Clinical trial NCT04508023
Conditions: Coronavirus Disease 2019 (COVID-19)
Sponsor: Janssen Research & Development, LLC
Start date: 2020-08-13; Completion date: 2022-06-01
Enrollment: 1284 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate whether rivaroxaban reduces the risk of a composite endpoint of major venous and arterial thrombotic events, all-cause hospitalization, and all-cause mortality compared with placebo in outpatients with acute, symptomatic Coronavirus Disease 2019 (COVID-19) Infection.

Detailed description:

Arms: arm 1: Participants will receive rivaroxaban 10 milligram (mg) tablet orally once daily for 35 Days along with standard of care treatment (SOC). arm 2: Participants will receive matching placebo tablet orally once daily for 35 Days along with SOC.
Interventions: intervention 1: Rivaroxaban intervention 2: Placebo intervention 3: Standard of Care (SOC)
Intervention descriptions: intervention 1: Participants will receive rivaroxaban 10 mg tablet orally once daily. intervention 2: Participants will receive matching placebo tablet orally once daily. intervention 3: SOC treatment will be determined by the investigator based on local practice and consists of supportive care.

Protocol documents:
Prot_002.pdf: 
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Status: Approved,  Date: 04 June 2020
Janssen Research & Development *
Clinical Protocol
Protocol Title
A multicenter, randomized, placebo-controlled, pragmatic Phase 3 study investigating the 
efficacy and safety of rivaroxaban to reduce the risk of major venous and arterial 
thrombotic events, hospitalization and death in medically ill outpatients with acute, 
symptomatic COVID-19 infection
PREVENT-HD
Protocol 39039039DVT3004; Phase 3
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 Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; 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 7 indications.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Status:
Approved  
Date:
04 June 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-RIM-60017, 1.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04508023


JNJ-39039039; BAY 59-7939 (rivaroxaban)
Clinical Protocol 39039039DVT3004
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Status: Approved,  Date: 04 June 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 4
1.
PROTOCOL SUMMARY ..................................................................................................................... 5
1.1.
Synopsis........................................................................................................................................... 5
1.2.
Schema .......................................................................................................................................... 15
1.3.
Schedule of Activities (SoA)........................................................................................................... 16
2.
INTRODUCTION................................................................................................................................ 20
2.1.
Study Rationale.............................................................................................................................. 20
2.2.
Background .................................................................................................................................... 21
2.3.
Dose Rationale............................................................................................................................... 23
2.4.
Benefit-Risk Assessment ............................................................................................................... 23
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 24
4.
STUDY DESIGN ................................................................................................................................ 26
4.1.
Overall Design................................................................................................................................ 26
4.2.
Scientific Rationale for Study Design............................................................................................. 28
4.2.1.
Study-Specific Ethical Design Considerations ...........................................................................29
4.3.
Justification for Dose...................................................................................................................... 30
4.4.
End of Study Definition................................................................................................................... 30
5.
STUDY POPULATION ...................................................................................................................... 31
5.1.
Inclusion Criteria ............................................................................................................................ 31
5.2.
Exclusion Criteria ........................................................................................................................... 32
5.3.
Lifestyle Considerations................................................................................................................. 33
5.4.
Screen Failures .............................................................................................................................. 34
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 34
6.1.
Study Interventions Administered .................................................................................................. 34
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 35
6.3.
Measures to Minimize Bias: Randomization and Blinding.............................................................36
6.4.
Study Intervention Compliance...................................................................................................... 37
6.5.
Continued Access to Study Intervention After the End of the Study ............................................. 37
6.6.
Treatment of Overdose .................................................................................................................. 37
6.7.
Concomitant Therapy..................................................................................................................... 37
6.7.1.
Rescue Medication ..................................................................................................................... 40
6.7.2.
Approach to the Subject with a Bleeding Event .........................................................................40
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ...............................................................................................41
7.1.
Discontinuation of Study Intervention ............................................................................................ 41
7.1.1.
Temporary Discontinuation......................................................................................................... 41
7.2.
Participant Withdrawal From the Study.......................................................................................... 42
7.3.
Lost-to-Follow up............................................................................................................................ 43
8.
STUDY ASSESSMENTS AND PROCEDURES ...............................................................................43
8.1.
Efficacy Assessments .................................................................................................................... 44
8.2.
Safety Assessments....................................................................................................................... 45
8.2.1.
Physical Examinations................................................................................................................ 46
8.2.2.
Pregnancy Testing...................................................................................................................... 46
8.3.
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 46
8.3.1.
Time Period for Collecting Adverse Event and Serious Adverse Event Information.................. 47
8.3.2.
Pregnancy................................................................................................................................... 48


JNJ-39039039; BAY 59-7939 (rivaroxaban)
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8.3.3.
Disease-related Events and Disease-related Outcomes Not Qualifying as Adverse 
Events or Serious Adverse Events .............................................................................................49
8.4.
Medical Resource Utilization and Health Economics .................................................................... 49
9.
STATISTICAL CONSIDERATIONS..................................................................................................50
9.1.
Statistical Hypotheses.................................................................................................................... 50
9.2.
Sample Size Determination ........................................................................................................... 50
9.3.
Populations for Analysis Sets ........................................................................................................ 51
9.4.
Statistical Analyses ........................................................................................................................ 51
9.4.1.
General Considerations.............................................................................................................. 51
9.4.2.
Primary Endpoint(s).................................................................................................................... 52
9.4.3.
Secondary Endpoint(s) ............................................................................................................... 53
9.4.4.
Tertiary/Exploratory Endpoint(s)................................................................................................. 54
9.4.5.
Safety Analyses .......................................................................................................................... 54
9.4.6.
Other Analyses ........................................................................................................................... 54
9.5.
Interim Analysis.............................................................................................................................. 55
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 56
10.1.
Appendix 1: Abbreviations and Definitions .................................................................................... 57
10.2.
Appendix 2: World Health Organization Research and Development Blueprint: Novel 
Coronavirus Scale for Clinical Improvement (Draft from WHO 2020) ........................................... 59
10.3.
Appendix 3: Endpoint Definitions ................................................................................................... 60
10.4.
Appendix 4: Nonmajor Clinically Relevant Bleeding Event Criteria............................................... 68
10.5.
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations......................................... 69
10.5.1.
Regulatory and Ethical Considerations ...................................................................................... 69
10.5.2.
Financial Disclosure.................................................................................................................... 72
10.5.3.
Informed Consent (Remote eConsent) Process ........................................................................ 72
10.5.4.
Data Protection ........................................................................................................................... 73
10.5.5.
Committees Structure................................................................................................................. 74
10.5.6.
Publication Policy/Dissemination of Clinical Study Data ............................................................74
10.5.7.
Data Quality Assurance.............................................................................................................. 75
10.5.8.
Case Report Form Completion................................................................................................... 76
10.5.9.
Source Documents ..................................................................................................................... 76
10.5.10.
Monitoring ................................................................................................................................... 77
10.5.11.
On-Site Audits............................................................................................................................. 77
10.5.12.
Record Retention........................................................................................................................ 78
10.5.13.
Study and Site Start and Closure ............................................................................................... 78
10.6.
Appendix 6: Adverse Events, Serious Adverse Events, Product Quality Complaints, and 
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting................................................................................................................................. 80
10.6.1.
Adverse Event Definitions and Classifications ...........................................................................80
10.6.2.
Attribution Definitions.................................................................................................................. 81
10.6.3.
Severity Criteria .......................................................................................................................... 81
10.6.4.
Procedures ................................................................................................................................. 82
10.6.5.
Product Quality Complaint Handling........................................................................................... 82
10.6.6.
Contacting Sponsor Regarding Safety, Including Product Quality............................................. 83
10.7.
Appendix 7: Contraceptive and Barrier Guidance .........................................................................84
11.
REFERENCES................................................................................................................................... 87
INVESTIGATOR AGREEMENT ................................................................................................................. 89


JNJ-39039039; BAY 59-7939 (rivaroxaban)
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Status: Approved,  Date: 04 June 2020
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Interactions of rivaroxaban with COVID-19 therapies .............................................................. 38
Table 2:
Reporting of Serious Unexpected and Related Events (Unless Otherwise Requested 
by Health Authorities or Ethics Committees) ............................................................................48
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 15


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Status: Approved,  Date: 04 June 2020
1.
PROTOCOL SUMMARY
1.1.
Synopsis
A multicenter, randomized, placebo-controlled, pragmatic Phase 3 study investigating the efficacy and 
safety of rivaroxaban to reduce the risk of major venous and arterial thrombotic events, hospitalization and 
death in medically ill outpatients with acute, symptomatic COVID-19 infection
Rivaroxaban is an oral, direct acting, Factor Xa (FXa) inhibitor anticoagulant that inhibits thrombus 
generation and thrombus formation. Rivaroxaban has been under development for the treatment of multiple 
thrombosis-mediated conditions. Rivaroxaban is marketed under the trade name XARELTO® and is 
approved for multiple indications worldwide. The clinical development program for rivaroxaban is 
extensive. Almost 200,000 participants have been studied from Phase 1 through multiple large Phase 4 
studies as of 15 September 2019, covering several indications and potential indications in the overall 
clinical development program, including 115,000 participants who received rivaroxaban. For the most 
comprehensive nonclinical and clinical information regarding rivaroxaban, refer to the latest version of the 
Investigator's Brochure (IB) for rivaroxaban.
OBJECTIVES AND ENDPOINTS
Objectives
Endpointsa
Primary (Intention-to-Treat [ITT] Population)
The primary objective will be to evaluate whether 
rivaroxaban reduces the risk of a composite 
endpoint of major venous and arterial thrombotic 
events, all-cause hospitalization, and all-cause 
mortality compared with placebo in outpatients 
with acute, symptomatic COVID-19 infection
The primary efficacy outcome variable will be the 
time to first occurrence of a composite endpoint of 
symptomatic venous thromboembolism (VTE), 
myocardial infarction (MI), ischemic stroke, acute 
limb 
ischemia, 
noncentral 
nervous 
system 
(non-CNS)
systemic 
embolization, 
all-cause 
hospitalization, and all-cause mortality up to 
Day 35
Secondary (ITT Population)
To evaluate whether rivaroxaban reduces the risk 
of all symptomatic VTE, major arterial thrombotic 
events (MI, ischemic stroke, acute limb ischemia, 
non-CNS systemic embolization) and all-cause 
mortality in outpatients with acute, symptomatic
COVID-19 infection
Time to first occurrence of a composite endpoint of 
symptomatic VTE, MI, ischemic stroke, acute limb 
ischemia, non-CNS systemic embolization, and all-
cause mortality up to Day 35
To evaluate whether rivaroxaban reduces all-cause 
hospitalization
Time 
to 
first 
occurrence 
of 
all-cause
hospitalization up to Day 35
To evaluate whether rivaroxaban reduces the risk 
of symptomatic VTE
Time to first occurrence of symptomatic VTE up to 
Day 35
To evaluate whether rivaroxaban reduces the need 
for emergency room (ER) visits
Time to first occurrence of an ER visit up to Day 35


JNJ-39039039; BAY 59-7939 (rivaroxaban)
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Status: Approved,  Date: 04 June 2020
Objectives
Endpointsa
To evaluate whether rivaroxaban reduces the risk 
of venous and arterial thrombotic events and all-
cause hospitalization
Time to first occurrence of symptomatic VTE, MI, 
ischemic stroke, acute limb ischemia, non-CNS 
systemic 
embolization, 
and 
all-cause 
hospitalization up to Day 35
To evaluate whether rivaroxaban reduces the 
percentage of participants who are hospitalized or 
dead on Day 35
Incidence of participants who are hospitalized or 
dead from any cause on Day 35
To evaluate whether rivaroxaban reduces all-cause 
mortality up to Day 35
Time to all-cause mortality up to Day 35
Safety Endpoints (Safety Population)
To evaluate whether rivaroxaban is associated with 
an increase in critical site and fatal bleeding
Time to first occurrence of International Society on 
Thrombosis and Hemostasis (ISTH) critical site 
and fatal bleeding on treatment (+2 days)
To evaluate whether rivaroxaban is associated with 
an increase in major bleeding
Time to first occurrence of ISTH major bleeding on 
treatment (+2 days)
To evaluate whether rivaroxaban is associated with 
an increase in nonmajor clinically relevant 
bleeding
Time to first occurrence of nonmajor clinically 
relevant bleeding on treatment (+2 days)
Tertiary/Exploratory (ITT Population)
To evaluate whether rivaroxaban improves 
participant status (eg, prevents worsening of World 
Health 
Organization 
[WHO] 
Research 
and 
Development 
[R&D] 
Blueprint: 
Novel 
Coronavirus Scale for Clinical Improvement) over 
time
WHO R&D Blueprint: Novel Coronavirus Scale 
for Clinical Improvement over time
To evaluate if rivaroxaban reduces individual 
component events of the primary efficacy endpoint
Time to first occurrence of a component event of 
the primary efficacy endpoint (MI, ischemic 
stroke, acute limb ischemia, and non-CNS 
systemic embolization) up to Day 35
To evaluate the ability of rivaroxaban to prevent 
the decline in oxygenation at rest or with 
ambulation
!
The incidence of participants achieving an 
oxygen saturation (O2sat) below 92% on room 
air at rest or with ambulation up to Day 35
!
The incidence of participants achieving an 
O2sat below 88% on room air at rest or with 
ambulation up to Day 35
To evaluate whether rivaroxaban can reduce the 
need for supplemental oxygen
The incidence of participants requiring
supplemental oxygen up to Day 35


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Status: Approved,  Date: 04 June 2020
Objectives
Endpointsa
To evaluate whether rivaroxaban can prevent the 
occurrence of severe disease in hospital or death as 
defined by WHO scale scores of 5, 6, 7, or 8
Time to first occurrence of the use of non-invasive 
ventilation or high-flow oxygen (WHO 5), 
Intubation and mechanical ventilation (WHO 6), or 
ventilation 
and 
additional 
organ 
support 
(vasopressors, renal replacement therapy [RRT], 
extracorporeal membrane oxygenation [ECMO]; 
WHO 7) or all-cause mortality (WHO 8) up to 
Day 35
To evaluate whether rivaroxaban can prevent the 
occurrence of acute renal failure
The incidence of participants requiring dialysis or 
having an estimated glomerular filtration rate 
(eGFR) <15 mL/min/1.73 m2 on 2 measurements 
more than 24 hours apart up to Day 35
To evaluate whether rivaroxaban can prevent the 
occurrence 
of 
disseminated 
intravascular 
coagulation (DIC)
Time to first occurrence of DIC up to Day 35
To evaluate whether rivaroxaban can prevent the 
occurrence of acute respiratory distress syndrome 
(ARDS)
Time to first occurrence of ARDS up to Day 35
To evaluate whether rivaroxaban can prevent the 
occurrence of COVID digit
The incidence of occurrence of COVID digit up to 
Day 35
Collect medical resource utilization (MRU) data
MRU data over time
Benefit-Risk
To evaluate the benefit-risk profile of rivaroxaban 
by evaluating the risk differences for key efficacy 
and safety endpoints through Day 35 
Evaluate the risk differences for the composite and 
components of the primary efficacy outcome 
compared with fatal and critical site bleeding 
through Day 35 
a
Study endpoints will be assessed and reported by a qualified investigator according to protocol-specified 
definitions.
Overall safety will be assessed.
Hypotheses
The primary hypothesis of this study is that rivaroxaban is superior to placebo in the prevention of major 
venous and arterial thrombotic events, hospitalization, and death in outpatients with acute, symptomatic
COVID-19 infection during the treatment period (Day 35). The secondary hypotheses are that rivaroxaban 
is superior to placebo in the prevention of: any thrombotic outcome (symptomatic VTE, MI, ischemic 
stroke, acute limb ischemia, and non-CNS systemic embolization) and all-cause mortality, all-cause
hospitalization, symptomatic VTE, ER visits, any thrombotic outcome and all-cause hospitalization, 
hospitalization or death at Day 35, and all-cause mortality.
OVERALL DESIGN
This is a randomized, multicenter, placebo-controlled, pragmatic, event-driven Phase 3 study of 
rivaroxaban (10 mg once daily) with a target enrollment of approximately 4,000 participants with acute, 


JNJ-39039039; BAY 59-7939 (rivaroxaban)
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Status: Approved,  Date: 04 June 2020
symptomatic COVID-19 infection. As this is an event-driven study, if the observed event rate is lower than 
expected, enrollment may exceed 4,000 participants, with up to approximately 5,000 participants without 
the need for a protocol amendment. 
The study will enroll participants from large, integrated, health networks in the United States involving a 
centralized study staff, as well as decentralized nonstudy physicians or nonstudy healthcare providers. 
There are no required in-person clinic visits required by the study. Participants who complete a COVID-19 
test for infection (eg, polymerase chain reaction [PCR] test) as part of standard of care within the health 
network and who test positive will be identified by the centralized study staff as potential study participants 
through review of existing electronic medical records (EMR). Potential study participants may also be 
recruited by nonstudy physicians in collaboration with the study sites. Participants meeting the eligibility 
criteria at an in-person or virtual outpatient contact will participate in an informed consent process and once 
consented will then be randomly allocated in a ratio of 1:1 to treatment with either rivaroxaban or placebo. 
At the time of screening, recently taken medications and the need for immediate anticoagulation will be 
considered to determine if any symptoms reported by study participants are related to a study endpoint at 
the time of the screening. 
Treatment assignment will be balanced within a clinical site by block randomization. The randomization 
will be stratified by the time from COVID-19 positive test to randomization (1 to 5 days inclusive, 
6 to 14 days inclusive). At the present time it is anticipated that the event rate or the treatment effect may 
be different in the 2 strata. These strata will be used as subgroup analyses to look for the comparability of 
the treatment effect begun early after the diagnosis or later after the diagnosis. To enable an adequate 
assessment in both strata, the sponsor may elect to limit enrollment in one of the strata. In addition, the 
sponsor will monitor baseline risk factors and may elect to cap enrollment of participants with a certain risk 
factor to enable an adequate assessment of subgroups with particular risk factors. 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 without the need for a protocol amendment. 
Study intervention will be shipped or delivered by courier from the drug depot and/or central pharmacy to 
the participant’s address and will be self-administered by the study participant. The study personnel will 
confirm receipt and initiation of study intervention by remote contact (eg, phone or email), reinforce the 
study purpose, review dosing instructions, and provide the participant with contact information in the event 
questions should arise. During the study, the study personnel will contact the participant in accordance with 
the Schedule of Activities (SoA) to collect specified information, including safety and efficacy outcome 
events, assess and document the events in the EMR or electronic case report form (eCRF). Study personnel 
will systematically question participants about any new or worsening symptoms suggestive of a study 
efficacy or safety endpoint. While assessing the nature and severity of symptoms reported by study 
participants, careful consideration will be given to symptoms that could be related to manifestations of 
either COVID-19 or venous and arterial thrombotic events (such as shortness of breath or chest pain) or 
overt bleeding events and will be encouraged to seek appropriate evaluation by their local health care 
providers. 
At the completion of study intervention treatment (Day 35), the study personnel will contact the participant 
to confirm vital status and ask about any signs/symptoms or diagnosis of venous and arterial thrombotic 
events, hospitalization and its duration, bleeding events, serious adverse event collection, and will document 
the participant’s feedback in the EMR or eCRF. The final follow-up will be on Day 49±7 days after 
randomization. Study intervention may be interrupted for any hospitalization and all antithrombotic therapy 
will be at the discretion of the admitting physician. Upon hospital discharge, the participants may resume 
study intervention or may permanently discontinue study intervention and may receive antithrombotic 
therapy per institutional guidelines. Study participants may temporarily interrupt study intervention
required for procedures or during evaluation for study endpoints and may be resumed if deemed appropriate 
by the local physician. All participants should be followed until the last follow-up on Day 49±7 days. In 
the event that the participant is unavailable (eg, hospitalized) or incapacitated (eg, on a ventilator), 


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information about the vital status and whereabouts of the participant and his/her status may be obtained 
from family and/or friends, EMR or other source records, and documented in the eCRF.  
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study.
NUMBER OF PARTICIPANTS
The target enrollment is approximately 4,000 participants with acute, symptomatic COVID-19 infection. 
As this is an event-driven study, if the observed event rate is lower than expected, enrollment may exceed
4,000 participants, with up to approximately 5,000 participants, without the need for a protocol amendment.
INTERVENTION GROUPS AND DURATION
Participants will be randomly allocated in a ratio of 1:1 to treatment with either rivaroxaban 10 mg once 
daily or matching placebo.
All participants are to self-administer study intervention (rivaroxaban or placebo) orally once daily, with or 
without food, at approximately the same time each day throughout the 35-day double-blind treatment 
period. The first dose should be taken as soon as possible after randomization and within 2 days of 
randomization if possible. The date and time of the study intervention should be recorded as accurately as 
possible.
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 participant takes a dose of study intervention on Day 35, the participant should discontinue study 
intervention and complete the Day 35 (±6 days) virtual outpatient contact. A final follow-up visit will occur 
on Day 49±7 days by virtual outpatient contact as well (refer to the SoA).
All participants will be allowed to be treated with standard of care medications for COVID-19 at the 
discretion of the participants’ local physician. If a medication must be given to a participant in the study 
that has an unacceptable drug interaction, the study intervention should be discontinued for as long as the 
negatively interacting drug must be given. Study intervention may be restarted at the discretion of the 
investigator if the drug with the negative interaction is discontinued. In the event that the participant wishes 
to participate in another study that is testing an experimental therapy, the participant should withdraw from 
this study. However, passive collection of EMR data and vital status may still be obtained through Day 49. 
EFFICACY EVALUATIONS
Efficacy outcomes will be assessed and documented per the SoA and will include all information necessary 
for the following key efficacy outcomes to be assessed via telephone/web contact, from review of the eCRF, 
EMR, claims databases, Social Security Death Index, or other source documents: all-cause mortality 
(and cause of death, if known), all-cause hospitalization, MI, stroke (ischemic, hemorrhagic, unknown 
etiology), acute limb ischemia, non-CNS systemic embolization, symptomatic VTE (ie, symptomatic deep 
vein thrombosis [DVT], and pulmonary embolism [PE]).
Any event that includes symptoms or signs suggestive of symptomatic VTE events, MI, ischemic stroke, 
acute limb ischemia, or non-CNS systemic embolization will be assessed and entered into the eCRF as a 
potential event by the investigator/study team. In identifying potential events, investigators are encouraged 
to give careful consideration to symptoms that may represent manifestations of major venous and arterial 
thrombotic events and encourage participants to seek medical care. Review of EMR data for health system 
encounters suggestive of study events (eg, hospitalizations) may also be conducted to identify study 
endpoints. Source documents may be requested from nonstudy physicians within the health network or 
from health care encounters outside of the investigator’s health network to assist in identifying all efficacy 
and safety outcome events.  


