation) of the protocol.
2.
Since the last contact did you experience new or increased?
Calf pain, tenderness or swelling
Yes 
    No 
Appearance of veins on the surface of the 
skin on legs
Yes 
    No 
Tenderness along deep veins of legs
Yes 
    No 
Swelling of entire leg
Yes 
    No 
Puffiness of leg
Yes 
    No 
If DVT is clinically suspected, perform objective testing and complete the adjudication package 
as described in Attachment 2 (Suspected Event Supporting Documentation) of the protocol.
3.
Since the last contact did you experience any?
Bleeding
Yes 
    No 
If yes, complete the adjudication package as described in Attachment 2 (Suspected Event 
Supporting Documentation) of the protocol.
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Attachment 5:
INT-1 to INT-5 / Amendment Changes
Amendment INT-5 (15 June 2015)
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 reasons for the amendment are to modify study procedures 
(including the risk score criterion) and to add patient training material.  
Applicable Section(s)
Description of Change(s)
Rationale: Emerging literature has indicated that the required risk score of the subjects enrolled were not sufficient 
to attain the desired event rate. Because the outcome events are all symptomatic in this study, additional site and 
subject training is necessary to ensure capturing events.
Applicable Section(s)
Description of Change(s)
Synopsis 
Objective and Hypothesis: 
Secondary Objectives, 
Exploratory Objectives, 
Hypothesis, Section 2.1, 
Objectives, Section 2.2, 
Hypothesis, 11.3.Efficacy 
Analyses, Secondary Efficacy 
Outcomes
Definition of VTE-related death was added. .
Composite outcome was added to Secondary Objectives and Hypothesis.
Synopsis
Overview Of Study Design, 
Section 3.1, Overview of Study 
Design
Definition of VTE-related death was added.
CHF was replaced with HF with reduced LVEF.
Upper limit of index hospitalization was changed to 10 days.
Additional inclusion criterion regarding VTE risk score was added.
Figure 3 was replaced and the new figure updates index hospitalization.
Synopsis
Subject Population
CHF was replaced with HF with reduced LVEF.
Upper limit of index hospitalization was changed to 10 days.
Additional inclusion criteria regarding VTE risk score were added.
Synopsis
Dosage and Administration,
Interruption of Study Drug
Statement that study drug needs to be discontinued was replaced with 
‘temporarily interrupted’.
Clarifications regarding use of anticoagulation thromboprophylaxis were added.
Synopsis
Efficacy Evaluations/Outcomes
Definition of VTE-related death was added. The composite outcome was added 
to efficacy outcomes.
Synopsis 
Exploratory Objectives
“Symptomatic” was added to upper extremity DVT and the composite outcome 
was deleted.
Synopsis
Dosage and Administration
Clarification was added that “Regardless of the day on which the Day 45 Visit 
occurs, no study drug may be taken after Day 45”.
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Applicable Section(s)
Description of Change(s)
Time and Events Schedule, and 
Section 9.1.2. Screening Phase
Treatment window upper limit on Day 7 and Day 21 was modified. 
Protocol activities were further clarified by modifying or adding more detailed 
footnotes, ie, admitting diagnosis, D-dimer screening, training on signs and 
symptoms of disease. Symptom Assessment and Subject Counseling were added. 
Consent language was changed to allow for screening to occur any time after 
admission of index hospitalization and once the informed consent is obtained.  
Also, drug accountability/dispensation at Day 7 was removed and Day 7 visit 
may now be performed by telephone.
Synopsis
Statistical Methods, Sample 
Size Determination,
Efficacy Analyses
Further details were added regarding stop of randomization. Definition of VTE-
related death was added. The composite outcome was added to efficacy analyses.
Throughout the
protocol
Definition of VTE-related death was added. CHF was replaced with ‘HF with 
reduced LVEF’.
Section 1.1.5, Studies 
Examining Extended 
Thromboprophylaxis in 
Patients Hospitalized for Acute 
Medical Conditions and 
MARINER Approach
Addition of paragraph regarding IMPROVE VTE risk score and missed diagnosis 
of PE.
Section 3.2, Study Design 
Rationale
Clarification regarding comparator treatment discontinuation was added. Non-
hemorrhagic was deleted from non-hemorrhagic stroke.
3.3.1, Executive Committee
Addition of ad hoc member appointment as necessary.
Section 3.3.3, Clinical Events 
Committee
Suspected outcome events were modified for DVT, MI, stroke, and bleeding.
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Status: Approved, 31 March 2017
Applicable Section(s)
Description of Change(s)
Rationale: Modified inclusion criteria to enrich for subjects with higher level of risk of VTE and to align with 
standard of care for stroke patients.
4. SUBJECT POPULATION, 
Section 4.1 Inclusion Criteria.
Consent language was changed to allow for screening to occur any time after 
admission of index hospitalization and once the informed consent is obtained.  
For Sections 4.1. Inclusion Criteria, 4.2. Exclusion Criteria and 4.3. Prohibitions 
and Restrictions, detailed protocol amendment modifications are described in 
Attachment 6, and a shorter version is provided in-text.
Inclusion Criterion # 1. 
The allowed duration of the hospitalization was decreased from 14 to 10 days.
Detail was added regarding the type and extent of CHF present to be eligible for 
the study.  Patients with preserved ventricular function will not be enrolled 
because of the lower risk of VTE than in patients with reduced ventricular 
function.
In the previous version of the protocol (INT-4), subjects were not allowed to have 
received fibrinolysis during the index hospitalization. This has been updated 
based on the standard of care for stroke patients.  
Inclusion Criterion # 2. 
An elevated D-dimer will now be required to be eligible if the VTE risk score is 2
or 3.  Direction to verify at randomization that the IMPROVE Risk Score 
calculated at screening was calculated correctly.
In Table 1, the footnote was simplified to mirror the cancer exclusion.
Inclusion Criterion # 4. 
Maximum daily dose of thromboprophylactic agents allowed was added to ensure 
that subjects have not received off-label use of thromboprophylaxis.   
Rationale: Modified exclusion criteria to align with standard of care and to provide more clarity for enrollment.
Section 4.2 Exclusion Criteria.
Exclusion Criterion #1. The phrase about recent bleeding that would allow the 
investigator to make a determination of whether or not the bleeding would 
contraindicate the use of pharmacologic thromboprophylaxis was removed.
Exclusion Criterion #2. Guidance on differentiating major from minor surgery 
has been added. 
According to the standard of care, ongoing thromboprophylaxis is generally not 
discontinued for the performance of cataract surgery, so the notation that recent 
cataract surgery is not an exclusion criterion has been added.
The exclusion period for recent head trauma was reduced from 3 months to 
4 weeks, based on expert input.
Exclusion Criterion #3. Reference was changed for consistency with the new 
location of the item referenced.
Exclusion Criterion #5. Addition of any intracranial bleeding.
Exclusion Criterion #6 was removed. 
Exclusion Criterion #7. For intracranial neoplasm, it was clarified that the 
presence of either a malignant or a benign neoplasm would result in exclusion.
Exclusion Criterion #10. Subjects with cancer not in remission will be excluded.  
The previous requirement for a remission of at least 6 months duration has been 
removed, allowing the clinician to determine what time period is appropriate.
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Applicable Section(s)
Description of Change(s)
Exclusion Criterion #19. Use of an intravascular device for blood pressure 
support during the index hospitalization was added as an exclusion because the 
vascular access required for the use of such devices would present an 
unacceptable bleeding risk.
Exclusion Criterion #23. In the previous version (INT-4) of the protocol, it was 
specified that the use of fibrinolysis during the index hospitalization precluded 
inclusion in the study.  This has been modified to accommodate the inclusion 
criterion revision that allows the inclusion of subjects with ischemic stroke and 
use of fibrinolysis, if fibrinolysis occurred at least 3 days before randomization.
Exclusion Criterion #24. The antiplatelet exclusion criteria have been grouped 
together and the prohibition of use of these antiplatelet regimens has been 
extended to the beginning of the index hospitalization instead of planned use 
during the study.  
Exclusion Criterion #27 was removed and was added to the list of medications 
excluded at index hospitalization within Exclusion Criterion #24.
Exclusion Criterion #28. Use of NSAIDs was further clarified.
Exclusion Criterion #31. The exclusion criterion related to PPIs and clopidogrel 
concomitant use has been removed as the drugs discussed are not study 
treatments.
Rationale: Modified exclusion criteria to align with standard of care and to provide more clarity for enrollment.
Section 4.3. Prohibitions and 
Restrictions
Discontinuation of the study drug was further clarified.
Criteria #1 and #5 were removed and content was added to criterion #7.1.
Criterion #7. The antiplatelet exclusion criteria have been grouped together and 
the prohibition of use of these antiplatelet regimens has been extended to the 
beginning of the index hospitalization instead of planned use during the study.  
Section 5. Treatment Allocation 
and Blinding, Treatment 
Allocation, Unblinding
To allow the ability to achieve a regionally heterogeneous population, this change 
allows the sponsor to cap enrollment by region without a protocol amendment.
A header identifying the position of description of unblinding processes has been 
added to better direct the reader.
A statement was added to indicate that even in the event of an outcome or 
bleeding event, an investigator will be able to unblind a subject’s treatment.
Section 5 Treatment Allocation 
and Blinding, Section 6. 
Dosage and Administration, 
Interruption of Study Drug,
10.2.1.Temporary Interruption 
of Study Treatment, Section 
10.2.2 Approach to Subjects 
with Dose Interruption, Section 
7. Treatment Compliance,
Section 9.2.2.
Approach to 
the Subject with an Efficacy 
Outcome Event
Study drug interruption and drug accountability were further clarified, and minor 
modifications were made to Table 6.
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Status: Approved, 31 March 2017
Applicable Section(s)
Description of Change(s)
Section 8. Prestudy and 
Concomitant Therapy
Further clarifications were added on medications taken during the index 
hospitalization and recording of drug identities.
Section 9.1.2. Screening Phase, 
9.5.3.Other Safety Assessments
A baseline D-dimer screening was added to assess its contribution to VTE risk in 
the study population.
Section 9.1.3. Double-Blind 
Treatment Phase
Details for the randomization and treatment visits were added to guide the reader.
Section 9.1.4. Post-treatment 
Phase (Follow-Up)
Details for follow-up visit were added.
Section 9.2. Efficacy 
Evaluations and Outcomes
Paragraph was added regarding the judicious diagnosis of PE by the 
investigators. 
Section 2.1. Objectives, Section 
9.2.1. Efficacy Evaluations and 
Outcomes
Requirements for submission of a suspected event for adjudication were added. 
For exploratory efficacy outcomes, “Symptomatic” was added for clarification to 
“Upper extremity DVT”.
Section 9.5.1. Bleeding Events, 
11.6. Safety Analyses, Bleeding 
Outcomes
Additional resource for CEC classification of bleeding events was added.
Section 11.2. Sample Size 
Determination
Further details were added regarding stop of randomization.
Section 11.3. Efficacy Analyses
For subgroup analyses, geographic regions were added, and admitting diagnosis 
was modified.
Section 11.8. Benefit-Risk 
Analysis
A bivariate approach to benefit-risk assessment that will be explored was added.
Section 12.3.1. All Adverse 
Events
Non-hemorrhagic was deleted from non-hemorrhagic stroke.  Adverse event 
reporting was clarified further.
Section 14.1. Physical 
Description of Study Drug(s)
Information about crushed tablets was added.
References
List was updated.
Attachment 1: Efficacy 
Outcomes
Assignment of death was modified for clarity. Stroke was modified for clarity 
(eg, non-hemorrhagic was removed).
Attachment 2: Suspected Event 
Supporting Documentation
All events, with the exception of death, were defined as suspected. For 4.) 
Suspected MI/ACS, Cardiac Biomarkers are now included for supporting 
documentation.
Attachment 4: Symptom 
Assessment
Attachment was added to capture clinical status for suspected outcome events 
and symptom assessment.
Attachment 5: INT-1 to INT-4/ 
Amendment Changes, and 
Attachment was added to the protocol. 
Attachment 6: Complete 
Amendment History of INT-5 
Inclusion and Exclusion 
Criteria, and Prohibitions and 
Restrictions for Data Collection 
Purposes
Attachment was added to the protocol.
Throughout the protocol
Minor grammatical, formatting, and spelling changes were made.
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Amendment INT-4 (19 January 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 it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is to provide further clarifications.  
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of study design and the correction to exclusionary medications.
Applicable Section(s)
Description of Change(s)
Time and Events Schedule, and 
Section 9.1.2. Screening Phase
Minor edits to footnotes for clarification. 
Section 4.2 Exclusion Criteria.
Exclusion criteria # 2.1 and #3.1 modified with correct references in parenthesis. 
Exclusion criteria #22.2.a and #22.2.b modified to specify correct exclusionary 
medications.
Section 4.3 Prohibitions and 
Restrictions
Prohibitions and Restrictions criteria #2 and 3 modified to specify correct 
exclusionary medications.
Amendment INT-3 (8 December 2014)
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 subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is to provide further clarifications 
in response to questions from regulatory agencies and investigator sites
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of study design, simplification of conduct, to enhance data collection, also to avoid 
scheduling difficulties, or subject population (in response to comments from sites in attendance at investigator 
meetings, health authority, site, or Ethics Committee queries), and congruent to the Statistical Analysis Plan.   
Synopsis Objective and 
Hypothesis: Primary Objective, 
Secondary Objectives, 
Exploratory Objectives, 
Hypothesis, Efficacy 
Evaluations/Outcomes; Section 
2.1. Exploratory Objectives; 
Section 2.2. Hypotheses; Section 
9.2. Efficacy Evaluations and 
Outcomes  
Increased the level of detail in the exploratory objectives. For symptomatic 
DVT, the additional descriptor "lower extremity" was added. For symptomatic 
PE, "non-fatal" was added in keeping with the SAP. For CV events, "fatal and 
non-fatal" was removed as the combination results simply in all CV events.
The paragraph “If a subject….drug treatment” was added to clarify that 
unblinding is unlikely to impact the care of the subjects.
The paragraph “Rivaroxaban will not be….benefit from study treatment” has 
been added as an explanation of whether or not study treatment will be provided 
after the subject completes participation in the study. 
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Applicable Section(s)
Description of Change(s)
Synopsis Overview of Study 
Design; Section 3. Study 
Design and Rationale
Synopsis Subject Population; 
Section 3.1. Overview of Study 
Design; 4.1 Inclusion Criteria
Re-worded subject population for better interpretation.
The term "hospital discharge" has been removed and replaced with “leaving the 
hospital”,
The phrase “new onset or exacerbation” has been added to reinforce that the 
reason for the hospitalization that qualifies a patient for inclusion is broadly 
defined.
The phrase “including spinal cord infarction” has been moved from its own 
inclusion criterion to be closer to the reason for hospitalization that it modifies.
The phrase, “placebo…hospital discharge” has been added to provide a rationale 
for selection of placebo as the comparator, with a more extensive explanation 
later in the protocol.
Time and Events Schedule
Minor edits, including addition of Discharge Destination to all visits, and change 
from +3d to +4d for the Day 45 visit.
Reformatted, added, and renamed protocol activity, eg, added LMWH/UFH use 
and index hospitalization and modified footnotes eg, collection of hemoglobin, , 
platelet count, vital signs clinical assessment requirement and criteria, and CrCl,
