Conditions: COVID-19
Keywords: Rivaroxaban Xarelto Coronavirus COVID-19 Coronavirus disease 2019
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 497
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess safety and clinical efficacy of rivaroxaban in people with mild Coronavirus Disease 2019 who are at increased risk of disease progression.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Rivaroxaban intervention 2: Placebo
Intervention descriptions: intervention 1: Participants self-administered rivaroxaban, 10 milligrams (mg) (1 tablet) orally once daily for 21 days. intervention 2: Participants self-administered rivaroxaban matching placebo orally once daily for 21 days.

Protocol document:
Prot_000.pdf: 
Bill & Melinda Gates Medical Research Institute 
Gates MRI – COD-01-T01-01 Version 4, Amendment 2 
CONFIDENTIAL 
27 January 2021 
1 
Protocol Title: A randomized, controlled, Phase 2b study to evaluate safety and efficacy of rivaroxaban
(Xarelto®) for high risk people with mild COVID-19   
Short Title: A randomized, controlled, Phase 2b trial to evaluate safety and efficacy of rivaroxaban 
Protocol Number: Gates MRI- COD-01-T01-01 Amendment 2 
Compound: Xarelto® (rivaroxaban), approved for use in the US since 2011 
Study Phase: 2b 
Sponsor Name: Bill & Melinda Gates Medical Research Institute (Gates MRI) 
Legal Registered Address:  
One Kendall Square  
Building 600, Suite 6-301 
Cambridge, MA 02139  
Regulatory Agency Identifier (Investigational New Drug [IND]) Number: 151445 
Medical Monitor/s name/s and contact information will be provided separately. 
Approval Date: Version 4, Amendment 2, 27 January 2021  
Refer to Section 13 for version history and amendment revisions. 
NCT Number: NCT04504032
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Bill & Melinda Gates Medical Research Institute 
Gates MRI – COD-01-T01-01 Version 4, Amendment 2 
CONFIDENTIAL 
27 January 2021 
2 
Version 4, Amendment 2 Sponsor Signatory 
 
See appended electronic signature page 
 
 
 
 
 
 
 
Bill & Melinda Gates Medical Research Institute 
  
 
Date 
 
 
 


Bill & Melinda Gates Medical Research Institute 
Gates MRI – COD-01-T01-01 Version 4, Amendment 2 
CONFIDENTIAL 
27 January 2021 
3 
 
Table of Contents 
List of Abbreviations and Terms .....................................................................................................7 
1. 
Synopsis ............................................................................................................................8 
2. 
Study Schedule of Procedures ........................................................................................11 
3. 
Background .....................................................................................................................12 
3.1. 
Severe Acute Respiratory Syndrome Coronavirus-2 ......................................................12 
3.1.1. 
SARS-CoV-2 Epidemiology and Disease ......................................................................12 
3.1.2. 
Therapeutic Approaches for COVID-19 .........................................................................13 
3.1.3. 
SARS-CoV-2 Immunothrombosis and Thromboembolic Events ...................................13 
3.2. 
Rivaroxaban ....................................................................................................................14 
3.2.1. 
Use in Specific Populations ............................................................................................16 
3.2.2. 
Rationale for the Use of Rivaroxaban for Treatment of Mild COVID-19 .....................16 
3.2.2.1. 
Rationale for a Limit of 7 Days of Mild COVID-19 Symptoms Prior 
to Randomization ........................................................................................................16 
3.2.3. 
Benefit/Risk Assessment ................................................................................................17 
3.2.3.1. 
Benefit/Risk Assessment of Rivaroxaban ...................................................................17 
3.2.4. 
Rivaroxaban Mechanism of Action ................................................................................18 
3.2.5. 
Rivaroxaban Pharmacokinetics .......................................................................................18 
4. 
Objectives and Endpoints ...............................................................................................19 
5. 
Study Design ...................................................................................................................20 
5.1. 
Overall Design ................................................................................................................20 
5.2. 
Study Population .............................................................................................................20 
5.3. 
Recruitment .....................................................................................................................20 
5.4. 
Pre-Screening for the Study ............................................................................................21 
5.4.1. 
Pre-Screening Inclusion Criteria .....................................................................................22 
5.4.2. 
Pre-Screening Procedures ...............................................................................................23 
5.5. 
Screening for the Study...................................................................................................24 
5.5.1. 
Inclusion and Exclusion Criteria .....................................................................................24 
5.5.2. 
Exclusion Criteria ...........................................................................................................25 
6. 
Study Intervention- Rivaroxaban or Placebo ..................................................................26 
6.1. 
Rationale for Study Intervention Selection .....................................................................27 
6.2. 
Management of Participants to Limit Risks of SARS-CoV-2 
Transmission ...................................................................................................................27 
6.3. 
Guidance on COVID-19 to Ensure Participant and Healthcare Worker 
Safety ..............................................................................................................................27 
6.4. 
Dose Modification and Toxicity Management ...............................................................27 
6.4.1. 
Definitions of Bleeding Severity ....................................................................................28 
6.4.1.1. 
Definition of Major Bleeding ......................................................................................28 
6.4.1.2. 
Definition of Clinically Relevant Non-Major Bleeding ..............................................28 
6.4.1.3. 
Definition of Minimal Bleeding ..................................................................................29 
6.5. 
Safety Monitoring ...........................................................................................................29 
6.6. 
Study Pausing Guidelines ...............................................................................................29 


Bill & Melinda Gates Medical Research Institute 
Gates MRI – COD-01-T01-01 Version 4, Amendment 2 
CONFIDENTIAL 
27 January 2021 
4 
6.7. 
Masking ..........................................................................................................................30 
6.8. 
Preparation/Handling/Storage/Accountability ................................................................30 
6.9. 
Study Intervention Compliance ......................................................................................30 
6.10. 
Concomitant Therapy .....................................................................................................30 
6.10.1. Prohibited Medications ...................................................................................................31 
6.10.2. Precautionary Medications..............................................................................................32 
6.11. 
Hospitalization ................................................................................................................32 
6.12. 
Treatment after the End of the Study ..............................................................................32 
7. 
Discontinuation/Withdrawal Criteria and Study Completion .........................................32 
7.1. 
Discontinuation of Study Intervention ............................................................................32 
7.2. 
Withdrawal from the Study.............................................................................................33 
7.3. 
Lost to Follow-up............................................................................................................33 
7.4. 
Study Completion ...........................................................................................................34 
8. 
Study Encounters ............................................................................................................34 
8.1. 
Screening Process and Procedures ..................................................................................34 
9. 
Study Assessments and Procedures ................................................................................35 
9.1. 
Day 1 (first day of study) ................................................................................................35 
9.2. 
Procedures at Visits from Day 4 through Day 28 ...........................................................36 
9.3. 
Procedures at Visit Day 35 .............................................................................................37 
9.4. 
Efficacy Assessments .....................................................................................................37 
9.4.1. 
Nasal Sampling ...............................................................................................................37 
9.5. 
Safety Assessments .........................................................................................................37 
9.5.1. 
Adverse Event Definition ...............................................................................................38 
9.5.2. 
Adverse Events of Special Interest Definition ................................................................38 
9.5.3. 
Serious Adverse Event Definition ..................................................................................38 
9.5.4. 
Toxicity Grading .............................................................................................................39 
9.5.5. 
Study Intervention-Related AEs and SAEs ....................................................................39 
9.6. 
Assessment of COVID-19 Signs and Symptoms ...........................................................39 
9.7. 
Overdose of Study Intervention ......................................................................................41 
9.8. 
Pregnancy........................................................................................................................41 
9.8.1. 
Contraceptive Guidance ..................................................................................................42 
9.9. 
Biohazard Containment ..................................................................................................42 
10. 
Statistical Considerations ................................................................................................43 
10.1. 
Sample Size Determination ............................................................................................43 
10.2. 
Statistical Hypothesis ......................................................................................................43 
10.3. 
Populations for Analyses ................................................................................................43 
10.3.1. Assigning Shared Controls across Multiple Intervention-Specific 
Analysis Populations .......................................................................................................44 
10.4. 
Primary and Key Secondary Endpoints ..........................................................................46 
10.5. 
Statistical Methods ..........................................................................................................47 
10.5.1. Efficacy Analyses ...........................................................................................................47 
10.5.2. Safety Analyses ...............................................................................................................48 
10.6. 
Interim Analysis ..............................................................................................................48 
11. 
Operational Considerations.............................................................................................48 


Bill & Melinda Gates Medical Research Institute 
Gates MRI – COD-01-T01-01 Version 4, Amendment 2 
CONFIDENTIAL 
27 January 2021 
5 
11.1. 
Independent Data Monitoring Committee ......................................................................48 
11.2. 
Informed Consent Process ..............................................................................................49 
11.2.1. Informed Consent Forms ................................................................................................49 
11.3. 
Data Protection ...............................................................................................................50 
11.4. 
Sample Retention and Future Use of Collected Biospecimen ........................................50 
11.5. 
Dissemination of Clinical Study Data ............................................................................50 
11.6. 
Data Quality Assurance ..................................................................................................51 
11.7. 
Source Documents ..........................................................................................................51 
11.8. 
Record Retention and Future Use of Medical Data ........................................................51 
11.9. 
Study Closure ..................................................................................................................52 
11.10. 
Publication Policy ...........................................................................................................52 
12. 
References .......................................................................................................................53 
13. 
Version History ...............................................................................................................56 
13.1. 
Amendment 1 dated 09 Sept 2020 ..................................................................................56 
13.2. 
Amendment 2 dated 27 January 2021.............................................................................63 
 


Bill & Melinda Gates Medical Research Institute 
Gates MRI – COD-01-T01-01 Version 4, Amendment 2 
CONFIDENTIAL 
27 January 2021 
6 
List of Tables, Figures and Appendix 
Table 1: 
Schedule of Activities ................................................................................................ 11 
Table 2: 
Bleeding events in MAGELLAN study ..................................................................... 16 
Table 3: 
Objectives and Endpoints ........................................................................................... 19 
Table 4: 
Pre-screening Schedule of Activities ......................................................................... 23 
Table 5: 
Rivaroxaban prohibited medications/foods/supplements .......................................... 31 
Table 6: 
COVID-19 Signs and Symptoms to be Recorded in the CRF/eCRF ......................... 40 
Table 7: 
Gates MRI COVID-19 Ordinal Scale Clinical Endpoint Definitions ........................ 40 
Table 8: 
WHO Ordinal Scale for Assessment of Clinical Status of COVID-19 Patients ........ 41 
Table 9: 
Populations for Analysis ............................................................................................ 43 
  
Figure 1: 
Study Screening Process .............................................................................................. 9 
Figure 2: 
Pre-Screening for the Study ....................................................................................... 21 
Figure 3: 
Randomization strategy for sites where 3 interventions are being studied ................ 45 
Figure 4: 
Randomization strategy for sites where 2 interventions are being studied ................ 46 
Figure 5: 
Randomization strategy for sites where only 1 intervention is being studied ............ 46 
 
 
Appendix 1: Platform Core Protocol 
 


Bill & Melinda Gates Medical Research Institute 
Gates MRI – COD-01-T01-01 Version 4, Amendment 2 
CONFIDENTIAL 
27 January 2021 
7 
List of Abbreviations and Terms  
Term 
Definition 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest  
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
CI 
Confidence Interval 
Cmax 
Maximum Concentration 
COVID-19 
Coronavirus Disease 2019 
CRF/eCRF 
(Electronic) Case Report Form 
CRO 
Contract research organization 
DOAC 
Direct Oral Anticoagulant  
DVT 
Deep Vein Thrombosis 
Eligible 
Qualified for enrollment into the study based upon adherence to 
inclusion/exclusion criteria 
Gates MRI 
Bill & Melinda Gates Medical Research Institute 
GCP 
Good Clinical Practices 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT  
Intention to Treat 
LRTI 
Lower Respiratory Tract Infection 
mITT 
Modified Intention to Treat 
Participant(s) 
Term used throughout the protocol to denote the enrolled individual(s) 
PD 
Pharmacodynamic 
PE 
Pulmonary embolism 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PP  
Per Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SoA 
Schedule of Activities 
US 
United States 
VTE 
Venous Thromboembolism 
WHO 
World Health Organization 