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There will be no independent adjudication by a Clinical Events Committee. Potential events will be 
adjudicated locally by a qualified site investigator who will review source documents, such as the EMR, 
eCRF, and other study records or source documents in a blinded and impartial manner to verify/adjudicate 
events according to the endpoint definitions. The qualified investigator will evaluate all available 
information from the eCRF, EMR or other source documents and will document in the eCRF whether the 
subject did or did not have any of the following events according to the protocol-specified definitions of 
the events:
!
Symptomatic VTE 
!
Myocardial infarction 
!
Stroke (ischemic, hemorrhagic or unknown etiology)
!
Acute limb ischemia
!
Non-CNS systemic embolization
Any clinical event that suggests the possibility that an efficacy outcome event has occurred (including acute 
coronary syndrome and transient ischemic attack) should be recorded in the eCRFs and will be assessed by
the investigator. COVID-19 has been associated with arterial emboli in a variety of locations, including 
internal organs (eg, mesenteric artery, renal artery). These should all be included in the endpoint of “non-
CNS systemic embolization.” Unusual locations for venous thrombosis have also been reported in 
association with COVID-19 such as thrombosis of the cerebral veins or sinuses. These will be captured 
under “symptomatic VTE”.
The analysis of study efficacy endpoint events will be based on the qualified investigator’s assessment in a 
blinded fashion using standardized event definitions. The EMR and/or eCRF will serve as supporting source 
records to document the endpoint and to verify or confirm study endpoints. 
SAFETY EVALUATIONS
Safety assessments will include monitoring of serious adverse events, nonserious adverse events that are 
severe or of particular interest and study safety endpoints (major bleeding, including critical site bleeding 
and fatal bleeding, and nonmajor clinically relevant bleeding).
Additionally, participant-reported adverse events at the virtual study visits that are serious will be collected 
and assessed by Janssen Global Medical Safety (GMS) per the sponsor’s standard operating procedure. 
Efficacy and safety endpoints including all bleeding events will not be considered as adverse events or 
serious adverse events. Safety evaluations will be assessed and reported by the investigator per the SoA.
Review of the eCRF, EMR, claims databases and/or Social Security Death Index or other source documents 
may be utilized for data collection.
Bleeding Events
The study will use the ISTH bleeding event classification to assess overt bleeding as major, nonmajor 
clinically relevant, or trivial. 
The safety endpoints for this study include major, critical site and fatal bleeding, and nonmajor clinically 
relevant bleeding as assessed by a qualified investigator and reported in the eCRF.
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


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!
A critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with
compartment syndrome, retroperitoneal, or
!
A fatal outcome
Nonmajor 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 intervention, or associated with discomfort for the participant
such as pain or impairment of activities of daily life. Refer to Appendix 4, Nonmajor Clinically Relevant 
Bleeding Event Criteria for examples of nonmajor clinically relevant bleeding.
Trivial bleeding is defined as any other overt bleeding episode that does not meet the ISTH criteria for 
major bleeding or nonmajor clinically relevant bleeding.
The Cunningham protocol may also be applied to automated health plan data to identify and classify 
bleeding events (Cunningham 2011) as an exploratory endpoint.
STATISTICAL METHODS
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 statistical analysis plan (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 confidence intervals (CI) at a nominal 2-sided level 
of 95%.
Sample Size Determination
This is an event-driven study. The targeted total number of primary efficacy outcome events is 333, based 
on the ITT analysis set and Up-to-Day-35 analysis phase. If a participant has multiple events, only the first 
is counted towards study size determination.
This targeted total number of events is determined using statistical software PASS 15 based on the primary 
efficacy analysis (defined later) and the following assumptions:
!
30% relative risk reduction (RRR) in the primary efficacy outcome based on the ITT analysis set and
Up-to-Day-35 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 333 events, it is estimated that a total of approximately 4,000 participants will need 
to be randomized to either rivaroxaban or placebo in a 1:1 ratio. This estimate is based on an estimated 
placebo incidence rate of the primary efficacy outcome of 10%.
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the eConsent
Randomized
All participants who were randomized in the study
Safety
All randomized participants who take at least 1 dose of study intervention 


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Key Analysis Sets and Analysis Phases
!
Intention-to-Treat (ITT): This analysis set consists of all randomized participants who have a signed
eConsent.
!
Safety: This analysis set is a subset of the ITT analysis set, consisting of participants who receive at 
least 1 dose of study intervention.
!
Up-to-Day-35: This analysis phase includes all data from randomization to Day 35 visit 
(Day 35+6 days)
!
On-treatment: This analysis phase includes all data from randomization to 2 days after the last dose of 
the study intervention.
Primary Endpoint(s)
The primary endpoint is time from randomization to the first occurrence of all major venous and arterial 
thrombotic events (symptomatic VTE, MI, ischemic stroke, acute limb ischemia, and non-CNS systemic 
embolization), all-cause hospitalization, and all-cause mortality Up-to-Day-35 analysis phase.
Estimand
The primary estimand is described according to the following 5 attributes:
!
Population: Medically ill outpatients with acute, symptomatic COVID-19 infection
!
Variable: time from randomization to the first occurrence of primary efficacy event Up-to-Day-35 
analysis phase
!
Treatments: Rivaroxaban 10 mg once daily versus placebo
!
Intercurrent events (events that preclude observation of the variable or affects its interpretation): 
treatment discontinuation. A treatment policy strategy will be used for these intercurrent events
!
Population-level summary: HR of rivaroxaban 10 mg versus placebo, along with the 2-sided 95% CI
This estimand targets the effect of rivaroxaban on the variable measured and follows an “ITT principle” 
strategy.
The primary statistical hypothesis will be tested using a stratified log-rank test by the time from COVID-19 
positive test to randomization (1 to 5 days inclusive, 6 to 14 days inclusive) with the treatment as the only 
variable. This primary efficacy analysis will be based on the ITT analysis set and Up-to-Day-35 analysis 
phase. Participants will be analyzed according to the treatment group to which they are randomized, 
regardless of actual treatment received. The 2-sided p-value will be reported and if it is less than the 2-sided 
alpha of 0.049 after the adjustment from the interim analysis (IA), then superiority of the study intervention
will be declared.
The point estimate and corresponding 95% CI for the HR (rivaroxaban to placebo) will be provided based 
on the stratified 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 evaluating the significance of an interaction term of treatment by 
logarithm-transformed time in the primary Cox model.
Secondary Endpoint(s)
The variables for the analysis of the secondary endpoint are time from randomization to the first occurrence 
of the following: any thrombotic outcome (symptomatic VTE, MI, ischemic stroke, acute limb ischemia, 
and non-CNS systemic embolization) and all-cause mortality, all-cause hospitalization, symptomatic VTE, 
ER visits, any thrombotic outcome and all-cause hospitalization, and all cause mortality in the ITT analysis 


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set and Up-to-Day-35 analysis phase. The other variable for the analysis of the secondary endpoint is 
hospitalization or death at Day 35.
Estimands
The estimands for the analysis of the secondary endpoints are the same as for the primary efficacy endpoint 
except for the hospitalization and all-cause death at Day 35.
The estimand for the analysis of the frequency of participants who are hospitalized or dead at Day 35 is the 
same as for the primary efficacy endpoint except variable and population-level summary.
!
Variable: Hospitalization or death at Day 35 (Day 35±6 days)
!
Population-level summary: Weighted relative risk (RR) of rivaroxaban 10 mg versus placebo, along 
with the 2-sided 95% CI
The analysis for all secondary efficacy outcomes will proceed as in the primary efficacy analysis, except 
for the incidence of all-cause hospitalization and all-cause mortality which will be based on 
Cochran-Mantel-Haenzel approach to estimate the Weighted RR and 95% CI.
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 using a hierarchical closed testing 
procedure, each at alpha of 0.05 (2-sided). The current proposed hierarchy is listed below. This may be 
updated/altered in the final SAP rather than requiring a protocol amendment. If an individual test during 
any step is not statistically significant, subsequent tests will not be declared to be statistically significant:
!
Any thrombotic outcome (symptomatic VTE, MI, ischemic stroke, acute limb ischemia, and non-CNS 
systemic embolization) and all-cause mortality
!
All-cause hospitalization
!
Symptomatic VTE
!
ER visits
!
Any thrombotic outcome and all-cause hospitalization
!
Hospitalization or death on Day 35
!
All-cause mortality 
Tertiary/Exploratory Endpoint(s)
Each exploratory outcome will be summarized by treatment groups based on the ITT analysis set and 
Up-to-Day-35 analysis phase.
Safety Analyses
All safety analyses will be made on the Safety Population.
Bleeding Outcomes
The principal safety outcome will be analyzed based on time from randomization to the first occurrence of 
fatal bleeding and critical site 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. Participants will be analyzed according to study 
intervention received. If a participant inadvertently receives both drugs, the participant will be analyzed as 
in the rivaroxaban group. The ISTH major, nonmajor clinically relevant, and trivial bleeding events will be 


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analyzed as described for the principal safety outcome. Major bleeding may also be assessed in an 
exploratory fashion using the Cunningham protocol (Cunningham 2011).
Adverse Events
The verbatim terms used in the EMR and/or eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Any adverse event occurring at or after 
the initial administration of study intervention through the day of last dose plus 2 days is considered to be 
treatment emergent. All reported treatment-emergent adverse events will be included in the analysis. For 
each adverse event, the percentage of participants who experience at least 1 occurrence of the given event 
will be summarized by intervention group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue intervention due to an adverse event, who have a major bleeding 
event or who experience a serious adverse event not captured as an endpoint.
Other Analyses
An IDMC will be established for this study.
Medical Resource Utilization and Health Economics Analyses
Medical resource utilization and health economics data collection will include the ER visits, hospitalization, 
and duration of hospitalization and other utilization of medical resources (eg, urgent care visits).
Medical resource utilization and health economics data will be descriptively summarized by intervention 
group.
Benefit-Risk Analyses
The benefit-risk profile of rivaroxaban versus 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 in a hypothetical population 
size (eg, 10,000 participants). 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 and fatal 
and critical site bleeding. This analysis phase includes all data from randomization up to Day 35 (inclusive), 
which is the period of treatment. In addition, the benefit-risk balance may be further assessed for other 
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.
Interim Analysis
An IA for futility or overwhelming superiority will be conducted when approximately 167 participants with 
a primary efficacy outcome have been observed (about 50% of the targeted total number of events). 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 and the study will use O’Brien-Fleming boundary (Z=2.96, alpha=0.003) to stop the 
study early for the overwhelming superiority. Alpha=0.049 will be used for the final analysis to control the 
family-wise type I error rate at an alpha of 0.05 (2-sided). The detailed rules about stopping the study early
will be specified in the SAP.


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1.2.
Schema
Figure 1:
Schematic Overview of the Study








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Period
Screeninga
Double-Blind Treatmentb, a
Posttreatmenta
Day -14
to Day -1c
TC or
IWI
Day 1
TC or IWI
Day 3 (±1 day)
TC
or
IWI
Day 14 
(±7 days)
TC or
IWI
Day 35 
(±6 days)
EOT
TC or
IWI
Day 49 
(±7 days)
EOS
TC
Notes
Medical Resource Utilization
X
MRU will be captured through 
Day 49 and include encounters 
such as ER visits, 
hospitalizations, and duration of 
hospitalization, days in ICU, and 
other utilization of medical 
resources (eg, such urgent care 
visits or days on a ventilator).
a.
In-person visit (s) may replace remote contact (s) (Telephone or Interactive Web Interface). 
b.
If the participant permanently discontinues study intervention prior to Day 35, the participant will continue to be followed according to the contact schedule to 
complete the final study contact at Day 49.
c.
Screening and randomization may occur on the same day (ie, Day 1)
d.
At the time of informed consent, 2 alternative means of contact for each participant will be collected (eg, contact information of the participant’s children, 
spouse, significant other, caretaker, legal representative, health care professional).
e.
In the event that multiple positive COVID-19 positive PCR tests are present, please record only the date of the first positive test.
f.
The study personnel will question the participant about dates of missed dose of study intervention and/or start and stop dates.
g.
Study endpoints will be assessed and reported by a qualified investigator according to protocol-specified definitions. 
COVID-19=coronavirus disease 2019; EMR=electronic medical record(s); EOS=end of study; EOT=end of treatment; ER=emergency room; ICU=intensive care unit;
IWI=Interactive Web Interface; MRU=medical resource utilization; PCR= polymerase chain reaction; TC=telephone call


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2.
INTRODUCTION
Rivaroxaban is an oral, direct-acting, Factor Xa (FXa) inhibitor anticoagulant that inhibits 
thrombus generation and thrombus formation. Rivaroxaban has been under development for the 
treatment of multiple thrombosis-mediated conditions. Rivaroxaban is marketed under the trade 
name XARELTO® and is approved for multiple indications worldwide. The clinical development 
program for rivaroxaban is extensive. Almost 200,000 participants have been studied from Phase 1 
through multiple large Phase 4 studies as of 15 September 2019, covering several indications and 
potential indications in the overall clinical development program, including 115,000 participants 
who received rivaroxaban. For the most comprehensive nonclinical and clinical information 
regarding rivaroxaban, refer to the latest version of the Investigator's Brochure (IB 2020) for 
rivaroxaban.
The term "rivaroxaban" throughout the protocol, refers specifically to the brand name XARELTO.
The term "study intervention" throughout the protocol, refers to rivaroxaban or placebo as defined 
in Section 6.1, Study Interventions Administered.
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.
The term "participant" throughout the protocol refers to the common term "subject".
2.1.
Study Rationale
Coronavirus disease 2019 (COVID-19) has become a pandemic associated with a high case fatality 
rate (ACC 2020). Early reports have demonstrated that the disease is associated with a 
coagulopathy in up to approximately 40 to 50% of patients as evidenced by elevation of D-dimer
(Tang 2020a, Tang 2020b), which has been associated with more severe disease, the development 
of acute respiratory distress syndrome (ARDS), disseminated intravascular coagulopathy (DIC),
and death (Zhou 2020). A meta-analysis of 4 studies has suggested that an elevated D-dimer in 
COVID-19 patients is associated with a 3-fold increased risk of severe disease (Lippi 2020). In 1
series of hospitalized patients with severe COVID-19 pneumonia without thromboprophylaxis, the 
incidence of deep vein thrombosis (DVT) was 25% (Cui 2020). Several subsequent series have 
demonstrated a high incidence of venous thromboembolism (VTE), which includes DVT or 
pulmonary embolism (PE) in hospitalized COVID-19 patients even when thromboprophylaxis is 
given (Klok 2020, Llitjos 2020). One retrospective study suggested that treatment with 7 days or 
more of thromboprophylaxis was associated with a lower mortality in patients with a D-dimer >6
times (x) the upper limit of normal (Tang 2020a, Tang 2020b). In an Italian series of 388 COVID-
19 positive patients consecutively admitted to the hospital, despite all intensive care unit (ICU)
patients receiving thromboprophylaxis and 75% of general ward patients receiving 
thromboprophylaxis, the overall incidence of arterial or venous thromboembolic events was 7.7% 
(Lodigiani 2020). Younger COVID-19 patients have been reported with ischemic stroke 
(Oxley 2020), and other patients with deterioration in oxygenation have been reported with at least 
transient improvement in ARDS with the use of fibrinolytic therapy (Wang 2020), suggesting that 


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some of the problem in oxygenation could be due to pulmonary thrombi. It has been hypothesized 
that viral infection and the subsequent inflammatory response may lead to in situ microthrombi in 
the lung in addition to pulmonary emboli from the extremities. This has now been observed in
several autopsy series that have reported both microthrombi and pulmonary emboli in a significant 
proportion of patients (Ackermann 2020, Lax 2020, Menter 2020, Wichmann 2020).
It is now clear that COVID-19 infection is accompanied by a significant coagulopathy in a 
significant proportion of patients and that the consequences may lead to both arterial and venous 
thromboemboli as well as in situ pulmonary thrombosis. Many of these complications are likely 
to lead to hospitalization and may rapidly progress to worsening pulmonary function, ARDS, the 
need for ventilation, DIC and death. It is also clear that thromboprophylaxis is warranted when a 
patient is hospitalized and is recommended in at least 3 guidelines (American College of 
Cardiology [ACC], World Health Organization [WHO], and the International Society on 
Thrombosis and Hemostasis [ISTH]) (ACC 2020, Thachil 2020, WHO 2020). However, the 
coagulopathy in many of these patients is already advanced at the time of admission and 
anticoagulation may not reverse some of the pathology. It is hypothesized that earlier 
administration of thromboprophylaxis soon after the diagnosis of COVID-19 prior to 
hospitalization may reduce the risk of venous and arterial thrombotic complications and may 
reduce the need for hospitalization and subsequent morbidity and mortality.
In a large series of 4,103 patients testing positive for COVID-19 in New York, 48.7% were 
hospitalized. Risk factors for hospitalization included older age, obesity, and a history of heart 
failure, while risk factors for critical illness included a low oxygen saturation and an elevated 
D-dimer among others (Petrilli 2020). More recent data would suggest that the rate of
hospitalization is currently approximately 10% in a large New York Heath Network
(Spyropoulos, personal communication).
In this study, we propose to evaluate whether rivaroxaban, an oral FXa inhibitor, when 
self-administered by the participant within 14 days of diagnosis of COVID-19 in the outpatient 
setting, can reduce the time to the first occurrence of venous and arterial thrombotic events, 
hospitalization, and death when self-administered as 10 mg once daily for 35 days.
2.2.
Background
Hospitalized COVID-19 patients are currently recommended for thromboprophylaxis as "acute, 
medically ill" patients per guidelines from ACC, WHO, and the ISTH (Driggen 2020, Spyropoulos 
2020, Thachil 2020, WHO 2020). Rivaroxaban is approved in the United States for the prophylaxis 
of VTE in hospitalized acute, medically ill patients who are at risk for VTE and at low risk for 
bleeding. Hospitalized COVID-19 patients are an example of such medically ill patients. 
Hospitalized ICU patients with COVID-19 have a high rate of DVT without thromboprophylaxis
(Cui 2020)
and have high rates
despite low molecular weight heparin (LMWH) 
thromboprophylaxis (approximately 25% to 40%)
(Klok 2020, Spyropoulos
personal 
communication). Patients with COVID-19 infection may not be hospitalized when they might 
otherwise have been due to low availability of hospital beds or a desire to limit exposure of less 
acutely ill COVID-19 patients to hospital personnel. Patients with COVID-19 infection may be 


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relatively immobile at home and are likely at risk for VTE, especially if their D-dimer level is 
elevated (Lodigiani 2020, Tang 2020a, Tang 2020b). Patients with COVID-19 infection appear to 
be at increased risk for arterial thrombotic events as well (Bikdeli 2020). Low molecular weight 
heparin (LMWH) prophylaxis, while preventing VTE, may also decrease thrombin generation and 
modify the course of DIC. Very preliminary results suggest a favorable effect from LMWH 
prophylaxis (Bikdeli 2020). Finally, a study of 83 COVID-19 patients suggests that when LMWH 
prophylaxis was initiated on hospital admission, progression to DIC was rare (Fogarty 2020).
No current guidelines recommend thromboprophylaxis prior to hospitalization in COVID-19 
patients, but venous and arterial thrombotic complications have been reported developing suddenly 
in the outpatient setting. It is hypothesized that starting thromboprophylaxis early after infection 
is diagnosed, may decrease thrombotic complications, reduce in situ pulmonary microthrombi, 
maintain better oxygenation, and reduce the need for hospitalization and ultimately reduce 
mortality.
Rivaroxaban 10 mg once daily is currently indicated in the United States for the prophylaxis of 
VTE and VTE-related death during hospitalization and post-hospital discharge in adult patients 
admitted for an acute medical illness who are at risk for thromboembolic complications due to 
moderate or severe restricted mobility and other risk factors for VTE and not at high risk of 
bleeding. This study will evaluate whether pre-hospital administration of rivaroxaban to 
symptomatic COVID-19 patients at risk for venous and arterial thrombotic complications may 
reduce their occurrence, the need for hospitalization or death.
Approved Indications
Rivaroxaban is approved in the United States for the following indications:
!
to reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation
!
for treatment of DVT
!
for treatment of PE
!
for reduction in the risk of recurrence of DVT or PE
!
for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip 
replacement surgery
!
to reduce the risk of major cardiovascular events in patients with chronic coronary artery 
disease (CAD) or peripheral artery disease (PAD)
!
for prophylaxis of VTE in acutely ill medical patients
Efficacy/Safety Studies
The efficacy and safety of rivaroxaban for prophylaxis of VTE in acutely ill medical patients at 
risk for thromboembolic complications was evaluated in the MAGELLAN study (Cohen 2013). 
MAGELLAN was a randomized study to compare the efficacy and safety of extended 
thromboprophylaxis in hospitalized medical patients with rivaroxaban 10 mg once daily for 35±4 
days versus standard of care with enoxaparin 10 ± 4 days followed by placebo. Rivaroxaban was 


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noninferior to enoxaparin and superior to placebo for reducing the risk of VTE but was associated 
with more than a 2-fold increased risk of bleeding. Subsequent analyses identified 5 key risk 
factors associated with the increase in bleeding, namely a history of bronchiectasis, pulmonary 
cavitation, or pulmonary hemorrhage, active cancer (ie, undergoing acute, in-hospital cancer 
treatment), active gastroduodenal ulcer in the 3 months prior to treatment, history of bleeding in 
the 3 months prior to treatment, or dual antiplatelet therapy. Excluding such patients from the 
MAGELLAN population lead to a subpopulation with preserved efficacy but reduced bleeding 
(Spyropoulos 2019). Based on these analyses, the Food and Drug Administration (FDA) approved 
the use of rivaroxaban in medically ill patients at risk for VTE but not at high risk for bleeding for 
31 to 39 days of treatment.
2.3.
Dose Rationale
The selection of a dose of 10 mg once daily of rivaroxaban is based primarily on the results of the 
MAGELLAN (Cohen 2013) and MARINER (Spyropoulos 2018) studies conducted for 
prophylaxis of VTE in acutely ill medical patients at risk for thromboembolic complications not 
at high risk of bleeding. This dose is also approved for the prevention of VTE after hip and knee 
surgery and for secondary prevention after 6 months of initial treatment in patients requiring longer 
treatment based on the results of the EINSTEIN CHOICE study (Weitz 2017). Lower doses have 
previously been explored in Phase 2 and in the MARINER study (7.5 mg once daily) and were 
found to not be effective (Spyropoulos 2018). Hence, it is anticipated that 10 mg once daily is 
likely to be the lowest effective dose for the prevention of VTE. In the EINSTEIN CHOICE study, 
20 mg once daily was also evaluated with similar efficacy but with increased bleeding. Finally, in 
the COMPASS study, a dose of 2.5 mg twice daily was utilized in addition to acetylsalicylic acid 
(ASA) compared to ASA alone (Eikelboom 2017) and was demonstrated to reduce the incidence 
of cardiovascular death, myocardial infarction (MI), and stroke but was associated with an increase 
in major bleeding. A dose of 5 mg twice daily without ASA was also tested and did not 
significantly reduce the primary endpoint compared with ASA alone but was associated with an 
increase in major bleeding. The dose of 5 mg twice daily has a similar trough as 20 mg once daily. 
The dosing regimen of 2.5 mg twice daily provides a similar trough level as rivaroxaban 10 mg 
once daily. Therefore, based on all of these considerations, the dose of 10 mg once daily has been 
chosen to optimize the benefit-risk profile in COVID-19 participants in this study.
2.4.
Benefit-Risk Assessment
The benefit-risk profile of rivaroxaban versus 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 participants). 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, MI, ischemic stroke, 
acute limb ischemia, noncentral nervous system (non-CNS) systemic embolization, all-cause 
hospitalization, and all-cause mortality) and the outcome of fatal and critical-site bleeding. This 
analysis phase includes all data from randomization to Day 35 (inclusive), which is the period of 
treatment. In addition, benefit-risk balance may be further assessed for secondary efficacy 


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outcomes in relation to major bleeding, while potentially taking into consideration the clinical 
importance of those events. Additional details for benefit-risk analysis will be specified in the 
statistical analysis plan (SAP).
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpointsa
Primary (Intention-to-Treat [ITT] Population)
The primary objective will be to evaluate whether 
rivaroxaban reduces the risk of a composite 
endpoint of major venous and arterial thrombotic 
events, all-cause hospitalization, and all-cause 
mortality compared with placebo in outpatients 
with acute, symptomatic COVID-19 infection
The primary efficacy outcome variable will be the 
time to first occurrence of a composite endpoint of 
symptomatic venous thromboembolism (VTE), 
myocardial infarction (MI), ischemic stroke, acute 
limb ischemia, noncentral nervous system (non-
CNS) 
systemic 
embolization, 
all-cause 
hospitalization, and all-cause mortality up to 
Day 35
Secondary (ITT Population)
To evaluate whether rivaroxaban reduces the risk 
of all symptomatic VTE, major arterial thrombotic 
events (MI, ischemic stroke, acute limb ischemia, 
non-CNS systemic embolization) and all-cause 
mortality in outpatients with acute, symptomatic
COVID-19 infection
Time to first occurrence of a composite endpoint of 
symptomatic VTE, MI, ischemic stroke, acute limb 
ischemia, non-CNS systemic embolization, and all-
cause mortality up to Day 35
To evaluate whether rivaroxaban reduces all-cause 
hospitalization
Time 
to 
first 
occurrence 
of 
all-cause 
hospitalization up to Day 35
To evaluate whether rivaroxaban reduces the risk 
of symptomatic VTE
Time to first occurrence of symptomatic VTE up to 
Day 35
To evaluate whether rivaroxaban reduces the need 
for emergency room (ER) visits
Time to first occurrence of an ER visit up to Day 35
To evaluate whether rivaroxaban reduces the risk 
of venous and arterial thrombotic events and all-
cause hospitalization
Time to first occurrence of symptomatic VTE, MI,
ischemic stroke, acute limb ischemia, non-CNS 
systemic 
embolization, 
and 
all-cause 
hospitalization up to Day 35
To evaluate whether rivaroxaban reduces the 
percentage of participants who are hospitalized or 
dead on Day 35
Incidence of participants who are hospitalized or 
dead from any cause on Day 35
To evaluate whether rivaroxaban reduces all-cause 
mortality up to Day 35
Time to all-cause mortality up to Day 35