D-dimer, fasting and PK samples, and instructions regarding discontinuing for 
consistency with protocol body and eCRF. Deleted hematocrit, hemogram (CBC) 
and auto differentiation.  
Section 4.1 Inclusion Criteria.
Inclusion Criteria 1, 2, 3, 4, and 6 were modified and Inclusion Criterion 5 was 
deleted.
Specifically:
Inclusion Criterion #1 was divided into 3 sub-criteria, “index hospitalization” 
definition added to improve the clarity of counting the number of days, term 
“hospital discharge” has been removed and “the day the patient leaves the 
hospital” has been edited. 
Inclusion Criterion #2, the explanations in the footnotes of the risk score table 
were expanded with content of INT-2 Appendices, age modified from > to ≥60
and split into 2 sub-sections to enhance data collection, and guidelines for the 
definition of major surgery have been added.
Inclusion Criterion #3, term “post-discharge” has been removed as unnecessary.
Inclusion Criterion #4, concrete guidance added regarding thromboprophylaxis.
Inclusion Criterion #5 deleted and content now incorporated into inclusion 
criterion #1.
Inclusion Criterion #6 modified to exclude legally acceptable representatives 
from providing informed consent.
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Clinical Protocol RIVAROXDVT3002 – Amendment INT-7
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Status: Approved, 31 March 2017
Applicable Section(s)
Description of Change(s)
Section 4.2, Exclusion Criteria
Criteria 2, 3, 5, 5, 6, 9, 10, 11, 12, 
14, 15, 1822, 23, 24, 25, 26, 27, and 28 were modified. Criterion 31 was added.
Specifically:
Exclusion Criterion #2 and #3, added references to the guidelines for the 
definition of major surgery.
Exclusion Criterion #4 modified to allow for normalization of the INR during the 
index hospitalization.
Exclusion Criterion #5 modified to include information that was formerly 
provided in an appendix.
Exclusion Criterion #6 modified to provide guidance clarifying the meaning of 
“severe head trauma”.
Exclusion Criterion #9 modified to allow for normalization of or spurious platelet 
counts during the index hospitalization.
Exclusion Criterion #10 modified to clarify that non-melanoma skin cancer is not 
an exclusion criterion and that leuprolide acetate is not a prohibited medication.
Exclusion Criterion #11modified to specify the anticoagulants that are prohibited.
Exclusion Criterion #12, added unilateral below the knee amputation.
Exclusion Criterion #14 modified to include a reference to calculating the 
creatinine clearance.
Exclusion Criterion #15 modified to indicate that the degree of liver insufficiency 
which would result in exclusion is liver disease associated with a coagulopathy.
Exclusion Criterion #18 modified to allow the investigator to use discretion in 
determining the degree of alcohol abuse that would lead to exclusion from the 
study.
Exclusion Criterion #22 modified to include both inducers and inhibitors and the 
most up-to-date language.
Exclusion Criterion #23 modified to remove “systemic” as any fibrinolysis 
during the index hospitalization will result in exclusion, and that actual receipt of 
a fibrinolytic would result in exclusion.
Exclusion Criterion #24 divided into 2 sub-sections to allow for enhanced data 
collection and a note has been added to indicate that dipyridamole is allowed.
Exclusion Criterion #25 modified to reflect current standard language.
Exclusion Criterion #26, minor wording changes.
Exclusion Criterion #27, minor wording changes.
Exclusion Criterion #28 minor wording changes.
Exclusion Criterion #31added to reflect the usual exclusion criteria language for 
the drug under study.
Overview of Study Design, 
Section 3.1 Overview of Study, 
Section 4.1, Inclusion Criteria
Definition of index hospitalization has been added to clarify the way days are 
counted for the index hospitalization.  
Overview of Study Design, 
Section 3.1 Overview of Study 
Design, 9.1.3. Double-Blind 
Treatment Phase
The definition of “discharge” has been clarified further, to allow the sites more 
flexibility with the timing of randomization relative to hospital discharge. 
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Applicable Section(s)
Description of Change(s)
Section 1.1 Background, 
Sections 1.2 Overall Rationale 
for the Study, Section 3.1 
Overview of Study Design, 
Dosage and Administration, 
Efficacy Analyses, Section 3.2 
Blinding Control Study 
Phase/Periods Treatment 
Groups, 3.2 Dose Selection, 3.2 
Pharmacokinetics Analysis, 
Section 5 Treatment Allocation 
& Blinding, Section 6. Dosage 
and Administration, 
Attachment 1, Section 11.3 
Primary Efficacy Outcome
To provide clarity regarding stratum assignment for subjects with CrCl >30 and 
<49 mL/min was changed to CrCl >30 and <50 mL/min.  
Synopsis Choice of Safety 
Measures, Section 3.2 Study 
Design Rationale, Section 
12.3.1 All Adverse Events
Addition of acute coronary syndrome and transient ischemic attack as serious 
adverse events.
Section 3.2 Study Design 
Rationale
Provided rationale for placebo comparator selection.
Overview of Study Design, 
Section 3.1 Overview of Study 
Design, 6. Dosage and 
Administration
Reinforced that the first dose of study drug should be administered as soon after 
randomization as possible.
Diagram of study design updated to reflect changes.
Overview of Study Design, 
Section 3.1 Overview of Study 
Design, 4.1 Inclusion Criteria
Section 1.1 Background
Parenteral anticoagulation requirement (LMWH, UFH) and duration were 
specified.
Section 3.3.3 Clinical Events 
Committee
Events to be adjudicated were clarified.  
Section 4. Subject Population
Clarified time to screening subjects relative to “discharge from hospital” and to 
“index hospitalization”.
Section 4.1 Inclusion Criteria, 
16.2.3 Informed Consent, 
Section 16.2.4 Privacy of 
Personal Data
Deleted option for legally acceptable representative to sign the informed consent 
on behalf of the subject.
Section 4.3 Prohibitions and 
Restrictions
Revised section to match exclusion criteria and detailed concomitant therapy that 
should not be administered before or during study and clarified restrictions.
Section 5 Treatment Allocation 
and Blinding
Added statement for risk factor groups to allow for a heterogeneous population.
Paragraph was added to clarify that unblinding is unlikely to impact the care of 
the subject.
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Applicable Section(s)
Description of Change(s)
Synopsis Dosage and 
Administration, Section 6. 
Dosage and Administration
Added clarification regarding the chronic therapy with rivaroxaban.
Added comment about dosing in the event of a change in creatinine clearance.
Added instructions about timing of first dose of study drug administration.
Added paragraph about whether study drug will be provided after the subject 
completes study participation.
Section 9.1.2. Screening Phase
Clarification was added regarding when screening activities may begin.
Statement was added regarding local D-dimer laboratory collection.
Added the details on creatinine clearance calculations, and deleted from INT-2 
attachment.
Section 9.1.3. Double-Blind 
Treatment Phase
Added more reasons for unscheduled visits and timing and location of 
randomization have been simplified and broadened.
Section 9.1.3 Post-treatment 
Phase (Follow-Up)
Added paragraph about whether study treatment will be provided after the subject 
completes study participation.
Section 9.2.1. Efficacy 
Evaluations and Outcomes
Added further clarification to outcome event processing, and adding ACS and 
TIA to encourage the investigator that events that suggest the possibility of MI or 
stroke be sent for adjudication.
Added instructions about the handling of images for enhanced submitting CEC 
packages.
Section 9.2.2 Approach to the 
Subject with an Efficacy 
Outcome Event
New section added to provide guidance to treating physician for efficacy
outcomes events.
Section 9.3.1 Evaluations
Modified to include non-fasting status for PK sampling.
Section 9.5 Safety Evaluations 
and Outcomes: Clinical 
Laboratory Tests
Serum pregnancy test added as an option to match the Time And Events 
Schedule.
Section 9.5.2. Approach to the 
Subject with a Bleeding Event
New section added to provide guidance for serious bleeding events.
Synopsis, Dosage and 
Administration, Section 3.2 
Study Design, Section 10.2 
Discontinuation of Study 
Treatment, 10.2.1 Temporary 
Discontinuation of Study 
Treatment, 16.1 Ethical 
Aspects.  
Added further guidance on any condition that in the investigator’s judgment 
requires anticoagulation, thromboprophylaxis, or fibrinolysis.
Added instructions about possibility for restarting study drug in the event that a 
low platelet count is noted
Section 10.2.1. Temporary 
Discontinuation of Study 
Treatment
Added instructions about possibility for restarting study drug in the event that a 
low platelet count is noted.
Section 10.2. Discontinuation 
of Study Treatment
Added paragraph about management in the event that the subject develops a need 
for anticoagulation.
Section 10.2.2. Approach to 
Subjects with Dose Interruption
Moved section from previous INT-2 Attachment for increased accessibility of the 
information.
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Applicable Section(s)
Description of Change(s)
Section 10.2.3 Permanent 
Discontinuation of Study 
Treatment
Added an additional criterion for discontinuation of study treatment to allow for 
drops in creatinine clearance to below the level that resulted in exclusion from 
the study.
Section 12.3.1 All Adverse 
Events
Section was modified and for more clarity, with addition of ACS and Transient 
ischemic attack, and new sub-categories, ie, Serious Adverse Events, Non-
Serious Adverse Events, and Reporting Timelines and Processes. ACS and TIA 
events will be sent for adjudication.
Section 12.3.3 Pregnancy
Added clarifications regarding partner pregnancy and infant follow-up.
Section 16.1. Study-Specific 
Design Considerations
Added guidance regarding required use of parenteral or oral anticoagulation.
Section 17.4 Source 
Documentation
Race was removed as an item recorded directly into the eCRF.
Throughout the protocol
Minor editorial changes. 
Added “lower extremity” to symptomatic DVT, added “non-fatal” to 
symptomatic PE.
Attachments, 
Attachment 1, Efficacy 
Outcomes
Added Attachment 2, Event Supporting Documentation.
Moved INT-2 Attachments 1, 2, 3, and 4 to main body of protocol. 
For INT-3 Attachment 1, the definitions of prior INT-2 Attachment 5 were 
updated to match the CEC charter.
Rationale: Modified safety and exclusion measures to ensure that adverse events secondary to the study agent are 
captured correctly.
Section 3.2 Choice of Safety 
Measures
Included ACS and transient ischemic attack as measures of efficacy.
Section 12.3.1. All Adverse 
Event
Section updated to provide clarification and addition of ACS and TIA as events 
to be exempt from unblinding and expedited reporting.
Rationale: Clarifications added to ensure consistency (eg, with charter, USPI)
Section 3.3.3 Clinical Events 
Committee.
Added ‘other bleeding’ to list of events to be adjudicated by CEC.
Section 4.2 Exclusion Criteria
Revised criterion related to strong CYP3A4 inhibitors and inducers.
Amendment INT-2 (11 April 2014)
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 subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is to provide clear description on 
study procedures.
Applicable Section(s)
Description of Change(s)
Rationale:
Clarification on baseline values.   
Time and Events Schedule and 
9.1.2. Screening Phase
Clarifications that the latest value will be taken as baseline if there are multiple 
values during screening period and that complete blood count and CrCl must be 
performed/calculated within defined time window before hospital discharge.
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Applicable Section(s)
Description of Change(s)
Section 3.3. Committees
Deleted section based on decision not to form a Steering Committee.
Synopsis Section 11. Statistical 
Methods
Replaced analysis population with analysis set to comply with International 
Conference on Harmonisation [ICH] E9 guideline.
Section 11.3. Efficacy analyses
Changed the subgroup definition to include the agent used (LMWH or UFH).
Section 12.3.1. All Adverse 
Events
Deleted “e-CRF” to address an inconsistent description in the section.
Amendment INT-1 (14 March 2014)
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 subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is to provide clear descriptions 
and/or definitions on study endpoints, visits, procedures, and terms. 
Applicable Section(s)
Description of Change(s)
Rationale: To provide more clarity on the EOT and EOS clinic visits and total study duration.
Synopsis; 
3.1. Overview of Study Design
Deletion of both the 30-day time point follow-up contact, and phone call as 
follow-up option.
Time and Events Schedule 
Addition of “EOT” to Header column for Day 45 and “EOS” for Day 75.
7. Treatment Compliance
Additional clarification regarding treatment compliance on Day 45. 
10.1. Completion
Replacement of statements regarding completion of the study with clarifying 
information on expected total duration of 75 days after randomization.
16.2.3. Informed Consent
Deletion of redundant collection information for subjects unable to return for an 
EOT and follow-up (EOS) visit.
Rationale: To emphasize zero tolerance on missing endpoint data.
Throughout the
protocol
Where appropriate, addition of “and other outcomes” to “vital status.
Rationale: To provide more clarity, including the definition of terms.
Throughout the
protocol
“Observation period” was changed to “analysis phase”.
“Approximately” was added to 9,000 subjects.
The IDMC charter was deleted.
11.6. Safety Analyses
“Temperature” was deleted from the vital signs that will have descriptive statistics 
provided.
Rationale: To provide more clarity on potential IDMC recommendations.
Throughout the
protocol
Clarification that the IDMC can recommend to modify and terminate the study 
prematurely for safety. 
Rationale: To delete redundant and unclear expressions as any single missing dose will be captured in eCRF.
6. Dosage and Administration
Deletion of statement that an occasionally forgotten dose need not be recorded, 
and limitation of reporting to unintentional stopping of study drug for >7 days.
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Applicable Section(s)
Description of Change(s)
Rationale: To reflect that hematocrit values are not part of the ISTH definition for major bleeding.
9.5. Safety Evaluations and 
Outcomes
Deletion of stated reduced drop in hemoglobin based on hematocrit values.
Rationale: Clarification that VTE is also a condition that requires permanent anticoagulation.
10.2.2. Permanent 
Discontinuation of Study 
Treatment
Addition of “VTE” as an example for a condition which requires permanent 
anticoagulation that will result in permanently discontinuing a subject from study 
drug.
Rationale: For consistency with T&E.
17.4. Source Documentation
Deletion of heart rate as source data for the eCRF.
Rationale: Update of instructions in Attachment 6 for sample analysis at the bioanalytical lab chosen for the study.
Attachment 6: 
Pharmacokinetic Sample 
Collection and Handling
Addition of K2EDTA usage for the preparation of plasma PK samples for 
rivaroxaban.
Correction of blood sample centrifugation time to 1 hour.
Addition of statement regarding the Study Lab Manual for proper shipping 
instructions.
Rationale: To avoid miscommunication of the applicable procedures for labeling and shipment of PK samples.
Attachments 7 and 8
Deletion of both attachments.
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Attachment 6: Complete Amendment History of INT-6 Inclusion and Exclusion Criteria, and Prohibitions 
and Restrictions for Data Collection Purposes
4.1. Inclusion Criteria 
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1. Criterion Modified per Amendment INT-3
1.1. Criterion Modified per Amendment INT-5
1.2.  
a. Subject must be a man or woman, ≥40 years of age.
b. The duration of the index hospitalization must have been at least 3 and no more than 
10 consecutive days. 
The index hospitalization is defined as a hospitalization that ended on the day of or 
the day before randomization and is a continuous period of time at an acute care 
facility (including hospital, observation unit, ER and/or transferring facility; 
collectively referred to as "hospital"). The first day that the subject spends any part of 
the day in the hospital will be counted when determining the duration of the index 
hospitalization, but the day the patient leaves the hospital will not be counted.
c. The reason for the index hospitalization must have been a new diagnosis or 
exacerbation of 1 of the following medical conditions:

Heart Failure (HF) 
Subject must have a documented LVEF ≤45% within 1 year before 
randomization or during the index hospitalization. The ejection fraction may 
be determined by one of the following methods: echocardiogram, nuclear 
multi-gated acquisition (MUGA) scan, cardiac magnetic resonance imaging 
(MRI), cardiac computed tomography (CT) scan, or left ventriculography). If 
more than 1 value for LVEF is available, the most recent one should be used.

Acute respiratory insufficiency or acute exacerbation of COPD

Acute ischemic stroke (including spinal cord infarction if no evidence of 
intramedullary, subdural or epidural hemorrhage) 
If the subject received fibrinolysis as part of the initial treatment for stroke, 
fibrinolysis must have been administered at least 3 full days before the 
subject is randomized. These subjects must have had a CT/MRI scan at 
presentation and a repeat scan performed at least 24 hours after 
administration of fibrinolysis that documents the absence of hemorrhage. 
Subjects with hemorrhagic transformation of an ischemic infarct prior to 
randomization are not excluded unless there is evidence of parenchymal 
hemorrhage (types PH-1 and PH-2). All planned diagnostic tests for stroke 
evaluation must be completed before randomization. Brain imaging and 24 
hour cardiac monitoring must have been repeated if new symptoms of 
stroke/TIA occurred after the initial stroke evaluation, as does 24-hour 
cardiac monitoring if symptoms suggestive of AF occur.
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
Acute infectious disease