Bill & Melinda Gates Medical Research Institute 
Gates MRI – COD-01-T01-01 Version 4, Amendment 2 
CONFIDENTIAL 
27 January 2021 
8 
1. 
Synopsis 
Protocol Title: A randomized, controlled, Phase 2b study to evaluate safety and efficacy of 
rivaroxaban (Xarelto®) for high risk people with mild COVID-19  
Short Title: A randomized, controlled, Phase 2b trial to evaluate safety and efficacy of 
rivaroxaban in high risk people 
Study Intervention and Rationale: 
Rivaroxaban is an approved, direct oral anticoagulant (DOAC) factor Xa inhibitor that is 
indicated for treatment and prophylaxis of thromboembolism. SARS-CoV-2 infection can trigger 
systemic inflammatory response, hypercoagulability, and a prothrombotic state in people whose 
coronavirus disease 2019 (COVID-19) progresses to severe disease [Bikdeli 2020]. 
Thromboembolic events are common in patients hospitalized with COVID-19. High levels of 
blood-clotting parameters are associated with severe COVID-19 and mortality [Wu 2020]. 
Widespread thrombosis with microangiopathy and alveolar capillary thrombi are prevalent in 
patients who die from COVID-19 [Ackermann 2020]. Anticoagulant therapy may decrease 
mortality in patients with severe COVID-19 with associated coagulopathy [Tang 2020]. There is 
evidence to suggest that abnormal coagulation and thrombosis are occurring in people with non-
severe COVID-19 and may place them at greater risk of severe disease [Fu 2020, Micco 2020, 
Nauka 2020]. 
Rivaroxaban is selected as a candidate treatment modality to reduce disease progression in 
people with mild COVID-19 who are at high risk for moderate or severe disease due to age, body 
mass index (BMI) and comorbidities, many of which are also thrombotic risks.  
Our hypothesis is that rivaroxaban will reduce COVID-19 progression from mild to moderate or 
severe disease category or higher. 
Rivaroxaban is a once-daily, oral medication with a well characterized safety profile, with no 
cold chain requirement. If proven to be efficacious in preventing COVID-19 progression, it has 
global scalability potential.  
Primary purpose: To assess the safety and clinical efficacy of rivaroxaban in reducing the 
proportion of participants who have progressed to moderate or severe disease category or higher 
in people with mild COVID-19 who are at increased risk of disease progression. 
Design: This is a randomized, Phase 2b, controlled study. People who are symptomatic and have, 
or are suspected to have, COVID-19, and are at increased risk for COVID-19 progression based 
on age, BMI or comorbidity will be enrolled (refer to Section 5.5 for eligibility criteria). 
This study is performed as part of the overall COVID-19 platform core protocol (refer to 
Appendix 1) that intends to provide data to: 
1. support decision and development plans for Phase 3 in consultation with key stakeholders. 
2. support recommendations by regulators and policy makers for use in treating COVID-19.  


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Consent and enter study screening
If eligibility is confirmed, enroll and randomize.
Fulfill key eligibility criteria
 Age ≥ 18 yrs old
 At high risk for severe COVID-19 
 Positive SARS-CoV-2 diagnostic  testing performed 
≤10 days at the time of screening 
 Mild COVID-19 symptoms present ≤7 days at the time of 
randomization 
 Laboratory test/s obtained and reviewed
 Willing to participate in COVID-19 treatment trial
Have COVID-19 symptoms
Study screening
≤5 days from screening 
to Day  1


Bill & Melinda Gates Medical Research Institute 
Gates MRI – COD-01-T01-01 Version 4, Amendment 2 
CONFIDENTIAL 
27 January 2021 
10 
Study sites: Participants from multiple sites in multiple countries may be included.  
Masking: Every effort will be made to mask the assigned treatment groups. The laboratories 
performing the SARS-CoV-2 diagnostic testing will be blinded to the treatment groups. The 
participants will not be told of the assigned treatment groups. Although the participants will not 
be informed that active and control treatment do not look identical, due to features such as 
embossing on the rivaroxaban tablets, the participants may attempt to identify the intervention 
they receive via computer image search. The active and placebo tablets will not be identical in 
appearance; but will be similar in size, shape and color. Moreover, the bottles will be identical.  
The study staff evaluating the participants will not be given the assigned treatment groups, but 
could possibly find out if the participant’s tablets become visible to them. Such occurrences will 
be documented. It is recognized that there is some risk of bias related to the outcome assessments 
by the participant and/or study staff, particularly for subjective measurements.  
Safety and efficacy monitoring: An independent data monitoring committee (IDMC) will be 
convened for this study (Section 11.1). Unblinded safety data review by the IDMC will occur 
monthly, and ad hoc as necessary. The IDMC will also review unblinded efficacy data at a pre-
specified interim analysis. Pausing guidelines will apply (refer to Section 6.6). 
Adverse events (AEs): All AEs must be recorded on the eCRFs if any of the following criteria 
have been met: 
 AEs meeting SAE definition 
 AEs leading to discontinuation of study intervention 
 Grade 3 and grade 4 AEs  
 Adverse events of special interest (AESI) including major bleeding (refer to Section 
6.4.1) and severe hypersensitivity to rivaroxaban.  
AEs will be recorded in the eCRF from the time of informed consent through Day 35 (14 days 
after the last dose of investigational product or IP).  
Analysis: The primary analysis will occur after all participants complete Day 35. There will be 1 
interim analysis to assess futility. The interim analysis will occur after the first approximately 
200 participants complete Day 28.  
If the trial does not cross the pre-specified boundaries to declare futility at the interim analysis, a 
final efficacy and safety analysis will occur after all participants complete Day 35.  


Bill & Melinda Gates Medical Research Institute 
Gates MRI – COD-01-T01-01 Version 4, Amendment 2 
CONFIDENTIAL 
27 January 2021 
11 
2. 
Study Schedule of Procedures 
Table 1: 
Schedule of Activities 
Visits 
Screening  
(≤5 days of 
Day 1) 
Day 
1 
Day 
4 
Day 
6 
Day 
8 
Day 
10 
Day 
12 
Day 
14 
Day 
18 
Day 
21 
Day 
24 
Day 
28 
Day 
35 
Obtain consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, past and 
current medical history 
including known 
pregnancy/lactation status, 
and medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Lab-confirmed SARS-CoV-2 
positive diagnostic testing1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention dose 
(Day 1 Day 21) and record 
adherence to dosing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinical status assessment 
using ordinal scales for Gates 
MRI and WHO 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
COVID-19 signs and 
symptoms, temperature, 
oxygen saturation  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bleeding events and severity 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Self-collection of nasal or 
oropharynx SARS-CoV-2 
sample for diagnostic testing3 
(X)1 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Note that visits will preferably take place remotely (refer to Section 8). 
SARS-CoV-2= Severe acute respiratory syndrome coronavirus 2 
Gates MRI= Bill & Melinda Gates Medical Research Institute 
WHO = World Health Organization 
1 If there is documented positive SARS-CoV-2 diagnostic testing performed with a sample collected ≤10 days prior to 
screening, the test does not need to be performed. If no documentation, the potential participant will be asked to collect a nasal 
or oropharynx swab sample to send for testing. 
2 If documentation of a previous positive SARS-CoV-2 test is not available and a test is performed at screening, randomization 
will occur after a positive result is obtained. 
 3 Participant will be asked to collect a sample per kit instructions. Discontinue collection during hospitalization and/or per 
physician’s discretion when two consecutive negative results are available at any time during the study.  
Note that an unscheduled visit may be required. Additional collection of a nasal swab sample may be performed based on the 
clinical judgement of the PI. 


Bill & Melinda Gates Medical Research Institute 
Gates MRI – COD-01-T01-01 Version 4, Amendment 2 
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27 January 2021 
12 
3. 
Background  
3.1. 
Severe Acute Respiratory Syndrome Coronavirus-2 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel beta coronavirus of 
zoonotic origin, similar to SARS-CoV and Middle East respiratory syndrome coronavirus 
(MERS-CoV). The case fatality rate for SARS-CoV-2 varies between age groups and people 
with or without risks as well as regions of the world. Based on current evidence, the overall case 
fatality risk is lower than that of SARS-CoV (~10%) and MERS-CoV (~40%) [Chen 2020]. 
However, SARS-CoV-2 has potentially higher transmissibility (R0: 1.4 to 5.5) than both SARS-
CoV (R0: 2 to 5) and MERS-CoV (R0: <1). 
Our understanding of the viral pathogenesis of SARS-CoV-2 remains limited. However, it 
appears that the virus cell entry depends on the binding of the viral spike (S) proteins to cellular 
receptors and on S protein priming by host cell proteases. SARS-CoV-2, like SARS-CoV, uses 
the angiotensin converting enzyme 2 (ACE2) receptor on pulmonary epithelial cells for entry and 
the transmembrane serine protease 2 for S protein priming [Hoffmann 2020]. The receptor 
binding domain of lineage B beta coronaviruses S protein is a single, continuous domain that 
contains all of the structural information necessary to interact with the host receptor. Fusion is 
mediated at the cell membrane, delivering the viral nucleocapsid inside the cell for subsequent 
replication. ACE2 expression is found in the lung epithelial cells, vascular endothelium, renal 
tubular epithelium, and epithelia of the small intestine. Viral shedding has been localized 
primarily to respiratory droplets and fecal samples [Zhu 2020]. 
3.1.1. SARS-CoV-2 Epidemiology and Disease 
Since the first reported case in December 2019, SARS-CoV-2 infection has spread globally 
[Chen 2020, Huang 2020, Zhu 2020]. WHO declared COVID-19 a Public Health Emergency of 
International Concern on 30 January 2020 [WHOa 2020] and a pandemic on 11 March 2020.  
United States declared a national emergency on 13 March 2020 [WHPR 2020]. As of September 
2020, approximately 26 million confirmed cases were reported globally, with over 859,000 
deaths [JHU 2020].  
SARS-CoV-2 infection is estimated to cause mild to moderate disease in about 80% of people 
but can cause severe lower respiratory tract infection (LRTI) in approximately 15-20%, 
particularly among those in high-risk groups, defined by advanced age (≥65 years), presence of 
comorbidities (e.g., cardiopulmonary disease, diabetes mellitus) or obesity [CDC-2020].  
Progression to LRTI appears to frequently result in hospitalization for supplemental oxygen 
therapy and may lead to need for ventilator respiratory support and ultimately death. Given the 
rapid spread of the SARS-CoV-2 pandemic, interventions that avert adverse outcomes and 
accelerate symptom resolution are needed. In addition, prolonged viral shedding has been noted 
after infection; therapeutic strategies that can effectively reduce viral shedding, and potentially 
onward transmission, have the potential to shift the trajectory of the pandemic. Intervening early 
in an outpatient setting before disease progression occurs is important to mitigate human 
suffering and healthcare utilization.  


Bill & Melinda Gates Medical Research Institute 
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27 January 2021 
13 
Most deaths and severe pulmonary and extra-pulmonary diseases have occurred particularly in 
adults over 65 years of age and in persons with underlying pulmonary or cardiac comorbidities, 
obesity or diabetes. In healthy adults, including pregnant women, it can cause a febrile, self-
limited pneumonia. Severe disease is seen less frequently in children and younger adults [Beigel 
2020, Cai 2020]. 
Manifestations of COVID-19 in persons with comorbidities, such as chronic malaria, 
tuberculosis, or HIV infection, are not well-characterized. Nevertheless, the burden of this 
pandemic to the global health and economic systems is substantial.  
As with many infectious epidemics, household contacts, first responders, caregivers, and medical 
personnel attending to persons with COVID-19 are at high risk of infection. The incubation time 
requires 10-14 days of quarantine for exposed individuals not wearing personal protective 
equipment [Linton 2020], and on 03 March 2020, WHO declared a global shortage of personal 
protective equipment, leaving doctors, nurses, and other frontline workers dangerously ill-
equipped to care for COVID-19 participants [WHO(b) 2020]. Extensive absences from the care 
network and health system will degrade the ability to care not only for those with COVID-19 but 
also for routine healthcare issues as well. At the height of local epidemic, the health care system 
becomes overburdened with individuals with respiratory illness. To date, rigorous self-isolation 
and lockdown have been required to contain the SARS-CoV-2 outbreak, leaving entire societies 
to abruptly stop normal life. Interventions are urgently needed to stop viral spread and to 
decrease the morbidity and mortality caused by the infection. The ability to stop viral replication 
to prevent transmission of the virus and to prevent LRTI, which is associated with need for 
hospitalization and possibly mechanical ventilatory support, will be of benefit to the individual, 
the hospital system, and the health of the public. 
3.1.2. Therapeutic Approaches for COVID-19 
As of September 2020, no standard of care for treatment of outpatients with COVID-19 has been 
established. Already-approved and available medications are ideal for immediate evaluation for 
SARS-CoV-2 treatment.  
There is an urgent need for controlled clinical studies for early treatment in people with mild 
COVID-19 to guide both policy makers and other clinical researchers on prioritized drugs, 
including a path toward future evaluations as data becomes available.  
3.1.3. This study is performed as part of an adaptive, randomized platform core 
protocol for treatment of early and mildly symptomatic individuals in out-patient 
settings with SARS-CoV-2 infection (Appendix 1). The platform protocol 
includes the contents of the adaptive, platform trial (e.g., background 
information and rationale, the trial design and conduct). The platform design is 
intended to support investigations of a broad array of therapeutic approaches 
such as antiviral therapies, host-directed therapies, monoclonal antibodies, and 
hyperimmunoglobulin.SARS-CoV-2 Immunothrombosis and Thromboembolic 
Events 
SARS-CoV-2 infection may be a trigger for venous thromboembolism (VTE), and several 
pathogenetic mechanisms are involved, including endothelial dysfunction, characterized by 