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Objectives
Endpointsa
Safety Endpoints (Safety Population)
To evaluate whether rivaroxaban is associated with 
an increase in critical site and fatal bleeding
Time to first occurrence of International Society on 
Thrombosis and Hemostasis (ISTH) critical site 
and fatal bleeding on treatment (+2 days)
To evaluate whether rivaroxaban is associated with 
an increase in major bleeding
Time to first occurrence of ISTH major bleeding on 
treatment (+2 days)
To evaluate whether rivaroxaban is associated with 
an increase in nonmajor clinically relevant 
bleeding
Time to first occurrence of nonmajor clinically 
relevant bleeding on treatment (+2 days)
Tertiary/Exploratory (ITT Population)
To evaluate whether rivaroxaban improves 
participant status (eg, prevents worsening of WHO 
Research and Development Blueprint: Novel 
Coronavirus Scale for Clinical Improvement) over 
time
WHO
Research and Development Blueprint: 
Novel Coronavirus Scale for Clinical Improvement 
over time
To evaluate if rivaroxaban reduces individual 
component events of the primary efficacy endpoint
Time to first occurrence of a component event of 
the primary efficacy endpoint (MI, ischemic 
stroke, acute limb ischemia, and non-CNS 
systemic embolization) up to Day 35
To evaluate the ability of rivaroxaban to prevent 
the decline in oxygenation at rest or with 
ambulation
!
The incidence of participants achieving an
oxygen saturation (O2sat) below 92% on room 
air at rest or with ambulation up to Day 35
!
The incidence of participants achieving an 
O2sat below 88% on room air at rest or with 
ambulation up to Day 35
To evaluate whether rivaroxaban can reduce the 
need for supplemental oxygen
The incidence of participants requiring 
supplemental oxygen up to Day 35
To evaluate whether rivaroxaban can prevent the 
occurrence of severe disease in hospital or death as 
defined by WHO scale scores of 5, 6, 7, or 8
Time to first occurrence of the use of non-invasive 
ventilation or high-flow oxygen (WHO 5), 
Intubation and mechanical ventilation (WHO 6), or 
ventilation 
and 
additional 
organ 
support 
(vasopressors, renal replacement therapy [RRT], 
extracorporeal membrane oxygenation [ECMO]; 
WHO 7) or all-cause mortality (WHO 8) up to 
Day 35
To evaluate whether rivaroxaban can prevent the 
occurrence of acute renal failure
The incidence of participants requiring dialysis or 
having an estimated glomerular filtration rate 
(eGFR) <15 mL/min/1.73 m2 on 2 measurements 
more than 24 hours apart up to Day 35


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Objectives
Endpointsa
To evaluate whether rivaroxaban can prevent the 
occurrence of DIC
Time to first occurrence of DIC up to Day 35
To evaluate whether rivaroxaban can prevent the 
occurrence of ARDS
Time to first occurrence of ARDS up to Day 35
To evaluate whether rivaroxaban can prevent the 
occurrence of COVID digit
The incidence of occurrence of COVID digit up to 
Day 35
Collect medical resource utilization (MRU) data
MRU data over time
Benefit-Risk
To evaluate the benefit-risk profile of rivaroxaban 
by evaluating the risk differences for key efficacy 
and safety endpoints through Day 35 
Evaluate the risk differences for the composite and 
components of the primary efficacy outcome 
compared with fatal and critical site bleeding 
through Day 35 
a. 
Study endpoints will be assessed and reported by a qualified investigator according to protocol-specified 
definitions.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESES
The primary hypothesis of this study is that rivaroxaban is superior to placebo in the prevention of 
major venous and arterial thrombotic events, hospitalization, and death in outpatients with acute, 
symptomatic COVID-19 infection during the treatment period (Day 35). The secondary 
hypotheses are that rivaroxaban is superior to placebo in the prevention of: any thrombotic 
outcome (symptomatic VTE, MI, ischemic stroke, acute limb ischemia, and non-CNS systemic 
embolization) and all-cause mortality, all-cause hospitalization, symptomatic VTE, ER visits, any 
thrombotic outcome and all-cause hospitalization, hospitalization or death at Day 35, and all-cause 
mortality.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomized, multicenter, placebo-controlled, pragmatic, event-driven Phase 3 study of 
rivaroxaban (10 mg once daily) with a target enrollment of approximately 4,000 participants with 
acute, symptomatic COVID-19 infection. As this is an event-driven study, if the observed event 
rate is lower than expected, enrollment may exceed 4,000 participants, with up to approximately 
5,000 participants without the need for a protocol amendment. 
The study will enroll participants from large, integrated, health networks in the United States
involving a centralized study staff, as well as decentralized nonstudy physicians or nonstudy 
healthcare providers. There are no required in-person clinic visits required by the study. 
Participants who complete a COVID-19 test for infection (eg, polymerase chain reaction [PCR]
test) as part of standard of care within the health network and who test positive will be identified 


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by the centralized study staff as potential study participants through review of existing electronic 
medical records (EMR). Potential study participants may also be recruited by nonstudy physicians 
in collaboration with the study sites. Participants meeting the eligibility criteria at an in-person or 
virtual outpatient contact will participate in an informed consent process and once consented will 
then be randomly allocated in a ratio of 1:1 to treatment with either rivaroxaban or placebo. At the 
time of screening, recently taken medications and the need for immediate anticoagulation will be 
considered to determine if any symptoms reported by study participants are related to a study 
endpoint at the time of the screening.
Treatment assignment will be balanced within a clinical site by block randomization. The 
randomization will be stratified by the time from COVID-19 positive test to randomization (1 to 
5 days inclusive, 6 to 14 days inclusive). At the present time it is anticipated that the event rate or 
the treatment effect may be different in the 2 strata. These strata will be used as subgroup analyses 
to look for the comparability of the treatment effect begun early after the diagnosis or later after 
the diagnosis. To enable an adequate assessment in both strata, the sponsor may elect to limit 
enrollment in 1 of the strata. In addition, the sponsor will monitor baseline risk factors and may 
elect to cap enrollment of participants with a certain risk factor to enable an adequate assessment 
of subgroups with particular risk factors. 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 without the need for a protocol amendment. 
Study intervention will be shipped or delivered by courier from the drug depot and/or central 
pharmacy to the participant’s address and will be self-administered by the study participant. The 
study personnel will confirm receipt and initiation of study intervention by remote contact (eg,
phone or email), reinforce the study purpose, review dosing instructions, and provide the 
participant with contact information in the event questions should arise. During the study, the study
personnel will contact the participant in accordance with the Schedule of Activities (SoA) to 
collect specified information, including safety and efficacy outcome events, assess and document 
the events in the EMR or electronic case report form (eCRF). Study personnel will systematically 
question participants about any new or worsening symptoms suggestive of a study efficacy or 
safety endpoint. While assessing the nature and severity of symptoms reported by study 
participants, careful consideration will be given to symptoms that could be related to 
manifestations of either COVID-19 or venous and arterial thrombotic events (such as shortness of 
breath or chest pain) or overt bleeding events and will be encouraged to seek appropriate evaluation 
by their local health care providers. 
At the completion of study intervention treatment (Day 35), the study personnel will contact the 
participant to confirm vital status and ask about any signs/symptoms or diagnosis of venous and
arterial thrombotic events, hospitalization and its duration, bleeding events, serious adverse event 
collection, and will document the participant’s feedback in the EMR or eCRF. The final follow-
up will be on Day 49±7 days after randomization. Study intervention may be interrupted for any 
hospitalization and all antithrombotic therapy will be at the discretion of the admitting physician. 
Upon hospital discharge, the participants may resume study intervention or may permanently 
discontinue study intervention and may receive antithrombotic therapy per institutional guidelines. 


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Study participants may temporarily interrupt study intervention required for procedures or during 
evaluation for study endpoints and may be resumed if deemed appropriate by the local physician. 
All participants should be followed until the last follow-up on Day 49±7 days. In the event that the 
participant is unavailable (eg hospitalized) or incapacitated (eg on a ventilator), information about 
the vital status and whereabouts of the participant and his/her status may be obtained from family 
and/or friends, EMR or other source records, and information in the eCRF. 
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study. Refer 
to Committees Structure in Appendix 5, Regulatory, Ethical, and Study Oversight Considerations 
for details.
A diagram of the study design is provided in Section 1.2, Schema.
4.2.
Scientific Rationale for Study Design
Blinded, Controlled, Randomized Study
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active intervention with rivaroxaban and to characterize 
the safety profile relative to a placebo control group. Having a control group is critical for the 
scientific validity of the study. In a fast-moving pandemic when hospitalization rates may be 
changing and background therapies may also evolve quickly, having a contemporaneous control 
group is important to enable valid inferences of statistical comparison across treatment arms. 
Randomization will be used to minimize bias in the assignment of participants to treatment arms, 
to increase the likelihood that known and unknown participant attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment arms, and to enhance the validity of 
statistical comparisons across treatment arms. Stratification will be done by time from diagnosis. 
The rationale for this is that it is anticipated that the earlier after the diagnosis, the better the 
thromboprophylaxis may work. This will ensure balance between treatment groups in participants 
entering early or later in the course of their disease.
Double-blind intervention will be used to reduce potential bias during data collection and
evaluation of clinical endpoints.
Study Population
The goal is to identify a participant population with confirmed, symptomatic COVID-19 disease
as defined in Inclusion Criterion #5 (see Section 5.1, Inclusion Criteria) and at least one additional 
risk factor for venous or arterial thromboembolic disease or more severe pulmonary disease. As 
all anticoagulants carry some risk of bleeding, these criteria are aimed at enriching the population 
likely to achieve an endpoint, reducing the risk of a serious bleeding event, while maintaining 
applicability to a relatively broad population of participants with symptomatic COVID-19 disease.
Choice of Endpoint
Inclusion of all major venous and arterial thrombotic events as part of the primary composite 
endpoint is based on the pharmacology, mechanism of action, and previous clinical study results 


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of rivaroxaban. All-cause hospitalization is part of the composite endpoint because it has become 
clear that the deterioration in lung function in COVID-19 patients is multifactorial and includes 
evidence of frequent in situ thrombosis in the pulmonary artery vasculature, as well as pulmonary 
emboli (Lodigiani 2020). Therefore, it is plausible that at least some of the deterioration in lung 
function and hypoxemia that results in hospitalization may result from ventilation perfusion (V-Q)
mismatching associated with reduced flow secondary to pulmonary thrombosis. All-cause death is 
included in the composite endpoint because of the significance of this outcome in COVID-19
patients and serves as clear measure of net clinical benefit that is easily ascertained and highly 
relevant for this population.
If treatment with rivaroxaban is successful in lowering the incidence of the primary endpoint, this 
may result in lower utilization of health services. Therefore, all available data regarding use of 
medical resource (eg, need for supplemental oxygen therapy, ER visits, ICU days, etc.) will be 
collected.
Screening Period of 14 Days
The choice of an up to 14-day period to screen potential study candidates who have tested positive 
for COVID-19 is intended to select for study participants with active disease and at risk for venous 
and arterial thromboembolic events. The median incubation period of COVID-19 has been 
reported to be approximately 5 days. Depending on the time interval between symptom onset and 
when a COVID-19 test is confirmed, the 14-day window for screening is expected to capture a 
large proportion of participants at risk for major venous and arterial thrombotic events. It is 
anticipated that rivaroxaban may have increased benefit if administered early after the diagnosis 
of COVID-19. To ensure balance between treatment groups for those randomized early or later 
after the diagnosis, the time from diagnosis to randomization will be stratified into the early cohort 
(Day 1 to 5) and the later cohort (Day 6 to 14). In the event that a participant has multiple 
COVID-19 positive PCR tests in the EMR, the screening period will begin with the first test, and 
the date of the first positive test should be recorded in the eCRF.
4.2.1.
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
study participation, including new standard-of-care treatments or risks of treatment that may 
emerge. 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 participants who are fully able to understand the risks, benefits, 
and potential adverse events of the study, and provide their consent voluntarily will be enrolled.
Participants may be simultaneously enrolled in observational registries of COVID-19 patients. 
However, if the participant wishes to enroll in another investigational, randomized study while 
participating in the current study, then the participant should withdraw from further participation 
in the current study. Passive collection of EMR data and vital status may still be obtained from 
such participants through Day 49.  


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The primary ethical concern is that rivaroxaban may not improve clinical outcomes of a participant 
with COVID-19. At the present time, there are no guidelines recommending treatment with any 
antithrombotic therapy prior to hospitalization in COVID-19 participants. Due to the potential for 
bleeding, there is clinical equipoise as to whether thromboprophylaxis should be initiated prior to 
hospitalization. All background standard-of-care therapy for COVID-19 may be administered to 
all study participants as long as no prohibited drug interactions exist. If such a background 
medication is required, study intervention may be temporarily or permanently discontinued (see 
Section 4.4, End of Study Definition). Participants may also be simultaneously enrolled in 
observational registries. Participants may receive therapies for COVID-19 at the discretion of the 
treating physician if it is part of the standard of care. Participants who wish to participate in another 
study that is testing an experimental therapy should withdraw from this study. In such a case, 
passive collection of EMR data and vital status may still be obtained through Day 49.
4.3.
Justification for Dose
Refer to Section 2.3, Dose Rationale.
4.4.
End of Study Definition
The end of study is considered as the last virtual outpatient contact for the last participant in the 
study (ie, Day 49 visit of last participant). The final data from the study site will be sent to the 
sponsor (or designee) after completion of the final participant virtual outpatient contact by the 
study personnel, in the time frame specified in the Clinical Trial Agreement (refer to the SoA).
Study Completion Definition for Study Participants
A participant will be considered to have completed the study, regardless of whether they continue 
study intervention treatment, if he or she has completed assessments at Day 49 of the double-blind
treatment period, or has experienced a clinical endpoint that precludes further continuation in the 
study (eg, early mortality). All study participant should have their last follow-up visit at Day 49 
regardless of when the last day that study intervention was taken.
Discontinuation of Study Intervention in Study Participants
Participants who prematurely discontinue study intervention for any reason before completion of 
the double-blind treatment phase should be informed that they are to continue to be followed 
according to the SoA and can be considered to have completed the study if they have completed 
the Day 49 assessments.
Consent Withdrawal
!
For participants who withdraw consent for follow-up, there should be documentation of the 
reason for withdrawal. Study staff should explicitly seek information about the possible 
contribution of efficacy or safety endpoints (including bleeding) or adverse events to the 
participant’s desire to withdraw and document any endpoints or adverse events that are 
identified in the adverse event section of the eCRF.
!
Early permanent discontinuation of study intervention should be distinguished from 
withdrawal of consent for follow up contacts, or medical records checks. Participants 


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requesting withdrawal from follow up will no longer be contacted and should be informed 
that withdrawal of consent for follow up will result in loss of important information about the 
benefits and risks of study intervention.
5.
STUDY POPULATION
Screening for eligible participants will be performed between Day -14 and Day 1. All screening 
assessments including obtaining informed consent, recording the date of positive COVID-19 test 
documenting infection, and recording the baseline D-dimer level, if available, which should be 
obtained within 14 days of the positive COVID-19 test and prior to randomization. SARS-CoV-2 
positivity, as determined locally by real time-PCR or any other commercial or public health assay, 
in any specimen at any time prior to randomization is acceptable and should not be repeated for 
inclusion in the study. Antibody tests for prior exposure to COVID-19 may not be used for study 
entry. If all eligibility criteria are met at screening, then randomization may occur on that same 
day. Refer to Section 5.4, Screen Failures for conditions under which the repeat of any screening 
procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the investigator should consult with the appropriate sponsor 
representative and resolve any issues before enrolling a participant in the study. Waivers are not 
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2, 
Sample Size Determination.
5.1.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1.
Male or female (according to their reproductive organs and functions assigned by 
chromosomal complement)
2.
18 years of age or older
3.
COVID-19 positive diagnosis by locally obtained viral diagnostic test (eg, PCR). This 
may be nasal swab or saliva test or other available technology to demonstrate current 
infection. (Note: this is not an antibody test or serology test that just indicate prior 
exposure to the disease. In the case of multiple positive COVID-19 PCR tests, only the 
date of the first test may be used).
4.
Confirm that participant is known to health system, with at least 1 contact in EMR prior 
to screening
5.
Symptoms attributable to COVID-19 (eg, fever, cough, loss of taste or smell, muscle 
aches, shortness of breath, fatigue)


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6.
Initial treatment plan does not include hospitalization
7.
Presence of at least 1 additional risk factor:
1) Age ≥60 years
2) Prior history of VTE
3) History of thrombophilia
4) History of CAD
5) History of PAD
6) History of cerebrovascular disease or ischemic stroke
7) History of cancer (other than basal cell carcinoma)
8) History of diabetes requiring medication
9) History of heart failure
10) Body Mass Index ≥35 kg/m2
11) D-dimer > upper limit of normal for local laboratory (within 2 weeks of the date of 
the COVID-19 test and prior to randomization)
8.
Must provide consent via eConsent indicating that he or she understands the purpose of,
and procedures required for, the study and is willing to participate in the study, including 
follow up
9.
Willing and able to adhere to the lifestyle restrictions specified in this protocol
5.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
1.
Increased risk of bleeding such as 1) significant bleeding in the last 3 months, 2) active 
gastroduodenal ulcer in the last 3 months, 3) history of bronchiectasis or pulmonary 
cavitation, 4) need for dual antiplatelet therapy or anticoagulation, 5) prior intracranial 
hemorrhage, 6) known severe thrombocytopenia (platelet count <50 x 109/L), or 7) 
active cancer and undergoing treatment
2.
Any illness or condition that in the opinion of the investigator would significantly 
increase the risk of bleeding (eg recent trauma, recent surgery, severe uncontrolled 


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hypertension, gastrointestinal cancer, renal failure requiring dialysis, severe liver 
disease, known bleeding diathesis)
3.
Known allergies, hypersensitivity, or intolerance to rivaroxaban or its excipients (refer 
to the IB)
4.
Positive COVID-19 antibody or serology test after 2-week period of acute, symptomatic
COVID-19 infection
5.
Known diagnosis of triple positive (ie, positive for lupus anticoagulant, anticardiolipin, 
and anti-beta 2-glycoprotein I antibodies) antiphospholipid syndrome
6.
Recently taken or required to take any disallowed therapies as noted in Section 6.7, 
Concomitant Therapy before the planned first dose of study intervention or required 
during the study. For example, the need for the use of strong cytochrome P450 (CYP) 
3A4 inhibitor or inducer per local prescribing information
7.
Received an investigational intervention (including investigational vaccines) or used an 
invasive investigational medical device within 30 days before the planned first dose of 
study intervention or is currently enrolled in an experimental, investigational study
(Note: participation in an observational registry is allowed)
8.
Women who are pregnant or breastfeeding and women of childbearing potential without 
proper contraceptive measures. (see Section 10.7, Appendix 7, Contraceptive and 
Barrier Guidance)
NOTE: The required source documentation to support meeting the enrollment criteria are noted 
in Section 10.5, Appendix 5, Regulatory, Ethical, and Study Oversight Considerations.
5.3.
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions 
during the course of the study to be eligible for participation:
1.
Refer to Section 6.7, Concomitant Therapy for details regarding prohibited and 
restricted therapy during the study
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements)
3. 
Female participants should avoid getting pregnant until the end of the study
4. 
A woman of childbearing potential must practice a highly effective, preferably 
user-independent method of contraception (failure rate of <1% per year when used 
consistently and correctly) and agree to remain on a highly effective method until the 
end of the study. The investigator should evaluate the potential for contraceptive 
method failure (eg, noncompliance, recently initiated) in relationship to the dose of 


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study intervention. Examples of highly effective methods of contraception are located 
in Section 10.7, Appendix 7, Contraceptive and Barrier Guidance.
5.
A male participant must wear a condom when engaging in any activity that allows for 
passage of ejaculate to another person until the end of the study. Male participants 
should also be advised of the benefit for a female partner to use a highly effective 
method of contraception as condom may break or leak.
5.4.
Screen Failures
Participant Identification, Enrollment, and Screening
The study will enroll participants from large, integrated, health system networks in the United 
States. No in-person clinic visits are required for the study. 
Potential study participants will be identified based on the following criteria:
!
Documented use of health system services as demonstrated by at least 1 contact in EMR prior
to screening
!
A positive COVID-19 test result (eg, PCR) documented in the EMR
All potential participants who electronically sign the remote e-consent will receive a unique 
identifier in the eConsent application held by a third-party representative. All data entered and 
collected via the eConsent application or system are time and date stamped for completeness. 
Reports will be available to permit a detailed listing of each participant from remote e-consent 
through the study.
Individuals who are not COVID-19 positive at the time of screening may be rescreened. A 
participant number will be assigned until rescreened. Participants should not be assigned the same
participant number as for the initial screening.
The participant identification and electronic enrollment log will be treated as confidential and will 
be filed by the investigator in the study file. To ensure participant confidentiality, no copy will be 
made. All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent. In cases where the participant is not randomized 
into the study, the date seen and age at initial informed consent will be used.
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1.
Study Interventions Administered
Rivaroxaban will be manufactured and provided under the responsibility of the sponsor. Refer to 
the IB for a list of excipients.
Participants need to receive study intervention preferably within 2 days after randomization.


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For details on rescue medications, refer to Section 6.7.1, Rescue Medication. For a definition of 
study intervention overdose, refer to Section 6.6, Treatment of Overdose.
Description of Interventions
All participants are to self-administer study intervention (rivaroxaban or placebo) orally once
daily, with or without food, at approximately the same time each day throughout the 35-day 
double-blind treatment period. The first dose should be taken as soon as possible after 
randomization and within 2 days of randomization if possible. The date and time of the study 
intervention should be recorded as accurately as possible.
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 participant takes a dose of study intervention on Day 35, the participant should 
discontinue study intervention and complete the Day 35 (±6 days) virtual outpatient contact. A 
final follow-up visit will occur on Day 49±7 days by virtual outpatient contact as well (refer to the 
SoA).
All participants will be allowed to be treated with standard of care medications for COVID-19 at 
the discretion of the participants' local physician. Please see Section 6.7, Concomitant Therapy for 
drugs with or without significant interactions with rivaroxaban. If a medication must be given to a 
participant in the study that has an unacceptable drug interaction, the study intervention should be 
discontinued for as long as the negatively interacting drug must be given. Study intervention may 
be restarted at the discretion of the investigator if the drug with the negative interaction is 
discontinued. In the event that the participant wishes to participate in another study that is testing 
an experimental therapy, the participant should withdraw from this study. However, passive 
collection of EMR data and vital status may still be obtained through Day 49. 
6.2.
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
For rivaroxaban tablets, no storage restrictions (temperature, humidity, light) apply. The storage 
recommendation for rivaroxaban is at room temperature (approximately 15°C to 30°C).
The drug depot and/or central pharmacy can refer to the pharmacy manual investigational product 
and procedures manual for additional guidance on study intervention preparation, handling, and 
storage.
The drug depot and/or central pharmacy is responsible for ensuring that all study intervention 
received at the depot is accounted for throughout the study. The dispensing of study intervention to 
the participant must be documented at the drug depot and/or central pharmacy.
Study intervention must be handled in strict accordance with the protocol and the container label and 
must be stored at the drug depot and/or central pharmacy in a secure area under appropriate 
environmental conditions.