Inflammatory disease, including rheumatic disease
2. Criterion Modified per Amendment INT-3
2.1. Criterion Modified per Amendment INT-5
2.2. The subject must be at increased risk for VTE by the total modified IMPROVE VTE 
Risk Score (Table 1; modified from Spyropoulos37) assessed at screening and verified at 
randomization.
a. If the total modified IMPROVE VTE Risk Score is ≥4, the subject meets this 
inclusion criterion.
b. If the total modified IMPROVE VTE Risk Score is 2 or 3, a D-dimer >2X ULN must 
have been obtained after the beginning of the index hospitalization and before 
randomization 
Table 1:
Modified IMPROVE VTE Risk Score
VTE Risk Factor
VTE Risk Score
Previous VTE
3
Known thrombophiliaa
2
Current lower limb paralysis or paresisb
2
History of cancerc
2
ICU/CCU stay
1
Complete immobilizationd ≥ 1 day
1
Age ≥60 years
1
CCU= cardiac care unit; ICU= intensive care unit; VTE= venous 
thromboembolism.
a: A congenital or acquired condition leading to excess risk of thrombosis 
(eg, factor V Leiden, lupus anticoagulant, factor C or factor S deficiency).
b: Leg falls to bed by 5 seconds, but has some effort against gravity (taken 
from NIH stroke scale).25
c: Cancer (excluding non-melanoma skin cancer) present at any time in the 
last 5 years (cancer must be in remission to meet eligibility criteria)
d: Immobilization is being confined to bed or chair with or without bath-
room privileges.
3. Criterion Modified per Amendment INT-3
3.1. Life expectancy of at least 3 months. 
4. Criterion modified per Amendment INT-3
4.1. Criterion modified per Amendment INT-5
4.2. Criterion modified per Amendment INT-6
4.3. Prescribed thromboprophylaxis (according to ACCP guidelines)20 with UFH or 
LMWH (eg, dalteparin and enoxaparin) not exceeding 15000 U on any given day for 
UFH and not exceeding 5000 U on any given day for LMWH.
Table 2 below provides the minimum number of doses required by index hospitalization 
duration. For ischemic stroke with thrombolysis, do not use the index hospital duration 
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to determine the number of doses required. Instead, use the number of days the patient 
was in the hospital after the first day the patient was prescribed thromboprophylaxis.
Table 2: Minimum Number of Heparin Doses Required for 
Study Eligibility by Duration of Index Hospitalization
Index Hospitalization 
Duration (days)
LMWH doses 
required
UFH doses 
required
3
2
3
4
2
4
5
3
6
6
4
7
7
4
8
8
5
10
9
6
11
10
6
12
LMWH= low molecular weight heparin, UFH= unfractionated heparin.
Note: In the event that both LMWH and UFH are used during the index 
hospitalization, the number of doses of LMWH received should be 
doubled and added to the number of UFH doses received, and the UFH 
doses required column should be used to determine whether the 
requirement was met.
5. Criteria deleted per Amendment INT-3
6. Criterion modified per Amendment INT-3
6.1. Each subject must sign an informed consent form (ICF) 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.  
Bleeding Risk-Related Criteria
1. Criterion Modified per Amendment INT-5
1.1. Any bleeding (defined as bleeding requiring hospitalization, transfusion, surgical 
intervention, invasive procedures, occurring in a critical anatomical site, or causing 
disability) within 3 months prior to randomization or occurring during index 
hospitalization. 
2. Criterion Modified per Amendment INT-3
2.1. Criterion Modified per Amendment INT-4
2.2. Criterion Modified per Amendment INT-5
2.3. Major surgery, biopsy of a parenchymal organ, ophthalmic surgery (excluding 
cataract surgery), or serious trauma (including head trauma) within 4 weeks before 
randomization.
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Investigator discretion should be applied, but the following guidance may be considered 
for the purpose of this study.
Major surgery often involves opening 1 of the major body cavities the abdomen, the 
chest, or the skull and can stress vital organs. Major surgery usually is done using 
general anesthesia in a hospital operating room by a surgeon(s) and usually requires a 
stay of at least 1 night in the hospital after surgery.
In contrast, with minor surgery, major body cavities are not opened. Minor surgery can 
involve the use of local, regional, or general anesthesia and may be done in an 
emergency department, an ambulatory surgical center, or a doctor's office. Vital organs 
usually are not stressed, and surgery can be done by a single doctor, who may or may 
not be a surgeon. Usually, the person can return home on the same day that minor 
surgery is done.
Investigator discretion should be applied, but fracture or concussion would be 
considered serious head trauma, while external trauma without fracture or concussion 
could be considered for inclusion.
3. Criterion Modified per Amendment INT-3
3.1. Criterion Modified per Amendment INT-4
3.2. Criterion Modified per Amendment INT-5
3.3. Any planned major surgery (see exclusion criterion #2.3) or major invasive 
diagnostic procedure intended during the duration of the trial.  
4. Criterion Modified per Amendment INT-3
4.1. Subjects with any known coagulopathy or bleeding diathesis, or an INR >1.5 during 
the index hospitalization without a subsequent value (the last value before randomization) 
that is ≤1.5. 
5. Criterion Modified per Amendment INT-3
5.1. Criterion Modified per Amendment INT-5
5.2. A history of hemorrhagic stroke or any intracranial bleeding at any time in the past, 
evidence of primary intracranial hemorrhage on CT or magnetic resonance imaging scan 
of the brain, or clinical presentation consistent with intracranial hemorrhage. This applies 
as well to subjects hospitalized for ischemic stroke upon randomization.
Subjects with hemorrhagic transformation of an ischemic infarct prior to randomization 
are not excluded unless there is evidence of parenchymal hemorrhage (types PH-1 and 
PH-2): 
Hemorrhagic infarction type 1 (HI-1) is defined as small petechiae along the margins of 
the infarct, and HI type 2 (HI-2) is defined as more confluent petechiae within the 
infarcted area but without space-occupying effect. PH type 1 (PH-1) is defined as 
hematoma in ≤30% of the infarcted area with some slight space-occupying effect; PH 
type 2 (PH-2) is defined as dense hematoma >30% of the infarcted area with 
substantial space-occupying effect or as any hemorrhagic lesion outside the infarcted 
area (Berger, 20012). 
Hemorrhagic infarction type 1 and HI-2 subjects are NOT excluded from this study, but 
PH-1 and PH-2 subjects ARE excluded from this study. 
6. Criterion Modified per Amendment INT-3
6.1. Criterion deleted per Amendment INT-5
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7. Criterion Modified per Amendment INT-5
7.1. Subject has a history of or current intracranial neoplasm (benign or malignant), 
cerebral metastases, arteriovenous (AV) malformation, or aneurysm.
8. Active gastroduodenal ulcer, defined as diagnosed within 3 months or currently symptomatic 
or known AV malformations of the gastrointestinal tract.
9. Criterion Modified per Amendment INT-3
9.1. Screening platelet count <75 x 109 cells/L. 
Concomitant Conditions or Diseases
10. Criterion Modified per Amendment INT-3
10.1. Criterion Modified per Amendment INT-5
10.2. Active cancer (excluding non-melanoma skin cancer) defined as cancer not in 
remission or requiring active chemotherapy or adjunctive therapies such as 
immunotherapy or radiotherapy. Chronic hormonal therapy (eg, tamoxifen, anastrazole, 
leuprolide acetate) for cancer in remission is allowed.
11. Criterion Modified per Amendment INT-3
11.1. Any medical condition (eg, atrial fibrillation) that requires use of any parenteral or 
oral anticoagulant(s) (eg, warfarin sodium or vitamin K antagonists, Factor II or Xa 
inhibitors, fibrinolytics) concomitantly with study medication.
12. Criterion Modified per Amendment INT-3
12.1. Bilateral and unilateral above-knee lower extremity amputation.
13. Subject has known allergies, hypersensitivity, or intolerance to rivaroxaban or any of its 
excipients.
14. Criterion Modified per Amendment INT-3
14.1. Severe renal insufficiency (baseline CrCl <30 mL/min calculated using the 
Cockcroft-Gault 6 formula provided in Section 9.1.2).
15. Criterion Modified per Amendment INT-3
15.1. Known significant liver disease (eg, acute hepatitis, chronic active hepatitis, 
cirrhosis) which is associated with coagulopathy or moderate or severe hepatic 
impairment. 
16. Known HIV infection.
17. Sustained uncontrolled systolic blood pressure (BP) of ≥180 mmHg or diastolic BP of 
≥100 mmHg at randomization despite treatment.
18. Criterion Modified per Amendment INT-3
18.1. Current drug or alcohol abuse, based on investigator’s assessment.
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19. Criterion Modified per Amendment INT-5
19.1. Cardiogenic or septic shock with the need for vasopressor(s) or devices for blood 
pressure support during index hospitalization.
20. Presence of inferior vena caval filter
21. Severe bronchiectasis or cavitary tuberculosis or any other pulmonary condition 
(eg, vasculitis) at risk for major hemoptysis 
Drugs or Procedures 
22. Criterion Modified per Amendment INT-3
22.1. Criterion Modified per Amendment INT-4
22.2.
a. 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 is prohibited within 7 
days before randomization and during the study. 
b. 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. 
23. Criterion Modified per Amendment INT-3
23.1. Criterion Modified per Amendment INT-5
23.2. Received fibrinolysis during index hospitalization, unless received for ischemic 
stroke at least 3 full days before randomization.
24. Criterion Modified per Amendment INT-3
24.1. Criterion Modified per Amendment INT-5
24.2. Use of antiplatelet therapy during the index hospitalization, including:
a. ASA >162 mg/day 
b. Clopidogrel >75 mg/day or ticlopidine >250 mg twice daily
c. Clopidogrel at any dose in combination with omeperazole or esomeprazole
d. Dipyridamole >400 mg/day
e. Cilostazol >200 mg/day
f. Dual therapy with 2 or more antiplatelet agents (dipyridamole with ASA is permitted) 
g. Other P2Y12 receptor antagonists (eg, prasugrel, ticagrelor)
h. Thrombin-receptor antagonists (eg, vorapaxar)
25. Criterion Modified per Amendment INT-3
25.1. Childbearing potential without proper contraceptive measures, pregnancy or breast 
feeding.
a. Before randomization, a woman must be either:
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
Not of childbearing potential: premenarchal; postmenopausal (>45 years 
of age with amenorrhea for at least 12 months or any age with amenorrhea for at 
least 6 months and a serum follicle stimulating hormone (FSH) level >40 IU/L]); 
permanently 
sterilized 
(eg, 
tubal 
occlusion, 
hysterectomy, 
bilateral 
salpingectomy); or otherwise be incapable of pregnancy,

Of childbearing potential and practicing a highly effective method of birth 
control consistent with local regulations regarding the use of birth control 
methods for subjects participating in clinical studies: eg, established use of oral, 
injected or implanted hormonal methods of contraception; placement of an 
intrauterine device or intrauterine system; barrier methods: condom with 
spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male 
partner sterilization (the vasectomized partner should be the sole partner for that 
subject); true abstinence (when this is in line with the preferred and usual lifestyle 
of the subject). 
Note: If the childbearing potential changes after start of the study (eg, woman 
who is not heterosexually active becomes active, premenarchal woman 
experiences menarche) a woman must begin a highly effective method of birth 
control, as described above. The initiation of hormonal contraception for the 
purpose of the study is not recommended.
A woman of childbearing potential must have a negative serum (β human 
chorionic gonadotropin [β hCG]) or urine pregnancy test at screening.  
b. A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a double-barrier method of birth control eg, either 
condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository, and all men must also not donate sperm during the 
study, from the time of the first dose to the last dose of study drug.
26. Participation in another pharmacotherapeutic study or experimental medical device within 
30 days before the start of study treatment.
27. Criterion deleted per Amendment INT-3
28. Criterion Modified per Amendment INT-3
28.1. Criterion Modified per Amendment INT-5
28.2. Prescribed daily use of nonsteroidal anti-inflammatory agents (NSAIDs) during the 
index hospitalization  
29. Subject is unwilling or unable to complete all study visits as well as follow-up visit.
30. Subject is an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, as well 
as family members of the employees or the investigator.
31. Criterion deleted per Amendment INT-5
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's status changes (including laboratory results or receipt of additional medical records) 
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after screening but before randomization such that he or she no longer meets all eligibility 
criteria, the subject should not be randomized. But if the subject has been randomized, he/she 
should not be excluded from participation in the study and must be followed until the Day 75 
(±5d) visit. 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. If subjects require or 
take prohibited medications during the study as outlined below, they must either temporarily 
interrupt or permanently discontinue the study drug, as appropriate for the duration of the 
therapy with the prohibited medication:
1. Criterion Modified per Amendment INT-3
1.1. Criterion deleted per Amendment INT-5
2. Criterion Modified per Amendment INT-3
2.1. Criterion Modified per Amendment INT-4
2.2. 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 is prohibited within 
7 days before randomization and during the study. 
3. Criterion Modified per Amendment INT-3
3.1. Criterion Modified per Amendment INT-4
3.2. 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. 
4. Criterion Modified per Amendment INT-5
4.1. Anticoagulant (eg, warfarin sodium or other vitamin K antagonists, Factor II or Xa 
inhibitors) is prohibited as concomitant therapy during the study. Study drug should be 
discontinued in subjects who develop any condition which requires anticoagulation or 
thromboprophylaxis (eg, atrial fibrillation, VTE) that will extend beyond the end of the 
study treatment phase. 
5. Criterion deleted per Amendment INT-5
6. Criterion Modified per Amendment INT-5
6.1. Fibrinolytic therapy (see Section 10.2.1 for guidance) 
7. Criterion Modified per Amendment INT-5
7.1. Use of antiplatelet therapy, including:
a. ASA >162 mg/day 
b. Clopidogrel >75 mg/day or ticlopidine >250 mg twice daily
c. Clopidogrel at any dose in combination with omeprazole or esomeprazole
d. Dipyridamole >400 mg/day
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e. Cilostazol >200 mg/day
f. Dual therapy with 2 or more antiplatelet agents (dipyridamole with ASA is 
permitted) 
g. Other P2Y12 receptor antagonists (eg, prasugrel, ticagrelor)
h. Thrombin-receptor antagonists (eg, vorapaxar)
i. Prescribed daily non-steroidal anti-inflammatory drugs (temporary use as needed is 
allowed).
8. Criterion deleted per Amendment INT-5
9. Modification of an effective pre-existing therapy should not be made for the explicit purpose 
of entering a subject into the study.
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Elliot Barnathan,MD, FACC
Institution:
Janssen Research & Development 
Signature:
electronic signature appended at the end of the protocol
Date:
31 March 2017
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
NCT02111564


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Elliot Barnathan
31Mar2017, 15:46:53 PM, UTC
Document Approval
NCT02111564