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increased levels of von Willebrand factor; systemic inflammation, by Toll-like receptor 
activation; and a procoagulatory state, by tissue factor pathway activation. Infection with SARS-
CoV-2 in severe patients progresses from a viral infection to a complex inflammatory condition 
characterized by sudden decline of patients due to hyperinflammation and thrombotic events 
[Bikdeli 2020]. In the absence of severe immune complications, SARS-CoV-2 infection is self-
limiting and typically mild. 
Hemostatic abnormalities including elevated levels of D-dimer and other thrombotic markers 
(e.g., platelets) are frequently seen at hospital admission for COVID-19; levels have been linked 
to disease severity in multiple studies. Increased D-dimer concentrations (indicating pulmonary 
vascular bed thrombosis with fibrinolysis) and elevated cardiac enzyme concentrations 
(indicating emergent ventricular stress induced by pulmonary hypertension) are key early 
features of severe pulmonary intravascular coagulopathy related to COVID-19 [McGonagle 
2020]. 
Thrombosis (mostly venous) and abnormal coagulation are seen in at least 30% of ICU patients. 
Pulmonary embolism (PE), deep vein thrombosis (DVT), ischemic stroke, myocardial infarction 
or systemic arterial embolism have been observed [2020]. DVT has also been reported in mild 
COVID cases [Nauka 2020]. 
Autopsies of patients who died of COVID-19 revealed PE and DVT (including in people not 
suspected to have DVT before death). Histomorphological findings were distinctive vascular 
features with severe endothelial injury, and diffuse alveolar capillary microthrombi that was 9 
times more prevalent in patients who died from COVID-19 than influenza [Ackermann 2020,  
Wichmann 2003]. Microthrombi in the pulmonary vasculature may explain the rapid 
deterioration and pulmonary collapse observed in patients who suddenly progress to acute 
respiratory distress syndrome. 
Hospitalized patients acutely ill from medical conditions such as infections and pneumonia are at 
increased risk of VTE, for whom anticoagulant could be indicated. Risk assessment modeling 
studies are reporting 40% VTE risk among hospitalized COVID-19 patients [Wang 2020]. The 
World Health Organization (WHO) interim guidance recommends in-hospital prophylactic daily 
low-molecular weight heparin or twice daily subcutaneous unfractionated heparin [WHO(c) 
2020]. Use of DOACs like rivaroxaban in the hospitalized population is limited by drug 
interactions with antiviral and other agents for treatment of COVID-19 or its complications. 
However, rivaroxaban may benefit high risk people with non-severe disease in the outpatient 
setting who are less likely to need those treatments with significant drug interaction with 
rivaroxaban.  
3.2. 
Rivaroxaban  
Xarelto® (rivaroxaban) is manufactured by Janssen Pharmaceutical Companies of Johnson & 
Johnson and was first approved by the FDA in 2011. Xarelto® is currently approved for the 
following indications [Xarelto® 2020]: 
 reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation (15 or 20mg 
daily) 
 treatment of DVT (20mg daily after initial treatment of 15mg twice daily for 21 days) 


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 treatment of PE (20mg daily after initial treatment of 15mg twice daily for 21 days) 
 reduce risk of recurrence of DVT or PE (10mg daily after at least 6 months of standard 
anticoagulation treatment) 
 prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement 
surgery (10mg once daily) 
 prophylaxis of VTE in acutely ill medical patients (10mg once daily during hospitalization 
and 31-39 days after hospital discharge) 
 reduce risk of major cardiovascular events in patients with chronic coronary artery disease 
or peripheral artery disease (2.5mg twice daily in combination with daily aspirin). 
During clinical development for these approved indications, Xarelto® was evaluated in 
approximately 30,000 patients. The contraindications for Xarelto are active pathological bleeding 
and severe hypersensitivity reaction to Xarelto®. They will be followed as AESIs in this study. 
The use of rivaroxaban for mild COVID-19 will follow usage guidelines for the prophylaxis of 
VTE in acutely ill medical patients 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. The recommended dosage for this use is 10mg once daily, in hospital and after hospital 
discharge, for a total recommended duration of 31 to 39 days. The dosing in this study of 10mg 
daily for 21 days is in line with the indicated dose. Renal considerations for dosage include 
CrCl≥15mL/min. This study will exclude people with severe chronic kidney disease (stage IV or 
receiving dialysis). 
According to the package insert, Xarelto® increases the risk of bleeding, and, although rare, can 
cause serious or fatal bleeding. Concomitant use of other drugs that impair hemostasis increases 
the risk of bleeding. Xarelto® is not for use for primary VTE prophylaxis in these hospitalized, 
acutely ill medical patients at high risk of bleeding. 
The efficacy and safety of Xarelto® for prophylaxis of VTE was evaluated in a multicenter, 
randomized, parallel group efficacy and safety study for the prevention of venous 
thromboembolism in hospitalized medically ill patients comparing rivaroxaban with enoxaparin, 
the MAGELLAN study, [NCT00571649]). MAGELLAN was a multicenter, randomized, 
double-blind, parallel-group efficacy and safety study comparing Xarelto® to enoxaparin, in the 
prevention of VTE in hospitalized acutely ill medical patients during the in-hospital and post-
hospital discharge period. Eligible patients included adults who were at least 40 years of age, 
hospitalized for an acute medical illness, at risk of VTE due to moderate or severe immobility, 
and had additional risk factors for VTE. Patients were randomized to receive either Xarelto® 10 
mg once daily for 35 ±4 days starting in hospital and continuing post hospital discharge 
(n=4050) or enoxaparin 40 mg once daily for 10 ±4 days starting in hospital followed by placebo 
post-discharge (n=4051) [Cohen 2013].  
Approximately 67% were 65 years and over and about 37% were >75 years. A principal safety 
outcome event occurred in 111 of 3997 patients (2.8%) in the rivaroxaban group [Cohen 2013]. 
Safety analysis of bleeding is shown in Table 2.  
Over the total study period, alanine aminotransferase elevations greater than three times the 
upper limit of the normal range with a concurrent elevation in the bilirubin level that was greater 


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than two times the upper limit of the normal range occurred in 7 of 3364 patients (0.2%) in the 
rivaroxaban group. 
Table 2: 
Bleeding events in MAGELLAN study  
Events 
XARELTO 10 mg 
N=3218 
n (%) 
Major bleeding ‡† 
22 (0.7) 
Critical site bleeding 
7 (0.2) 
Fatal bleeding § 
3 (<0.1) 
Clinically relevant non-major bleeding events  
93 (2.9) 
Safety Analysis Set- On Treatment Plus 2 Days  
† Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to 
multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. 
‡ Defined as clinically overt bleeding associated with a drop in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red 
blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. 
§ Fatal bleeding is adjudicated death with the primary cause of death from bleeding. 
3.2.1. Use in Specific Populations 
Pregnancy: Xarelto® dosing in pregnancy has not been studied. The limited available data on 
Xarelto® in pregnant women are insufficient to inform a drug-associated risk of adverse 
developmental outcomes. There is a risk of pregnancy-related hemorrhage due to the potential 
for obstetric hemorrhage and/or emergent delivery. Rivaroxaban should only be used if benefits 
outweigh risk. Pregnancy is a known risk factor for VTE but not for COVID-19. This study will 
exclude pregnant women. 
Lactation: There is insufficient data to determine the effect of rivaroxaban on the breastfed child 
or on milk production. This study will exclude lactating women. 
3.2.2. Rationale for the Use of Rivaroxaban for Treatment of Mild COVID-19 
COVID-19 progression requiring hospitalization generally occurs from the second week of 
illness and is characterized by intense systemic inflammation and hypercoagulability. People 
who present with mild COVID-19 during the first week are likely transitioning from the active 
viral replication phase to the inflammatory phase of the disease [Siddiqi 2020]. This offers a 
unique opportunity to intervene early and prevent further progression of disease by evaluating a 
thromboprophylactic drug, rivaroxaban, in people at risk for COVID-19 progression.  
There is precedent for the use of approved drugs with a well-characterized and favorable safety 
profile to be considered for treatment of COVID-19. For example, remdesivir, although not 
approved as a treatment for COVID-19, has received FDA Emergency Use Authorization for 
hospitalized COVID-19 patients [FDA 2020].  
3.2.2.1. 
Rationale for a Limit of 7 Days of Mild COVID-19 Symptoms Prior to 
Randomization 
The incubation period from exposure to early manifestations of COVID-19 ranges from 2 to 14 
days. During the first 3 days of illness, COVID-19 symptoms may be non-specific and include 


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cough, fever, headache, lethargy, and/or diarrhea. During the next 3-5 days some patients 
develop worsened symptoms but some patients may show signs of recovery. The second week of 
illness, Days 8-12, is when progression to signs and symptoms indicative of a 
hyperinflammatory phase is more likely to occur. These may include dyspnea, abnormal imaging 
of the lungs, respiratory failure, ARDS, and/or cytokine storm syndrome. In a large series of 410 
patients with COVID-19 hospitalized in Italy [Ciceri 2020], the median (IQR) days from 
COVID-19 symptoms onset to hospitalization was 8 days (5-11) days. Approximately 50% of 
these patients were aged >65 years and approximately 60% had one or more comorbidities.  
The primary endpoint of this study is the time to progression of COVID-19 from Scale 2 to Scale 
3 or higher – a situation that would likely require hospitalization of the participant. The data 
from the cited Italian study can inform the choice of the interval between onset of symptoms and 
the expected time of initiation of study drug therapy. Because the interval from onset of 
symptoms to randomization should be no more than 7 days resulting in the worst-case scenario 
of an interval of around 9 days from onset of symptoms to first dose of study treatment 
(assuming two days for shipment of IP and supplies). Nine days falls within the IQR reported by 
Ciceri, et al [Ciceri 2020]. 
3.2.3. Benefit/Risk Assessment  
The elderly (≥65 years of age) and those with medical comorbidities (e.g., cardiopulmonary 
disease, diabetes mellitus) or obesity are at high risk of poor outcomes from COVID-19 [Chen 
2020, Huang 2020, Richardson 2020, Zhu 2020]. In a large case series of COVID-19 patients in 
New York City, the risks for hospitalization were 10-times and 40-times higher in people 65 to 
74 years old and over 75 years old compared to those younger than 45 years old. People with 
high BMI and comorbidities are 2 to 5 times more likely to be hospitalized compared to those 
without risk. Similarly, mortality rates are higher in people with these risk factors [Petrilli 2020]. 
It is estimated that 20% to 30% of people with risk factors will progress to moderate or severe 
COVID-19 [Williams 2020]. The benefit-to-risk ratio for testing treatment is favorable in this 
population.  
3.2.3.1. 
Benefit/Risk Assessment of Rivaroxaban 
Without any approved treatment for outpatients with COVID-19, there is a favorable benefit-risk 
ratio for using rivaroxaban in the target population at increased risk for progressing to moderate 
and severe COVID-19.  
Rivaroxaban is an approved drug with a well-characterized and favorable safety profile.  
The dose selected for this study (10mg/day) is the same as the licensed prophylactic dose for 
VTE in acutely ill patients and fits the purpose of preventing thromboembolic events in people 
with acute COVID-19 illness. This study will exclude people who may be at increased risk for 
adverse events or drug interactions due to rivaroxaban as well as those with severe renal and 
liver impairment, and pregnant and breastfeeding women.  


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3.2.4. Rivaroxaban Mechanism of Action 
Rivaroxaban is a selective inhibitor of factor Xa, the activated form of coagulation factor X. It 
does not require a cofactor (such as anti-thrombin III) for activity. Rivaroxaban inhibits free 
factor Xa and prothrombinase activity. Rivaroxaban has no direct effect on platelet aggregation, 
but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, 
rivaroxaban decreases thrombin generation. 
3.2.5. Rivaroxaban Pharmacokinetics 
Absorption 
The absolute bioavailability of rivaroxaban is dose-dependent. For the 2.5 mg and 10 mg dose, it 
is estimated to be 80% to 100% and is not affected by food. Rivaroxaban 2.5 mg and 10 mg 
tablets can be taken with or without food. For the 20 mg dose in the fasted state, the absolute 
bioavailability is approximately 66%.  
Coadministration of rivaroxaban with food increases the bioavailability of the 20 mg dose (mean 
area under the curve (AUC) and maximum concentrations (Cmax), increasing by 39% and 76% 
respectively, with food).  
The Cmax of rivaroxaban appears 2 to 4 hours after tablet intake.  
Distribution 
Plasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with 
albumin being the main binding component. The steady-state volume of distribution in healthy 
subjects is approximately 50 L. 
Metabolism 
Approximately 51% of an orally administered [14C]-rivaroxaban dose was recovered as inactive 
metabolites in urine (30%) and feces (21%). Oxidative degradation catalyzed by CYP3A4/5 and 
CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the 
predominant moiety in plasma with no major or active circulating metabolites. 
Excretion 
In a Phase 1 study, following the administration of [14C]-rivaroxaban, approximately one third 
(36%) was recovered as unchanged drug in the urine and 7% was recovered as unchanged drug 
in feces. Unchanged drug is excreted into urine, mainly via active tubular secretion and to a 
lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the 
efflux transporter proteins, P-glycoprotein (P-gp) and ABCG2 (also abbreviated Bcrp). 
Rivaroxaban’s affinity for influx transporter proteins is unknown. 
 
Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in 
healthy volunteers following intravenous administration. The terminal elimination half-life of 
rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years, and 11 to 13 hours in the 
elder participants aged 60 to 76 years 
 


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Pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban were not influenced by 
gender, but by race (higher exposure in healthy Japanese) and severe renal and liver impairment 
(which are exclusion criteria in this study). Please refer to package insert for more information. 
Refer to Section 6.4 for dose modification and toxicity management. 
4. 
Objectives and Endpoints 
Objectives and endpoints are provided in Table 3.  
Table 3: 
Objectives and Endpoints 
Objectives 
Endpoints  
Primary 
To characterize safety of 
study intervention 
 
Through Day 35 
 Frequencies of grade 3 AEs and grade 4 AEs  
 AEs resulting in study intervention discontinuation  
 All SAEs 
To assess efficacy of 
study intervention  
 Proportion of participants who progress to moderate or 
severe disease category or higher (Gates MRI ordinal scale 
≥3) through Day 28  
Secondary  
To assess clinical efficacy 
of study intervention  
 Time to disease resolution, defined as BOTH viral clearance 
(two consecutive negative diagnostic tests) and symptoms 
resolution (new onset COVID-19 symptoms resolved, and 
pre-existing symptoms returned to baseline*) through Day 
28 
  Time to disease resolution, defined as symptoms resolution 
only (new onset COVID-19 symptoms resolved, and pre-
existing symptoms returned to baseline*) through Day 28 
 Proportion of participants who progress to moderate or 
severe disease category or higher (Gates MRI ordinal scale 
≥3) at Days 8, 14 and 21 
 Proportion of participants who achieve disease resolution at 
Days 8, 14, 21 and 28  
 Gates MRI scale score at Days 8, 14, 21 and 28  
 WHO ordinal scale score at Days 8, 14, 21 and 28  
 Incidence and number of days of hospitalization at Days 8, 
14, 21 and 28  
Exploratory objectives 
To assess virological 
efficacy  
 Quantity (and change from baseline) of SARS-CoV-2 virus 
at Days 8, 14, 21 and 28  
To assess viral sequence 
 Phylogenetic relationships of SARS-CoV-2 viruses 
sequenced from positive nasal swab samples 
*Baseline refers to health status prior to contracting COVID-19. 


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5. 
Study Design 
5.1. 
Overall Design 
This is a randomized, controlled study for treatment of mild COVID-19 in people at high risk for 
disease progression.  
Mild COVID-19 is determined by Gates MRI mild COVID-19 clinical endpoint definition (refer 
to Table 7). 
High risk is defined based on age, BMI or presence of a comorbidity. 
Primary purpose: To assess the safety and clinical efficacy of rivaroxaban in reducing the 
proportion of participants who have progressed to moderate or severe disease category or higher 
in people with mild COVID-19 who are at increased risk of disease progression. 
Interventional model: Participants will be randomized 1:1 to either the rivaroxaban or the 
placebo group, in parallel for the duration of the study. Randomization will be stratified by site 
and by number of days since onset of symptoms (<6 days vs. ≥6 days). 
Intervention groups:  
- 
Study intervention group: Rivaroxaban, 10 mg (1 tablet) orally daily for 21 days. 
- 
Control group: placebo-equivalent (multi-vitamin supplement) 1 tablet orally daily for 21 
days. 
Masking: Every effort will be made to mask the assigned treatment groups. Participants and 
study staff evaluating them will not be told of the assigned treatment groups. The laboratories 
performing the SARS-CoV-2 diagnostic testing will be blinded. Refer to Section 6.7 for details. 
Study visits: Every effort will be made to conduct the study protocol visits virtually (defined in 
Section 8) with the study participants. A web-based video conferencing tool will be employed to 
allow for virtual (remote) interactions to take place between the study staff and the participant, 
for screening and all study visits.    
Safety and efficacy monitoring: Refer to Section 6.5 for safety monitoring. An IDMC will be 
convened for this study for safety and efficacy with expertise in COVID-19 or respiratory viruses 
and emerging epidemics as well as biostatistics. Refer to Section 11.1 for details regarding the 
IDMC.  
5.2. 
Study Population 
The total number of participants enrolled will be approximately 600, with 300 participants per 
group.  
Refer to Section 5.5.1 for eligibility criteria. 
5.3. 
Recruitment  
Study screening processes will occur for participants at high risk for severe COVID-19 who are 
mildly symptomatic and have or suspected to have COVID-19 (refer to Section 5.4 for pre-
screening and to Section 5.5 for screening). There is an opportunity for high risk participants 


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Have COVID-19 
symptoms
Consent and eligibility check
Day 1 to Day 10

Notify study team if symptomatic

Daily contact with study team 
to check if symptomatic
Fulfill key eligibility criteria

Age ≥ 18 yrs old

At high risk for severe COVID-19

Positive SARS-CoV-2 test ≤7 days at day 1 of pre-screening

No COVID-19 symptoms

Laboratory tests obtained and reviewed

Willing to be contacted by study team

Interested in participating in study
No COVID-19 symptoms
Exit pre-screening 
if no symptoms at Day 10 after diagnosis or Day 10 of pre-screening, whichever comes first 
Pre-screening  
Proceed to 
study screening


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5.4.1. Pre-Screening Inclusion Criteria  
Age 
1. ≥18 years of age at the time of informed consent 
Type of Participant  
2. Participants must be at high-risk for COVID-19 progression by fulfilling at least one of the 
following criteria at screening: 
 
Age ≥65 years  
 
Presence of a chronic disease requiring daily treatment (such as diabetes, lung disease, 
heart disease, hypertension or cancer) 
 
Self-reported obesity  
 
Any other high-risk criteria per national guidelines. 
COVID-19 characteristics 
3. Documented positive SARS-CoV-2 diagnostic testing with sample collected ≤7 days at 
Day 1 of pre-screening  
4. No COVID-19 symptoms (defined as fever, chills, myalgia, arthralgia, headache, fatigue, 
cough, sore throat, nasal congestion, anosmia, ageusia, nausea, vomiting, or diarrhea, that 
are either new onset or have worsened from baseline*). 
*Baseline refers to health status prior to contracting COVID-19. 
Informed Consent 
5. Capable of giving informed consent, which includes compliance with the requirements and 
restrictions listed in the Pre-screening informed consent form (ICF)  
Sex 
6. Male or female 
Others 
7. Willing to be contacted by study team and to notify study team if any COVID-19 symptom 
occurs 
8. Interested in participating in a treatment trial if symptoms of COVID-19 occur. 


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5.4.2. Pre-Screening Procedures  
The pre-screening Schedule of Activities is shown in Table 4. 
Table 4: 
Pre-screening Schedule of Activities 
Pre-screening Visits1 
Eligibility check 
(≤72 hrs) 
Pre-screening 
(Day 1 to Pre-screening 
Day 10) 
Obtain informed consent  
X 
 
Eligibility criteria 
X 
 
SARS-CoV-2 diagnostic testing1 
X 
 
Daily contact with study team to check 
if symptomatic for COVID-192 
 
X 
No AEs will be collected  
1If documented positive SARS-CoV-2 testing is not available at the eligibility check visit, testing may be performed 
provided that the potential participant has had a high risk exposure to SARS-CoV-2, defined as being an immediate 
household contact of a confirmed COVID-19 case and/or having occupational exposure to a confirmed COVID-19 
case (for example, healthcare worker or first responder). 
2Participant will exit the pre-screening phase if he/she remains asymptomatic at day 10 after diagnosis or day 10 of 
the pre-screening phase, whichever comes first. 
After the pre-screening ICF is signed and eligibility is confirmed, participants are asked to notify 
the study staff immediately if any COVID-19 symptom occurs. Study staff will also contact 
participants daily by phone or text or electronically to inquire about symptoms. If a participant 
does not have any COVID-19 symptoms at day 10 from SARS-CoV-2 diagnosis or day 10 of the 
pre-screening follow-up, the participant will be asked to exit the pre-screening phase. 
Note that no data during the pre-screening stage will be recorded in the database or in a case 
report form. 


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5.5. 
Screening for the Study  
Refer to Section 8.1 for screening procedures.  
5.5.1. Inclusion and Exclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. ≥18 years of age at the time of informed consent 
Type of Participant  
2. Participants must be at high-risk for COVID-19 progression by fulfilling at least one of the 
following criteria at screening: 
 
Age ≥65 years  
 
Presence of chronic pulmonary disease, chronic obstructive pulmonary disease (COPD), 
pulmonary hypertension 
 
Diabetes mellitus (type 1 or type 2), requiring oral medication or insulin for treatment  
 
Hypertension, requiring at least one oral medication for treatment  
 
Immunocompromised status due to disease (e.g., those living with human 
immunodeficiency virus with a CD4 T-cell count of <200/mm3) 
 
Immunocompromised status due to medication (e.g., taking 20 mg or more of 
prednisone equivalents a day, anti-inflammatory monoclonal antibody therapies, cancer 
therapies) 
 
Any chronic disease that is associated with high risk for severe COVID disease in the 
opinion of the site investigator 
 
Body mass index ≥35 kg/m2 (based on self-reported weight and height). 
COVID-19 Characteristics 
3. Documented positive SARS-CoV-2 diagnostic testing with a sample collected ≤10 days of 
screening. 
4. Symptomatic for COVID-19 for ≤7 days at time of randomization 
(symptomatic is defined as having at least one of the following symptoms of COVID-19 that 
is of new onset or has worsened from baseline: fever, chills, myalgia, arthralgia, headache, 
fatigue, cough, sore throat, nasal congestion, nausea, vomiting, or diarrhea).  
Informed Consent 
5. Capable of giving informed consent, which includes compliance with the requirements and 
restrictions listed in the ICF and in this protocol 
Sex 
6. Male or female 


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Other Requirements: 
7. Agree to participate in all remote, in-person or home visits as required in the protocol and 
provide updated contact information as necessary.  
8. Female of childbearing potential must agree to practice adequate contraception during the 
study (Section 9.8.1). 
5.5.2. Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions or history 
1. Currently hospitalized or under immediate consideration for hospitalization at screening 
and Day 1 
2. Have new onset shortness of breath or increased shortness of breath from pre-COVID-19 
(for people with known COPD) at screening and Day 1 
3. Hypoxemia (oxygen saturation<94% in ambient air or oxygen saturation below pre-
COVID-19 oxygen saturation [if known] for people with known COPD) at Day 1 
4. Require supplemental oxygen (new requirement or increase in requirement from pre-
COVID-19 condition) at screening and Day 1 
5. Have a history of (in the past 3 months) or current active pathological bleeding 
6. Have a history of hemorrhagic stroke or intracranial hemorrhage  
7. Have a recent severe head trauma within 30 days which includes concussion, skull fracture 
or hospitalization for head injury 
8. Have known intracranial neoplasm, cerebral metastases, arteriovenous malformation or 
aneurysm 
9. Have history of pregnancy-related hemorrhage 
10. Have active gastroduodenal ulcer or other gastrointestinal bleeding diagnosed in the past 3 
months 
11. Currently are in a hemodynamically unstable state 
12. Currently require thrombolysis or pulmonary embolectomy 
13. Have history of severe hypersensitivity reaction to Xarelto® 
14. Currently have a prosthetic heart valve 
15. Have known diagnosis of triple positive antiphospholipid syndrome 
16. Have known diagnosis of chronic kidney disease (stage IV or receiving dialysis)  
17. Have a history of thrombocytopenia or known platelet count < 100,000 cells/mm3 
18. Have a history of bronchiectasis and pulmonary cavitation 
19. Have active cancer (eg, receiving chemotherapy or treatment for complication of the active 
cancer) 


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Other: 
20. Had epidural or neuraxial anesthesia or spinal puncture in the past 2 weeks or plan to 
undergo these procedures during the study 
21. Had surgery in the past 4 weeks or plan to undergo surgery during the study 
22. Currently is pregnant or plans to become pregnant (refer to Section 9.8) 
23. Currently is breastfeeding  
24. Share household with an enrolled participant in this study 
25. Co-enrollment in any clinical trial that includes prohibited procedures (spinal puncture or 
surgery) or that includes treatments within the same drug class as rivaroxaban or treatments 
for which co-administration with rivaroxaban are prohibited* 
*Note that any co-enrollment other than this requires approval by the Sponsor. For any co-
enrolled study, the total volume of blood samples collected across the studies should not exceed 
275 mL in 4 weeks. 
Medications: 
26. Currently using and plan to use the following medications during the study 
 Rivaroxaban or drugs in the same class 
 Dual anti-platelets therapy 
 Other anticoagulants (Table 5) 
 Combined P-gp and CYP3A inhibitors and inducers (Table 5). 
6. 
Study Intervention- Rivaroxaban or Placebo 
Participants will be randomly assigned to either the rivaroxaban group or placebo, in parallel to 
receive:  
 Rivaroxaban group: 10mg (1 tablet) taken orally each day for 21 days. 
 Placebo group: 1 tablet taken orally each day for 21 days.  
The rivaroxaban (10mg) used in the active group will be Xarelto® 10mg tablet commercially 
marketed in the US.  
For the placebo group, a placebo-equivalent will be used. This will be an over the counter dietary 
multi-vitamin supplement tablet, commercially marketed with their Product # 501-01 in the US 
by Geri-Care Pharmaceuticals Corp, based on its suitability to maintain masking to the extent 
possible.  
The active and placebo tablets will not be identical in appearance; but will be similar in size, 
shape and color. Moreover, the bottles will be identical.  
The bottle of medication the participants receive will not identify the treatment allocation. The 
active or placebo bottles will be labeled for investigational use with a randomized number to 
maintain blinding.  
Refer to Section 6.8 for preparation, handling, storage and accountability of the study IPs.  