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Study intervention will be delivered to the participant by a qualified member of the drug depot, 
vendor, central pharmacy, or designee. Study intervention will be supplied only to participants of the
study. Participants will be instructed on how to store study intervention and how to destroy any 
unused study intervention at the end of the 35-day, double-blind treatment period.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 intervention groups (rivaroxaban or placebo) based on a computer-generated 
randomization schedule prepared before the study by or under the supervision of the sponsor. The 
randomization will be balanced by using randomly permuted blocks in the sites and a stratification 
factor. The interactive voice response system (IVRS) or interactive web response system (IWRS) 
will assign a unique intervention code, which will dictate the intervention assignment and 
matching study intervention kit for the participant. The requestor must use his or her own user 
identification and personal identification number when contacting the IVRS/IWRS and will then 
give the relevant participant details to uniquely identify the participant. The study will be stratified 
by the time from positive diagnostic of COVID-19 test to first dose into an early cohort (1 to 
5 days) and a later cohort (6 to 14 days). The kit number will dictate the study intervention 
assignment and the matching study intervention bottle to be shipped or delivered to the participant 
directly from the drug distribution vendor or central pharmacy.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IVRS or IWRS, which has the functionality to allow the investigator to break the blind 
for an individual participant.
Data that may potentially unblind the intervention assignment 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.
Under normal circumstances, the blind should not be broken until all participants have completed 
the study and the database is finalized. The investigator may in an emergency determine the 
identity of the intervention by contacting the IVRS/IWRS. While the responsibility to break the 
intervention code in emergency situations resides solely with the investigator, it is recommended 
that the investigator contact the sponsor or its designee if possible, to discuss the particular 
situation, before breaking the blind. Telephone contact with the sponsor or its designee will be 
available 24 hours per day, 7 days per week. In the event the blind is broken, the sponsor must be 
informed as soon as possible. The date and reason for the unblinding must be documented in the 
source document.


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Participants who have had their intervention assignment unblinded should continue to return for 
scheduled evaluations.
6.4.
Study Intervention Compliance
Participants will receive instructions on compliance with study intervention administration at the 
screening visit and during the course of the study, according to the SoA. Due to health concerns
associated with handling unused study intervention from COVID-19 infected participants, the 
study personnel will assess study intervention compliance by questioning the participant about 
dates of missed dose of study intervention and/or start and stop dates.
6.5.
Continued Access to Study Intervention After the End of the Study
No continued access will be proposed for this study. Participants will be instructed that study 
intervention will not be made available to them after they have completed/discontinued study 
intervention and that they should return to their primary physician to determine standard of care.
6.6.
Treatment of Overdose
Overdose of rivaroxaban may lead to hemorrhage. Discontinue rivaroxaban and initiate 
appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban 
systemic exposure is not further increased at single doses >50 mg due to limited absorption. The 
use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered. 
Due to the high plasma protein binding, rivaroxaban is not dialyzable (see Clinical Pharmacology 
[Section 12.3] of the United States Prescribing Information [USPI]). Partial reversal of laboratory 
anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the 
anti-FXa activity of rivaroxaban is available (Andexanet alpha, Andexxa®). Please see the 
prescribing information for further details regarding administration.
6.7.
Concomitant Therapy
Prestudy therapies administered up to 30 days before first dose of study intervention must be 
recorded at screening.
Because all the participants enrolled in the proposed study are COVID-19 positive with infection 
symptoms, they will be managed according to local treatment guidelines, including the latest 
version of Centers for Disease Control (CDC) Information for Clinicians on Therapeutic Options 
for Patients with COVID-19. Open or off‑label use of agents that are intended to inhibit SARS-
CoV-2 viral activity are permitted in the study, including those listed in the CDC guidelines on 
Therapeutic Options for patients with COVID-19. In the event that a participant wishes to 
participate in another study that is testing an experimental therapy, the participant should withdraw 
from this study. However, passive collection of EMR data and vital status may still be obtained 
through Day 49.
Interactions of Rivaroxaban with COVID-19 Therapies
Based on the European Society of Cardiology Guidance for the Diagnosis and Management of CV 
Disease during the COVID-19 Pandemic (ESC 2020), the interactions of rivaroxaban with 


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COVID-19 therapies are outlined in Table 1. The list of COVID-19 therapies should not be 
considered exhaustive. Additional information regarding new COVID-19 therapies and/or possible 
interactions with rivaroxaban may be provided to investigators outside of the protocol.
Table 1:
Interactions of rivaroxaban with COVID-19 therapies
COVID-19 Therapies
(impact on rivaroxaban)
Rivaroxaban
(interaction with COVID-19 therapy)
Chloroquine (up*)
(2) No clinically significant interaction
Hydroxychloroquine (up*)
(2) No clinically significant interaction
Azithromycin (up*)
(3) Potential interaction 
Darunavir/Cobicistat (up*)
(4) No coadministration
Atazanavir/Cobicistar (up*)
(4) No coadministration
Lopinavir/Ritonavir (up*)
(4) No coadministration
Ribavirin
(2) No interaction 
Remdesivir
(2) No interaction
Favipiravir
(2) No interaction 
Bevacizumab
(1) No info
Eculizumab
(1) No info
Tocilizumab (down*)
(2) No clinically significant interaction
Fingolimod
(1) No info 
Interferon
(1) No info
Pirfenidone
(1) No info 
Methylprednisolone
(1) No info 
Nitazoxanide
(2) No interaction 
Key:
Up*: potentially increases patient exposure to rivaroxaban;
Down*: potentially decreases patient exposure to rivaroxaban;
(1) No info: No information found
(2) No interaction: No clinically significant interaction is expected, or potential interaction is likely to be of weak 
intensity, not requiring additional action/monitoring or dose adjustment;
(3) Potential interaction: Potential interaction which may require additional monitoring;
(4) No coadministration: the drugs should not be co-administered.
Source: Adapted from the European Society of Cardiology Guidance for the Diagnosis and Management of CV 
Disease during the COVID-19 Pandemic, Table 16.
Allowed Concomitant Medications
Antiplatelet therapy with a single oral agent such as ASA (aspirin) ≤162 mg, dipyridamole, or 
monotherapy with a chemoreceptor for adenosine diphosphate (P2Y12) inhibitor (ie, clopidogrel
≤75 mg, ticlopidine ≤250 mg, prasugrel or ticagrelor) is allowed. Dual antiplatelet therapy (eg, 
ASA plus a P2Y12 inhibitor) is not allowed, with the exception of ASA and dipyridamole. All 
antiplatelet therapy must be recorded throughout the study beginning with start of the first dose of 
study intervention. Nonsteroidal anti-inflammatory drugs (NSAID) are allowed.
Note: Coadministration of rivaroxaban with ASA, clopidogrel or other P2Y12 inhibitors, or
chronic NSAID use may increase the risk of bleeding.


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Disallowed Concomitant Medications
Potential participants 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 participants require or 
take prohibited medications during the study as outlined below, they must either temporarily 
interrupt or permanently discontinue the study intervention, as appropriate for the duration of the 
therapy with the prohibited medication:
!
Combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitors (such as but not limited to 
ketoconazole, 
telithromycin 
or
ritonavir, 
lopinavir, 
atazanavir/cobicistat, 
and 
darunavir/cobicistat) 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.
!
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.
!
Anticoagulant (eg, warfarin sodium or other vitamin K antagonists, Factor II or Xa inhibitors) 
is prohibited as concomitant therapy during the study. Study intervention should be 
discontinued in participants who are hospitalized and receive open-label thromboprophylaxis 
per guidelines, develop any condition that requires anticoagulation (eg, atrial fibrillation, 
VTE) that will extend beyond the end of the study intervention treatment phase.
!
Use of antiplatelet therapy, including:
∀
ASA >162 mg/day
∀
Clopidogrel >75 mg/day or ticlopidine >250 mg twice daily
∀
Cilostazol >200 mg/day
∀
Dual therapy with 2 or more antiplatelet agents (dipyridamole with ASA is permitted)
∀
Thrombin-receptor antagonists (eg, vorapaxar)
!
Modification of an effective pre-existing therapy should not be made for the explicit purpose 
of entering a participant into the study.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.


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6.7.1.
Rescue Medication
An agent to reverse the anti-FXa activity of rivaroxaban is available (Andexanet alpha, Andexxa®).
Because of high plasma-protein binding, rivaroxaban is not dialyzable (see Clinical Pharmacology 
[Section 12.3] of the USPI). Protamine sulfate and vitamin K are not expected to affect the 
anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin 
complex concentrate (PCC), activated prothrombin complex concentrate, or recombinant factor 
VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. 
Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (prothrombin time 
[PT], international normalized ratio [INR] or activated partial thromboplastin time [aPTT]) or anti-
FXa activity is not recommended. However, measurement of anti-FXa activity using rivaroxaban-
specific calibrators and controls correlates closely with plasma concentrations and can be a marker 
for plasma concentration. 
The study site will not be supplied with rescue medication by the sponsor.
6.7.2.
Approach to the Subject with a Bleeding Event
If a subject has a serious bleeding event during study intervention, the subject should be referred 
for evaluation at the appropriate facility such as an urgent care center or emergency department 
depending on the severity of the bleeding. The following routine measures should be considered:
Delay the next administration of study intervention or discontinue treatment if indicated. 
Rivaroxaban has a plasma (or terminal elimination) half-life of 5 to 9 hours in healthy young 
subjects (aged 20 to 45 years) and 11 to 13 hours in elderly subjects (aged 60 to 76 years). 
Therefore, temporary cessation of study intervention may allow control of bleeding. Unblinding 
of study intervention should not be necessary.
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 (ie, rule out DIC, thrombocytopenia, and other coagulopathies; 
kidney and liver dysfunction; concomitant medications), 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):
!
Activated PCC
!
PCC
!
Recombinant factor VIIa (NovoSeven®)
!
Andexanet alpha (Andexxa)
Any products administered to control bleeding should be entered in the eCRF.


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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 intervention may be considered based on 
the clinical judgment of the investigator.
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:
!
The participant withdraws consent to receive study intervention,
!
The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the participant to discontinue study intervention,
!
If a participant requires hospitalization for COVID-19 (ie, the combined total of inpatient 
and/or ER stay ≥24 hours),
!
The participant experiences symptomatic VTE, MI, ischemic stroke, acute limb ischemia, 
non-CNS systemic embolization,
!
The participant develops any condition, which in the investigator’s judgment requires 
long-term anticoagulation, thromboprophylaxis, or fibrinolysis,
!
The participant develops renal failure requiring dialysis or has an eGFR <15 ml/min/1.73m2,
!
The participant becomes pregnant,
!
The participant is required to take a medication known as a strong CYP3A4 inhibitor.
If a participant discontinues study intervention for any reason before the end of the study, 
assessments should continue in accordance with the SoA with all scheduled visits. If the participant
permanently discontinued study intervention prior to Day 14, the Day 35 and Day 49 visits will 
still occur. Study intervention assigned to the participant who discontinued study intervention may 
not be assigned to another participant.
7.1.1.
Temporary Discontinuation
If a participant is hospitalized for reason(s) not related to COVID-19 illness, has not experienced 
an event of symptomatic VTE, MI, ischemic stroke, acute limb ischemia, or non-CNS systemic
embolization, or bleeding, the participant may be restarted on study intervention after being 
discharged unless the participant requires post-hospitalization anticoagulation, at the discretion of 
the investigator.
If the participant requires an invasive procedure or surgery as an outpatient, study intervention 
should be stopped at least 24 hours before the procedure to reduce the risk of bleeding. In deciding 
whether a procedure should be delayed until 24 hours after the last dose of study intervention, the 
increased risk of bleeding should be weighed against the urgency of the procedure. Study 


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intervention may be restarted after the surgical or other procedures once adequate hemostasis has 
been established, if deemed appropriate by the local treating physician.
Participants hospitalized for worsening of COVID-19 disease should temporarily discontinue 
study intervention during the hospitalization as guidelines now recommend thromboprophylaxis 
in most patients who do not have a contraindication. After discharge, study intervention may be 
restarted. However, if it is the policy of the hospital to routinely provide anticoagulation after 
hospital discharge, then study intervention should be permanently discontinued.
7.2.
Participant Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
!
Lost to follow-up
!
Withdrawal of consent
In the event a participant withdraws consent and does not agree to any kind of follow-up and 
specifically refuses any further contact with study staff, this must be documented in the study 
database. Vital status may be obtained at study end through the participant’s physician, medical 
claims, alternate contacts (eg, family and/or friends) or public information according to local 
guidelines and as allowed by local regulations.
Participants in the study may participate in an observational registry without need for withdrawal 
from the study. Participants wishing to enter another investigational study must withdraw from 
this study. However, passive collection of EMR data and vital status through the end of this study 
(Day 49) will still be obtained even if the participant withdraws from the study to participate in 
another investigational study.
Withdrawal of Consent
A participant declining to continue with scheduled virtual outpatient contacts does not constitute 
withdrawal of consent. Alternate follow-up mechanisms that the participant agreed to when 
signing the eConsent may be utilized (eg, consult with family members, contacting the 
participant’s other physicians, medical records, database searches, use of locator agencies at study 
completion,) as local regulations permit. For participants who withdraw consent for any kind of 
follow-up, the participant’s vital status will be obtained through applicable information sources 
according to local guidelines and as allowed by local regulations. Passive collection of EMR data 
will continue to be allowed unless consent for the use of this EMR data is specifically withdrawn 
by the participant.
Withdrawal of consent should be an infrequent occurrence in clinical studies (Rodriguez 2015).
Therefore, prior to the start of the study, the sponsor and the investigator should discuss and reach 
a clear understanding of what constitutes withdrawal of consent in the context of the available 
reduced follow-up mechanisms listed.


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7.3.
Lost-to-Follow up
To reduce the chances of a participant being deemed lost-to-follow up, attempts should be made
prior to randomization to obtain contact information from each participant, eg, home, work, and 
mobile telephone numbers and email addresses for both the participant as well as appropriate 
family members.
A participant will be considered lost-to-follow up if he or she repeatedly is unable to be contacted 
by the study personnel or the status cannot be verified based on the participant’s medical record. 
A participant cannot be deemed lost-to-follow up until all reasonable efforts made by the study 
personnel to contact the participant are deemed futile. The following actions should be taken if a 
participant cannot be reached at a scheduled point of contact:
!
The study personnel should attempt to contact the participant to reschedule the missed virtual 
outpatient contact as soon as possible, to counsel the participant on the importance of 
maintaining the schedule of virtual outpatient contacts, to ascertain whether the participant 
wishes to or should continue in the study.
!
Before a participant is deemed lost-to-follow up, the investigator or designee must make every 
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, 
e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address, 
or local equivalent methods). Locator agencies may also be used as local regulations permit. 
These contact attempts should be documented in the participant’s medical records.
Should the participant continue to be unreachable, they will be considered to have withdrawn from 
the study.
Study personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those who 
did not get study intervention. Public sources may be searched for vital status information. If vital 
status is determined as deceased, this will be documented, and the participant will not be 
considered lost-to-follow up. Sponsor personnel will not be involved in any attempts to collect 
vital status information.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot 
reach the participant to inform them, their contact information will be transferred to another study 
site.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The SoA summarizes the frequency and timing of efficacy, MRU, benefit-risk, health economic, 
and safety measurements applicable to this study.
Medical resource utilization and health economics data will be collected. Refer to Section 8.4, 
Medical Resource Utilization and Health Economics for details.
No blood collection will be required.


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Study-Specific Materials
The investigator will be provided with the following supplies including but not limited to:
!
IB
!
IWRS Manual
!
Sample eConsent
!
Contact Information Page(s)
!
Electronic Data Capture (eDC) Manual
8.1.
Efficacy Assessments
Efficacy outcomes will be assessed and documented per the SoA and will include all information 
necessary for the following key efficacy outcomes to be assessed via telephone/web contact, from 
review of the eCRF, EMR, claims databases, Social Security Death Index, or other source 
documents: all-cause mortality (and cause of death if known), all-cause hospitalization, MI, stroke 
(ischemic, hemorrhagic, unknown etiology), acute limb ischemia, non-CNS systemic 
embolization, symptomatic VTE (ie, symptomatic DVT, and PE).
Any event that includes symptoms or signs suggestive of symptomatic VTE events, MI, ischemic 
stroke, acute limb ischemia, or non-CNS systemic embolization will be assessed and entered into 
the eCRF as a potential event by the investigator/study team. In identifying potential events, 
investigators are encouraged to give careful consideration to symptoms that may represent 
manifestations of major venous and arterial thrombotic events and encourage participants to seek 
medical care. Review of EMR data for health system encounters suggestive of study events (eg,
hospitalizations) may also be conducted to identify study endpoints. Source documents may be 
requested from nonstudy physicians within the health network or from health care encounters 
outside of the investigator’s health network to assist in identifying all efficacy and safety outcome 
events.  
There will be no independent adjudication by a Clinical Events Committee. Potential events will 
be adjudicated locally by a qualified site investigator who will review source documents, such as 
the EMR, eCRF, and other study records or source documents in a blinded and impartial manner 
to verify/adjudicate events according to the endpoint definitions in Section 10.3, Appendix 3, 
Endpoint Definitions. The qualified investigator will evaluate all available information from the 
eCRF, EMR or other source documents and will document in the eCRF whether the subject did or 
did not have any of the following events according to the protocol-specified definitions of the 
events:
!
Symptomatic VTE
!
MI
!
Stroke (ischemic, hemorrhagic or unknown etiology)
!
Acute limb ischemia


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!
Non-CNS systemic embolization
Any clinical event that suggests the possibility that an efficacy outcome event has occurred 
(including acute coronary syndrome and transient ischemic attack) should be recorded in the 
eCRFs and will be assessed by the investigator. COVID-19 has been associated with emboli in a 
variety of locations, including internal organs (eg, mesenteric artery, renal artery). These should 
all be included in the endpoint of “non-CNS systemic embolization.” Unusual locations for venous 
thrombosis have also been reported in association with COVID-19 such as thrombosis of the 
cerebral veins or sinuses. These will be captured under “symptomatic VTE” per the guidelines in
Section 10.3, Appendix 3, Endpoint Definitions. 
The analysis of study efficacy endpoint events will be based on the qualified investigator’s 
assessment in a blinded fashion using standardized event definitions. The EMR and/or eCRF will 
serve as supporting source records to document the endpoint and to verify or confirm study 
endpoints. Event definitions for verifying or confirming study endpoints are provided in 
Section 10.3, Appendix 3, Endpoint Definitions. Details regarding the process for identification of 
events, verification or adjudication of study endpoints against event definitions, and for retaining 
source documentation not available in the clinical database will be provided in a Site Event 
Manual. Upon request, all pertinent data outside the clinical database that was used for event 
verification or adjudication must have all participant-identifying information masked or redacted 
and made available to the sponsor or designee. Any modifications, clarifications or corrections to 
endpoint definitions will be noted in the SAP rather than requiring a protocol amendment.
8.2.
Safety Assessments
Safety assessments will include monitoring of serious adverse events, nonserious adverse events 
that are severe or of particular interest and study safety endpoints (major bleeding, including 
critical site bleeding and fatal bleeding, and nonmajor clinically relevant bleeding).
Additionally, participant-reported adverse events at the virtual study visits that are serious will be 
collected and assessed by Janssen Global Medical Safety (GMS) per the sponsor’s standard 
operating procedure. Efficacy and safety endpoints including all bleeding events will not be 
considered as adverse events or serious adverse events (see Section 8.3, Adverse Events, Serious 
Adverse Events, and Other Safety Reporting). Safety evaluations will be assessed and reported by 
the investigator per the SoA. Review of the eCRF, EMR, claims databases, and/or Social Security 
Death Index, or other source documents may be utilized for data collection.
Bleeding Events
The study will use the ISTH bleeding event classification to assess overt bleeding as major, 
nonmajor-clinically relevant, or trivial. 
The safety endpoints for this study include major, critical site and fatal bleeding, and nonmajor 
clinically relevant bleeding as assessed by a qualified investigator and reported in the eCRF. 
An ISTH major bleeding event is defined as overt bleeding that is associated with
(Schulmann 2005):


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!
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
Nonmajor 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 intervention, or associated with discomfort 
for the participant such as pain or impairment of activities of daily life. Refer to Section 10.4, 
Appendix 4, Nonmajor Clinically Relevant Bleeding Event Criteria for examples of nonmajor 
clinically relevant bleeding.
Trivial bleeding is defined as any other overt bleeding episode that does not meet the ISTH criteria 
for major bleeding or nonmajor clinically relevant bleeding. 
The Cunningham protocol may also be applied to automated health plan data to identify and 
classify bleeding events (Cunningham 2011) as an exploratory endpoint.
Details regarding the IDMC are provided in Section 10.5.5, Committees Structure of Appendix 5, 
Regulatory, Ethical, and Study Oversight Considerations.
8.2.1.
Physical Examinations
No physical examinations will be performed. Height and weight will be assessed and reported by 
the participant or obtained from medical records.
8.2.2.
Pregnancy Testing
No screening serum pregnancy test will be obtained before the first dose of study intervention on 
Day 1. Female participants of childbearing potential will be screened for pregnancy status utilizing 
information from the EMR and if the participant suspects she may be pregnant, the study personnel
will encourage that an at home self-pregnancy test be conducted prior to randomization.
8.3.
Adverse Events, Serious Adverse Events, and Other Safety Reporting
All participant-reported adverse events at the virtual study visits that are serious will be collected 
and assessed by Janssen GMS per the sponsor’s standard operating procedure. Queries for these 
cases will go to the principal investigator as appropriate. If follow up is needed with the 
participant’s treating physician, it will be done either through the principal investigator or directly 
with the treating physician. Participants will agree to provide their treating physician’s contact 
information to the study team. All serious adverse events will be assessed by Janssen GMS for 
potential suspected unexpected serious adverse reactions (SUSARs) for expedited regulatory 
reporting.
Efficacy and safety endpoints including all bleeding will be captured in the EMR and/or eCRF as 
endpoints only and will be waived from unblinding and exempt from expedited reporting. 


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Special Reporting Situations
Safety events of interest on a sponsor study intervention that may require expedited reporting 
and/or safety evaluation include, but are not limited to:
!
Overdose of a sponsor study intervention
!
Suspected abuse/misuse of a sponsor study intervention
!
Inadvertent or accidental exposure to a sponsor study intervention
!
Medication error involving a sponsor product (with or without participant exposure to the 
sponsor study intervention, 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.
Non-Serious Adverse Events 
The following should be reported in the eCRF:
!
Non-serious adverse events leading to permanent study intervention discontinuation.
!
All severe nonserious adverse events (regardless of relation to study intervention) will be 
collected except for study endpoints.
!
Any adverse event of particular concern to the investigator may be recorded in the eCRF to 
alert the sponsor.
Any other nonserious adverse events do not require reporting. 
8.3.1.
Time Period for Collecting Adverse Event and Serious Adverse Event
Information
All Adverse Events
All participant-reported serious adverse events, nonserious adverse events that are severe or of 
particular interest, and bleeding events will be collected from the time a signed and dated eConsent
is obtained until the participant completes their participation on Day 49 of the posttreatment period. 
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study personnel within 24 hours of their knowledge of the event.
Regulatory Reporting Requirements for Serious Adverse Events
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 SUSARs. The investigator (or sponsor where required) must report 
SUSARs to the appropriate Independent Ethics Committee (IEC)/Institutional Review Board 
(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 (See Table 2).