SAP_001.pdf: 
1
Approved, Date: 4 April 2017
Janssen Research & Development *
Statistical Analysis Plan
Medically Ill Patient Assessment of Rivaroxaban Versus Placebo IN Reducing Post-
Discharge Venous Thrombo-Embolism Risk (MARINER)
Protocol RIVAROXDVT3002; Phase 3
JNJ-39039039; BAY 59-7939  (rivaroxaban)
Amendment 1
Status:
Approved
Date:
4 April 2017
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-82523399:5.0
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
LIST OF IN-TEXT TABLES.......................................................................................................................... 3
LIST OF IN-TEXT FIGURES ........................................................................................................................ 3
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 9
1.
INTRODUCTION................................................................................................................................ 10
1.1.
Trial Objectives .............................................................................................................................. 10
1.2.
Trial Design .................................................................................................................................... 12
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 14
1.4.
Sample Size Justification ............................................................................................................... 15
1.5.
Randomization and Blinding .......................................................................................................... 16
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 16
2.1.
Definition of Trial Dates.................................................................................................................. 16
2.2.
Pooling Algorithm........................................................................................................................... 18
2.3.
Analysis set and Analysis Phase ................................................................................................... 18
2.3.1.
Primary Efficacy Analysis Set..................................................................................................... 19
2.3.2.
Secondary Efficacy Analysis Set ................................................................................................ 19
2.3.3. 
Safety Analysis Set..................................................................................................................... 19
2.4.
Definition of Subgroups.................................................................................................................. 19
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 20
4.
SUBJECT INFORMATION................................................................................................................ 21
4.1.
Demographics and Baseline Characteristics ................................................................................. 21
4.2.
Disposition Information................................................................................................................... 22
4.3.
Treatment Compliance................................................................................................................... 23
4.4.
Extent of Exposure......................................................................................................................... 23
4.5.
Protocol Deviations ........................................................................................................................ 23
4.6.       Prior and Concomitant Medications............................................................................................... 24
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 Outcome.............................................................................................................. 24
5.2.1.
Definition..................................................................................................................................... 24
5.2.2.
Analysis Methods........................................................................................................................ 25
5.3.
Secondary Efficacy Outcomes....................................................................................................... 27
5.3.1.
Definition..................................................................................................................................... 27
5.3.2.
Analysis Methods........................................................................................................................ 27
5.4.
Multiple Testing Procedure ............................................................................................................ 27
5.5.
Other Efficacy Outcomes ............................................................................................................... 28
5.5.1.
Definition..................................................................................................................................... 28
5.5.2.
Analysis Methods........................................................................................................................ 29
6.
SAFETY............................................................................................................................................. 29
6.1.
Bleeding Events ............................................................................................................................. 29
6.2.
Adverse Events .............................................................................................................................. 30
6.3.
Clinical Laboratory Tests................................................................................................................ 30
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6.4.
Vital Signs and Physical Examination Findings ............................................................................. 30
7.
BENEFIT/RISK ASSESSMENT ........................................................................................................ 31
8.
PHARMACOKINETICS ..................................................................................................................... 33
9.
HEALTH ECONOMICS ..................................................................................................................... 34
REFERENCES............................................................................................................................................ 35
ATTACHMENTS......................................................................................................................................... 36
Attachment 1: 
Template of CONSORT Statement 2010 flow diagram ............................................. 36
LIST OF IN-TEXT TABLES
Table 1: 
Approximate Number of Subjects Needed to Observe 161 Events ......................................... 16
Table 2: 
Conditional Power (CP) Based on the Assumption of the Various Underlying RRRs in 
the Remaining Study................................................................................................................. 21
LIST OF IN-TEXT FIGURES
Figure 1: 
Schematic Overview of the Study Design by Country.............................................................. 14
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AMENDMENT HISTORY
SAP AMENDMENT 1
The original Statistical Analysis Plan (SAP) was finalized and issued on May 29th, 2014, based 
on the Clinical Protocol RIVAROXDVT3002 Amendment INT-2, finalized on April 11th, 2014.
This document is the SAP Amendment 1 that incorporates further changes and clarifications
based on the Protocol Amendments INT-3, INT-4, INT-5, INT-6, and the Protocol Amendment 
INT-7 that was finalized on March 31th, 2017.
Listed below are further changes and clarifications in SAP Amendment 1 (with major changes
underlined and bolded).
Topic or Section
Description of further changes or clarification in SAP Amendment 1
Section 1 
Introduction
Clarification on SAP Amendment 1: This SAP Amendment 1 is based on 
the Protocol RIVAROXDVT3002 Amendment INT-3, INT-4, INT-5, INT-6 
and the Protocol RIVAROXDVT3002 Amendment INT-7, finalized on 
March 31th, 2017. Unless the key analysis method for efficacy and/or safety 
needs to be updated, a SAP amendment will not take place, regardless of a 
protocol amendment.
Section 1.1 Trial 
Objectives
Clarification of terminology and added 1 endpoint in secondary efficacy 
endpoints and deleted 1 exploratory endpoint: 
Added: The composite of symptomatic VTE (lower extremity DVT and 
non-fatal PE), myocardial infarction (MI), non-hemorrhagic stroke and 
cardiovascular (CV) death (death due to a known CV cause and death in 
which a CV cause cannot be ruled out; by this definition, a VTE-related 
death is considered a CV death)
Deleted: The composite of the primary efficacy outcome and cardiovascular 
(CV) events (fatal and non-fatal myocardial infarction [MI] and non-
hemorrhagic stroke)
Section 1.2 Trial 
Design
Clarification on the randomization, the first dose date, visit schedules, 
interim analysis (IA) timing.
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Clarification: The total number of subjects that may be randomized 
was increased from approximately 9,000 to approximately 12,000 
subjects
Added a statement: The total number of VTE-related death events may also 
be taken into account when deciding to stop randomization.
Clarification: when approximately 50% of  subjects with an 
adjudicated primary efficacy outcome have been observed (about 50% 
of the expected total number of events based on the actual observed 
blinded pooled event rate even if this event rate is lower than the 
assumed rate)
Section 1.3 
Statistical 
Hypotheses for 
Trial Objective
Added 1 endpoint in secondary efficacy endpoints: The composite of 
symptomatic VTE (lower extremity DVT and non-fatal PE), myocardial 
infarction (MI), non-hemorrhagic stroke and cardiovascular (CV) death 
(death due to a known CV cause and death in which a CV cause cannot be 
ruled out; by this definition, a VTE-related death is considered a CV death)
Section 1.4 
Sample size 
Justification
Clarification: The total number of subjects that may be randomized 
was increased from approximately 9,000 to approximately 12,000 
subjects
Added a statement: The total number of VTE-related death events may also 
be taken into account when deciding to stop randomization
Added more cases in Table 1:Approximate Number of Subjects Needed to 
Observe 161 Events
Section 1.5 
Randomization 
and Blinding
Clarification: changed CrCl 30 to 49 to CrCl ≥30 and <50
Section 2.1 
Definition of Trial 
Dates
Changed ’the date of the last visit at which study drug is dispensed plus the 
number of pills in the drug bottle(s) dispensed at that visit’ to ‘the latest 
logically possible date on or after the first dose date’ 
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Section 2.3 
Analysis Sets and 
Analysis Phase
Changed ‘Major’ protocol deviation to ‘Key’ protocol deviation
Clarification: updated inclusion/exclusion numbers
Section 2.3.1 
Primary Efficacy 
Analysis Set
Added: Subjects will be analyzed according to the treatment randomized.
Section 2.4 
Definition of 
Subgroups
Clarification and added ‘and not limited to the following subgroups’, Use 
of US approved thromboprophylaxis (ie UFH, enoxaparin and dalteparin) vs 
other and Baseline D-dimer level (> 2xULN vs ≤ 2xULN)
Section 3 Interim 
Analysis and Data 
Monitoring 
Committee
Clarification: An IA for futility will be conducted when approximately 
50% of subjects with adjudicated primary efficacy outcome have been 
observed (about 50% of the expected total number of events based on 
the actual observed blinded pooled event rate even if this event rate is 
lower than the assumed rate) 
Observed primary efficacy outcome incidence rate by Day 45 in placebo at IA is 
too low that findings are not likely clinically meaningful
Section 4.1 
Demographics 
and Baseline 
Characteristics
Clarification: changed congestive heart failure to heart failure (HF) with 
reduced ejection fraction
Added ‘and not limited to the following demographics and baseline 
characteristics’, Use of US approved thromboprophylaxis (ie UFH, 
enoxaparin and dalteparin) vs other and Baseline D-dimer level (> 2xULN 
vs ≤ 2xULN)
Section 5.2.1 
Definition
Clarification: (death due to PE or death in which PE cannot be ruled out as 
the cause)
Section 5.2.2 
Analysis Methods
Added: The additional sensitivity analyses of the primary efficacy outcome 
may be necessary to exclude subjects (e.g., significant quality issues, Good 
Clinical Practice (GCP) violations, data integrity issues, regulatory agency 
commitment)
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Section 5.3.1 
Definition
Added: The composite of symptomatic VTE (lower extremity DVT and
non-fatal PE), myocardial infarction (MI), non-hemorrhagic stroke and 
cardiovascular (CV) death (death due to a known CV cause and death in 
which a CV cause cannot be ruled out; by this definition, a VTE-related 
death is considered a CV death)
Section 5.4 
Multiple Testing 
Procedure
Added: The composite of symptomatic VTE, myocardial infarction 
(MI), non-hemorrhagic stroke and cardiovascular (CV) death (death 
due to a known CV cause and death in which a CV cause cannot be 
ruled out; by this definition, a VTE-related death is considered a CV 
death)
Section 5.5.1 
Definition
Deleted: The composite of the primary efficacy outcome and cardiovascular 
(CV) events (fatal and non-fatal myocardial infarction [MI] and non-
hemorrhagic stroke)
Added: Fatal MI or  fatal stroke are defined as death occurred within 30 
days of the MI or stroke and death was directly related to the MI/stroke 
respectively
Section 6.1 
Added: bleeding by Bleeding Academic Research Consortium (BARC)
classification
Section7 Net 
Clinical Benefit
Clarification: (lower extremity DVT, non-fatal PE), (death due to PE or 
death in which PE cannot be ruled out as the cause)
Added 3 risk endpoints: Non-fatal, non-critical site bleeding requiring 
transfusion ≥2 units, Non-fatal, non-critical site Hgb drop ≥ 2 g/dL, and  
Non-fatal, non-critical site Hgb drop ≥ 2 g/dL not associated with 
transfusion ≥2 units   
Added: A bivariate analysis may be explored as post hoc analysis
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Section 8 
Pharmacokinetics
Added: Statistical summary of concentration (e.g. geometric mean, standard 
deviation, median, 5th and 95th percentile, range) by nominal sampling time 
window as specified in protocol will be provided. Statistical summary will 
also be stratified by CrCl groups. Results will be provided separately from 
the clinical study report
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ABBREVIATIONS
ACM
all-cause mortality
AE
adverse event
ATC
Anatomical Therapeutic Chemical
BARC
Bleeding Academic Research Consortium
CCU
cardiac care unit
CEC
Clinical Event Committee
CI
confidence interval
CMH
Cochran–Mantel–Haenszel
CrCl
creatinine clearance
DPS
DVT
Data Presentation Specifications
deep vein thrombosis
eCRF
electronic case report form
EC
Executive Committee
EOS
end of study
EOT
end of treatment
ER
emergency room
GCP
Good Clinical Practice
HF
heart failure
HR
hazard ratio
ICH
International Conference on Harmonization
ICU
intensive care unit
IDMC
Independent Data Monitoring Committee
IMPROVE
International Medical Prevention Registry On Venous Thromboembolism
ISTH
International Society on Thrombosis and Haemostasis
ITT
intention-to-treat
LMWH
low molecular weight heparin
LOS
length of stay
MedDRA
PE
Medical Dictionary for Regulatory Activities
pulmonary embolism
PK
pharmacokinetic(s)
PP
per-protocol
RRR
relative risk reduction
SAE
serious adverse event
SAP
Statistical Analysis Plan
TE
treatment-emergent
UFH
unfractioned heparin
VTE
venous thromboembolism
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1.
INTRODUCTION
This Statistical Analysis Plan (SAP) Amendment 1 specifies definitions of analysis sets, key 
derived variables, and statistical methods for analysis of efficacy and safety for the Phase 3 study
RIVAROXDVT3002 (also known as MARINER). This SAP Amendment 1 is based on the
Protocol RIVAROXDVT3002 Amendment INT-3, INT-4, INT-5, INT-6 and the Protocol 
RIVAROXDVT3002 Amendment INT-7, finalized on March 31th, 2017. Unless the key analysis 
method for efficacy and/or safety needs to be updated, a SAP amendment will not take place, 
regardless of a protocol amendment. Titles, mock-ups and programming instructions for all 
statistical outputs (tables, figures, and listings) are provided in a separate document entitled Data 
Presentation Specifications (DPS).
An Independent Data Monitoring Committee (IDMC) will monitor safety during this study,
review interim safety/efficacy results, and make a recommendation whether the study should be 
continued as planned, modified or terminated early for futility or safety. There is no plan to stop 
the study for the superiority of the primary efficacy outcome. Safety data to be reviewed by the 
IDMC periodically and additional details for the planned interim analysis are specified in the 
IDMC SAP, which is specifically prepared for IDMC reviews.
1.1.
Trial Objectives
The primary objective is to assess the efficacy and safety of rivaroxaban, compared with placebo
in the prevention of symptomatic venous thromboembolism [VTE] (lower extremity deep vein 
thrombosis [DVT] and non-fatal pulmonary embolism [PE]) and VTE-related death (death due to 
PE or death in which PE cannot be ruled out as the cause) post-hospital discharge in high-risk, 
medically ill patients.
The secondary objectives are to compare rivaroxaban with placebo in the following post-hospital 
discharge outcomes in high-risk, medically ill patients:

VTE-related death (death due to PE or death in which PE cannot be ruled out as the 
cause)

Symptomatic VTE (lower extremity DVT and non-fatal PE)

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE) and all-
cause mortality (ACM) 
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
The composite of symptomatic VTE (lower extremity DVT and non-fatal PE), 
myocardial infarction (MI), non-hemorrhagic stroke and cardiovascular (CV) death 
(death due to a known CV cause and death in which a CV cause cannot be ruled out; by 
this definition, a VTE-related death is considered a CV death)

All-cause mortality (ACM)
The exploratory objectives are to compare rivaroxaban with placebo, in the following post-
hospital discharge outcomes in high-risk, medically ill patients:

Symptomatic lower extremity DVT

Symptomatic non-fatal PE

Symptomatic upper extremity DVT

MI  

Non-hemorrhagic stroke

Re-hospitalization for symptomatic VTE (lower extremity DVT and non-fatal PE)
within 30 days after randomization
The pharmacokinetic (PK) objective is to assess the kinetics of rivaroxaban in high-risk, 
medically ill patients, to describe drug exposure based on creatinine clearance (CrCl). 
The Health Economics objective is to assess the following cost drivers, ie, re-hospitalization 
(including length of stay [LOS]), emergency room (ER) visits, intensive care unit (ICU) and 
cardiac care unit (CCU) stays, including LOS and subject discharge disposition between the 2 
treatment groups.
The safety objectives are to compare rivaroxaban with placebo in the following bleeding 
outcomes in high-risk, medically ill patients:

Major bleeding using validated International Society on Thrombosis and Haemostasis 
(ISTH) bleeding criteria.