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6.1. 
Rationale for Study Intervention Selection 
Refer to Section 3.2.2 for the rationale for use of rivaroxaban for treatment of mild COVID-19 
and to Section 3.2.3.1 for benefits and risks of rivaroxaban. 
6.2. 
Management of Participants to Limit Risks of SARS-CoV-2 Transmission 
To limit the transmission of SARS-CoV-2, remote monitoring will be done as much as it is 
feasible via video conference, text message, telephone or other methods, as appropriate. In-
person or home visits may be required for administration or monitoring. 
For any in-person contact, local guidance for COVID-19-related safety measures will be 
followed. 
6.3. 
Guidance on COVID-19 to Ensure Participant and Healthcare Worker Safety 
COVID-19 specific guidance from public health authorities in the country in which the study 
will be conducted should be followed.  
As an example, the FDA Guidance for Industry on COVID-19 provides general considerations to 
assist the Sponsor in assuring the safety of trial participants, maintaining compliance with good 
clinical practice (GCP), and minimizing risks to trial integrity for the duration of the COVID-19 
public health emergency [FDA 2020]. For example, the Sponsor should consider each 
circumstance, focusing on the potential impact on the safety of trial participants, and modify 
study conduct accordingly. Sponsors, in consultation with clinical principal investigators (PIs) 
and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), may determine 
that the protection of a participant’s safety, welfare, and rights is best served by continuing a 
study participant in the trial as per the protocol or by discontinuing the administration or use of 
the investigational product or even participation in the trial. Such decisions will depend on 
specific circumstances, including the nature of the investigational product, the ability to conduct 
appropriate safety monitoring, etc. 
Changes in study visit schedules, missed visits, or patient discontinuations may lead to missing 
information (e.g., for protocol-specified procedures). It will be important to capture specific 
information in the case report form that explains the basis of the missing data, including the 
relationship to COVID-19 for missing protocol-specified information (e.g., from missed study 
visits or study discontinuations due to COVID-19).  
For instances where efficacy endpoints are not collected, the reasons for failing to obtain the 
efficacy assessment should be documented (e.g., identifying the specific limitation imposed by 
COVID-19 leading to the inability to perform the protocol-specified assessment).  
6.4. 
Dose Modification and Toxicity Management 
There will be no dose modification.  
Participants who experience major bleeding or clinically relevant non-major bleeding will have 
the study intervention discontinued (see Section 7.1) and managed according to standard of care.  


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Participants who experience other AEs due to the study medication may discontinue the study 
medication per the clinical judgment of the investigator. 
At each visit, the participant will be asked if any bleeding events have occurred. Major bleeding 
events will be recorded as AESIs and non-major bleeding events will be recorded as AEs, in the 
eCRF. The following definitions will apply.  
6.4.1. Definitions of Bleeding Severity  
The following definitions are based on the guidance for non-surgical patients by the International 
Society on Thrombosis and Hemostasis (ISTH)/Scientific and Standardization Committee 
(SCC). 
6.4.1.1. 
Definition of Major Bleeding  
 Fatal bleeding AND/OR 
 Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with 
compartment syndrome. AND/OR 
 Bleeding causing a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more or leading to 
transfusion of two or more units of whole blood or red cells.  
6.4.1.2. 
Definition of Clinically Relevant Non-Major Bleeding 
A clinically relevant non-major bleed is an acute or subacute clinically overt bleed that does not 
meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one 
of the following:  
 A hospital admission for bleeding, OR 
 A physician guided medical or surgical treatment for bleeding, OR 
 A change in antithrombotic therapy (including interruption or discontinuation of study 
drug). 
In addition, bleeding events that lead to participant’s discomfort, and impairment of activities of 
daily life are considered clinically relevant non-major bleeding. 
Examples of clinically relevant non-major bleeding are: 
 
Epistaxis if it lasts for more than 5 minutes, if it is repetitive (i.e., 2 or more episodes of true 
bleeding, i.e., not just spots on a tissue, within 24 hours), or leads to an intervention 
(packing, electrocoagulation, etc) 
 
Gingival bleeding if it occurs spontaneously (i.e., 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 (e.g., catheter placement or surgery) of the urogenital tract 


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 
Macroscopic gastrointestinal hemorrhage: at least 1 episode of melena/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 
 
Large subcutaneous hematoma (more than 25 cm2)  
 
Multiple source bleeding. 
6.4.1.3. 
Definition of Minimal Bleeding 
Other bleeding events that do not meet the criteria for either major bleeding or clinically relevant 
non-major bleeding are considered minimal bleeding.  
6.5. 
Safety Monitoring 
Safety monitoring will take place once the informed consent has been signed. On Day 1, prior to 
IP, the participant will be asked about his or her health and about any bleeding issues prior to 
taking the first dose. The participant will then be in frequent contact with the study staff, with the 
final visit being 14 days after the last medication dose.  
The participant will have a contact number to call the staff at any time should he or she have a 
non-emergency study related health issue that they need to discuss in between visits. As 
previously mentioned, if needed, additional contact with the study clinician or staff will be 
conducted at the request of the participant (e.g., if developing concerning symptoms or an AE). 
Refer to Section 8 for more information. 
If it is a health emergency, they will be asked to call the country nationwide health emergency 
number (like 911 in the USA). Refer to Section 8 for more information regarding study 
procedures for safety. 
6.6. 
Study Pausing Guidelines 
Pausing guidelines are put in place to address medical events necessitating a pause in enrollment 
and in participant dosing, and trigger IDMC reviews. Therefore, these guidelines are in effect 
during the active enrollment and dosing period. Any of the below conditions, if identified either 
by the study staff, investigator, the Sponsor or the IDMC, will trigger a pause of the enrollment 
and pause of administration of study intervention until the IDMC has reviewed the safety data 
and made a recommendation on how to proceed: 
1. One report of anaphylaxis with or without bronchospasm within 4 hours of taking study 
intervention indicative of an immediate hypersensitivity reaction to the study intervention 
2. One report of major bleeding judged as related to study intervention by the investigator. 


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6.7. 
Masking 
Every effort will be made to mask the assigned treatment groups. The participants will not be 
told of the assigned treatment groups and will not be informed that active and control treatment 
do not look identical. However, the participant could possibly find out this information because 
of features like embossment on the rivaroxaban tablets, which are not present on the placebo-
equivalent tablets.  
The study staff evaluating the participants will not be given the assigned treatment groups but 
could possibly find out if the participant’s tablets become visible to them. Such occurrences will 
be documented. It is recognized that they could potentially bias the outcome assessments by the 
participant and study staff particularly for subjective measurements. 
In order to preserve masking, household members of an enrolled participant will be excluded 
from participating in this study. 
6.8. 
Preparation/Handling/Storage/Accountability  
Each participant will receive a bottle containing twenty-two (22) tablets of active or placebo 
based on the randomization. Twenty-one (21) tablets are meant for each participant’s 21 days of 
daily dosing. One extra tablet is provided as overage.  
Xarelto®, per US Commercial Package Insert, is to be stored at 25°C (77°F) or room 
temperature with excursions permitted to 15° to 30°C (59° to 86°F). The same conditions will 
apply to the placebo-equivalent. The temperature conditions will be printed on the 
investigational label applied on the bottle.  
Documentation of receipt, dosing, and disposal of unused medication to be maintained as per 
study procedures. 
Study medication may be dispensed by a qualified study representative, according to dispensing 
instructions. Study medication may also be shipped directly to the participant’s home depending 
on evolving circumstances related to COVID-19. Instructions will be included with the drug 
shipment to the participants. 
Date of IP dispensing and adherence to IP administration will be recorded. 
6.9. 
Study Intervention Compliance 
The IP will be self-administered at home, and the participants will be contacted to ensure that 
they have received and appropriately stored the IP. Study participants will be asked about 
adherence to the IP. 
6.10. 
Concomitant Therapy 
The prohibited medications in this study are other anticoagulants, and combined P-gp and 
CYP3A inhibitors and inducers because of their significant PK and PD interactions with 
rivaroxaban. Should administration of any prohibited drug (Table 5) be indicated for 
participants’ clinical care, the study medication must be discontinued. Other drugs may have PK 
and PD interactions with rivaroxaban and thus are considered precautionary medications.  


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Refer to Section 6.10.1 for prohibited medications and to Section 6.10.2 for precautionary 
medications. 
Whether the study medication should be discontinued or allowed to be used with these 
precautionary medications will be under the clinical judgement of the treating physician (i.e., 
either the PI, or the physician responsible for the patient’s care if the participant is hospitalized). 
Pharmacodynamic Interactions 
The concurrent use of rivaroxaban with other anticoagulants, antiplatelet agents, and 
nonsteroidal anti-inflammatory agents is expected to increase the risk of bleeding in 
comparison to use of rivaroxaban alone (refer to Table 5).  
Pharmacokinetic Interactions 
The absorption of rivaroxaban is mediated by P-gp. P-gp inhibitors can increase the absorption 
of rivaroxaban, increasing both AUC and Cmax. Conversely, P-gp inducers can reduce the 
absorption of rivaroxaban, decreasing AUC and Cmax. 
The metabolism of rivaroxaban is mediated by CYP3A4. CYP3A4 inhibitors can decrease the 
metabolism of rivaroxaban, increasing both AUC and Cmax. Conversely, CYP3A4 inducers can 
increase the metabolism of rivaroxaban, decreasing AUC and Cmax. 
Agents that interfere with both P-gp and CYP3A4 are likely to cause more significant 
interactions with rivaroxaban than agents that interfere with P-gp or CYP3A4 alone. 
6.10.1. Prohibited Medications 
Table 5: 
Rivaroxaban prohibited medications/foods/supplements 
Drug Class 
Examples (based on human in vivo data1) 
Known or Probable Effect 
Anticoagulants 
warfarin sodium (Coumadin®, Jantoven®), 
any medicine that contains heparin, including 
low molecular weight heparins, apixaban, 
Pradaxa [dabigatran], Savaysa [edoxaban], 
Bevyxxa [betrixaban], non-study Xarelto 
[rivaroxaban]  
Increased risk of bleeding 
 
Combined P-gp 
inhibitors and 
strong CYP3A4 
inhibitors 
cobicistat, conivaptan, indinavir, 
 itraconazole, ketoconazole, posaconazole, 
ritonavir, saquinavir, telaprevir, 
telithromycin 
Significant increase in rivaroxaban 
concentration 
Combined P-gp 
inhibitors and 
moderate 
CYP3A4 
inhibitors OR 
strong CYP3A4 
inhibitors alone 
amiodarone, azithromycin, clarithromycin, 
cyclosporine, diltiazem, dronedarone, 
erythromycin, fluconazole, grapefruit, 
lapatinib, mifepristone, nefazodone, 
nicardipine, ranolazine, tamoxifen, 
ticagrelor, verapamil, voriconazole 
Moderate increase in rivaroxaban 
concentration in patients with 
normal renal function. 
Significant increase in rivaroxaban 
concentrations in patients with renal 
impairment 
Combined P-gp 
inducers and 
strong CYP3A4 
inducers 
carbamazepine, dexamethasone, rifampin, St 
John's wort 
  