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Adverse Events as Study Endpoints
All events that are assessed by the investigator as possibly being 1 of the components of the 
primary composite endpoint, including symptomatic DVT or PE, MI, ischemic stroke, acute limb 
ischemia, non-CNS systemic embolization, all-cause hospitalization, and all-cause mortality, or a 
secondary efficacy endpoint or a safety endpoint (ie, major bleeding, critical site bleeding and fatal 
bleeding and nonmajor clinically relevant bleeding) including all bleeding should be handled as 
follows.
Investigator Responsibilities:
All confirmed study endpoint events must be reported to the sponsor. Investigators are also 
required to retain source records used to verify or confirm the outcome of endpoint events if not 
available in the clinical database. If requested by the sponsor, details on assembly and submission 
of source records associated with the event will be provided.
Sponsor Responsibilities (or Designee):
To protect the integrity of the study, components of the primary endpoint, secondary endpoints,
and bleeding endpoints will not be unblinded or reported to either Health Authorities (HAs) or 
investigators as safety reports unless otherwise requested by HAs or Ethics Committees. After 
study completion, these events will be included in the final analysis, which will be unblinded and
submitted to HAs with the study report.
Refer to Table 2 for a summary of the reporting process for serious unexpected and related events.
8.3.2.
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be 
reported to the sponsor by the study personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious 
adverse events and must be reported using a serious adverse event reporting form. Participants who 
become pregnant should permanently discontinue study intervention. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
Table 2:
Reporting of Serious Unexpected and Related Events (Unless Otherwise Requested by Health 
Authorities or Ethics Committees) 
Event Type
Expedited Report to 
Health Authorities and 
Investigators
Unblinding to Health 
Authorities
Unblinding to 
Investigators
Study endpoint events (including all 
bleeding)
N
N
N
Non-endpoint serious adverse events
Y
Y
N


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8.3.3.
Disease-related Events and Disease-related Outcomes Not Qualifying 
as Adverse Events or Serious Adverse Events
The following events are considered COVID-19 infection-related events as per WHO assessment 
and do not require sponsor reporting to the sponsor and HAs:
Most Common Symptoms:
!
Fever
!
Dry cough
!
Tiredness
Less Common Symptoms:
!
Aches and pains
!
Sore throat
!
Diarrhea 
!
Conjunctivitis
!
Headache
!
Loss of taste or smell
!
A rash on skin, or discoloration of fingers or toes
Serious Symptoms:
!
Difficulty breathing or shortness of breath
!
Chest pain or pressure
!
Loss of speech or movement
In addition, serious or nonserious adverse events that are known to be associated with COVID-19 
(eg, “COVID-19 digits”, ARDS, DIC) do not have to be reported as adverse events, but may be 
captured in the eCRF as endpoints. Symptoms listed above that are reported to study personnel 
should be evaluated as to whether they might be related to study endpoints such as PE, MI or 
ischemic stroke. Study participants with such symptoms should be referred to their local physician 
or ER for evaluation. Study participants with worsening shortness of breath that may represent 
worsening viral pneumonia should also seek prompt medical attention.
8.4.
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data, associated with medical encounters, will 
be collected in the eCRF or via EMR or from other source documents by the investigator and study 
personnel for all participants throughout the study. Protocol-mandated procedures, tests, and 
encounters are excluded. The data collected may be used to conduct exploratory economic 
analyses and will include:


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!
Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient)
!
Duration of hospitalization (total days length of stay, including duration by wards; eg, ICU)
!
Number and character of diagnostic and therapeutic tests and procedures
!
Outpatient medical encounters and treatments (including physician or ER visits, tests and 
procedures, and medications)
9.
STATISTICAL CONSIDERATIONS
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 data is outlined 
below. Specific details will be provided in the SAP that will be finalized within 3 months after the 
first participant is randomized.
9.1.
Statistical Hypotheses
The primary hypothesis is to evaluate whether rivaroxaban reduces the risk of a composite 
endpoint of major venous and arterial thrombotic events, hospitalization and all-cause mortality 
compared with placebo in outpatients with acute, symptomatic COVID-19 infection during the 
treatment period (Day 35). The primary statistical alternative hypothesis is that rivaroxaban is 
superior to placebo on the primary efficacy outcome, that is, time to the first event for the 
rivaroxaban group is stochastically later than that for the placebo group from randomization up to 
Day 35. 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.
The secondary hypotheses are that rivaroxaban is superior to placebo in the prevention of: any 
thrombotic outcome (symptomatic VTE, MI, ischemic stroke, acute limb ischemia and non-CNS 
systemic embolization) and all-cause mortality, all-cause hospitalization, symptomatic VTE,
ER visits, any thrombotic outcome and all-cause hospitalization, hospitalization or death at Day 
35, and all-cause mortality.
9.2.
Sample Size Determination
This is an event-driven study. The targeted total number of primary efficacy outcome events is 
333, based on the ITT analysis set and Up-to-Day-35 analysis phase. If a participant has multiple 
events, only the first is counted towards study size determination.
This targeted total number of events is determined using statistical software PASS 15 based on the 
primary efficacy analysis (defined later) and the following assumptions:


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!
30% relative risk reduction (RRR) in the primary efficacy outcome based on the ITT analysis 
set and Up-to-Day-35 analysis phase (RRR is defined as 1 minus the HR of rivaroxaban versus 
placebo)
!
Power of 90% assuming the above RRR
!
Two-sided significance level of 0.05
To observe the targeted 333 events, it is estimated that a total of approximately 4,000 participants
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 10%.
9.3.
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the eConsent
Randomized
All participants who were randomized in the study
Safety
All randomized participants who take at least 1 dose of study intervention
Key Analysis Sets and Analysis Phases
!
Intention-to-Treat (ITT): This analysis set consists of all randomized participants who have a 
signed eConsent
!
Safety: This analysis set is a subset of the ITT analysis set, consisting of participants who 
receive at least one dose of study intervention
!
Up-to-Day-35: This analysis phase includes all data from randomization to Day 35 visit 
(Day 35+6 days)
On-treatment: This analysis phase includes all data from randomization to 2 days after the last 
dose of the study intervention
9.4.
Statistical Analyses
The SAP will be finalized prior to 3 months after the first participant is randomized and it will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints.
9.4.1.
General Considerations
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.


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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 confidence intervals (CI) at 
a nominal 2-sided level of 95%.
9.4.2.
Primary Endpoint(s)
The primary endpoint is the time from randomization to the first occurrence of all major venous 
and arterial thrombotic events (symptomatic VTE, MI, ischemic stroke, acute limb ischemia, and 
non-CNS systemic embolization), all-cause hospitalization, and all-cause mortality Up-to-Day-35 
analysis phase.
Estimand
The primary estimand is described according to the following 5 attributes:
!
Population: Medically ill participants with acute, symptomatic COVID-19 infection
!
Variable: time from randomization to the first occurrence of primary efficacy event Up-to-
Day-35 analysis phase
!
Treatments: Rivaroxaban 10 mg once daily versus placebo
!
Intercurrent events (events that preclude observation of the variable or affects its
interpretation): treatment discontinuation. A treatment policy strategy will be used for these
intercurrent events
!
Population-level summary: HR of rivaroxaban 10 mg versus placebo, along with the 2-sided
95% CI
This estimand targets the effect of rivaroxaban on the variable measured and follows an “ITT 
principle” strategy.
The primary statistical hypothesis will be tested using a stratified log-rank test by the time from 
COVID-19 positive test to randomization (1 to 5 days inclusive, 6 to 14 days inclusive) with the 
treatment as the only variable. This primary efficacy analysis will be based on the ITT analysis set 
and Up-to-Day-35 analysis phase. Participants will be analyzed according to the treatment group 
to which they are randomized, regardless of actual treatment received. The 2-sided p-value will be 
reported and if it is less than the 2-sided alpha of 0.049 after the adjustment from IA, then 
superiority of the study intervention will be declared.
The point estimate and corresponding 95% CI for the HR (rivaroxaban to placebo) will be provided 
based on the stratified 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 evaluating the significance of an interaction term 
of treatment by logarithm-transformed time in the primary 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 will be assessed by subgroups and their interactions with 
treatment. Pre-specified subgroups and the analysis methods will be detailed in the SAP.


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9.4.3.
Secondary Endpoint(s)
The variables for the analysis of the secondary endpoint are time from randomization to the first 
occurrence of the following: any thrombotic outcome (symptomatic VTE, MI, ischemic stroke, 
acute limb ischemia, and non-CNS systemic embolization) and all-cause mortality, all-cause 
hospitalization, symptomatic VTE,
ER visits,
any thrombotic outcome and all-cause 
hospitalization, and all-cause mortality in the ITT analysis set and Up-to-Day-35 analysis phase.
The other variable for the analysis of the secondary endpoint is hospitalization or death at Day 35.
Estimands
The estimands for the analysis of the secondary endpoints are the same as for the primary efficacy 
endpoint except for the hospitalization and all-cause death at Day 35.
The estimand for the analysis of the frequency of participants who are hospitalized or dead at 
Day 35 is the same as for the primary efficacy endpoint except variable and population-level 
summary.
!
Variable: Hospitalization or death at Day 35 (Day 35±6 days)
!
Population-level summary: Weighted relative risk (RR) of rivaroxaban 10 mg versus placebo, 
along with the 2-sided 95% CI
The analysis for all secondary efficacy outcomes will proceed as in the primary efficacy analysis, 
except for the incidence of all-cause hospitalization and all-cause mortality which will be based 
on Cochran-Mantel-Haenzel approach to estimate the Weighted RR and 95% CI.
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 using a 
hierarchical closed testing procedure, each at alpha of 0.05 (2-sided). The current proposed 
hierarchy is listed below. This may be updated/altered in the final SAP rather than requiring a 
protocol amendment. If an individual test during any step is not statistically significant, subsequent 
tests will not be declared to be statistically significant:
!
Any thrombotic outcome (symptomatic VTE, MI, ischemic stroke, acute limb ischemia, and 
non-CNS systemic embolization) and all-cause mortality
!
All-cause hospitalization
!
Symptomatic VTE
!
ER visits
!
Any thrombotic outcome and all-cause hospitalization
!
Hospitalization or death on Day 35
!
All-cause mortality 


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9.4.4.
Tertiary/Exploratory Endpoint(s)
Each exploratory outcome will be summarized by treatment groups based on the ITT analysis set 
and Up-to-Day-35 analysis phase.
9.4.5.
Safety Analyses
All safety analyses will be made on the Safety Population.
Bleeding Outcomes
The principal safety outcome will be analyzed based on time from randomization to the first 
occurrence of fatal bleeding and critical site 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. Participants will 
be analyzed according to study intervention received. If a participant inadvertently receives both 
drugs, the participant will be analyzed as in rivaroxaban group. The ISTH major, nonmajor 
clinically relevant, and trivial bleeding events will be analyzed as described for the principal safety 
outcome. Major bleeding may also be assessed in an exploratory fashion using the Cunningham 
protocol (Cunningham 2011).
Adverse Events
The verbatim terms used in the EMR and/or eCRF by investigators to identify adverse events will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Any adverse event
occurring at or after the initial administration of study intervention through the day of last dose 
plus 2 days is considered to be treatment emergent. All reported treatment-emergent adverse events 
will be included in the analysis. For each adverse event, the percentage of participants who 
experience at least 1 occurrence of the given event will be summarized by intervention group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue intervention due to an adverse event, who have a major 
bleeding event or who experience a serious adverse event not captured as an endpoint.
9.4.6.
Other Analyses
An IDMC will be established as noted in Section 10.5.5, Committees Structure in Appendix 5, 
Regulatory, Ethical, and Study Oversight Considerations.
Medical Resource Utilization and Health Economics Analyses
Medical resource utilization and health economics data collection will include the ER visits,
hospitalization, and duration of hospitalization and other utilization of medical resources 
(eg, urgent care visits).
Medical resource utilization and health economics data will be descriptively summarized by 
intervention group.


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Benefit-Risk Analyses
The benefit-risk profile of rivaroxaban versus 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 in
a hypothetical population size (eg, 10,000 participants). 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 and fatal and critical-site bleeding. This analysis phase 
includes all data from randomization up to Day 35 (inclusive), which is the period of treatment. In 
addition, the benefit-risk balance may be further assessed for other 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.
9.5.
Interim Analysis
An interim analysis for futility or overwhelming superiority will be conducted when approximately 
167 participants with a primary efficacy outcome have been observed (about 50% of the targeted 
total number of events). 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 and the study will use 
O’Brien-Fleming boundary (Z=2.96, alpha=0.003) to stop the study early for the overwhelming 
superiority. Alpha=0.049 will be used for the final analysis to control the family-wise type I error 
rate at alpha of 0.05 (2-sided). The detailed rules about stopping the study early will be specified 
in the SAP.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS


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10.1.
Appendix 1: Abbreviations and Definitions
ACC
American College of Cardiology
ARDS
acute respiratory distress syndrome
ASA
acetylsalicylic acid
CABG
coronary artery bypass grafting
CAD
coronary artery disease
CDC
Centers for Disease Control and Prevention
CI
confidence interval(s)
CT
computed tomography
cTn
cardiac troponin
COVID-19
coronavirus disease 2019
CYP
cytochrome P450
DIC
disseminated intravascular coagulopathy
DVT
deep vein thrombosis
EC
Executive Committee
ECG
electrocardiogram
ECMO
extracorporeal membrane oxygenation
eCRF
electronic case report form
eDC
electronic data capture
eGFR
estimated glomerular filtration rate
EMR
electronic medical record(s)
ER
emergency room
ESC
European Society of Cardiology
FDA
Food and Drug Administration
FOIA
Freedom of Information Act
FSH
follicle stimulating hormone
FXa
factor Xa
GCP
Good Clinical Practice
GMS
Global Medical Safety
HA(s)
Health Authority (Authorities)
HR
hazard ratio
HRT
hormonal replacement therapy
IA
interim analysis
IB
Investigator's Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
ICU
intensive care unit
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISTH
International Society on Thrombosis and Hemostasis
ITT
Intention-to-Treat
IVRS
interactive voice response system
IWRS
interactive web response system
LBBB
left bundle branch block
LMWH
low molecular weight heparin
non-CNS
noncentral nervous system
NSAID
nonsteroidal anti-inflammatory drugs
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MRU
medical resource utilization
O2sat
oxygen saturation
P2Y12
chemoreceptor for adenosine diphosphate
P-gp
P-glycoprotein
PAD
peripheral artery disease


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PCC
prothrombin complex concentrate
PCI
percutaneous coronary intervention
PCR
polymerase chain reaction
PE
pulmonary embolism
PQC
Product Quality Complaint
RR
relative risk
RRR
relative risk reduction
RRT
renal replacement therapy
SAP
statistical analysis plan
SoA
Schedule of Activities
ST-T
ST-segment–T wave
SUSAR
suspected unexpected serious adverse reaction
URL
upper reference limit
US
United States
USPI
United States Prescribing Information
V-Q
ventilation-perfusion
VTE
venous thromboembolism
WHO
World Health Organization
x
times
Definitions of Terms
Electronic source 
system
Contains data traditionally maintained in a hospital or clinic record to document medical 
care or data recorded in an eCRF as determined by the protocol. Data in this system may 
be considered source documentation.


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10.2.
Appendix 2: World Health Organization Research and Development
Blueprint: Novel Coronavirus Scale for Clinical Improvement (Draft from 
WHO 2020)
Patient State
Descriptor
Score
Uninfected
No clinical or virological evidence of infection
0
Ambulatory
No limitation of activities
1
Limitation of activities
2
Hospitalized 
Mild Disease
Hospitalized, no oxygen therapy
3
Oxygen by mask or nasal prongs
4
Hospitalized 
Severe Disease
Non-invasive ventilation or high-flow oxygen
5
Intubation and mechanical ventilation
6
Ventilation + additional organ support – vasopressors, RRT, 
ECMO
7
Death
8


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10.3.
Appendix 3: Endpoint Definitions
For all endpoints, qualified investigators will review all available source documentation available, 
including information from the eCRF, EMR, Claims data, Social Security Death Index, other 
source documents to make decisions as to whether or not there is sufficient information, in their 
clinical judgment to satisfy the definition of each endpoint event as noted below. In certain 
instances, additional information may be requested if insufficient information is available to make 
a decision. However, the qualified investigator will ultimately make a decision that the event is 
most likely present or absent to the best of his/her ability, blinded to study intervention treatment 
assignment.
Symptomatic Deep Vein Thrombosis (DVT)
Displaying signs or symptoms of proximal or distal lower extremity DVT, upper extremity DVT, 
or other DVT based on 1 or more of the following diagnostic criteria:
a. a non-compressible venous segment on compression ultrasonography, or in participants
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. imaging evidence of cerebral vein or sinus thrombosis, or
d. imaging evidence of other DVT (eg mesenteric vein, renal vein, inferior vena cava, superior 
vena cava, jugular vein), or
e. DVT documented at autopsy.
Participants with a history of previous DVT or incomplete documentation of the previous episode 
is available, additional criteria may be integrated with 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.
Symptomatic PE
Displaying signs or symptoms suggestive of PE and based on 1 or more of the following diagnostic 
criteria. (Note: as COVID-19 may also be associated with in situ pulmonary arterial thrombosis, 
evidence of such associated with symptoms of PE or with deterioration of oxygenation will be 
considered a symptomatic PE):
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


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e. in the absence of imaging test in a hemodynamically unstable participant, evidence of right
ventricular dysfunction by transthoracic or trans esophageal echocardiogram (ESC criteria),
or
f. CT or other imaging evidence of in situ thrombosis in one or more pulmonary arterial
branches, or
f. PE or in situ pulmonary arterial thrombosis documented at autopsy.
The anatomic extent of PE will be classified as either segmental or greater, or subsegmental. The 
totality of available clinical, imaging and laboratory findings should be considered.
Myocardial Infarction
The definition of MI is based on the evidence of myocardial necrosis in a clinical setting consistent 
with acute myocardial ischemia, conforming to the reporting conventions proposed in the Fourth 
universal definition of MI (Thygesen 2018).
Under these conditions any 1 of the following criteria meets the diagnosis for MI. In addition to 
the overall adjudication of MI, the subtypes below will also be reported:
!
Type 1, spontaneous: Detection of a rise and/or fall of cardiac biomarker values (preferably
cardiac troponin [cTn]) with at least 1 value above the 99th percentile of the upper reference
limit (URL) and with at least 1 of the following:
o
Symptoms of acute myocardial ischemia
o
New or presumed new, significant ST-segment–T wave (ST–T) changes or new left
bundle branch block (LBBB)
o
Development of pathological Q waves in the electrocardiogram (ECG)
o
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality in a pattern consistent with an ischemic etiology
o
Identification of an intracoronary thrombus by angiography or autopsy
!
Type 2, ischemic imbalance: Detection of a rise and/or fall of cardiac biomarker values
(preferably [cTn]) with at least 1 value above the 99th percentile of the URL and evidence of
an imbalance between myocardial oxygen supply and demand unrelated to acute coronary
atherothrombosis, requiring at least 1 of the following:
o
Symptoms of acute myocardial ischemia
o
New or presumed new, significant ST–T changes or new LBBB
o
Development of pathological Q waves in the ECG
o
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality in a pattern consistent with an ischemic etiology
!
Type 3: Cardiac death with symptoms suggestive of myocardial ischemia and presumed new
ischemic ECG changes or ventricular fibrillation, but death occurred before cardiac
biomarkers were obtained or before cardiac biomarker values would be increased, or MI is
detected by autopsy examination.


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!
Type 4a: Percutaneous coronary intervention (PCI) related MI is defined as MI associated 
with, and occurring within 48 hours of PCI, with elevation of cardiac biomarker levels (>5 x 
99th percentile URL) in participants with normal baseline values (≤99th percentile URL); or 
a rise of cardiac biomarker levels values >20% if the baseline values are elevated and are 
stable or falling as long as the absolute post-procedure value is still >5 x 99th percentile URL. 
In addition, at least 1 of the following:
o
New ischemic ECG changes or new LBBB
o
Development of new pathologic Q waves (Isolated development of new pathological 
Q waves meets the Type 4a MI criteria if cTn values are elevated and rising but less 
than 5 x the 99th percentile URL)
o
Angiographic findings consistent with a procedural flow-limiting complication such 
as coronary dissection, occlusion of a major epicardial artery or a side branch 
occlusion/thrombus, disruption of collateral flow, or distal embolization
o
Post-mortem demonstration of a procedure-related thrombus in the culprit artery, or 
a macroscopically large circumscribed area of necrosis with or without 
intra-myocardial hemorrhage
!
Type 4b: Stent thrombosis-associated with MI when detected by coronary angiography or 
autopsy in the setting of acute myocardial ischemia (as in Type 1 MI) and with a rise and/or 
fall of cardiac biomarker values with at least 1 value above the 99th percentile URL.
!
Type 4c: Stent restenosis-associated MI, as detected by coronary angiography or at autopsy, 
occurring >48 hours after PCI, without evidence of stent thrombosis but with symptoms 
suggestive of myocardial ischemia, and with elevation of cardiac biomarker values with at 
least one value above the 99th percentile URL. The following criteria are also required:
∀
Does not meet criteria for any other classification of MI
∀
Presence of a ≥50% stenosis at the site of previous successful stent PCI or a complex 
lesion and no other obstructive CAD of greater severity following either initially 
successful stent deployment, or dilation of a coronary artery stenosis with balloon 
angioplasty to <50% stenosis.
!
Type 5: Coronary artery bypass grafting- (CABG-)-related MI is defined as MI associated 
with, and occurring within 48 hours of PCI, with elevation of cardiac biomarker levels (>10 x 
99th percentile URL) in participants with normal baseline values (≤99th percentile URL); or 
a rise of cardiac biomarker levels values >20% if the baseline values are elevated and are 
stable or falling as long as the absolute post-procedure value is still >10 x 99th percentile 
URL. In addition, at least one of the following:
∀
Development of new pathologic Q waves (isolated development of new pathological 
Q waves meets the Type 5 MI criteria if cTn values are elevated and rising but less than 
10 times the 99th percentile URL)
∀
Angiographic documented new graft occlusion or new native coronary artery occlusion 
∀
Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality in a pattern consistent with an ischemic etiology.
Reviewers should also consider possible alternative causes of elevated cardiac biomarkers of 
necrosis (eg, myocarditis, heart failure, hypertensive crisis, PE, renal failure, sepsis).


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Acute Myocardial Infarction, Spontaneous Reinfarction
!
For participants with no recent revascularization in whom biomarkers from a recent MI remain 
elevated, Criteria 1 and 2 must be met:
∀
Cardiac biomarker re-elevation defined as:
o
Greater than the 99th percentile of the URL; and
o
Increase by ≥20% of the previous value; and
o
Documentation that the biomarker assayed was decreasing prior to the suspected new 
MI
AND
∀
At least 1 of the following additional supportive criteria:
o
Ischemic discomfort at rest lasting ≥10 minutes; or
o
New ECG changes (distinct from the first MI) meeting the criteria outlined above;
!
Within 48 hours after PCI a participant must have
∀
Cardiac biomarker >3× the 99th percentile of the URL and, if the pre-PCI biomarker was 
>99th percentile of the URL, both an increase by ≥20% over the previous value and 
documentation that the biomarker was decreasing prior to the event.
Note: symptoms are not required.
!
Within 72 hours after CABG a participant must have BOTH:
∀
Cardiac biomarker >5× the 99th percentile of the URL and, if the pre-CABG biomarker 
was >99th percentile of the URL, both an increase by at least ≥20% over the previous 
value and documentation that the biomarker was decreasing prior to the event.
AND
∀
At least 1 of the following supportive criteria:
o
Development of new, abnormal Q waves (>30 msec in duration and ≥0.1 mV in 
depth) in ≥2 contiguous leads, or new abnormal R waves (≥30 msec in duration and 
> depth of the S wave) in V1 and V2 consistent with posterior infarction, or new 
LBBB, OR
o
Angiographically documented new graft or native coronary occlusion, OR
o
Imaging evidence of new loss of viable myocardium.
Note: symptoms are not required.
Note: For periprocedural MIs, CK-MB remains the preferred biomarker given the greater 
experience. However, if cardiac troponin measurements are the only cardiac biomarker data 
available, they may be used by the CEC, along with the ECG and clinical scenario, in the 
adjudication of suspected MI after revascularization.