Non-major clinically relevant bleeding 

Other bleeding 
Overall safety will also be assessed.
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1.2.
Trial Design
This is a multicenter, prospective, randomized, double-blind, placebo-controlled, event-driven 
study designed to evaluate rivaroxaban, compared with placebo, in the prevention of 
symptomatic VTE (lower extremity DVT and non-fatal PE) events and VTE-related deaths 
(death due to PE or death in which PE cannot be ruled out as the cause) for a period of 45 days 
post-hospital discharge. The first dose of study drug should be administered no later than the day 
after the subject leaves the hospital and as soon after randomization (Day 1) as possible. Subjects 
will be instructed to discontinue study drug after they take a dose on Day 45. The subject 
population comprises men and women age 40 and over who had been hospitalized for at least 3 
and no more than 10 consecutive days prior to randomization for a specific acute medical illness 
and have other risk factors for VTE.  Subjects who meet all of the inclusion and none of the 
exclusion criteria will be randomly assigned to receive rivaroxaban or placebo. Randomization 
should occur on the same day as or the day after the subject leaves the hospital, and may occur at 
the hospital, clinic, or other discharge destination. Subjects will be randomized by strata (by 
subjects with a CrCl ≥30 mL/min and <50 mL/min versus subjects with CrCl ≥50 mL/min, and 
by country) by an interactive web response system (IWRS). After randomization, subjects will 
receive double-blind treatment with rivaroxaban 10 mg (7.5 mg for subjects with a CrCl ≥30
mL/min and <50 mL/min) daily or matching placebo daily.
The targeted total number of primary efficacy outcome in this event-driven study is 161. It is 
estimated that a total of approximately 8,000 subjects will need to be randomized to either 
rivaroxaban or placebo in 1:1 ratio.  This estimate is based on an estimated placebo incidence 
rate of the primary efficacy outcome of 2.5%. In the event that the actual observed blinded 
pooled event rate is lower than the assumed rate, more subjects may be enrolled to accumulate 
additional outcome events. Randomization in this study may be stopped at approximately 12,000 
subjects for administrative considerations even if the targeted 161 events have not been observed 
by then. The total number of VTE-related death events may also be taken into account when 
deciding to stop randomization.
An interim analysis for futility will be conducted when approximately 50% of subjects with an 
adjudicated primary efficacy outcome have been observed (about 50% of the expected total 
number of events based on the actual observed blinded pooled event rate even if this event rate is 
lower than the assumed rate).
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Prior to randomization, all subjects must have received treatment during the index hospitalization
with LMWH or UFH. The study consists of a screening phase, a 45-day double-blind treatment 
phase, and a 30-day follow-up. The total duration for a subject who completes the study after 
randomization is expected to be 75 days.
If the subject permanently discontinues treatment before Day 45, he/she should be instructed to 
complete an unscheduled visit and the remaining scheduled visits, including the Day 7 and Day 
21 visits (if not yet completed) and the Day 45 (+4d) and Day 75 (±5d) visits
If a subject withdraws consent from the study or is lost to follow-up, his or her vital status and 
outcomes will be collected at the day 75 (±5d) visit either by telephone or in person, or if 
applicable, by a review of subject’s medical or public records unless this contact is not allowed 
by local regulations.  
For population PK analyses, based on the model performance and high variability of the PK
parameters observed in the MAGELLaN study, at the Day 7 visit 2 blood samples (at pre-dose; 
1-4 hours after study drug administration) and again at Day 21 visit (Visit 4) 2 blood samples (at 
3 to 7 and 7 to 12 hours after study drug administration) will be collected for each subject for 
about 600 subjects (300 rivaroxaban subjects [200 subjects in the 10 mg QD group and 100 
subjects in the 7.5 mg QD group] and 300 in the placebo group). The sparse blood samples for 
PK analyses will be collected in selected sites only.
An Executive Committee (EC), an Independent Data Monitoring Committee (IDMC) and a 
Clinical Event Committee (CEC) will be commissioned for this study.
The EC has overall responsibility for the design, conduct and reporting of the study. The EC will 
monitor overall safety during the study and will receive any recommendations from the IDMC 
regarding possible additional analyses or modifications to the study and decide whether to accept 
them. The EC will oversee the implementation of any modifications to the study. 
The IDMC will review unblinded safety data periodically to ensure the safety of study subjects. 
If necessary or requested by the IDMC, subject level unblinded data may be provided to the 
IDMC. In addition, the IDMC will review results of the planned interim analysis and make a 
recommendation whether the study should be terminated prematurely due to futility. Detailed 
stopping guidelines are specified in the section 3.
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The Clinical Event Committee (CEC) will adjudicate all suspected outcome events in a 
consistent and unbiased manner according to the definitions in the CEC charter while blinded to 
treatment assignment. 
All committees will be governed by separate charters.  
A diagram of the study design is provided below in Figure 1:
Figure 1: 
Schematic Overview of the Study Design by Country 
1.3.
Statistical Hypotheses for Trial Objectives
The primary statistical alternative hypothesis is that rivaroxaban is superior to placebo on the 
primary efficacy outcome, that is, time to event for the rivaroxaban group is stochastically later 
than that for the placebo group from randomization up to Day 45. More specifically, the survival 
function for the placebo group is lower than that for the rivaroxaban group.  The null hypothesis 
is the negation of the alternative hypothesis, that is, the survival function for the placebo group is 
not lower than that for the rivaroxaban group.  As a further illustration of the hypotheses, for the 
case where hazard functions are proportional, the above alternative hypothesis can be expressed 
as that the hazard ratio (HR) of rivaroxaban versus placebo is less than 1, and the null hypothesis 
is that the HR is at least 1.
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The secondary hypotheses are that rivaroxaban is superior to placebo in the prevention of 1) 
VTE-related death (death due to PE or death in which PE cannot be ruled out as the cause), 2) 
symptomatic VTE (lower extremity DVT and non-fatal PE), 3) the composite of symptomatic 
VTE and ACM, 4) the composite of symptomatic VTE (lower extremity DVT and non-fatal PE), 
MI, non-hemorrhagic stroke and CV death (death due to a known CV cause and death in which a 
CV cause cannot be ruled out; by this definition, a VTE-related death is considered a CV death)  
and 5) ACM alone.
1.4.
Sample Size Justification
This is an event driven study. The targeted total number of primary efficacy outcome is 161, 
based on the ITT analysis set and Up-to-Day-45 analysis phase.  If a subject has multiple events,
only the first is counted towards study size determination.
This targeted total number of events is determined using statistical software East 5.3 based on the 
primary efficacy analysis (defined later) and the following assumptions:

40% relative risk reduction (RRR) in the primary efficacy outcome based on the ITT 
analysis set and Up-to-Day-45 analysis phase (RRR is defined as 1 minus the hazard 
ratio (HR) of rivaroxaban versus placebo.)   

Power of 90% assuming the above RRR

Two-sided significance level of 0.05. 
To observe the targeted 161 events, it is estimated that a total of approximately 8,000 subjects 
will need to be randomized to either rivaroxaban or placebo in 1:1 ratio.  This estimate is based 
on an estimated placebo incidence rate of the primary efficacy outcome of 2.5%. In the event that 
the actual observed blinded pooled event rate is lower than the assumed rate, more subjects may 
be enrolled to accumulate additional outcome events. Randomization in this study may be 
stopped at approximately 12,000 subjects for administrative considerations even if the targeted 
161 events have not been observed by then. The total number of VTE-related death events may 
also be taken into account when deciding to stop randomization.
Table 1 below additionally shows the approximate numbers of randomized subjects needed to 
observe 161 events based on several other placebo incidence rates.
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Table 1: 
Approximate Number of Subjects Needed to Observe 161 Events
Placebo Incidence Rate
Number of Subjects*
3.0%
6,700
2.75%
7,300
2.5%
8,000
2.25%
9,000
2.0%
10,100
1.5%
13,400
1.25%
16,100
*calculated based on 40% RRR
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups based on a computer-generated randomization schedule prepared before 
the study under the supervision of the sponsor. The randomization will be balanced by using 
randomly permuted blocks and will be stratified by subjects with CrCl ≥30 and <50 mL/min 
versus subjects with CrCl ≥ 50 ml/min and by country.
2.
GENERAL ANALYSIS DEFINITIONS
Summaries by treatment group using appropriate descriptive statistics will be provided for all 
study variables including demographic and baseline characteristics. No imputation will be 
applied, unless specified otherwise in the SAP. Descriptive statistics such as mean, median, 
standard deviation, minimum, and maximum will be used to summarize continuous variables. 
Counts and percentages will be used to summarize categorical variables. Kaplan-Meier method 
will be used to summarize time-to-event variables. Graphical data displays may also be used to 
summarize the data.
Unless stated otherwise, subjects will be analyzed according to the treatment group they are 
assigned, irrespective of the actual treatment received.
Unless stated otherwise, all adjudicated efficacy and bleeding outcomes will be used in the 
analyses.
2.1.
Definition of Trial Dates
Trial reference start date: the date of randomization of the subject.
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Trial reference end date: the date of the last trial-related procedure for the subject and is defined 
as the maximum of the following dates:

Dates of all study-related visits (including scheduled or unscheduled visits)

Dates of all study-related procedures, findings and events, including, but not limited to, 
adverse events, concomitant medications, disposition, clinical laboratories, vital signs, 
death
First dose date: the date on which the first dose of study drug is taken by the subject. If missing 
or incomplete for a subject who takes study drug, the first dose date is set to the earliest logically 
possible date on or after randomization. More specifically, the first dose date is defined as the 
maximum of the randomization date and the first day of the month if only day is missing, and is 
defined as the randomization date if day and month are missing.
Last dose date: the date on which the last dose of study drug is taken by the subject. If missing or 
incomplete for a subject who takes study drug, the last dose date is in general set to the latest 
logically possible date on or after the first dose date.
To ensure consistency with other data of the trial, more specifically, the above date will be 
further 

capped by (that is, taking the minimum with) Day 45 date, death date, trial reference end 
date, and the upper bound of the logically possible range if partial date is available, and 

further bounded below by (that is, taking the maximum with) the (imputed) first dose 
date, any complete temporary drug stop and re-start date, or the lower bound of the 
logically possible range. 
Upper bound of the logically possible range is defined as the last day of the month if only day is 
missing and is defined as the last day of the following month after randomization if day and 
month are missing.  Lower bound of the logically possible range is defined the maximum of the 
randomization date and the first day of the month if only day is missing and is defined as the 
randomization date if day and month are missing.  
Last outcome-evaluation date: the date of last study visit (clinic/phone) while the subject is alive 
during which the outcome status is ascertained.
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2.2.
Pooling Algorithm
No pooling by country will be done for by-country analysis.
2.3.
Analysis set and Analysis Phase
Each analysis involves the following 2 aspects: 1) analysis set, specifying the subjects to be 
included; and 2) analysis phase, specifying the time window within which data will be included.  
Key analysis sets and analysis phases are defined below.
Analysis sets

Intention-to-Treat (ITT) (as termed Full Analysis Set in the International Conference on 
Harmonisation [ICH] E9 guideline): This analysis set consists of all randomized subjects 
who have a signed valid informed consent. 

Per-Protocol (PP): This analysis set is a subset of the ITT analysis set.
Subjects with the key protocol deviations will be excluded from the PP analysis set. The 
categories and terms of the key protocol deviations will include the following:
o
Did not meet the following inclusion or met the following exclusion criteria;
INT-2, INT-3, INT-4: subject with index hospitalization > 14 days, inclusion 
criteria 1, 2, 4, 6, exclusion criteria 10, 11, 14, 22, 24, 27 
INT-6, INT-7: inclusion criteria 1.2, 2.2, 4.3, 6.1, exclusion criteria 10.2, 11.1, 
14.1, 22.2, 24.2 without c
o
Did not take any assigned study drug or took wrong study drug
o
Did not discontinue study drug permanently according to the protocol (The subject 
becomes pregnant, develops any condition which requires permanent anticoagulation, has 
a fall in CrCl to below 20 mL/min during the study, or has a hemorrhagic stroke or 
intracranial bleeding)
o
Had been taking prohibited concomitant therapies as specified in the protocol
INT-2: 2, 3, 
INT-3, INT-4: 2, 3, 4, 6, 7, 8
INT-6, INT-7: 2.2, 3.2, 4.1, 7.1 without c and i
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
Safety: This analysis set is a subset of the ITT analysis set, consisting of subjects who receive 
at least one dose of study drug.
Analysis phases

Up-to-Day-45: This analysis phase includes all data from randomization to Day 45
(inclusive). 
For time to event analyses, subjects who do not have events to be analyzed on or before Day 45 
will be censored on Day 45 or the last outcome-evaluation date whichever occurs first.