Significant reduction in rivaroxaban 
concentration 


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Drug Class 
Examples (based on human in vivo data1) 
Known or Probable Effect 
Effect may persist for several weeks 
following discontinuation of strong 
inducers of P-gp and/or CYP3A4 
Inducers of P-gp 
tipranavir 
Significant reduction in rivaroxaban 
concentration 
Effect may persist for several weeks 
following discontinuation of strong 
inducers of P-gp and/or CYP3A4 
Strong inducers 
of CYP3A4 
bosentan, efavirenz, etravirine, fosphenytoin, 
nafcillin, nevirapine, phenobarbital, 
phenytoin, primidone, rifabutin, rifapentine 
 
Significant reduction in rivaroxaban 
concentration 
Effect may persist for several weeks 
following discontinuation of strong 
inducers of P-gp and/or CYP3A4 
Modified from [UW 2020] 
6.10.2. Precautionary Medications 
Participants are discouraged from using the following medications that may increase the risk of 
bleeding during the study period. 
 aspirin or aspirin-containing products 
 long-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs) 
 clopidogrel (Plavix®) 
 selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake 
inhibitors (SNRIs) 
 other medicines to prevent or treat blood clots. 
6.11. 
Hospitalization 
If a participant clinically worsens, such as requiring hospitalization, it is expected that standard 
clinical care will be provided. Hospitalized participants may continue to receive study 
intervention if maintained on the originally randomized study-intervention regimen.   
Accommodations will be made to facilitate these encounters within this specific setting. Clinical 
outcomes in hospitalized participants will be confirmed through the electronic health record, if 
possible. 
6.12. 
Treatment after the End of the Study 
No additional treatment or study intervention will be provided at the end of the study. 
7. 
Discontinuation/Withdrawal Criteria and Study Completion 
7.1. 
Discontinuation of Study Intervention 
Study intervention will be discontinued for the following reasons: 


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 Hospitalization, if the in-patient provider decides continuation of study treatment is 
contraindicated.   
 Requirement for prohibited concomitant medications or other contraindication to study 
product 
 Occurrence of an AE requiring discontinuation of study intervention (i.e., severe 
hypersensitivity, major bleeding or clinically relevant non-major bleeding) 
 Request by participant to terminate study intervention  
 Clinical reasons believed to be life-threatening by the physician, even if not addressed in 
this protocol 
 Pregnancy. 
Participants who stop study intervention should continue study participation while off of the 
study intervention, with continued evaluations as per the SoA. The reason for study intervention 
discontinuation should be recorded. 
7.2. 
Withdrawal from the Study 
A participant may withdraw from the study at any time at the participant’s request or may be 
withdrawn at any time for the following reasons: 
 At the request of the primary care provider if being in the study is no longer in the best 
interest of the participant 
 Participant is judged by the PI to be at significant risk of failing to comply with the 
provisions of the protocol as to cause harm to self or seriously interfere with the validity of 
the study results 
 At the discretion of the IRB/IEC or government agencies as part of their duties, PI, or 
Sponsor. 
 The participant progressed to moderate or severe COVID-19 (or worse) prior to initiation of 
IP dosing on Day 1 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such withdrawal of consent. 
Upon withdrawal from the study, the participant may request destruction of any biological 
samples taken and not tested, and the PI or designee must document this in the site study records. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if the participant is unable to be contacted by 
the study site. 
The following actions must be taken if a participant fails to comply with required study 
procedures: 


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 The site must attempt to contact the participant as soon as possible and counsel the 
participant on the importance of maintaining the assigned procedure schedule and 
ascertain whether or not the participant wishes to and/or should continue in the study. 
 Before a participant is deemed lost to follow-up, the PI or designee must make every 
effort to regain contact with the participant. These contact attempts should be 
documented in the participant’s medical record. 
 Should the participant continue to be unreachable, the participant will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
7.4. 
Study Completion 
A participant is considered to have completed the study after completion of the last scheduled 
procedure shown in the SoA. 
This study will be considered completed when all participants have completed the study. 
Pregnant and lactating females can remain in the study but must discontinue the study 
medication (refer to Section 9.8). 
8. 
Study Encounters  
Study encounters will be done remotely, via web-based video conference, text message, 
telephone or other methods, as appropriate to limit the transmission of SARS-CoV-2. In-person 
and home visits are not anticipated, but may be needed on an ad hoc basis for some participants 
when remote monitoring is inadequate to fulfill the requirement of the study, or if deemed 
necessary for the safety of the participant based on the clinical judgement of the study staff.  
Maintenance of participant’s privacy is important for all types of study encounters. For each 
encounter, the study investigators or designees and the trial participants should confirm their 
respective identities with one another before engaging in the visit. 
Participants will be instructed to seek clinical care should they manifest any signs or symptoms 
of COVID-19 progression requiring medical intervention and notify the treating physician about 
trial participation. 
8.1. 
Screening Process and Procedures 
The following procedures must occur ≤5 days prior to the Day 1 visit. All screening evaluations 
must be completed and reviewed to confirm that potential participants meet all eligibility criteria.  
The PI/study staff will maintain a screening log to record details of all participants screened and 
to confirm eligibility or record reasons for screening failure, as applicable. This does not apply to 
any pre-screening procedures.  
Procedures conducted as part of the participant’s routine clinical management and obtained 
before signing the informed consent form may be utilized for screening purposes provided that 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA. 
The study staff conducting the Screening visit will: 


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 Introduce themselves and their role to the participant, and confirm the identity of the 
participant. 
 Confirm that the means of contact is adequate to conduct the contact/visit 
 Obtain informed consent (refer to Section 11.2 for details) 
 Collect demographic information -age, sex, race and ethnicity and personal information 
including name and address 
 Collect information in past and current medical conditions, including known pregnancy 
and/or lactation status 
 Collect concomitant medication information (refer to Section 6.10 for details). 
 Collect documented positive SARS-CoV-2 diagnostic testing performed with a sample 
collected ≤10 days of screening. If no document is available, SARS-CoV-2 diagnostic 
testing will be performed at screening. 
 Check inclusion and exclusion criteria. 
Eligible participants who meet all criteria will be enrolled and randomized to a study group and 
will receive supplies and study IP, delivered to the participant at home, or if deemed necessary, it 
may be picked up at study site or other methods may be used as appropriate.  
Eligible participants will receive the following: 
 Study IP with dosing direction and storage information 
 An oximeter and a thermometer, with user instructions 
 Nasal test kit, with user instructions 
 Personal protective equipment (face masks, shields and gloves). 
9. 
Study Assessments and Procedures 
Refer to the Section 2, Table 1, for the Schedule of Activities (SoA). Note that unscheduled 
visits may be required. Additional collection of a swab sample may be performed based on the 
clinical judgement of the PI or designee. 
Immediate safety concerns should be addressed by the PI as soon as he or she becomes aware of 
the concern to determine if the participant should continue or discontinue study IP. The PI will 
inform the Sponsor immediately upon occurrence or awareness. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.  
9.1. 
Day 1 (first day of study) 
The study staff conducting the visit will: 
 Introduce themselves and their role to the participant and confirm the identity of the 
participant  
 Confirm that the means of contact is adequate to conduct the contact/visit 


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 Confirm that the supplies and the study IP were received in good condition, review the 
contents received and instructions.  
 Remind the participant not to show the study IP tablets if it is a video enabled contact or 
describe the tablets detailed appearance to maintain the masking of the study staff. 
 Collect information on COVID-19 symptoms and signs  
 Assess the Gates MRI and WHO ordinal scales and confirm that participant continues to 
meet criteria for Scale 2 of Gates MRI COVID-19 Ordinal Scale (Table 7) 
 Collect information on AEs (note that AEs will be collected from the time the participant 
signs the informed consent). 
 Collect information on concomitant medications 
 Collect information on adherence to study IP and any dosing error (if applicable)  
 Ask participant to collect nasal sample, temperature, and oxygen saturation during the 
encounter (study staff will document temperature and oxygen saturation). 
 Inquire about pregnancy, as appropriate. 
9.2. 
Procedures at Visits from Day 4 through Day 28 
At each of these visits on Days 4, 6, 8, 10, 12, 14, 18, 21, 24, 28, the study staff conducting the 
visit will: 
 Introduce themselves, explain their role to the participant, and confirm the identity of the 
participant  
 Confirm that the means of contact is adequate to conduct the contact/visit 
 Collect information on COVID-19 symptoms and signs 
 Assess the Gates MRI and WHO ordinal scales 
 Collect information on AEs 
 Collect information on bleeding events and severity 
 Collect information on concomitant medications 
 Remind the participant to take the dose daily through Day 21, and not to show the study IP 
tablets or describe the tablets detailed appearance, to maintain the masking of the study 
staff. 
 Collect information on adherence to study IP and any dosing error (if applicable)  
 Ask participant to collect temperature, and oxygen saturation during the encounter (study 
staff will document temperature and oxygen saturation) 
 Ask participant to collect nasal sample during the encounter for Days 4, 8, 14, 21 and 28 
 Inquire about pregnancy, as appropriate. 


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As needed, additional contact with the study clinician or staff will be conducted at the request of 
the participant (e.g., if developing concerning symptoms or an AE).  
9.3. 
Procedures at Visit Day 35 
This will be the last visit. The study staff conducting the contact/visit will: 
 Introduce themselves and their role to the participant and confirm the identity of the 
participant  
 Confirm that the means of contact is adequate to conduct the contact/visit 
 Collect information on AEs 
 Collect information on bleeding events and severity 
 Collect information on concomitant medications 
 Inquire about pregnancy, as appropriate. 
9.4. 
Efficacy Assessments 
The proportion of participants who progress to moderate or severe category or higher (Gates 
MRI ordinal scale ≥3) will be assessed at study visits indicated in the SoA. 
9.4.1. Nasal Sampling 
Nasal sampling for SARS-CoV-2 diagnostic testing will follow study instruction document from 
the testing laboratory. Nasal sampling collection will be discontinued during hospitalization 
and/or, per physician’s discretion, when two consecutive negative results are available at any 
time during the study. 
Instructions on handling, storage and shipment or delivery of nasal swabs that are collected by 
the participant will be provided to the participant and explained during the visit. 
Additional nasal swab collection may be performed based on the clinical judgement of the PI or 
designee. 
9.5. 
Safety Assessments  
Safety will be assessed at study encounters by the study investigator or designee. Note that 
unscheduled visits may be required.  
Participants will be interviewed by study staff for AEs. 
AEs will be collected from the time informed consent is obtained through Day 35 (14 days after 
the last dose of IP).  
SAEs and AESIs (major bleeding and severe hypersensitivity to rivaroxaban) will be reported to 
the Sponsor or designee immediately (within less than 24 hours), as also any follow-up 
information.  
All AEs must be recorded on the eCRFs if any of the following criteria have been met: 


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 AEs meeting SAE definition 
 AEs leading to discontinuation of study intervention 
 Grade 3 and grade 4 AEs  
 Adverse events of special interest (AESI) including major bleeding (refer to Section 
6.4.1) and severe hypersensitivity to rivaroxaban.  
AEs will be assessed at the time of the collection by the investigator as related or not related to 
the study.  
The Sponsor will be responsible for the expectedness assessment according to the available 
reference safety information and for complying to applicable expedited and periodic AE 
reporting obligations to regulatory authorities, investigators and other entities.  
All AEs will be followed until resolution, stabilization, lost to follow-up, or until the end of the 
study (Day 35). 
9.5.1. Adverse Event Definition 
An AE is any untoward medical occurrence that occurs in a participant administered an IP. An 
AE can be any unfavorable and unintended sign (including abnormal laboratory findings), 
symptom, or disease temporally associated with the use of an IP, whether or not considered 
related to the product. 
AEs may include the onset of new illness and the exacerbation of pre-existing medical 
conditions. An AE can include an undesirable medical condition occurring at any time, including 
baseline, even if no study intervention has been administered. 
9.5.2. Adverse Events of Special Interest Definition 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the Sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the Sponsor can be appropriate.  
9.5.3. Serious Adverse Event Definition 
An SAE is defined as any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is an important medical event 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. 


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9.5.4. Toxicity Grading 
All AEs that are recorded must include an intensity grade. To grade AEs, sites should refer to the 
specific toxicity grading by Division of Acquired Immunodeficiency Syndrome (DAIDS) AE 
Grading Table [DAIDS 2017]. 
9.5.5. Study Intervention-Related AEs and SAEs 
A study intervention-related AE is defined as any new AE that begins, or any preexisting 
condition that worsens in severity, after at least 1 dose of study intervention has been 
administered and is considered by the PI to be related to the study intervention. 
All AEs and SAEs should have attribution recorded as study IP-related or not study IP-related, in 
the judgment of the site investigator. 
All SAEs, regardless of whether related or not to the IP, will be followed until resolution, 
stabilization, lost to follow-up, or until the end of the study (Day 35). 
9.6. 
Assessment of COVID-19 Signs and Symptoms  
COVID-19 signs and symptoms reported to the study staff to be recorded in the CRF/eCRF are 
shown in Table 6. Other symptoms or signs considered by the PI to be related to COVID-19 can 
be added as necessary. Of note, anosmia and ageusia will be collected but not included in the 
symptom endpoint analysis as they may be long-lasting despite resolution of other symptoms 
(possibly due to direct viral damage of the olfactory and gustatory receptors). Therefore, their 
continued presence post therapy may not be indicative of a poor response to study 
intervention(s). 
The PI or designee will query the participants about the symptoms listed below and determine 
symptom resolution (yes or no) since their last visit. 