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Ischemic Stroke
An acute episode of neurological dysfunction caused by focal or global brain vascular injury and 
includes all strokes that are not of a primary hemorrhagic etiology. This includes fatal and nonfatal 
strokes. Any sudden onset of a neurologic deficit that last for more than 24 hours will be consider 
a stroke. If it is determined that a stroke has occurred, it will be further categorized into 1) ischemic 
stroke, 2) hemorrhagic stroke and 3) undetermined stroke as defined below.
Ischemic Stroke
!
Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction 
caused by an infarction of CNS tissue. Hemorrhage may be a consequence of ischemic stroke. 
In this situation, the stroke is an ischemic stroke with hemorrhagic transformation and not a 
hemorrhagic stroke.
Hemorrhagic Stroke
!
Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal 
dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage.
Undetermined Stroke
!
Undetermined stroke is defined as an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by presumed brain, spinal cord, or retinal vascular injury as a result of 
hemorrhage or infarction but with insufficient information to allow categorization as ischemic 
or hemorrhagic stroke.
Acute Limb Ischemia
Acute ischemia in the limb caused by arterial emboli, arterial thrombosis, or arterial trauma from 
a vascular procedure with
!
Clinical history suggesting a rapid or sudden decrease in limb perfusion, and either of the 
following below:
!
New pulse deficit with associated rest pain, pallor, paresthesia, or paralysis,
OR
Confirmation of arterial obstruction by imaging (including ultrasound, CT, magnetic 
resonance imaging, or conventional angiography), surgical findings, or pathology
Non-CNS Systemic Embolization
Non-CNS systemic embolism is defined as abrupt vascular insufficiency associated with clinical 
or radiological evidence of arterial occlusion in the absence of other likely mechanisms, (eg, 
trauma, atherosclerosis, instrumentation). In the presence of atherosclerotic peripheral vascular 
disease, diagnosis of embolism to the lower extremities should be made with caution and requires 
angiographic demonstration of abrupt arterial occlusion.


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Because COVID-19 participants may develop in situ thrombosis or arterial thromboembolism that
may be difficult to differentiate, for the purposes of this protocol, any documented arterial 
obstruction of blood flow to an internal organ (eg kidney, small intestine, large intestine) or to an 
extremity will be considered a non-CNS systemic embolization.  
Deaths 
The primary cause of death will be documented based on the example categories summarized 
below. Deaths will also be documented to be either related to COVID-19 or not related to 
COVID-19. 
Because some COVID-19-related causes of death may be attributable to cardiovascular causes (eg, 
MI) and some may be attributable to non-cardiovascular causes (eg, respiratory failure, viral 
pneumonia), subsequent categorizations of the cause of death may be defined in summary analyses 
based on details provided in the SAP.
Death Causes
!
Cardiac arrest due to respiratory failure
!
MI
!
Ischemic stroke
!
Intracranial hemorrhage
!
Congestive heart failure 
!
Coronary heart disease 
!
Cardiogenic shock
!
PE
!
Atherosclerotic vascular disease
!
Sudden or unwitnessed death
!
Hemorrhage, not intracranial
!
Other cardiovascular
!
Accidental / trauma
!
Respiratory failure, viral pneumonia
!
Respiratory failure
!
Infection
!
Malignancy
!
Suicide
!
Liver failure
!
Renal failure


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Sepsis
!
Hemorrhage, not intracranial
!
Other noncardiovascular
Sudden death would include any death in which there is an abrupt collapse of the respiratory and 
cardiovascular systems and death occurs during which time no other evaluations are performed 
either with ECG monitoring, imaging, or other laboratory testing.
Unwitnessed death is a death where the subject is discovered dead after last having been seen in 
a stable state. An unwitnessed death would not include death from a chronic, deteriorating 
noncardiovascular illness such as cancer.
Unknown Cause
If no information is available regarding the cause of death other than an oral communication from 
a relative, friend, or authorized representative without any information regarding the immediate 
cause, the primary investigator/investigative study staff will classify the cause of death as 
unknown.
The primary investigator/investigative study staff should record all efforts made to obtain 
information of the cause of death in the source documents.
Acute Renal Failure
Acute renal failure will be diagnosed if either of the following criteria are satisfied:
!
Dialysis is administered (Note: participants already on dialysis at screening are excluded from 
study participation)
!
Two consecutive eGFR of <15 mL/min/1.73m2 are observed occurring greater than 24 hours 
apart
COVID Digit
COVID digit will be defined as new onset and unexplained manifestations of pain, burning, 
swelling or discoloration of the fingers and toes and unlikely to be attributable to other causes (eg, 
insect bite, allergic reaction) (Landa 2020).
Acute Respiratory Distress Syndrome (ARDS)
Acute Respiratory Distress Syndrome is defined as a type of acute diffuse, inflammatory lung 
injury, leading to increased pulmonary vascular permeability, increased lung weight, and loss of 
aerated lung tissue. The clinical hallmarks are hypoxemia and bilateral radiographic opacities, 
associated with increased venous admixture, increased physiological dead space, and decreased 
lung compliance. The morphological hallmark of the acute phase is diffuse alveolar damage (ie, 
edema, inflammation, hyaline membrane, or hemorrhage).
The Berlin definition of ARDS include the following criteria (ARDS 2012):


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Timing: within 1 week of a known clinical insult or new or worsening respiratory symptoms
!
Chest imaging (chest radiograph or computed tomography scan): bilateral opacities – not fully 
explained by effusions, lobar/lung collapse, or nodules
!
Origin of edema: respiratory failure not fully explained by cardiac failure or fluid overload. 
Need objective assessment (eg, echocardiography) to exclude hydrostatic edema if no risk 
factor present.
!
Oxygenation (if altitude is higher than 1,000 m, the correction factor should be calculated as 
follows: [PaO2/FIO2 x (barometric pressure/760)]): 
∀
Mild: 200 mm Hg ˂PaO2/FIO2 ≤300 mm Hg with PEEP or CPAP ≥5 cm H2O
∀
Moderate: 100 mm Hg ˂PaO2/FIO2 ≤200 mm Hg with PEEP ≥5 cm H2O
∀
Severe: PaO2/FIO2 ≤100 mm Hg with PEEP ≥5 cm H2O


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10.4.
Appendix 4: Nonmajor Clinically Relevant Bleeding Event Criteria
Nonmajor 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 intervention treatment, or associated with 
discomfort for the subject such as pain or impairment of activities of daily life.
Examples of nonmajor 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)
!
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
!
Intramuscular hematoma
!
Subcutaneous hematoma if the size is larger than 25 cm2 or larger than 100 cm2 if provoked
!
Multiple-source bleeding


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10.5.
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations
10.5.1.
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current International Conference on Harmonisation (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 participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
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 participants, 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) involve only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
listed in the Contact Information page(s), which will be provided as a separate document. Except 
in emergency situations, this contact should be made before implementing any departure from the 
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the 
situation and agree on an appropriate course of action. The data recorded in the eCRF and source 
documents will reflect any departure from the protocol, and the source documents will describe 
this departure and the circumstances requiring it.
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.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:


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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, eConsent, any recruiting materials, and if 
applicable, participant 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 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 
participant:
!
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
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 eConsent (and any other written materials to be provided to the 
participants)
!
IB (or equivalent information) and amendments/addenda
!
Sponsor-approved participant recruiting materials


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Information on compensation for study-related injuries or payment to participants 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 participants
!
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 
participants, data or study conduct, unless required locally), the eConsent, applicable recruiting 
materials, and participant compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:
!
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
!
Revision(s) to eConsent and any other written materials to be provided to participants
!
If applicable, new or revised participant recruiting materials approved by the sponsor
!
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
!
New edition(s) of the IB and amendments/addenda
!
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB
(at least annually)
!
Reports of adverse events that are serious, unlisted/unexpected, and associated with the study
intervention
!
New information that may adversely affect the safety of the participants or the conduct of the
study
!
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
!
Report of deaths of participants 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 participants, data or study conduct), the amendment and applicable eConsent
revisions must be submitted promptly to the IEC/IRB for review and approval before 
implementation of the change(s).


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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1, Study-Specific Ethical 
Design Considerations.
10.5.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
10.5.3.
Informed Consent (Remote eConsent) Process
Each participant (or a legally acceptable representative) must give remote eConsent according to 
local requirements after the nature of the study has been fully explained. The remote e-consent
must be electronically signed before performance of any study-related activity. The remote 
e-consent(s) that is/are used must be approved by both the sponsor and by the reviewing IRB and 
be in a language that the participant can read and understand. The remote e-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. After having obtained the 
consent, a copy of the remote e-consent must be sent to the participant.
Before enrollment in the study, the investigator or an authorized member of the study personnel 
must explain to potential participants or their legally acceptable representatives the aims, methods, 
reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Participants will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the participant will receive. Participants will 
be told that refusal to take part in the study will not prejudice future treatment. Finally, they will 
be told that the investigator will maintain a participant identification register for the purposes of 
long-term follow-up if needed and that their records may be accessed by HAs and authorized 
sponsor personnel without violating the confidentiality of the participant, to the extent permitted 
by the applicable law(s) or regulations. By electronically signing the remote eConsent, the 
participant or legally acceptable representative is authorizing such access, which includes 
permission to obtain information about his or her survival status. It also denotes that the participant 
agrees to allow his or her study physician to recontact the participant for the purpose of obtaining 
consent for additional safety evaluations, and subsequent disease-related treatments, if needed.


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The participant or legally acceptable representative will be given sufficient time to read the 
eConsent and the opportunity to ask questions via phone, Interactive Web Interface and/or in-
person visit. Once the participant or legally acceptable representative understands all aspects of 
the remote eConsent, consent should be appropriately recorded by means of the participant’s or 
legally acceptable representative’s personally dated signature via electronic signature. After 
having obtained the consent, the participant will receive a copy of the remote eConsent for their 
records.
Sites will use an electronic system to obtain informed consent instead of a paper process as allowed 
by local regulations and IRB. The ability for participants or their legally acceptable representatives 
to review the paper informed consent form is always an option at sites utilizing electronic informed 
consent. Overall the consent/assent process will remain the same, as described in this section.
A participant who is rescreened is not required to sign another eConsent if the rescreening occurs 
within 14 days from the previous eConsent signature date.
If the participant [or legally acceptable representative] 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 eConsent after the oral 
consent of the participant [or legally acceptable representative] is obtained.
10.5.4.
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of participants confidential.
The informed consent obtained from the participant (or his or her legally acceptable representative) 
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 participant 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.


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10.5.5.
Committees Structure
Independent Data Monitoring Committee
An IDMC will be established to monitor the progress of the study and ensure that the safety of 
participants enrolled in the study is not compromised. The IDMC will include, but is not limited 
to, a clinical chairman, physician(s) experienced in clinical studies, 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 IA
and make a recommendation whether the study should be continued as planned, modified, or 
terminated prematurely due to futility or safety.
Executive Committee
The Executive Committee (EC) consists of members of the academic leadership of the study and 
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.
10.5.6.
Publication Policy/Dissemination of Clinical Study Data
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 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 derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study.
Study participant 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.


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Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter) 
data and information without approval from the investigator. The investigator has the right to 
publish study-site-specific data after the primary data are published. If an investigator wishes to 
publish information from the study, a copy of the manuscript must be provided to the sponsor for 
review at least 60 days before submission for publication or presentation. Expedited reviews will 
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will 
not mandate modifications to scientific content and does not have the right to suppress information. 
For multicenter study designs and substudy approaches, secondary results generally should not be 
published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual study site until the combined results from the completed study have been 
submitted for publication, within 18 months after the study end date, 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 ICMJE Recommendations 
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
state that the named authors must have made a significant contribution to the conception or design 
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law. The disclosure of the final study results will be performed after the end of study in order 
to ensure the statistical analyses are relevant.
10.5.7.
Data Quality Assurance
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 and review of protocol procedures with the investigator 
and study personnel before the study.
Guidelines for eCRF completion will be provided and reviewed with participating study personnel
before the start of the study.  The sponsor will review eCRF data for accuracy and completeness 
via centralized, remote, and/or on-site monitoring methods; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.


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10.5.8.
Case Report Form Completion
Electronic case report forms are prepared and provided by the sponsor for each participant. All 
data relating to the study that is not collected directly from the EMR into the eDC tool must be 
recorded in eCRF. All eCRF entries, corrections, and alterations must be made by the investigator 
or authorized study personnel. The investigator must verify that all data entries in the eCRF are 
accurate and correct.
Specified study data will be transcribed by study personnel from the source documents onto an 
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the participant's source documents. Data must be entered into 
eCRF in English. The eCRF must be completed as soon as possible after a participant visit and the 
forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, symptom assessment or other questionnaires) should be 
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a eCRF are needed after 
the initial entry into the eCRF, this can be done in either of the following ways:
!
Investigator and study 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).
!
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study 
personnel.
10.5.9.
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant 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; 
and date of study completion and reason for early discontinuation of study intervention or 
withdrawal from the study, if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).
The following data will be recorded directly into the eCRF and will be considered source data (if 
the data is not captured from EMR):
!
Race


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!
Height and weight
!
Smoking status (current or past smoker)
!
Assessment of Symptoms
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and Section
5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
Appendix 1
Referral letter from treating physician, or
Appendix 2
Complete history of medical notes at the site, or
Appendix 3
Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or 
clinic record to document medical care (eg, electronic source documents) as well as the clinical 
study-specific data fields as determined by the protocol. This data is electronically extracted for 
use by the sponsor. If eSource is utilized, references made to the eCRF in the protocol include the 
eSource system but information collected through eSource may not be limited to that found in the 
eCRF.
10.5.10.
Monitoring
The sponsor will use a combination of monitoring techniques (central, remote, and/or on-site 
monitoring) to monitor this study. Due to the ongoing pandemic, on-site monitoring visits may not 
take place. For any remote contacts, it is expected that study personnel will be available to provide 
an update on the progress of the study at the site. Central monitoring will take place for data 
identified by the sponsor as requiring central review.
10.5.11.
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. Participant privacy must, however, be 
respected. The investigator and study 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.


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10.5.12.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and 
all source documents that support the data collected from each participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 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.
10.5.13.
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study/Site 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 HAs, the sponsor's procedures, or GCP guidelines


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!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development


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10.6.
Appendix 6: Adverse Events, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.6.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered 
a pharmaceutical (investigational or non-investigational) product. An adverse event does not 
necessarily have a causal relationship with the intervention. 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)
Note: The sponsor collects adverse events starting with the signing of the eConsent (refer to All 
Adverse Events under Section 8.3.1, Time Period for Collecting Adverse Event and Serious 
Adverse Event Information, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and European Union 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 participant 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
!
Results in persistent or significant disability/incapacity
!
Is a congenital anomaly/birth defect
!
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 participant 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 (including all bleeding events) will 
not be considered as adverse events or serious adverse events.
Serious Adverse Events Confirmed as Study Endpoints
Study endpoint events (ie, symptomatic DVT, PE, MI, ischemic stroke, acute limb ischemia, 
non-CNS systemic embolization, hospitalizations, all-cause death, and major, critical site and fatal 
bleeding, and nonmajor clinically relevant bleeding) and non-endpoint bleeding will undergo 


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verification/adjudication by qualified study investigators. To protect the integrity of the study, 
events that are confirmed to be endpoints will not be unblinded or reported to either HAs or 
investigators as safety reports unless otherwise requested by HAs or Ethics Committees. After 
study completion, these events will be included in the final analysis which will be unblinded and 
submitted to HAs with the study report.
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 IB.
10.6.2.
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is determined by the investigator. The following 
selection should be used to assess all adverse events.
Related
There is a reasonable causal relationship between study intervention administration and the 
adverse event.
Not Related
There is not a reasonable causal relationship between study intervention administration and the 
adverse event.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.6.3.
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 participant (eg, laboratory abnormalities).


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10.6.4.
Procedures
All Adverse Events
Adverse events must be recorded using medical terminology in the EMR and/or eCRF. 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 in the EMR and/or eCRF their opinion 
concerning the relationship of the adverse event to study therapy. All measures required for 
adverse event management must be recorded in the source document and reported according to 
sponsor instructions.
Serious Adverse Events
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon the participant's discontinuation from 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 intervention or to factors unrelated 
to study conduct
!
It becomes unlikely that any additional information can be obtained (participant or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to Adverse Event 
Definitions and Classifications in Appendix 6, Adverse Events, Serious Adverse Events, Product 
Quality Complaints, and Other Safety Reporting: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting).
Information regarding serious adverse events will be transmitted to the sponsor using a serious 
adverse event reporting form and safety report form of the eCRF, which must be completed and 
reviewed by a physician from the study site and transmitted in a secure manner to the sponsor 
within 24 hours. The initial and follow-up reports of a serious adverse event should be transmitted 
in a secure manner electronically or by facsimile (fax). Telephone reporting should be the 
exception and the reporter should be asked to complete the appropriate form(s) first.
10.6.5.
Product Quality Complaint Handling
Definition
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, 


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durability, reliability, or performance of a distributed product, including its labeling, drug delivery 
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product.
In addition, it includes any technical complaints, defined as any complaint that indicates a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product or the drug delivery system.
Procedures
All initial PQCs must be reported to the sponsor by the study personnel within 24 hours after being 
made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until 
a shipment request is received from the sponsor.
10.6.6.
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.


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10.7.
Appendix 7: Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.3.2, Pregnancy and 
Appendix 6, Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other 
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential
!
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
!
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the 
postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of 
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required 
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if 
she wishes to continue HRT during the study.
!
permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations 
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should 
be consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.


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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used 
consistently and correctly.
!
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
!
Intrauterine device (IUD)
!
Intrauterine hormone-releasing system
!
Bilateral tubal occlusion
!
Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.
!
Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
∀oral
∀intravaginal
∀transdermal
∀injectable
!
Progestogen-only hormone contraception associated with inhibition of ovulationb
∀oral
∀injectable
!
Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not 
considered to be highly effective - failure rate of #1% per year)
!
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
!
Male or female condom with or without spermicidec
!
Cap, diaphragm, or sponge with spermicide
!
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c
!
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
!
Withdrawal (coitus-interruptus)
!
Spermicides alone
!
Lactational amenorrhea method (LAM)


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a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may 
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception 
may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).


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11.
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SAP_003.pdf: 
CONFIDENTIAL 
1
Status: Approved, Date: 23 May 2022
Janssen Research & Development
Statistical Analysis Plan
A multicenter, randomized, placebo-controlled, pragmatic Phase 3 study investigating the 
efficacy and safety of rivaroxaban to reduce the risk of major venous and arterial 
thrombotic events, hospitalization and death in medically ill outpatients with acute,
symptomatic COVID-19 infection
Protocol 39039039DVT3004; Phase 3
JNJ-39039039; BAY 59-7939  (rivaroxaban)
Amendment 1
Status:
Approved
Date:
23 May 2022
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-RIM-163331, 2.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04508023


JNJ-39039039; BAY 59-7939  (rivaroxaban)
Statistical Analysis Plan 39039039DVT3004 – Amendment 1
CONFIDENTIAL 
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Status: Approved, Date: 23 May 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 3
AMENDMENT HISTORY.............................................................................................................................. 4
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Objectives ........................................................................................................................................ 6
1.2.
Study Design.................................................................................................................................... 7
2.
STATISTICAL HYPOTHESES.......................................................................................................... 11
3.
SAMPLE SIZE DETERMINATION....................................................................................................11
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS.....................................................................11
5.
STATISTICAL ANALYSES............................................................................................................... 12
5.1.
General Considerations ................................................................................................................. 12
5.1.1.
Visit Windows ............................................................................................................................. 12
5.2.
Participant Dispositions.................................................................................................................. 13
5.3.
Primary Endpoint(s) Analysis......................................................................................................... 14
5.3.1.
Definition of Endpoint(s) ............................................................................................................. 14
5.3.2.
Estimand..................................................................................................................................... 14
5.3.3.
Analysis Methods........................................................................................................................ 14
5.3.4.
Supplemental Analysis for Primary Efficacy and ER Visits ........................................................16
5.3.5.
Supplemental Analyses for Bayesian Borrowing........................................................................ 16
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 18
5.4.1.
Key Confirmatory Secondary Endpoint(s) .................................................................................. 18
5.4.1.1.
Definition of Endpoint(s) .......................................................................................................... 18
5.4.1.2.
Estimand(s).............................................................................................................................. 18
5.4.1.3.
Analysis Methods .................................................................................................................... 18
5.5.
Multiple Testing Procedure ............................................................................................................ 18
5.6.
Tertiary/Exploratory Endpoint(s) Analysis...................................................................................... 19
5.7.
Safety Analyses ............................................................................................................................. 20
5.7.1.
Extent of Exposure ..................................................................................................................... 20
5.7.2.
Bleeding Events.......................................................................................................................... 21
5.7.3.
Adverse Event ............................................................................................................................ 21
5.7.4.
Additional Safety Assessments (if applicable)............................................................................22
5.7.4.1.
Clinical Laboratory Tests......................................................................................................... 22
5.7.4.2.
Vital Signs and Physical Examination Findings.......................................................................22
5.8.
Other Analyses............................................................................................................................... 22
5.8.1.
Medical Resource Utilization and Health Economics Analyses ................................................. 22
5.8.2.
Benefit-Risk Analyses................................................................................................................. 22
5.8.3.
Definition of Subgroups .............................................................................................................. 25
5.9.
Interim Analyses............................................................................................................................. 27
5.9.1.
Independent Data Monitoring Committee (IDMC) or Other Review Board ................................ 27
6.
SUPPORTING DOCUMENTATION ..................................................................................................28
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 28
6.2.
Appendix 2 Demographics and Baseline Characteristics..............................................................29
6.3.
Appendix 3 Protocol Deviations ..................................................................................................... 30
6.4.
Appendix 4 Prior and Concomitant Medications............................................................................31
6.5.
Appendix 5 Bayesian Dynamic Borrowing..................................................................................... 32
7.
REFERENCES................................................................................................................................... 33


JNJ-39039039; BAY 59-7939  (rivaroxaban)
Statistical Analysis Plan 39039039DVT3004 – Amendment 1
CONFIDENTIAL 
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Status: Approved, Date: 23 May 2022
VERSION HISTORY
Table 1:
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
10SEP2020
Not Applicable
Initial release
2
23MAY2022
Yes
See amendment history


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Statistical Analysis Plan 39039039DVT3004 – Amendment 1
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Status: Approved, Date: 23 May 2022
AMENDMENT HISTORY
SAP AMENDMENT 1
The original Statistical Analysis Plan (SAP) was finalized and issued on 10 September 2020, based on the 
Clinical Protocol 39039039DVT3004. This document is the SAP Amendment 1 that incorporates additional 
pre-specified supplemental analyses. Listed below are the changes in SAP Amendment 1.
Section and Topic
Description of changes in SAP Amendment 1
Section 1.1 
“Tertiary/exploratory 
Objectives” 
An additional endpoint for the composite of the primary efficacy outcome 
and emergency room visits has been included as a pre-specified exploratory 
endpoint of clinical interest. 
Added:
To evaluate whether rivaroxaban reduces the risk of a composite of all 
symptomatic venous thromboembolic events (VTE), major arterial 
thrombotic events (myocardial infarction [MI], ischemic stroke, acute limb 
ischemia, noncentral nervous system [non-CNS] systemic embolization), 
all-cause hospitalization, all-cause mortality, and emergency room (ER 
visits)
Section 1.2 “Study 
Design”
A paragraph has been added updating the summary of the general statistical 
analysis, to reflect study closure due to operational reasons (with planned 
database lock on the 29 June 2022) and not reaching the requisite number of 
events for the original planned interim analysis.  
Added:
Updated planned analysis
Due to the current state of the pandemic and the lower than expected 
blinded pooled event rate of the primary efficacy outcome, the study 
Executive Committee and Sponsor have recommended for the completion of 
enrollment on 31 March 2022 for operational reasons. The total number of 
primary efficacy outcomes have not reached the requisite targeted number 
of events (167 events, 50% of the original targeted number of events) for 
conducting an interim analysis.
The study is planning to close with a planned database lock planned on the 
29 June 2022. Given that there will be no interim analysis conducted, the 
final analysis will be based on an alpha of 0.05 (2-sided).
Section 4 “Population 
(Analysis Sets) for 
Analysis”
An additional analysis phase is added to the table of analysis sets and 
analysis phases. This additional analysis phase is called “First Dose to Up-
to-Day 35” to enable conducting a supplemental modified intention-to-treat 
analysis to evaluate the impact of the virtual nature of the trial.
Added (in table):
This analysis phase includes all data from first dose date to Day 35 visit 
(Day 35 +6 days, Day 41)
Section 5.3.3 
Supplemental Analyses
An additional supplemental analysis has been added.
Added (third bullet point):
Analysis of primary composite endpoint in the ITT population and from 
First Dose to Up-to-Day 35 analysis phase for a modified ITT analysis. For 
subjects who do not take study medication, the first dose date will be 
imputed as the randomization date + the median number of days from 


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Section and Topic
Description of changes in SAP Amendment 1
randomization date to treatment start date using the data from subjects who 
did take study medication. 
Section 5.3.4 
“Supplemental Analysis 
of Primary Efficacy and 
ER Visits”
Section 5.3.4 has been added to fully describe the analysis method of the 
additional exploratory endpoint of the composite of primary efficacy and 
ER visits. 
Section 5.3.5 
“Supplemental Analyses 
for Bayesian 
Borrowing”
Section 5.3.5 has been added which rationalizes and pre-specifies a planned 
supplemental Bayesian analysis of the primary efficacy endpoint using 
information borrowed from a concurrent and similarly designed, 
randomized, double-blind Phase 2b trial of rivaroxaban compared to 
placebo in COVID-19 for disease progression sponsored by the Bill & 
Melinda Gates Medical Research Institute.
Section 5.6 
“Tertiary/Exploratory 
Endpoint(s) Analysis”
The pre-specified endpoint for the composite of primary efficacy and ER 
visits has also added/listed in Section 5.6.
Added (first bullet point): 
Time to first occurrence of the composite of primary efficacy and ER visits 
defined as all symptomatic venous thromboembolic events (VTE), major 
arterial thrombotic events (myocardial infarction [MI], ischemic stroke, 
acute limb ischemia, noncentral nervous system [non-CNS] systemic 
embolization), all cause hospitalization, all-cause mortality, and ER visits 
Section 6.5 Appendix 5 
“Bayesian Dynamic 
Borrowing”
Appendix 5 has been added to fully describe the statistical methods of 
Bayesian Borrowing using the Robust Mixture Prior. 
Typographic and 
grammatical corrections
!
Consistency in capitalization updated: “on-treatment” has been 
updated to “On-Treatment” throughout.
!
Consistency in capitalization updated: “up-to-last contact” has been 
updated to “Up-to-Last-Contact” throughout.
!
“Day 35 visit (Day 35+ days, ie, Day 41)” has been updated to 
“Day 35 visit (Day 35 +6 days, Day 41)” to fix a typographical 
error.