On-Treatment: This analysis phase includes all data from randomization to 2 days after the 
last dose of the study drug (inclusive).  
For time to event analyses, subjects who do not have events to be analyzed during this phase will 
be censored on the last dose + 2 or the last outcome-evaluation date whichever occurs first.
2.3.1.
Primary Efficacy Analysis Set
The primary efficacy analysis set for all efficacy outcomes is the ITT analysis set. Subjects will 
be analyzed according to the treatment randomized.
2.3.2.
Secondary Efficacy Analysis Set
The PP analysis set will be used to assess the consistency with the primary efficacy analysis.
2.3.3. 
Safety Analysis Set
The primary safety analysis set for all safety outcomes is the safety analysis set.  Subjects will be 
analyzed according to the actual treatment received.  
2.4.
Definition of Subgroups
Homogeneity of treatment effects, both in HR and direction, will be assessed in the following 
subgroups classified at baseline and not limited to the following subgroups:

Age (< 65 vs ≥65; <75 vs ≥75 years)

Sex (men vs women)

Race (White vs others)

Race (White, Black, Asian, others)
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
Geographic region (North America, South America, Western Europe, Eastern Europe, 
other)

CrCl (≥30 to < 50, ≥50 to <80, ≥80 mL/min)

Body Mass Index (<25, ≥25 to <35, ≥35 kg/m2)

Admitting diagnosis (HF with reduced ejection fraction (LVEF ≤ 45%), acute respiratory 
insufficiency or acute exacerbation of COPD, acute ischemic stroke, acute infectious 
disease, and inflammatory diseases)

History of diabetes (yes vs no)

History of cancer (yes vs no)

Baseline D-dimer level (> 2xULN vs ≤ 2xULN)

Baseline aspirin use (yes vs no)

Baseline thienopyridine use (yes vs no)

Baseline proton pump inhibitor use (yes vs no)

Duration of index hospitalization (3 to 6, 7 to 10, > 10 days)

Duration of anticoagulation during index hospitalization (3 to 6, 7 to 10, > 10days)

LMWH or UFH during index hospitalization (LMWH vs UFH)

Use of US approved thromboprophylaxis (ie UFH, enoxaparin and dalteparin) vs other

Total modified IMPROVE risk factor score (2, 3, ≥4)
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
An interim analysis for futility will be conducted when approximately 50% of subjects with 
adjudicated primary efficacy outcome have been observed (about 50% of the expected total 
number of events based on the actual observed blinded pooled event rate even if this event rate is 
lower than the assumed rate).
There will be no alpha adjustment to the final analysis. The IDMC will review results of the 
planned interim analysis and make a recommendation whether the study should be continued as 
planned, modified, or terminated prematurely due to futility or safety.
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The study may be stopped early for futility when it would be unlikely to establish superiority on 
the primary efficacy outcome and/or a positive benefit over risk of rivaroxaban compared with 
placebo, if the study were to run to completion. The IDMC are encouraged to make a judgment 
for early stopping for futility when any one of 3 conditions below meets:

Estimated HR on the primary efficacy outcome is 1.0 or higher based on the interim 
analysis. (Refer to Table 2 below for the corresponding conditional power)

Observed primary efficacy outcome incidence rate by Day 45 in placebo at IA is too low 
that findings are not likely clinically meaningful

Observed incidence rate of major bleeding on-treatment in rivaroxaban at IA is high 
enough that the overall benefit-risk profile would be unlikely to be positive at the final 
analysis as discussed in section 7  
Table 2:
Conditional Power (CP) Based on the Assumption of the Various Underlying RRRs in the 
Remaining Study.
Estimated HR=1 at IA
90% CI: (0.69, 1.44)
70% CI: (0.79, 1.26)
50% CI: (0.86, 1.16)
RRR in the Remaining Study
CP
40%
32%
30%
12%
20%
4%
10%
1%
0%
0.3%
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Descriptive statistics by treatment group will be provided for the following baseline 
demographics and disease characteristics, and not limited to the following baseline demographics 
and disease characteristics:

Age 

Sex 

Race 

Geographic region 

CrCl 

Body Mass Index 
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
Admitting diagnosis (HF with reduced ejection fraction, acute respiratory insufficiency or 
acute exacerbation of COPD, acute ischemic stroke, acute infectious disease, and 
inflammatory diseases) 

History of diabetes 

History of cancer 

Baseline aspirin use 

Baseline thienopyridine use 

Baseline proton pump inhibitor use 

Duration of index hospitalization 

Duration of anticoagulation during index hospitalization 

LMWH or UFH during index hospitalization 

Use of US approved thromboprophylaxis (ie UFH, enoxaparin and dalteparin) vs other

Total modified IMPROVE risk factor score

Baseline D-dimer level (> 2xULN vs ≤ 2xULN)
4.2.
Disposition Information
A subject will be considered a completer of the double-blind treatment if his/her last dose is at 
least at Day 45, at death date, or at primary efficacy outcome date.  The number of non-
completers of the double-blinded treatment and the reason for discontinuation will be 
summarized by treatment group.  The distribution of time from the randomization to the last dose
date will be shown by Kaplan-Meier plot.
The primary objective of this study will be addressed by primary efficacy outcome up to Day 45. 
Therefore, a subject will be considered a non-completer of the study if the subject’s last 
outcome-evaluation date is before Day 45 date and the subject doesn’t have a primary efficacy 
outcome or death before Day 45. The number of non-completers of the study and the reason for 
discontinuation will be summarized by treatment group.  The distribution of time from the 
randomization to the last outcome-evaluation date will be shown by Kaplan-Meier plot.
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A diagram similar to CONSORT Statement 2010 Flow Diagram1 (Schulz et al, 2010) will be 
provided. A template of the diagram can be found in Attachment 1.
4.3.
Treatment Compliance
For each subject, the treatment compliance rate is estimated as follows
Compliance rate (%) = 100 * actual treatment duration / intended treatment duration
More specifically, the actual treatment duration will be calculated by minimum of [Day 45 date, 
last dose date, and the first primary efficacy outcome date] - first dose date + 1 - dose 
interruption days up to Day 45. The intended treatment duration will be calculated by minimum 
of [Day 45 date, death date, and the first primary efficacy outcome date] - first dose date + 1 -
dose interruption days up to Day 45 due to the reasons specified in protocol 10.2.1 (for example, 
hospitalization, bleeding, and other AEs).
Compliance rate will be summarized by treatment group. 
4.4.
Extent of Exposure
The number of subjects who take at least one dose of study drug will be provided for each 
treatment group.
Subject level duration of treatment exposure is defined as the duration between the first dose date
and last dose date. Note that temporary study drug interruptions are included in this definition.
Duration of treatment exposure will be summarized by treatment.
4.5.
Protocol Deviations
Protocol deviations will be summarized by treatment group. The categories of protocol 
deviations may include, but are not limited to, the following:

Did not meet the inclusion or exclusion criteria

Received wrong treatment or incorrect dose

Did not discontinue study drug permanently according to the protocol

Had been taking prohibited concomitant therapies as specified in the protocol
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4.6.      Prior and Concomitant Medications
Medication will be coded using the Anatomical Therapeutic Chemical (ATC) dictionary. The
prevalence of medication use by ATC term will be summarized by treatment group and by study
phase (prior to the first dose of study drug, during the study drug therapy period, and after last 
dose of study drug [post-treatment]).  A medication that starts prior to the first dose of study drug 
is considered as a prior medication.  A medication with a use period overlapping with the period 
between the first and last dose of study drug is considered as a concomitant medication.  A 
medication that starts after the day of the last dose of study drug is considered as a post-treatment 
medication.  Note that a medication use can be categorized into multiple study phases if its use 
spans into more than one study phase.  In such a case, the medication use will be included in 
more than one summary.
5.
EFFICACY
Unless otherwise stated, interim and final efficacy analyses will be based on CEC adjudicated 
events.
5.1.
Analysis Specifications
5.1.1.
Level of Significance
Unless otherwise specified, all statistical tests will be interpreted at a 2-sided nominal
significance level of 0.05 and all confidence intervals at a 2-sided level of 95%.
5.1.2.
Data Handling Rules
If the date of an outcome event is missing or partially missing, the earliest logically possible date 
after randomization will be used as the event date. The date of an outcome event is defined as the 
maximum of randomization and the first day of month if only day is missing and is defined as 
the first day of the following month after randomization if day and month are missing.
5.2.
Primary Efficacy Outcome
5.2.1.
Definition
The primary efficacy outcome is the composite of all symptomatic VTE events (lower extremity 
DVT, non-fatal PE) and VTE-related death (death due to PE or death in which PE cannot be 
ruled out as the cause).
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5.2.2.
Analysis Methods
The primary efficacy outcome will be analyzed based on the time from randomization to the first 
occurrence of symptomatic VTE and VTE-related death in the ITT analysis set and Up-to-Day-
45 analysis phase. The primary statistical hypothesis will be tested using Cox proportional 
hazards model, stratified by subjects with CrCl from ≥30 to <50 mL/min versus subjects with 
CrCl ≥50 mL/min, with the treatment (as randomized) as the only covariate. Subjects will be 
analyzed according to the treatment group to which they are randomized, regardless of actual 
treatment received.  As an operational arrangement, the 2-sided p-value will be reported, and if it 
is less than the 2-sided alpha of 0.05, then superiority of the study drug will be declared when the 
observed survival functions favor rivaroxaban. Note that the above testing procedure is 
equivalent to stratified logrank test2. The use of the Cox model format facilitates a consistent 
presentation of tests and CIs from analyses of efficacy and safety outcomes and from subgroup 
and sensitivity analyses. 
The point estimate and corresponding 95% CI for the HR (rivaroxaban to placebo) will be 
provided based on the Cox proportional hazards model. For the CIs, the plausibility of 
proportional hazards assumption will be assessed by visually comparing the plot of the log of 
cumulative hazard between treatments, and additionally checked by adding a treatment by 
logarithm-transformed time interaction into the Cox model.  If there is strong indication that the 
proportional hazards assumption is not valid, the 95% CI for relative risk of rivaroxaban versus 
placebo based on the incidence of the primary efficacy outcome from randomization up to 
Day 45 will be additionally provided, using the Cochran–Mantel–Haenszel (CMH) statistic with 
stratification by CrCl groups.
The cumulative event rate derived from the Kaplan-Meier method will be displayed graphically 
to evaluate the treatment effect over time. 
The following sensitivity analyses of the primary efficacy outcome will be conducted to assess 
the robustness of the conclusion from primary efficacy analysis: a) stratified Cox model as in the 
primary efficacy analysis but additionally stratified by region, b) stratified Cox model as in the 
primary efficacy analysis but based on the per-protocol analysis set and on-treatment analysis 
phase. The additional sensitivity analyses of the primary efficacy outcome may be necessary to 
exclude subjects (e.g., significant quality issues, GCP violations, data integrity issues, regulatory 
agency commitment). Additional post-hoc analyses may be conducted to investigate unexpected 
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results. Off-treatment primary efficacy outcome events, defined by the events from the 3 days 
after the last dose date, will be summarized by treatment groups.
Extensive efforts will be made to collect complete event and vital status data for all subjects 
randomized in this study.  The amount of unavoidable missing follow-up in this study with 
relatively short treatment duration of 45 days is not expected to influence the conclusion from 
the efficacy analyses.  To illustrate the extent of missingness for the primary efficacy outcome, 
the numbers of subjects with missing follow-up and the percentages of total missing follow-up 
time out of total supposed follow-up time will be summarized.  A non-completer of the study
will be considered as a missing follow-up subject. Missing follow-up time will be calculated by 
Day 45 date - last outcome-evaluation date for a missing follow-up subject. For a subject, 
supposed follow-up time will be calculated by minimum of [Day 45 date, death date, first 
primary efficacy event date] - randomization date +1. Sensitivity analyses will be conducted to 
estimate any additional events
from the rivaroxaban and placebo group during the missing 
follow-up time that are needed to overturn a superiority conclusion from the primary efficacy 
analysis. Similar sensitivity analyses may be conducted for each component of the primary 
efficacy outcome.
Homogeneity of treatment effects, both in HR and direction, in the subgroups defined in section 
2.4 will be explored via a test for treatment by subgroup interaction in the stratified Cox model
with treatment, subgroup and the treatment-by-subgroup interaction as the covariates, stratified 
by CrCl group (≥30 to <50,  ≥50 mL/min) (at a 2-sided significance level of 0.05). For CrCl 
subgroups, unstratified Cox model will be used. Lack of a significant interaction will imply that 
the results are consistent across subgroups. If a significant interaction is observed, the results will 
be examined to determine whether the interaction is qualitative in nature using Pan and Wolfe 
approach3 (1997). If the interaction is qualitative in nature, clinical explanations of the 
significant interaction will be explored. 
For each individual subgroup, the estimate and CI for HR will be constructed based on the 
stratified Cox model except for the CrCl subgroups. If the number of subjects with a primary 
efficacy outcome in a treatment-by-stratum cell in a subgroup is less than 5, interpretation of the 
CI needs to be done with caution.
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5.3.
Secondary Efficacy Outcomes
5.3.1.
Definition
The secondary efficacy outcomes are the following:

VTE-related death (death due to PE or death in which PE cannot be ruled out as the cause)

Symptomatic VTE (lower extremity DVT and non-fatal PE)

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE) and all-
cause mortality (ACM) 

The composite of symptomatic VTE (lower extremity DVT and non-fatal PE), 
myocardial infarction (MI), non-hemorrhagic stroke and cardiovascular (CV) death 
(death due to a known CV cause and death in which a CV cause cannot be ruled out; by 
this definition, a VTE-related death is considered a CV death)

All-cause mortality (ACM)
5.3.2.
Analysis Methods
Each secondary outcome will be analyzed based on time from randomization to the first
occurrence in the ITT analysis set, and the Up-to-Day-45 analysis phase. The same stratified Cox 
model as that for the primary efficacy outcome will be used.
Other analyses described above for the primary efficacy outcome may be performed for 
secondary efficacy outcomes.
5.4.
Multiple Testing Procedure
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 hierarchical order as listed in 5.3.1, each at 
alpha of 0.05 (2-sided). If an individual test during any step is not statistically significant, later 
tests will not be declared to be statistically significant.
The following is a diagram of the multiple testing procedure.
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      Diagram of Multiple Testing Procedure
5.5.
Other Efficacy Outcomes
5.5.1.
Definition
Exploratory efficacy outcomes are:

Symptomatic lower extremity DVT

Symptomatic non-fatal PE

Symptomatic upper extremity DVT

MI 

Non-hemorrhagic stroke

Re-hospitalization for symptomatic VTE (lower extremity DVT and non-fatal PE) within 
30 days after randomization
Fatal MI or fatal stroke are defined as death occurred within 30 days of the MI or stroke
and death was directly related to the MI or stroke respectively.
Superiority on Primary Efficacy Outcome
(Based on ITT analysis set and Up-to-Day-45 analysis phase)
Superiority on Symptomatic VTE 
(Based on ITT analysis set and Up-to-Day-45 analysis phase)
Superiority on VTE-related Death
(Based on ITT analysis set and Up-to-Day-45 analysis phase)
Superiority on ACM
(Based on ITT analysis set and Up-to-Day-45 analysis phase)
Superiority on the Composite of Symptomatic VTE and ACM
(Based on ITT analysis set and Up-to-Day-45 analysis phase)
Superiority on the Composite of Symptomatic VTE, MI, Non-hemorrhagic 
Stroke and CV Death (Based on ITT analysis set and Up-to-Day-45 analysis phase)
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5.5.2.
Analysis Methods
Each exploratory outcome will be summarized by treatment groups based on the ITT analysis set
and Up-to-Day-45 analysis phase. 
6.
SAFETY
Unless otherwise stated, all safety summaries and analyses will be performed based on the safety 
analysis set. Subjects will be analyzed according to study drug received.
6.1.
Bleeding Events
Unless otherwise stated, interim and final analyses of the principal safety outcome and non-
major clinically relevant bleeding will be based on CEC adjudicated events.
The principal safety outcome is ISTH major bleeding. Treatments will be compared using the 
same Cox proportional hazards model as that for the primary efficacy outcome described earlier.  
The analysis will be based on the safety analysis set and on-treatment analysis phase. Treatments 
will also be compared using Anderson-Gill model for the time to multiple occurrences of the 
principal safety outcome. The analysis will be based on the safety analysis set and on-treatment 
analysis phase.
The homogeneity of treatment effects on the first occurrence of the principal safety outcome 
across subgroups defined in section 2.4 will be examined (at a 2-sided significance level of 0.05)
via the test used for the primary efficacy outcome, based on the safety analysis set and on-
treatment analysis phase.
Off-treatment major bleeding events, defined by the events from the 3 days after the last dose 
date, will be summarized by treatment groups.
Other safety outcomes are non-major clinically relevant bleeding and other bleeding.
Non-major clinically relevant bleeding will be analyzed based on time from randomization to the 
first occurrence. The same analysis as that for the principal safety outcome will be used.
All bleeding, other bleeding, bleeding by BARC classification as well as sub-categories of major 
bleeding, including critical sites, will be also summarized by treatment groups.
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6.2.
Adverse Events
For the purposes of this study (and after discussion with appropriate regulatory agencies) a 
value-driven approach to safety data collection will be utilized. Certain non-serious adverse 
events will not be collected, while certain events will be collected as outcome and therefore not 
reported as serious adverse events. All data on safety and outcomes will be reviewed regularly by 
an unblinded IDMC. For AEs that are collected, the verbatim terms reported in the eCRF by 
investigators to identify adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).
Treatment-emergent adverse events (TEAE) are defined as those adverse events that start 
between the first study drug and the last study drug + 2 days. 
Summary of the following adverse events will be provided by treatment group:

Post-baseline (on or after the first study drug) adverse events

Treatment-emergent adverse events

Adverse events with onset > 2 days from the stop of study drug

Post-baseline serious adverse events

Treatment-emergent serious adverse events (TESAE)

Serious adverse events with onset > 2 days from the stop of study drug

Adverse events leading to permanent study drug discontinuation

Adverse events with outcome of death
In addition, incidences of some of the above adverse events by system organ class and 
dictionary-derived (preferred) term will be provided.
Additional summaries, listings, or subject narratives may be provided, as appropriate.
6.3.
Clinical Laboratory Tests
Because this study will not collect laboratory data routinely, laboratory data will not be
summarized. Local lab data may be discussed in subject narratives.
6.4.
Vital Signs and Physical Examination Findings
Descriptive statistics of pulse, blood pressure, and findings will be provided.
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7.
BENEFIT/RISK ASSESSMENT
This section describes several key elements for benefit-risk assessment, including 1) 
quantification method for benefits and risks, 2) efficacy and safety outcomes included in the 
evaluation, 3) analysis set and analysis phase, and 4) reporting format of the results.
These analyses are primarily intended to structure an integrated evaluation of the key benefits 
and risks in the study.  They are complementary to other efficacy, safety analyses described 
elsewhere in this document.  The overall benefit-risk profile of the study drug will be interpreted 
in consideration of the analyses described here and the totality of the data.
Quantification Methods for Measuring Benefits and Risks
As noted in previous sections, the treatment RRRs for efficacy and safety will be assessed using 
hazard ratios (Cox proportional hazards model).  Because of difference in background event rate 
across different types of outcome events, a preferred metric used to evaluate treatment difference 
for benefit-risk assessment purpose is risk difference.  For the current benefit-risk assessment, 
the treatment comparison of rivaroxaban vs. placebo will be evaluated based on the excess 
number of events between treatments, including events intended to be reduced (benefits) and 
events that may be caused (risks).  The excess number of events is defined as the difference in 
event rates times a hypothetical population size (e.g., 10,000 patients). The event rate will be 
calculated using the following approaches:

Event rate, expressed as the percentage of patients developing the event

Kaplan-Meier Product-Limit estimates of cumulative event rates for the duration of study
In addition, number-needed-to-treat to benefit (NNT) or harm (NNH) also will be used to 
quantify benefits and risks of the treatment, respectively, which are calculated as the reciprocal 
of the differences in corresponding event rates.
Efficacy and Safety Outcomes for Benefit-Risk Evaluation
The efficacy and safety outcomes that will be included in benefit-risk evaluation are generally 
consistent with those specified in the efficacy and safety sections of this document, with some 
minor modifications as noted below.  
A series of analyses will compare excess numbers of events for several pairs of key, mutually 
exclusive efficacy and safety endpoints:  
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
Composite of symptomatic VTE (lower extremity DVT, non-fatal PE) and VTE-related 
death (death due to PE or death in which PE cannot be ruled out as the cause) vs. ISTH 
major bleeding

Composite of non-fatal PE and VTE-related death vs. composite of critical site bleeding 
and fatal bleeding

VTE related death vs. fatal bleeding
To enable assessing the benefit-risk profile as a whole with mutually exclusive outcomes, we 
will also examine excess numbers of events for the following sets of outcomes:

Benefits
o
The composite of VTE-related death, fatal MI and fatal ischemic stroke
o
Non-fatal ischemic stroke
o
Non-fatal MI
o
Non-fatal symptomatic PE
o
Symptomatic lower extremity DVT

Harms
o
Fatal bleeding
o
Non-fatal critical site bleeding
o
Non-fatal, non-critical site bleeding requiring transfusion ≥2 units and non-fatal, 
non-critical site Hgb drop ≥ 2 g/dL 
o
Non-fatal, non-critical site bleeding requiring transfusion ≥2 units
o
Non-fatal, non-critical site Hgb drop ≥ 2 g/dL
o
Non-fatal, non-critical site Hgb drop ≥ 2 g/dL not associated with transfusion ≥2 
units
In addition, other major efficacy and safety outcomes identified in the protocol will also be 
evaluated in a similar fashion to support the overall benefit-risk evaluation.  
Analysis Set and Analysis Phase
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The primary analysis for benefit-risk evaluation will be based on the ITT analysis set and the Up-
to-Day-45 analysis phase.  However, additional analyses using analysis sets defined by other 
subject analysis sets and/or analysis phases as defined in the protocol or in this SAP may be 
performed as supportive analyses.
The benefit-risk analyses are not intended for hypothesis testing.  Therefore, no multiplicity 
adjustment will be applied.  When 95% CIs for point estimates of the excess number of events 
are provided as appropriate, nominal statistical significance at the alpha level of 0.05 (2-sided) 
will be declared if the confidence interval excludes zero.
The benefit-risk assessment will also be explored for the subgroups specified in Section 2.4.
A bi-variate analysis may be explored as post hoc analysis.
Reporting Format of the Results
To facilitate the comparison and interpretation of the results, data will be presented in one of the 
following formats as appropriate:

Table format showing the between-treatment differences in benefits and risks (e.g., 
excess number of events and NNT or NNH)

Kaplan-Meier plots depicting between-treatment differences in benefits and risks over 
time

Forest plots for comparing key benefits and risks, as well as other key efficacy and safety 
outcome measures
8.
PHARMACOKINETICS
Statistical summary of concentration (e.g. geometric mean, standard deviation, median, 5th and 
95th percentile, range) by nominal sampling time window as specified in protocol will be 
provided. Statistical summary will also be stratified by CrCl groups. 
The population PK analysis will be done to predict the overall exposure of rivaroxaban and 
estimate the PK model parameters for medically ill patients and to describe the effect of dosing 
modification on exposure for subjects with CrCl between ≥30 and <50 mL/min.
Results will be provided separately from the clinical study report.
Separate analysis plan document will be provided.
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9.
HEALTH ECONOMICS
For medical resource utilization and health economics, exploratory outcomes include re-
hospitalization (including LOS), ER visits, ICU and CCU stays, including LOS and subject 
discharge destination (after re-hospitalization).
Each exploratory outcome will be descriptively summarized by treatment group.
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REFERENCES
1.
Schulz KF, Altman DG, Moher D, for the CONSORT Group (2010). CONSORT 2010 Statement: updated 
guidelines for reporting parallel group randomised trials. BMJ: 340:c332
(http://www.bmj.com/content/340/bmj.c332).
2.
Therneau, Terry M. and Patricia M. Grambsch (2000). Modeling Survival Data: Extending the Cox Model. 
Statistics for Biology and Health. Springer, New York. 
3.
Guohua Pan and Douglas A. Wolfe (1997). Test for Qualitative Interaction of Clinical Significance. Statistics 
in Medicine, Vol. 16, 1645-1652.
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ATTACHMENTS
Attachment 1: Template of CONSORT Statement 2010 flow diagram
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