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Table 6: 
COVID-19 Signs and Symptoms to be Recorded in the CRF/eCRF 
Temperature (fever >100.4°F or >38°C) 
Oxygen saturation 
Chills 
Muscle pain 
Joint pain 
Headache 
Fatigue 
Cough 
Sore throat 
Nose congestion 
Nausea 
Vomiting 
Diarrhea 
Shortness of breath 
Chest pain 
Loss of sense of smell (anosmia) 
Loss of sense of taste (ageusia) 
Other symptoms and signs may be added 
The Gates MRI COVID-19 Ordinal Scale (Table 7) and the WHO Ordinal Scale for Clinical 
Status (Table 8) will be completed by the PI or a medically qualified designee.  
Table 7: 
Gates MRI COVID-19 Ordinal Scale Clinical Endpoint Definitions  
Scale 
Category 
Endpoint definition 
1 
Asymptomatic/symptoms 
similar to pre-COVID status 
 
No symptoms and signs AND 
 
No limitation of daily activities 
2 
Mild 
 
Symptomatic AND 
 
No shortness of breath AND 
 
No hypoxemia (O2 saturation ≥94% in ambient air)  
3 
Moderate or severe 
 
Symptomatic AND 
 
Shortness of breath* OR tachypnea (respiratory rate ≥ 20 
min)* OR hypoxemia (<94% in ambient air)* 
4 
Critically ill 
 
 Symptomatic AND 
 
Receiving high flow oxygen OR non-invasive mechanical 
ventilation 
5 
Critically ill with invasive 
mechanical ventilation or 
extrapulmonary complication 
 
Symptomatic AND 
 
Receiving invasive mechanical ventilation OR Life 
threatening or debilitating extrapulmonary complications 
6 
Critically ill with Extra-
Corporeal Membrane 
Oxygenation (ECMO) 
 
Symptomatic AND 
 
Receiving ECMO  
7 
Death 
 
Death 
*For known COPD participants, moderate or severe category requires worsening of shortness of breath or 
respiratory rate or oxygen saturation from pre-COVID-19 status  


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Table 8: 
WHO Ordinal Scale for Assessment of Clinical Status of COVID-19 Patients 
Participant Status 
Descriptor 
Score 
Uninfected 
Uninfected; no viral RNA detected 
0 
Ambulatory mild disease 
Asymptomatic; viral RNA detected 
1 
Symptomatic; independent 
2 
Symptomatic; assistance needed 
3 
Hospitalized moderate 
disease 
Hospitalized; no oxygen therapy* 
4 
Hospitalized; oxygen by mask or nasal prongs 
5 
Hospitalized severe 
disease 
Hospitalized; oxygen by NIV or high flow 
6 
Intubation and mechanical ventilation, pO2/FiO2 ≥150 or 
SpO2/FiO2 ≥200 
7 
Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or 
vasopressors 
8 
Mechanical ventilation pO2/FiO2 <150 and vasopressors, 
dialysis, or ECMO 
9 
Dead 
Dead 
10 
WHO clinical progression scale, WHO Working group [WHO(c) 2020] 
ECMO=extracorporeal membrane oxygenation.  
FiO2=fraction of inspired oxygen. 
NIV=non-invasive ventilation. 
 
 
pO2=partial pressure of oxygen. SpO2=oxygen saturation.  
*If hospitalized for isolation only, record status as for ambulatory patient 
9.7. 
Overdose of Study Intervention  
Study medication overdose (rivaroxaban and placebo) including misuse or abuse of the product 
and medication errors, should be reported to the study investigator immediately and reported in 
the clinician notes and the eCRF.  
An approved reversal agent for rivaroxaban is andexanet alfa. Its use will be based on the clinical 
judgement of the treating physician. 
9.8. 
Pregnancy 
The investigator or designee will be required to inquire about pregnancy at screening and every 
study visit but pregnancy testing will not be required.  
Pregnancies occurring in participants enrolled in this study must be reported, and details 
collected including outcome of the pregnancy. 
If pregnancy is reported, the participant should be withdrawn from study treatment but continue 
to be followed for safety. Details of the pregnancy as well as outcome should be followed and 
recorded. 
Pregnancy alone is not regarded as an AE unless there is a possibility that the study IP may have 
interfered with the effectiveness of a contraceptive medication. Elective abortions without 
complications should not be considered AEs unless they were therapeutic abortions. 
Hospitalization for normal delivery of a healthy newborn should not be considered an SAE. 
Pregnancy is not considered an SAE unless there is an associated abnormal pregnancy outcome 
(e.g. spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy). 


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Any abnormal pregnancy outcomes during the study (e.g. spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) should be reported as an SAE. 
9.8.1. Contraceptive Guidance  
Women with history of hysterectomy, bilateral salpingectomy or bilateral oophorectomy are not 
considered females of childbearing potential. 
Women physically capable of pregnancy must agree to use adequate contraception during the 
study. Examples include:  
 abstinence from penile-vaginal intercourse, when this is their preferred and usual lifestyle 
 oral contraceptives, either combined or progestogen alone 
 injectable progestogen 
 implants of etonogestrel or levonorgestrel 
 estrogenic vaginal ring 
 percutaneous contraceptive patches 
 intrauterine device or intrauterine system 
 male partner sterilization prior to the female participant’s entry into the study, and this male 
is the sole partner for that participant  
 male condom combined with a vaginal spermicide (foam, gel, film, cream or suppository), 
 male condom combined with a female diaphragm, either with or without a vaginal 
spermicide (foam, gel, film, cream, or suppository). 
Adequate contraception does not apply to participants of child-bearing potential with same sex 
partners, when this is their preferred and usual lifestyle. 
9.9. 
Biohazard Containment 
All dangerous goods and materials, including diagnostic specimens and infectious substances, 
will be handled and transported based on requirements of relevant local regulatory authorities.  


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10. 
Statistical Considerations  
10.1. 
Sample Size Determination 
Efficacy 
The total number of participants planned to be enrolled is approximately 600 (300 per group). If 
the true control rate for progression to moderate or severe category or greater is at least 30%, 294 
participants per group will result in 80% power when the true Study Intervention effect is 35%. 
This sample size assumes a drop-out rate of 10% and a 1-sided Type I error rate of 2.5%. 
Safety 
With 300 participants in the rivaroxaban intervention group, there is 80% probability to observe 
at least one SAE related to rivaroxaban when the true SAE rate is at least 0.54%.  
10.2. 
Statistical Hypothesis 
Primary Hypothesis: Treatment with the DOAC rivaroxaban will reduce progression to moderate 
or severe disease category or higher (Gates MRI ordinal scale ≥3) relative to placebo in high risk 
participants with mild COVID-19.  
10.3. 
Populations for Analyses 
For the purposes of analysis, populations are defined in Table 9. 
Table 9: 
Populations for Analysis 
Population 
Description 
Intention to treat (ITT) 
population 
All participants randomly assigned to study intervention. Participants will be 
analyzed according to the intervention to which they were randomized. 
Modified intention to 
treat (mITT) 
populations 
All participants randomly assigned to study intervention, who received the 
study intervention and have mild disease at study entry. Participants will be 
analyzed according to the intervention they actually received.  
Per Protocol (PP) 
population 
All participants randomly assigned to study intervention, who received the 
study interventions as planned, have mild disease at study entry, and did not 
substantially deviate from the protocol procedures. 
Participants will be analyzed according to the intervention they actually 
received. 
Safety population 
All participants randomly assigned to study intervention, who received the 
study intervention. Participants will be analyzed according to the intervention 
they actually received. 


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10.3.1. Assigning Shared Controls across Multiple Intervention-Specific Analysis 
Populations  
Each intervention may be initiated and stopped at different time frames, and within different 
sites. Depending on the number of interventions that a participant can be eligible to receive, a 
participant randomized to a control arm may be part of multiple intervention-specific analysis 
populations for the purposes of comparing a single intervention to control. We note the following 
core principles associated with sharing controls across intervention-specific analysis populations: 
 Controls will only be shared across multiple intervention-specific populations when there 
is randomization across those interventions and the control. All participants will only be 
randomized once. 
 A participant who is eligible for multiple interventions at a site will be randomized 
equally to receive one of the interventions for which they are eligible vs control. 
Participants randomized to control will be equally likely to receive the matched control of 
each intervention for which they are eligible. If the participant is randomized to control, 
they will be assigned to each of the intervention-specific analysis populations included in 
the randomization. A participant randomized to control will not be assigned to an 
intervention-specific analysis population that was not included in the randomization. 
 Controls will only be shared contemporaneously. A participant can only be used in the 
intervention-specific population(s) that were available and included at the time of their 
randomization.  
 A control does not have to receive the intervention-specific matched control to be eligible 
for an intervention-specific population. For example, a participant randomized 1:1:1 to 
receive two available interventions vs control would serve as a control for each of the 
interventions even if randomized to the matched control of the first interventions. The 
primary comparison will utilize eligible participants in the control arm with all control 
formulations. 
The randomization strategy for up to 3 contemporaneously available interventions is shown in 
Figure 3. Strategies for 2 interventions and for 1 intervention are shown in Figure 4 and Figure 5, 
respectively.  
This randomization strategy can easily be generalized beyond 3 contemporaneously available 
interventions and will ensure approximately equal randomization of each intervention to control, 
while helping to maintain blinding and minimize possible bias. 
Participants randomized to rivaroxaban or control under the principles listed above will be 
assigned to the rivaroxaban-specific analysis population. 


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10.5. 
Statistical Methods 
The statistical analysis plan will be developed and finalized before database lock and will 
describe the detailed analytical plans and procedures for the interim and final analyses, and 
accounting for missing data.  
10.5.1. Efficacy Analyses 
Primary efficacy endpoints 
The primary efficacy analysis will be conducted in the ITT population. Within the rivaroxaban 
analysis population as defined in Section 10.3.1, participants randomized to rivaroxaban will be 
compared to participants randomized to placebo/standard of care.  
The proportion of participants who progress to moderate or severe disease category or greater 
through Day 28 will be summarized by treatment group. The absolute difference in the risk of 
progression to moderate or severe disease category or greater will be assessed using the stratified 
Miettinen and Nurminen method to compare the difference between two rates [Miettinen 1985]. 
Sensitivity analyses will be repeated as described above using the mITT and PP populations, to 
assess the robustness of the primary results. 
Secondary endpoints 
Secondary analyses will primarily be conducted in the ITT population, with sensitivity analyses 
performed in the mITT and PP populations. Specific details of each analysis will be provided in 
the SAP. 
For time to disease resolution endpoints, a stratified Log-rank test will be used. A stratified Cox 
PH model will be used to estimate the hazard ratios and corresponding CIs associated with the 
rate of disease resolution for the study intervention relative to control. Due to anticipated 
heterogeneity in the rate of disease resolution, pre-specified baseline variables, including age, 
BMI, and days of symptoms at time of enrollment may be included in the model to increase 
precision. The appropriateness of the proportional hazard ratio assumption will be assessed. 
The proportion of participants who achieve disease resolution at each time point through Day 28 
will be summarized by treatment group with 95% exact CIs. Differences in the proportion of 
participants achieving disease resolution between each intervention and control will be assessed 
using the stratified Miettinen and Nurminen method to compare the difference between two rates 
[Miettinen 1985]. 
The distributions of the Gates MRI scale score and WHO ordinal score will be summarized by 
day and treatment group. The overall burden of disease for an individual participant may be 
calculated as the area under the curve over time. Differences in disease scores will be assessed 
using a linear model assessing the impact of treatment on disease burden, while controlling for 
baseline disease burden, age, BMI, and days of symptoms at time of enrollment. Differences in 
disease severity at key timepoints (e.g., Day 14) will also be assessed using a proportional odds 
model.  