JNJ-39039039; BAY 59-7939  (rivaroxaban)
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1.
INTRODUCTION
This statistical analysis plan (SAP) specifies definitions of analysis sets, key derived variables, and 
statistical methods for analysis of efficacy and safety for the Phase 3 study 39039039DVT3004
(also known as PREVENT-HD). Unless the key analysis method for efficacy and/or safety needs 
to be updated, an 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).
1.1.
Objectives
Primary objective
!
To evaluate whether rivaroxaban reduces the risk of a composite endpoint of major venous 
and arterial thrombotic events, all-cause hospitalization, and all-cause mortality compared 
to placebo in outpatients with acute, symptomatic COVID-19 infection
Secondary objectives
!
To evaluate whether rivaroxaban reduces the risk of all symptomatic venous 
thromboembolic events (VTE), major arterial thrombotic events (myocardial infarction 
[MI], ischemic stroke, acute limb ischemia, noncentral nervous system [non-CNS] systemic 
embolization) and all-cause mortality in outpatients with acute, symptomatic COVID-19 
infection
!
To evaluate whether rivaroxaban reduces all cause hospitalization
!
To evaluate whether rivaroxaban reduces the risk of symptomatic VTE
!
To evaluate whether rivaroxaban reduces the need for emergency room (ER) visits
!
To evaluate whether rivaroxaban reduces the risk of venous and arterial thrombotic events 
and all-cause hospitalization
!
To evaluate whether rivaroxaban reduces the percentage of participants who are 
hospitalized or dead on Day 35
!
To evaluate whether rivaroxaban reduces all-cause mortality
Tertiary/exploratory objectives
!
To evaluate whether rivaroxaban reduces the risk of a composite of all symptomatic venous 
thromboembolic events (VTE), major arterial thrombotic events (myocardial infarction 
[MI], ischemic stroke, acute limb ischemia, noncentral nervous system [non-CNS] systemic 
embolization), all-cause hospitalization, all-cause mortality, and emergency room (ER 
visits)
!
To evaluate whether rivaroxaban improves participant status (e.g., prevents worsening of 
World Health Organization [WHO] Research and Development [R&D] Blueprint: Novel 
Coronavirus Scale for Clinical Improvement) over time
!
To evaluate if rivaroxaban reduces the individual component events of the primary efficacy 
endpoint


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!
To evaluate the ability of rivaroxaban to prevent the decline in oxygenation at rest or with 
ambulation
!
To evaluate whether rivaroxaban can reduce the need for supplemental oxygen
!
To evaluate whether rivaroxaban can prevent the occurrence of severe disease in hospital or 
death as defined by WHO scale scores of 5, 6, 7, or 8
!
To evaluate whether rivaroxaban can prevent the occurrence of acute renal failure
!
To evaluate whether rivaroxaban can prevent the occurrence of disseminated intravascular 
coagulation (DIC)
!
To evaluate whether rivaroxaban can prevent the occurrence of acute respiratory distress 
syndrome (ARDS)
!
To evaluate whether rivaroxaban can prevent the occurrence of COVID digit (defined as 
new onset and unexplained manifestation of pain, burning, swelling or discoloration of the 
fingers and toes and unlikely to be attributable to other causes)
!
Collect medical resource utilization (MRU) data
Safety objectives
!
To evaluate whether rivaroxaban is associated with an increase in critical site and fatal 
bleeding as defined by the International Society on Thrombosis and Hemostasis (ISTH) 
scale
!
To evaluate whether rivaroxaban is associated with an increase in ISTH major bleeding
!
To evaluate whether rivaroxaban is associated with an increase in non-major clinically 
relevant bleeding
Benefit-risk objectives
!
To evaluate the benefit-risk profile of rivaroxaban by evaluating the risk differences for key 
efficacy and safety endpoints through Day 35  
1.2.
Study Design
This is a randomized, multicenter, placebo-controlled, pragmatic, event-driven Phase 3 study of 
rivaroxaban (10 mg once daily) with a target enrollment of approximately 4,000 participants with 
acute, symptomatic COVID-19 infection. As this is an event driven study, if the observed event 
rate is lower than expected, enrollment may exceed 4,000 participants up to approximately 5,000 
participants without the need for a protocol amendment. 
The study will enroll participants from large, integrated, health networks in the United States (US). 
There are no required in-person clinic visits required by the study. Central randomization will be 
implemented in this study. Participants meeting the eligibility criteria at an in-person or virtual 
outpatient visit will participate in an informed consent process and once consented will then be 
randomly allocated in a ratio of 1:1 to treatment with either rivaroxaban 10 mg once daily or 
matching placebo. Treatment assignment will be balanced within a clinical site by block 
randomization. The randomization will be stratified by the time from COVID-19 positive test to 


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randomization (1 to 5 days inclusive, 6 to 14 days inclusive). At the present time it is anticipated 
that the event rate or the treatment effect may be different in the 2 strata. These strata will be used 
as subgroup analyses to look for the comparability of the treatment effect begun early after the 
diagnosis or later after the diagnosis. To enable an adequate assessment in both strata, the sponsor 
may elect to limit enrollment in one of the strata. 
All participants are to self-administer study drug (rivaroxaban or placebo) orally once daily, with 
or without food, at approximately the same time each day throughout the 35-day double-blind 
treatment period. The first dose should be taken as soon as possible after randomization and within 
3 days of randomization if possible. The date and time of the study drug should be recorded as 
accurately as possible. 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 participant takes a dose of study drug on Day 35, the participant should discontinue study 
drug and complete the Day 35 (±6 days) virtual visit. The final follow-up will be on Day 49±7 
days after randomization. Study drug may be interrupted for any hospitalization and all 
antithrombotic therapy will be at the discretion of the admitting physician. Upon hospital 
discharge, the participants may resume study drug or may permanently discontinue study drug 
treatment and may receive antithrombotic therapy per institutional guidelines. All participants 
should be followed until the last follow-up on Day 49±7 days. In the event that the participant is 
unavailable (e.g., hospitalized) or incapacitated (e.g., on a ventilator), information about the vital 
status and whereabouts of the participant and his/her status may be obtained from family and/or 
friends and information obtained should be documented in the electronic case report form (eCRF), 
electronic medical record (EMR) or other source records.
Original planned analysis
An interim analysis for futility or early superiority will be conducted when approximately 167 
participants with primary efficacy outcome have been observed (about 50% of the targeted total 
number of events). 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 and the study will use 
O’Brien-Fleming boundary (Z=2.96, 2-sided alpha=0.003) to stop the study early for the early
superiority. Alpha=0.049 will be used for the final analysis to control the family-wise type I error 
rate at an alpha of 0.05 (2-sided). 
Updated planned analysis
Due to the current state of the pandemic and the lower than expected blinded pooled event rate of 
the primary efficacy outcome, the study Executive Committee and Sponsor have recommended 
for the completion of enrollment on 31 March 2022 for operational reasons. The total number of 
primary efficacy outcomes have not reached the requisite targeted number of events (167 events, 
50% of the original targeted number of events) for conducting an interim analysis.


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The study is planning to close with a planned database lock planned on the 29 June 2022. Given 
that there will be no interim analysis conducted, the final analysis will be based on an alpha of 
0.05 (2-sided). 
Double-blind intervention will be used to reduce potential bias during data collection and 
evaluation of clinical endpoints. Data that may potentially unblind the intervention assignment will 
be handled with special care to ensure that the integrity of the blind is maintained and the potential 
for bias is minimized.
An Independent Data Monitoring Committee (IDMC) will be established to monitor the progress 
of the study and ensure that the safety of participants enrolled in the study is not compromised. In 
addition, the IDMC will review results of the planned interim analysis and make a recommendation 
whether the study should continue as planned, continue with modification, or be terminated 
prematurely due to futility, safety, or early superiority.
A diagram of the study design is provided below in Figure 1:


JNJ-39039039; BAY 59-7939  (rivaroxaban)
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Figure 1:
Schematic Overview of the Study


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2.
STATISTICAL HYPOTHESES
The primary hypothesis is to evaluate whether rivaroxaban reduces the risk of a composite 
endpoint of major venous and arterial thrombotic events, all-cause hospitalization and all-cause 
mortality compared to placebo in outpatients with acute, symptomatic COVID-19 infection during 
the treatment period (Day 35). The primary statistical alternative hypothesis is that rivaroxaban is 
superior to placebo on the primary efficacy outcome, that is, time to the first event for the 
rivaroxaban group is stochastically later than that for the placebo group from randomization up to 
Day 35. More specifically, the survival function for the placebo group is lower than that for the 
rivaroxaban group. The null hypothesis is that the survival function for both groups are the same.
The secondary hypotheses are that rivaroxaban is superior to placebo in the prevention of any 
thrombotic outcome (symptomatic VTE, MI, ischemic stroke, acute limb ischemia and non-CNS 
systemic embolization) and all-cause mortality, all-cause hospitalization, symptomatic VTE, ER 
visits, any thrombotic outcome and all-cause hospitalization, hospitalization or death on Day 35 
and all-cause mortality.
3.
SAMPLE SIZE DETERMINATION
This is an event-driven study. The targeted total number of primary efficacy outcome events is 
333, based on the Intention-to-Treat (ITT) analysis set and Up-to-Day-35 analysis phase. If a 
participant has multiple events, only the first is counted towards study size determination.
This targeted total number of events is determined using statistical software PASS 15 based on the 
primary efficacy analysis (defined later) and the following assumptions:
!
30% relative risk reduction (RRR) in the primary efficacy outcome based on the ITT analysis 
set and Up-to-Day-35 analysis phase (RRR is defined as 1 minus the HR of rivaroxaban versus 
placebo)
!
Power of 90% assuming the above RRR
!
Two-sided significance level of 0.05
To observe the targeted 333 events, it is estimated that a total of approximately 4,000 participants 
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 10%.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
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.


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Analysis sets and analysis phases are defined below.
Analysis Sets
Description
Enrolled
All participants who sign the ICF
Randomized
The randomized analysis set includes all participants who 
were randomized in the study
Full Analysis Set (FAS)/Intent-To-Treat (ITT)
The full analysis set (FAS)/Intent-To-Treat (ITT) 
includes all randomized participants who have provided 
informed consent
Safety
The safety analysis set includes participants in ITT who 
received at least 1 dose of study intervention.
Analysis Phases
Description
Up-to-Day 35
This analysis phase includes all data from the 
randomization to Day 35 visit (Day 35 +6 days, Day 41)
On-Treatment
This analysis phase includes all data from the 
randomization to 2 days after the last dose of study 
intervention
Up-to-Last Contact
This analysis phase includes all data from the 
randomization to the last contact date or the death date, 
whichever is earlier.
First Dose to Up-to-Day 35
This analysis phase includes all data from first dose date
to Day 35 visit (Day 35 +6 days, Day 41)
5.
STATISTICAL ANALYSES
5.1.
General Considerations
Summaries by intervention 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 this 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 presented at a nominal (that is, without 
adjustment for multiplicity) 2-sided significance level of 0.05 and all confidence intervals (CI) at 
a nominal 2-sided level of 95%.
5.1.1.
Visit Windows
As participants do not always adhere to the protocol visit schedule, the following rules are applied 
to assign actual visits to analysis visits. Listed below are the visit windows and the target days for 
each visit. The reference day is Study Day 1, defined as the day of randomization. If a participant
has 2 or more actual visits in 1 visit window, the visit closest to the target day will be used as the 
protocol visit for that visit window. If 2 actual visits are equidistant from the target day within a 
visit window, the later visit is used.


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All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the endpoint. Listed below 
(Table 2) are the analysis visit windows and the target days for each visit defined in the protocol.
Table 2:
Visit Windows
Scheduled Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time Point
(Day)
1
Screening^
< 1
-14 to -1
2
Baseline/Day 1
1
1
3
Day 3
2 to 4
3
4
Day 14
7 to 21
14
5
Day 35
29 to 41
35
6
Day 49
42 to 56
49
*Relative to Study Day 1;
^ Screening may also occur on the same day as randomization (Day 1)
5.2.
Participant Dispositions
Screened participants and reason for screen failures will be summarized overall.
The number of participants in the following disposition categories will be summarized throughout 
the study by intervention group and overall:
!
Participants randomized
!
Participants who received study intervention
!
Participants who completed the study
!
Participants who discontinued study intervention
!
Reasons for discontinuation of study intervention
!
Participants who terminated study prematurely
!
Reasons for termination of study
The distribution of the time to discontinuation of study intervention will be displayed with Kaplan-
Meier curves. Participants who terminate study intervention prematurely at any time will be 
considered an ‘Event’ and their date of study intervention discontinuation will be used in the time 
to event calculation. Participants who complete the study intervention will be censored and the 
date of last dose of study intervention will serve as the time of censoring. (Note: If the participant 
wishes to enroll in another investigational, randomized study while participating in the current 
study, then the participant should withdraw from further participation in the current study. Passive 
collection of EMR data and vital status may still be obtained from such participants through 
Day 49.)
Listings of participants will be provided for the following categories:
!
Participants who discontinued study intervention prematurely
!
Participants who terminated study prematurely


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!
Participants who were unblinded during the study period
!
Participants who were randomized yet did not receive study intervention
5.3.
Primary Endpoint(s) Analysis
5.3.1.
Definition of Endpoint(s)
The primary efficacy endpoint is time from randomization to the first occurrence of all major 
venous and arterial thrombotic events (symptomatic VTE, MI, ischemic stroke, acute limb 
ischemia, and non-CNS systemic embolization), all-cause hospitalization, and all-cause mortality 
Up-to-Day-35 analysis phase.
5.3.2.
Estimand
The primary estimand is described according to the following 5 attributes:
!
Population: medically ill outpatients with acute, symptomatic COVID-19 infection
!
Variable: time from randomization to the first occurrence of primary efficacy event Up-to-
Day-35 analysis phase
!
Treatments: Rivaroxaban 10 mg once daily vs placebo
!
Intercurrent events (events that preclude observation of the variable or affects its 
interpretation): treatment discontinuation. A treatment policy strategy will be used for these 
intercurrent events, that is all data collected during the study irrespective of the treatment 
discontinuation.
!
Population-level summary: HR of rivaroxaban 10 mg versus placebo, along with the 2-sided 
95% Confidence Interval (CI)
This estimand targets the effect of rivaroxaban on the variable measured and follows an “ITT 
principle” strategy.
5.3.3.
Analysis Methods
The primary statistical hypothesis will be tested using stratified log-rank test by the time from 
COVID-19 positive test to randomization (1 to 5 days inclusive, 6 to 14 days inclusive) with the 
treatment as the only variable. This primary efficacy analysis will be based on the ITT analysis set 
and Up-to-Day-35 analysis phase. Participants will be analyzed according to the intervention group
to which they are randomized, regardless of actual treatment received. The 2-sided p-value will be 
reported and if it is less than the 2-sided alpha of 0.049 (adjusted for the interim analysis) at the 
final analysis, then superiority of the study drug will be declared.
The point estimate and corresponding 95% CI for the HR (rivaroxaban to placebo) will be provided 
based on the stratified 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 evaluating the significance of an interaction term 
of treatment by logarithm-transformed time in the primary Cox model. The sensitivity analysis for 


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the primary efficacy endpoint will be conducted using the unstratified Cox proportional hazards 
model. The following supplementary analyses will be performed:
!
Analyses of primary composite endpoint in the safety population and the On-Treatment 
analysis phase. 
!
Analyses of primary composite endpoint in the ITT population and the Up-to-Last-Contact 
analysis phase.
!
Analysis of primary composite endpoint in the ITT population and from First Dose to Up-to-
Day 35 analysis phase for a modified ITT analysis. For subjects who do not take study 
medication, the first dose date will be imputed as the randomization date + the median number 
of days from randomization date to treatment start date using the data from subjects who did 
take study medication. 
!
Analysis of the effect size of rivaroxaban versus placebo in terms of recurrent episodes of
primary efficacy outcome based on the ITT analysis set and Up-to-Day 35 analysis phase, 
where the total event count can be analyzed using regression methods appropriate for count 
data. The time at risk of recurrent primary efficacy outcome, which starts at randomization 
and continues until the earlier of Day 35 visit or last contact. The negative binomial regression 
model1 is derived from this approach using generalized Poisson regression, with treatment as 
variable.
!
Andersen-Gill model2 will be explored for the time to multiple primary efficacy events. The 
hazard ratio for rivaroxaban versus placebo with respect to the recurrent events of primary 
efficacy outcome will be estimated using an unstratified Cox proportional hazards model with 
treatment as the only covariate, a robust estimate of the variance will be used for intra-subject 
correlation. The point estimate and corresponding 95% CI will be reported.
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, in the subgroups defined in 
Section 5.8.3 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 the time from COVID-19 positive test to randomization (1 to 5 days inclusive, 6 to 
14 days inclusive) (at a 2-sided significance level of 0.05). For time from COVID-19 positive test 
to randomization 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 
Gail-Simon test3. 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 Cox model except for the time from COVID-19 positive test to 
randomization 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


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5.3.4.
Supplemental Analysis for Primary Efficacy and ER Visits 
A supplemental analysis will be performed using a composite endpoint of primary efficacy 
endpoint and ER visits defined as all symptomatic venous thromboembolic events (VTE), major 
arterial thrombotic events (myocardial infarction [MI], ischemic stroke, acute limb ischemia,
noncentral nervous system [non-CNS] systemic embolization), all-cause hospitalization, all-cause 
mortality, and ER visits.
The analysis will be similar to the primary estimand, using the Cox proportion hazard model, 
stratified by time from COVID-19 positive test to randomization (1 to 5 days inclusive, 6 to 14 
days inclusive), with treatment as the only covariate. The point estimate and corresponding 95% 
CI for the HR (rivaroxaban to placebo) will be provided
Recurrent events will also be analyzed for the composite of the primary efficacy and ER visits, 
using same methods in Section 5.3.3 describing the negative binomial regression and Andersen-
Gill models. Both these recurrent events analyses will use the ITT population and Up-to-Day 35 
analysis phase.   
5.3.5.
Supplemental Analyses for Bayesian Borrowing
During the trial conduct, a literature search was conducted to identify similar externally sponsored 
clinical trials of anti-coagulant therapy in COVID-19. Several concurrent trials of rivaroxaban in 
COVID-19 treatment were identified, with results that have been formally published.
The Michelle Trial4 is an investigator-led, open-label randomized trial in Brazil of rivaroxaban 
compared to no anti-coagulation for post-discharge thromboprophylaxis after hospitalization for 
COVID-19. Adult hospitalized with COVID-19 at increased risk of VTE (IMPROVE score ≥4 or 
2-3 with D-dimer >500 ng/mL) were randomly assigned 1:1 at hospital discharge to rivaroxaban 
10 mg per day or no anticoagulation for 35 days. The primary efficacy endpoint is a composite of 
symptomatic or fatal VTE, asymptomatic VTE on bilateral ultrasound and CT pulmonary 
angiogram, symptomatic arterial thromboembolism, and CV death at Day 35. The study showed 
in the ITT analysis, that 5/159 (3%) participants assigned to rivaroxaban and 15/159 (9%)
participants assigned to no anti-coagulation arm had a primary efficacy outcome (RR = 0.33, 95% 
CI 0.12 – 0.90).
The ROXANE trial5 is an investigator-led, open-label randomized trial conducted in India of 
rivaroxaban compared to enoxaparin for the prevention of all major, clinically relevant 
hemorrhagic and thrombotic events. In-patient hospitalized adults with confirmed mild or 
moderate COVID-19 were randomized to receive either once-daily rivaroxaban (10 mg or 15 mg) 
or once-daily subcutaneous enoxaparin (40 mg or 60 mg) for the intended duration of the hospital 
stay. The primary efficacy outcome is progression of disease requiring treatment escalation, 
including need for supplemental oxygen, high-flow oxygen devices or non-invasive mechanical 
ventilation and/or ECMO. The study showed in the ITT analysis that 4/115 (3.5%) participants
assigned to rivaroxaban and 16/113 (14.2%) participants assigned to enoxaparin arm had a primary 
efficacy outcome of disease progression (HR = 0.207, 95% CI 0.069 – 0.621).  


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The Bill & Melinda Gates Medical Research Institute (Gates MRI) conducted a Phase 2b double-
blind, placebo-controlled randomized trial6 in the US to assess the safety and efficacy of 
rivaroxaban in people with mild COVID-19 disease who are at increased risk of disease 
progression, with at least one risk factor for high risk of disease progression. Participants were 
randomized 1:1 to either daily rivaroxaban 10 mg or placebo equivalent for 21 days, with outcomes 
followed-up for 35 days. Primary endpoints were safety (Grade 3/4 AE/SAEs) and progression of 
disease (by Gates MRI scale). Secondary endpoints included all-cause hospitalization. Reasons for 
all AEs were also collected and reported, including all-cause mortality and DVT. Although the 
trial did not show any difference in the progression of disease based on the Gates MRI scale, the 
ITT analysis of the secondary endpoints showed that 3/222 (1.4%) participants assigned to
rivaroxaban and 7/222 (3.2%) participants assigned to placebo had all-cause hospitalization 
through Day 28 (RR = 0.43, 95% CI 0.10 – 1.65). Hospitalizations at any time during the study
(through Day 35) in the ITT analysis occurred in 3/222 (1.4%) participants assigned to rivaroxaban 
and 8/222 (3.6%) assigned to placebo (RR = 0.38, 95% CI 0.10 – 1.40). 
Of the published studies of rivaroxaban, there were similar degree of reductions with regards to 
the point estimates for similar clinical endpoints. However, the Michelle Trial and the Rivaroxaban 
Prophylaxis Trial were conducted in hospitalized or post-discharge populations. The Gates MRI 
study was conducted in the US in an outpatient population, with similarities to the PREVENT-HD 
inclusion criteria, with participants requiring similar VTE risk factors. Due to the similarities in 
trial design, including the country (US sites only), population inclusion/exclusion criteria, study 
medication and dosage (10 mg daily rivaroxaban), treatment duration, follow-up duration, and 
study endpoints collected, the Gates MRI trial results will therefore be used to construct a prior 
distribution for a supplemental Bayesian analysis of the primary efficacy outcome. The most 
similar endpoint, where possible, will be identified from the Gates MRI trial results to map to the 
primary efficacy outcome of the PREVENT-HD study. Where possible, additional prior 
distributions may be constructed for exploratory analysis of other primary, secondary, or tertiary 
endpoints collected by the Gates MRI trial. 
By borrowing information from Gates MRI trial, a supplemental Bayesian analyses of primary
efficacy outcome in the ITT population and using the Up-to-Day 35 analysis phase will be 
performed. A robust mixture prior7 will be used consisting of two components: 1) informative 
prior based on Gates MRI trial results and a 2) vague prior to express some degree of skepticism 
on the borrowing strength, each with an assumed equal mixing weight of 0.5. The base-case weight 
of 0.5 for the prior distribution is considered a reasonable assumption, given that the PREVENT-
HD trial is over double the size of the Gates MRI trial. Furthermore, the mixture also combines an
equal weight of 0.5 for a vague or non-informative prior to express a degree of skepticism on the
underlying borrowing strength to account for the heterogeneity between the two studies.
Mean, median, and 95% credible intervals of posterior distribution of HR will be provided and the 
posterior probability that HR <1. Tipping/sensitivity point analysis with mixing weights varying 
from 0 to 1 by intervals of 0.05 will be performed to assess the robustness of the assumption of the
borrowing strength, which will identify the weight that the posterior distribution ( < 1) ≥
97.5%, that is, the upper limit of 95% credible interval less than 1. For each weight, mean, median,


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95% credible intervals of posterior distribution will be provided. A plot of the median with 95% 
credible intervals over increasing levels of borrowing strength (weight) will also be presented.
Details of the analysis methods are provided Appendix 5.
5.4.
Secondary Endpoint(s) Analysis
5.4.1.
Key Confirmatory Secondary Endpoint(s)
5.4.1.1.
Definition of Endpoint(s)
The variables for the analysis of the secondary endpoint are time from randomization to the first 
occurrence of the following: any thrombotic outcome (symptomatic VTE, MI, ischemic stroke, 
acute limb ischemia, and non-CNS systemic embolization) and all-cause mortality, all-cause 
hospitalization, symptomatic VTE, ER visits, any thrombotic outcome and all-cause 
hospitalization and all-cause mortality Up-to-Day-35 analysis phase. The other variable for the 
analysis of the secondary endpoint is hospitalization or death at Day 35.
5.4.1.2.
Estimand(s)
The estimands for the analysis of all time to event secondary endpoints are similar as for the 
primary efficacy endpoint except for the attribute of variable.
The estimand for the analysis of the secondary endpoint of hospitalization or death at Day 35 is 
similar as for the primary efficacy endpoint except variable and population-level summary.
!
Variable: hospitalization or death at Day 35 (Day 35±6)
!
Population-level summary: Weighted relative risk (RR) of rivaroxaban 10 mg versus placebo, 
along with the 2-sided 95% CI
5.4.1.3.
Analysis Methods
The analysis for all secondary efficacy outcomes will proceed as in the primary efficacy analysis, 
except for the incidence of all-cause hospitalization and all-cause mortality which will be based 
on Cochran-Mantel-Haenzel approach to estimate the Weighted RR and 95% CI.
Other analyses described above for the primary efficacy outcome may be performed for secondary 
efficacy outcomes.
5.5.
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 using a 
hierarchical closed testing procedure in the order listed below, each at alpha of 0.05 (2-sided). If 
an individual test during any step is not statistically significant, subsequent tests will not be 
declared to be statistically significant.


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The following is a diagram of the multiple testing procedure.
Superiority on primary efficacy endpoint 
(Based on ITT analysis set and Up-to-Day-35 analysis phase)
∀
Superiority on any thrombotic outcome (symptomatic VTE, MI, ischemic stroke, acute limb 
ischemia, and non-CNS systemic embolization) and all-cause mortality
(Based on ITT analysis set and Up-to-Day-35 analysis phase)
∀
Superiority on all-cause hospitalization
(Based on ITT analysis set and Up-to-Day-35 analysis phase)
∀
Superiority on symptomatic VTE
(Based on ITT analysis set and Up-to-Day-35 analysis phase)
∀
Superiority on ER visits
(Based on ITT analysis set and Up-to-Day-35 analysis phase)
∀
Superiority on any thrombotic outcome and all-cause hospitalization
            (Based on ITT analysis set and Up-to-Day-35 analysis phase)
∀
Superiority on hospitalization or death at Day 35
(Based on ITT analysis set and Day 35 visit (Day 35±6 days))
                                                                             ∀
5.6.
Tertiary/Exploratory Endpoint(s) Analysis
Tertiary/exploratory endpoints are:
!
Time to first occurrence of the composite of primary efficacy and ER visits defined as all 
symptomatic venous thromboembolic events (VTE), major arterial thrombotic events 
(myocardial infarction [MI], ischemic stroke, acute limb ischemia, noncentral nervous system 
[non-CNS] systemic embolization), all cause hospitalization, all-cause mortality, and ER 
visits 
!
WHO R&D Blueprint: Novel Coronavirus Scale for Clinical Improvement over time
!
Time to first occurrence of a component event of the primary efficacy endpoint MI, ischemic 
stroke, acute limb ischemia, non-CNS systemic embolization, and all-cause hospitalization) 
up to Day 35
!
The incidence of participants achieving an O2sat below 92% on room air up to Day 35
!
The incidence of participants achieving an O2sat below 88% on room air up to Day 35
!
The incidence of participants requiring supplemental oxygen up to Day 35
Superiority on all-cause mortality
                        (Based on ITT analysis set and Up-to-Day-35 analysis phase)


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!
Time to first occurrence of the use of non-invasive ventilation or high-flow oxygen (WHO 5),
intubation and mechanical ventilation (WHO 6), or ventilation and additional organ support 
(vasopressors, renal replacement therapy [RRT], extracorporeal membrane oxygenation 
[ECMO]; WHO 7) up to Day 35
!
The incidence of participants requiring dialysis or having an estimated glomerular filtration 
rate (eGFR) < 15 ml/min/1.73 m2 on two measurements more than 24 hr apart up to Day 35
!
Time to first occurrence of Disseminated Intravascular Coagulation (DIC) up to Day 35
!
Time to first occurrence of Acute Respiratory Distress (ARDS) up to Day 35
!
The incidence of occurrence of COVID digit up to Day 35
!
MRU data over time
Each tertiary/exploratory endpoint will be summarized by intervention groups based on the ITT 
analysis set and Up-to-Day-35 analysis phase.
5.7.
Safety Analyses
All safety analyses will be based on the safety analysis set based on actual intervention received, 
unless otherwise specified.
For all continuous safety variables, descriptive statistics by intervention group will include the N, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by intervention group using frequency counts and percentages.
5.7.1.
Extent of Exposure
The number and percentage of participants who receive at least one dose of study intervention will 
be summarized for each intervention group. 
Descriptive statistics for duration of study intervention (N, mean, SD, median, and range 
[minimum, maximum]) will be summarized by treatment. 
Study intervention duration is defined as date of last dose of study intervention – date of first dose 
of study intervention + 1.
For each subject, the study intervention compliance rate is estimated as follows
Compliance rate (%) = 100 * actual study intervention duration / intended study intervention 
duration
More specifically, the actual study intervention duration will be calculated by minimum of [last 
dose date, and the first primary efficacy outcome date] - first dose date + 1 - dose interruption days 
up to Day 35. The intended study intervention duration will be calculated by minimum of [Day 35 
date, and the first primary efficacy outcome date] - first dose date + 1.
Study intervention compliance will be summarized descriptively.


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5.7.2.
Bleeding Events
The principal safety outcome will be analyzed based on time from randomization to the first 
occurrence of fatal bleeding and critical site bleeding as defined in ISTH scale. Treatments will be 
compared using the same analysis models as those for the primary efficacy outcome described 
earlier. The analysis will be based on the safety analysis set and On-Treatment analysis phase. 
Participants will be analyzed according to study drug received. If a participant inadvertently 
receives both drugs, the participant will be analyzed as in rivaroxaban group. 
The homogeneity of treatment effects on the first occurrence of the principal safety outcome across 
subgroups defined in Section 5.8.3 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.
ISTH major, non-major clinically relevant, trivial bleeding, and all bleeding events 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. Major bleeding may also be assessed in an exploratory 
fashion using the Cunningham protocol (Cunningham 2011).
5.7.3.
Adverse Event
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the 
initial administration of study intervention through the day of last dose plus 2 days is considered 
to be treatment emergent. If the event occurs on the day of the initial administration of study 
intervention, and either event time or time of administration are missing, then the event will be 
assumed to be treatment emergent. If the event date is recorded as partial or completely missing, 
then the event will be considered to be treatment emergent unless it is known to be prior to the first 
administration of study intervention based on partial onset date or resolution date. All reported 
adverse events will be included in the analysis. For each adverse event, the number and percentage 
of participants who experience at least 1 occurrence of the given event will be summarized by 
intervention group.
Summary tables will be provided for adverse events:
!
Post-baseline (on or after the first study drug) AEs
!
Treatment-emergent adverse events
!
Adverse events with onset > 2 days from the stop of study drug
!
Post-baseline Serious AEs (SAEs)
!
Treatment-emergent SAEs (TESAEs)
!
SAEs with onset > 2 days from the stop of study drug
!
AEs leading to permanent study drug discontinuation
!
AEs by severity


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!
AEs by relationship to study intervention
!
AEs 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.
In addition to the summary tables, listings will be provided for participants who:
!
Had SAEs
!
Had AEs leading to discontinuation of study intervention
Deaths will be displayed by actual intervention received. Frequencies for the following parameters 
will be included in the summary table:
!
Number of participants who died
!
Cause of death
!
Relationship to study intervention (yes/no)
A listing of participants who died will be provided.
5.7.4.
Additional Safety Assessments (if applicable)
5.7.4.1.
Clinical Laboratory Tests
No routine laboratory testing will be required. However, all testing available in the EMR may be 
utilized to assess efficacy and safety outcome events including adverse events.
5.7.4.2.
Vital Signs and Physical Examination Findings
No vital signs and physical examinations will be performed. Height and weight will be assessed 
and reported by the participant or obtained from medical records.
5.8.
Other Analyses
5.8.1.
Medical Resource Utilization and Health Economics Analyses
Medical resource utilization and health economics data collection will include the ER visits, 
hospitalization, and duration of hospitalization and other utilization of medical resources (e.g., 
urgent care visits).
Medical resource utilization and health economics data will be descriptively summarized by 
intervention group.
5.8.2.
Benefit-Risk Analyses
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.


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These analyses are primarily intended to evaluate the key benefits and risks associated with the 
study treatment using a structured approach. They are complementary to other efficacy and 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 differences in background event rate
across different types of outcome events, a preferred metric for benefit-risk assessment is rate 
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 (harms). The excess number 
of events is defined as the rate difference (i.e., 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:
!
Incident proportions, expressed as the percentage of patients developing the event
!
Kaplan-Meier Product-Limit estimates of cumulative event rates for the duration of study (up 
to day 35)
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.
A series of analyses will compare excess numbers of events for several pairs of key efficacy and 
safety endpoints:
!
Primary efficacy endpoint vs. fatal bleeding and critical site bleeding
!
Primary efficacy endpoint excluding fatal bleeding and hospitalization primarily due to
bleeding (symptomatic VTE, MI, non-hemorrhagic stroke, acute limb ischemia, non-CNS 
systemic embolization, non-hemorrhagic cause hospitalization, and non-hemorrhagic death) 
vs. fatal bleeding and critical site bleeding 
!
All major venous and arterial thrombotic events (symptomatic VTE, MI, non-hemorrhagic
stroke, acute limb ischemia, and systemic embolization) and non-hemorrhagic death vs. fatal 
bleeding and critical site bleeding
!
Non-hemorrhagic death vs. fatal bleeding
To enable assessing the benefit-risk profile as a whole with mutually exclusive outcomes, we may
also examine excess numbers of events and NNT or NNH for the following sets of outcomes:
!
Benefits


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#
Non-hemorrhagic death
#
The composite of fatal MI and fatal non-hemorrhagic stroke
#
Non-fatal non-hemorrhagic stroke
#
Non-fatal MI
#
Non-fatal acute limb ischemia
#
Non-fatal non-CNS systemic embolism
#
Non-fatal VTE
o
Non-fatal symptomatic PE
o
Symptomatic lower extremity DVT
!
Harms
#
Fatal bleeding
#
Non-fatal critical site bleeding
#
Non-fatal, non-critical site bleeding requiring transfusion ≥2 units and non-fatal, non-
critical site Hgb drop ≥2 g/dL
#
Non-fatal, non-critical site bleeding requiring transfusion ≥2 units
#
Non-fatal, non-critical site Hgb drop ≥2 g/dL not associated with transfusion ≥2 units
In addition, other major efficacy, safety and exploratory 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
The primary analysis for benefit-risk evaluation will be based on the ITT analysis set and the Up-
to-Day-35 analysis phase, for both efficacy and safety outcomes. However, additional analyses 
using analysis sets defined by other subject analysis sets and/or analysis phases as defined in this 
SAP may be performed as supportive analyses (e.g., safety analysis set and On-Treatment analysis 
phase).
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.  Additions to these benefit-risk analyses may be 
made following unblinding to include unexpected adverse events, new subgroups of interest, or 
other additions as the data warrant.
The benefit-risk assessment may also be explored for the subgroups specified in Section 5.8.3, 
particularly for the benefit-risk pairs specified above.


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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
5.8.3.
Definition of Subgroups
Homogeneity of treatment effects will be assessed by subgroups and their interactions with 
treatment. Subgroups classified at baseline may include, but are not limited to, the following:
Subgroup
Variant
Definition
Age Group
1
! 18-<60 years
!
>=60 years
Age Group
2
! <60 years
! 60-<75 years
! >=75 years
Sex
! male
! female
Race
1
! White
! Others
Race
2
! White
! Black
! Asian
! Others
eGFR
1
! missing
! 15-<30 mL/min/1.73 m2
! 30-<50 mL/min/1.73 m2
! >=50 mL/min/1.73 m2
eGFR
2
! missing
! 15-<30 mL/min/1.73 m2
! 30-<60 mL/min/1.73 m2
! 60-<90 mL/min/1.73 m2
! >= 90 mL/min/1.73 m2
BMI
! <25 kg/m2
! 25-<35 kg/m2
! >=35 kg/m2
Baseline smoking status
! former
! current
! never
COVID-19 positive test
! at 1-5 days
! at 6-14 days
COVID-19 respiratory 
symptoms
! yes
! no
COVID-19 constitutional 
symptoms
! yes
! no


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Subgroup
Variant
Definition
COVID-19 neurological 
symptoms
! yes
! no
COVID-19 gastrointestinal 
symptoms
! yes
! no
COVID-19 
musculoskeletal symptoms
! yes
! no
History of diabetes
requiring medication
! yes
! no
History of cancer
! yes
! no
History of VTE
! yes
! no
History of CAD
! yes
! no
History of PAD
! yes
! no
History of heart failure
! yes
! no
History of thrombophilia
! yes
! no
History of hypertension
! yes
! no
History of cerebrovascular 
disease or ischemic stroke
! yes
! no
History of COPD
! yes
! no
History of asthma
! yes
! no
Baseline aspirin use
! yes
! no
Baseline P2Y12 use
! yes
! no
Baseline aspirin or P2Y12 
use
! yes
! no
Baseline D-dimer level
1
! <= 1xULN
! > 1xULN
! No baseline D-dimer available
Baseline D-dimer level
2
! <= 1xULN
! > 1xULN -<= 2xULN
! > 2xULN
! No baseline D-dimer available
Baseline D-dimer level
3
! <= 2xULN
! >2xULN -<6xULN
! >=6xULN
! No baseline D-dimer available
Number of baseline risk 
factors
! 1
! 2
! 3
! 4
! 5 or more


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5.9.
Interim Analyses
An interim analysis (IA) for futility or early superiority will be conducted when approximately 
167 participants with primary efficacy outcome have been observed (about 50% of the targeted 
total number of events). 
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, safety, or early superiority.
The study may be stopped early for futility when it would be unlikely to establish superiority 
and/or a positive benefit over risk of rivaroxaban compared with placebo, if the study were to run 
to completion.
Judgment for early stopping for futility should be made when any one of 2 conditions below meets:
!
Estimated HR on the primary efficacy outcome is 1.0 or higher based on the interim analysis
(Refer to Table 3 below for the corresponding conditional power [CP]). 
!
Observed incidence rate of fatal bleeding or critical site bleeding On-Treatment in rivaroxaban 
at IA is high enough that the overall benefit-risk profile would be unlikely to be positive when 
assessed at the final analysis.
Table 3:
Conditional Power (CP) Based on the Assumption of the Various Underlying RRRs in the 
Remaining Study
Estimated HR=1 at IA
90% CI: (0.77, 1.29)
70% CI: (0.85, 1.17)
RRR in the Remaining Study
CP
30%
33%
20%
10%
10%
2%
0%
0.3%
The analysis method for the primary efficacy outcome described in Section 5.3 will be used for 
the interim analysis. The alpha spent in the interim analysis for the testing of the primary efficacy 
outcome is 0.003 (two-sided) if the analysis is conducted at exact 167 events, which is determined 
by the O’Brien-Fleming boundary. 
The IDMC should also consider the benefit-risk assessment using clinical judgment for early 
stopping for efficacy.
5.9.1.
Independent Data Monitoring Committee (IDMC) or Other Review 
Board
An IDMC will be established and will review unblinded safety data periodically to ensure the 
safety of study subjects. In addition, the IDMC will review results of the planned interim analysis 
and make a recommendation whether the study should continue as planned, continue with 
modification, or be terminated prematurely due to futility, safety, or early superiority.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse events
BMI
body mass index
CI
confidence interval(s)
COA
clinical outcome assessment (paper or electronic as appropriate for this study)
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CRF
case report form(s) (paper or electronic as appropriate for this study)
CTCAE
Common Terminology Criteria for Adverse Events
DIC
disseminated intravascular coagulopathy
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
DVT
deep vein thrombosis
ECMO
extracorporeal membrane oxygenation
eCRF
electronic case report form
EMR
electronic medical record(s)
ER
emergency room
FOIA
Freedom of Information Act
GCP
Good Clinical Practice
HR
hazard ratio
IA
interim analysis
ICF
informed consent form
IDMC
Independent Data Monitoring Committee
ISTH
International Society on Thrombosis and Hemostasis
ITT
Intention-to-Treat
LMWH
low molecular weight heparin
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MRU
medical resource utilization
NCI
National Cancer Institute
PE
pulmonary embolism
RRR
relative risk reduction
RRT
renal replacement therapy
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
US
United States
VTE
venous thromboembolism
WHO
World Health Organization


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6.2.
Appendix 2 Demographics and Baseline Characteristics
The number of participants in each analysis set will be summarized and listed by intervention 
group and overall. In addition, the distribution of participants by site ID will be presented unless 
otherwise noted.
Table 4 presents a list of the demographic variables that will be summarized by intervention group
and overall, for the ITT analysis set(s).  
Table 4:
Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Age (18 -<60 years, >=60 years)
Frequency distribution with the 
number and percentage of 
participants in each category.
Age (<60 years, 60-<75 years, >=75 years)
Sex (male, female)
Race (White, others)
Race (White, Black, Asian, others)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
BMI (<25 kg/m2, 25-<35 kg/m2, >=35 kg/m2)
Baseline smoking status (former, current, never)
eGFR (missing, 15 -< 30 mL/min/1.73 m2, 30 -< 50 mL/min/1.73 
m2, >=50 mL/min/1.73 m2)
eGFR (missing, 15 -< 30 mL/min/1.73 m2, 30 -< 60 mL/min/1.73 m2, 60 -
< 90 mL/min/1.73 m2, >=90 mL/min/1.73 m2)
COVID-19 positive test (at 1-5 days, at 6-14 days)
COVID-19 respiratory symptoms (yes, no)
COVID-19 constitutional symptoms (yes, no)
COVID-19 neurological symptoms (yes, no)
COVID-19 gastrointestinal symptoms (yes, no)
COVID-19 musculoskeletal symptoms (yes, no)
History of diabetes requiring medication (yes, no)
History of cancer (yes, no)
History of VTE (yes, no)
History of CAD (yes, no)
History of PAD (yes, no)
History of heart failure (yes, no)
History of thrombophilia (yes, no)
History of hypertension (yes, no)
History of cerebrovascular disease or ischemic stroke (yes, no)
History of COPD (yes, no)
History of asthma (yes, no)
Baseline aspirin use (yes, no)
Baseline P2Y12 use (yes, no)
Baseline aspirin or P2Y12 use (yes, no)
Baseline D-dimer level (<= 1xULN, > 1xULN, No baseline D-dimer)
Baseline D-dimer level (<= 1xULN, > 1xULN -<= 2xULN, > 2xULN, No 
baseline D-dimer)
Baseline D-dimer level (<= 2xULN, > 2xULN -< 6xULN, >=6xULN, No 
baseline D-dimer)
Number of baseline risk factors (1, 2, 3, 4, 5 or more)


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6.3.
Appendix 3 Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
Participants with major protocol deviations will be identified prior to database lock and the 
participants with major protocol deviations will be summarized by intervention 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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6.4.
Appendix 4 Prior and Concomitant Medications
Prior medications are defined as any therapy used before the day of first dose (partial or complete) 
of study intervention. Concomitant medications are defined as any therapy used on or after the 
same day as the first dose of study intervention, including those that started before and continue 
on after the first dose of study intervention.
Summaries of concomitant medications will be presented by Anatomical Therapeutic Chemical 
(ATC) term, intervention group, and 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]). The proportion of 
participants who receive each concomitant medication will be summarized as well as the 
proportion of participants who receive at least 1 concomitant medication. 
Prior medications will be summarized by intervention group and ATC term.


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6.5.
Appendix 5 Bayesian Dynamic Borrowing
Bayesian models are informed by new data acquired during a trial (the likelihood) and by other 
sources of information which are incorporated into the analysis via a prior distribution.
Specifically, the data gathered in this current trial will form the likelihood function in the analysis 
of rivaroxaban compared to placebo, while Gates MRI Trial data will partially inform the prior 
distribution. The Bayesian model then summarizes the information in the form of a posterior 
distribution on the treatment effect of rivaroxaban compared to placebo. This method relies 
primarily on data generated from the PREVENT-HD study but also allows for the possibility of 
leveraging information from a concurrent and similarly designed Gates MRI trial of rivaroxaban 
compared to placebo.
Reparameterization
With the proportional hazards assumption, the log-transformed estimated HR (rivaroxaban to 
placebo) approximates a normal distribution with variance 1/ + 1/, where  and  are the 
numbers of events in two treatment groups. Let  = log(HR) be the parameter of interest, the 
estimate of  can be viewed as calculated base on two samples from normal distributions N(, 1)
and N(, 1) with sample size  and  respectively, where  − = .
Robust Mixture Prior
The supplemental analyses of primary composite endpoint use a Bayesian model with robust 
mixture prior as below:
 ∗() + (1 −) ∗ (),
where 
!
() denotes the informative prior of  based on the Gates Foundation trial, which is a
normal distribution. Specifically, the mean and standard deviation are the estimated log(HR)
and corresponding standard error from the stratified Cox proportional hazards model will be 
used where possible. If stratification factor of time from COVID-19 positive test to 
randomization is not available in the data, then the unstratified Cox proportional hazards 
model will be used.  
!
 () denotes the vague prior of . It is a normal distribution with mean 0, which indicates 
that there is no treatment effect of rivaroxaban compared to placebo. The standard deviation 
is set to be the standard error of estimated  with “one subject” per group. Therefore, two trial
subjects will follow N(, 1) and N(, 1), respectively, with the standard deviation of
1+1=2.
!
 denotes the mixing weight, and interpreted as the prior probability that the source 
information from Gates MRI trial is relevant for this study. 
The robust mixture prior model assumes the treatment effect in the target population is similar to 
the reference population, but also expressing some degree of skepticism towards borrowing 
strength. By selecting  = 0.5, a moderately informative prior is chosen as the base-case.
Tipping point analysis with  varying from 0 to 1, with intervals of 0.05, will be performed to 
assess the sensitivity of this method.


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7.
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