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The proportion of hospitalized participants will be summarized by treatment group with 95% 
exact CIs. The relative risk of hospitalization for patients randomized to each intervention 
relative to control will be assessed using a stratified analysis for the comparison of two rates. 
Exploratory endpoints 
SARS-CoV-2 viral load measures will be assessed using a linear mixed effects model, with fixed 
effects of time, baseline viral load, age, BMI, and days of symptoms at time of enrollment, and a 
random effect for participant. The measures may be transformed to satisfy the normality 
assumption needed for the linear mixed effects model fit. Mean viral concentrations will be 
summarized by treatment group and compared over time based on the model fit. 
Viral sequencing may be used to assess the phylogenetic relationships between SARS-CoV-2 
viruses obtained from positive nasal swab samples. Phylogenetic trees will be generated to 
determine whether participants were part of a transmission cluster. 
10.5.2. Safety Analyses 
Safety analyses will be conducted in the safety population. 
The proportion of participants with Grade 3 AEs, Grade 4 AEs, AEs resulting in study 
intervention discontinuation, and SAEs will be summarized by treatment group, with 95% exact 
CIs. 
In addition, reported AESIs will be summarized overall and by group. 
10.6. 
Interim Analysis 
The primary analysis will occur after all participants complete Day 35. There will be 1 
prespecified interim analysis to assess futility. If the trial does not cross the pre-specified 
boundaries to declare futility at the interim analysis, a final efficacy and safety analysis will 
occur after all participants complete the study Day 35 of follow-up.  
A group sequential design strategy will be used to assess futility at the interim analysis. The 
interim analysis will occur after approximately 200 participants have completed Day 28 of 
follow-up. A Hwang-Shih-DeCani beta spending approach will be used [Jennison 2000]. The 
gamma parameter used will be -4, which is similar to the boundaries from the O’Brien-Fleming 
method [O’Brien 1979]. The lower bound for futility will be binding. 
 
11. 
Operational Considerations  
11.1. 
Independent Data Monitoring Committee  
An IDMC will be convened for this study with expertise in COVID-19 or respiratory viruses and 
emerging epidemics as well as biostatistics.  


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The purpose of the IDMC is to monitor the study for safety and efficacy. The IDMC may request 
additional information, or a pause in recruitment and dosing, while safety data are being 
evaluated. 
The IDMC will operate according to a charter and the structure, participants, meeting 
information and other details will be provided in the charter. The charter will be available prior 
to study start.  
The IDMC will meet monthly or ad hoc, if necessary, to review safety data, and may request 
additional information, or a pause, while safety data are being evaluated.  
The IDMC will also review unblinded efficacy data at a pre-specified interim analysis. Pausing 
guidelines will apply (refer to Section 6.6). 
All procedures associated with this review will be documented. 
The IDMC will make a formal recommendation as needed. 
The recommendations of the IDMC, along with the Sponsor’s decision, will be communicated to 
the PIs and the IRBs/IECs and the national regulatory authorities as required. The Sponsor or its 
designee agrees to abide by any directives issued by the national regulatory authority or the 
IRB/IEC. 
The IDMC will review the Pausing Guidelines (Section 6.6 Study Pausing Guidelines). 
11.2. 
Informed Consent Process 
The PI or designee will explain the study to the participant and answer all questions regarding 
the study. The PI or designee will conduct the consent discussions on an individual basis with 
each participant. Adequate time will be allowed for all questions to be addressed. Potential 
participants will be interviewed to ensure that they meet all entry criteria relating to history. 
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of FDA Code of Regulations 
(CFR) 21 CFR 50, local regulations, International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and the IRB/IEC or study 
center. 
Written informed consent must obtained before the participant is enrolled in the study, and the 
date the written consent was obtained must be documented. The authorized person obtaining the 
informed consent must also sign the ICF (see Section 11.2.1). 
A copy of the ICF must be provided to the participant. 
The intention for this study is that the consenting process will be conducted through 
remote/virtual contact and may use electronic consent functionality to obtain the participant’s 
signature and date. Alternatively, an in-person visit may be conducted for consent if needed. 
11.2.1. Informed Consent Forms 
The study ICF contains a section that addresses the use of remaining mandatory samples for 
research not described in the protocol, e.g., assay development and assay quality control. 


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Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. Any test results from the samples 
collected before withdrawing consent may still be used for the study. 
11.3. 
Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant record or dataset 
that is transferred to the Sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred to the Sponsor. 
The participant must be informed that the participant’s study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of data disclosure must also be 
explained to the participant. 
The participant must be informed that the participant’s medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
11.4. 
Sample Retention and Future Use of Collected Biospecimen 
Biospecimens collected during the study will be retained securely for up to 10 years. 
Collected biospecimens may also be used for future research. In addition, and only with the 
explicit and optional consent of study participants, samples or partial sample volumes that 
remain once a protocol-defined assay has been completed, may be stored and used for purposes 
other than protocol-related endpoints. Such “future research studies” would include, but not be 
limited to, assay development, assay quality control and development of methods related to 
COVID-19 research.  
Biospecimens may be shared with research partners for scientific research purposes. Samples 
will not be sold, loaned, or given to any other independent groups for their own use. Research 
partners working with the Sponsor are not allowed to share samples with anyone who is not 
authorized by the Sponsor. The Sponsor will control what is done with all biospecimens.  
11.5. 
Dissemination of Clinical Study Data 
Study information from this protocol will be posted on publicly available clinical trials registers 
(for example, clinicaltrials.gov) before enrollment of participants begins. Summaries of the 
results of the study will also be posted on the same website. 
The final CSR will include all available data through the final study visit. The database will be 
locked prior to preparation of the final CSR when all of the above data have been entered, 
reviewed, and all queries related to the data have been addressed.  
Modifications or additions to the analyses will be included in the relevant SAP. Any decisions to 
deviate from the planned analyses described in the protocol and in the SAP will be described in 
detail in the final CSR. The CSR will be reviewed and approved by the Sponsor signatory and 
the lead PI.  


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11.6. 
Data Quality Assurance 
All participant data relating to the study will be recorded on a printed CRF or, by an electronic 
CRF (eCRF) using an Electronic Data Capture (EDC) system or transmitted to the Sponsor or 
designee electronically (e.g., laboratory data). The PI is responsible for verifying that data entries 
are accurate and correct by physically signing or electronically signing the CRF. 
The PI must maintain accurate documentation that supports the information entered in the 
CRF/eCRF. 
The study will be monitored regularly by the Sponsor or its designee throughout the study 
period. The PI must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. Remote 
monitoring is preferred in this study. 
The Sponsor or designee is responsible checking the accuracy and completeness of the data 
reported in the CRFs and the consistency with the source documents. The Sponsor assumes 
accountability for actions delegated to other individuals (e.g., contract research organization 
[CRO]). 
Study monitors will perform ongoing source data verification remotely to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
electronic source documents provided; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
11.7. 
Source Documents 
Source documentation, either paper or electronic, consists of existing medical records and/or 
study records developed and maintained by the PI. Source documents provide evidence for the 
existence of the participant and substantiate the integrity of the data collected.  
Data recorded on source documents will be transcribed onto CRFs either paper, or electronically 
using an EDC system. 
Data entered in the CRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The PI may need to request previous 
medical records or transfer records, depending on the study.  
11.8. 
Record Retention and Future Use of Medical Data  
Records and documents pertaining to the conduct of this study must be retained by the PI for a 
minimum of 10 years after study completion unless local regulations or institutional policies 
require a longer retention period.  


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No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written notification 
to the Sponsor. 
In addition, medical data collected from this study may be used for future use and may be shared 
with research partners for scientific research purposes. The information may be analyzed, used, 
or combined with other results, information, and data from other studies for the purpose of this 
study, in research registries or databases, for future research purposes that may or may not be 
related to this study for scientific publications or presentations, for submission to governmental 
authorities, for legal or regulatory purposes, or to seek approval of a study drug or study 
treatment for marketing from governmental authorities.  If the results of the study are published, 
your identity will remain confidential. 
11.9. 
Study Closure 
The Sponsor reserves the right to close the study or terminate the study at any time for any 
reason at the sole discretion of the Sponsor.  
Reasons for the early closure of a study site by the Sponsor may include but are not limited to: 
 
Failure of the PI to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP 
guidelines 
 
Inadequate recruitment of participants by the PI 
 
Discontinuation of further study intervention development. 
11.10. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the PI agrees to submit all manuscripts or abstracts to the Sponsor before submission. This 
allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating PI will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 


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Ackermann M. Verleden S, Kuehnel M. Pulmonary vascular endothelialitis, thrombosis, and 
angiogenesis in COVID-19. NEJM. 2020. DOI: 10.1056/NEJMoa2015432 
Bikdeli B, Madhavan M, Jimenez D, et al. J Am Col Cardio. 2020;75(3):2950-73. COVID-19 
and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, 
and follow-Up. https://dio.org/10.1016/jacc.2020.04.031. 
Beigel H, Tomashek K, Dodd L. et al. Remdesivir for the treatment of COVID-19 - Preliminary 
Report. NEJM. 2020 May 22: DOI: 10.1056/NEJMoa2007764 
Cai J, Xu J, Lin D, et al. A case series of children with 2019 novel coronavirus infection: clinical 
and epidemiological features. Clin Infect Dis. 2020 Feb. pii: ciaa198. 
Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 
novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 
2020 Feb;395(10223):507-513. 
Ciceri F, Castagna A, Rovee-Querini P, De Cobelli F, et al. Early predictors of clinical outcomes 
of COVID-19 outbreak in Milan, Italy. Clin Immunol 2020;217:108509 
https://doi.org/10.1016/j.clim.2020.108509 
Cohen A, Spiro T, Büller H, et al. Rivaroxaban for Thromboprophylaxis in Acutely Ill Medical 
Patients. N Engl J Med. 2013;368:513-523. DOI: 10.1056/NEJMoa1111096. 
Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of 
Health US Department of Health and Human Services (DAIDS) Regulatory Support Center. 
2017. Table for grading the severity of adult and pediatric adverse events. Corrected version 2.1. 
https://rsc.tech-res.com/docs/default-source/safety/division-of-aids-(daids)-table-for-grading-the-
severity-of-adult-and-pediatric-adverse-events-corrected-v-2-1.pdf.  
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency Guidance for Industry, PIs, and Institutional Review Boards March 2020. 
Updated on May 14, 2020. https://www.fda.gov/media/136238/download. 
FDA. Letter of Authorization for Emergency Use of remdesivir for the treatment of COVID-19. 
May 1, 2020. https://www.fda.gov/media/137564/download. 
Fu J. Kong J, Wang W, et al. The clinical implication of dynamic neutrophil to lymphocyte ratio 
and D-dimer in COVID-19: A retrospective study in Suzhou China. Thromb Res. 2020;192:3-8. 
doi.org/10.1016/j.thromres.2020.05.006. 
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 
and TMPRSS2 and is blocked by a clinically proven protease inhibitor. 2020 Mar; Cell. pii: 
S0092-8674(20)30229-4 (pre-publication).  
Huang C, Wang Y, Li X, et al. Clinical features of participants infected with 2019 novel 
coronavirus in Wuhan, China. Lancet. 2020 Feb;395(10223):497-506. 
Jennison C, Turnbull BW. Group sequential methods with applications to clinical trials. 2000. 
Boca Raton: Chapman and Hall. 
Johns Hopkins University (JHU) and Medicine. 2020. Coronavirus resource center. 
https://coronavirus.jhu.edu/us-map. Accessed 02 September 2020. 


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Lee JS, Adhikari NKJ, Kwon HY, et al. Anti-ebola therapy for participants with Ebola virus 
disease: a systematic review. BMC Infect Dis. 2019 May;19(1):376.  
Li CC, Wang XJ, Wang HR. Repurposing host-based therapeutics to control coronavirus and 
influenza virus. Drug Discov Today. 2019 Mar;24(3):726-736.  
Linton NM, Kobayashi T, Yang Y, et al. Incubation period and other epidemiological 
characteristics of 2019 novel coronavirus infections with right truncation: a statistical analysis of 
publicly available case data. J Clin Med. 2020 Feb;9(2). pii: E538.  
McGonagle D, O’Donnell J, Sharif K, et al. Immune mechanisms of pulmonary intravascular 
coagulopathy in COVID-19 pneumonia. Lancet Rheumatol. 2020 Published Online May 7, 2020. 
https://doi.org/10.1016/S2665-9913(20)30121-1. 
Miettinen O, Nurminen M. Comparative analysis of two rates.1985;4(2):213-226. 
https://doi.org/10.1002/sim.4780040211. 
Micco P, Russo V, Carannante N, et al. Clotting Factors in COVID-19: Epidemiological 
association and prognostic values in different clinical presentations in an Italian cohort. J. Clin. 
Med. 2020;9:1371. DOI:10.3390/jcm9051371. 
Nauka P, Oran E, Chekuri S. Deep venous thrombosis in a non-critically ill patient with novel 
COVID-19 infection. Thromb Res. 2020;192:27-8. 
https://www.thrombosisresearch.com/article/S0049-3848(20)30187-0/pdf. 
O’Brien, PC, Fleming, TR. A Multiple Testing Procedure for Clinical Trials. Biometrics. 
1979;35:549–56. 
Petrilli C, Jones SA, Yang J, et al. Factors associated with hospital admission and critical illness 
among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. 
BMJ 2020;369:m1966. 
Richardson S, Hirsch J, Narasimhan, M, et al. Presenting characteristics, comorbidities, and 
outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA. 
2020;323(20):2052-2059. 
Siddiqi H, Mehra MR. COVID-19 illness in native and immunosuppressed states: A 
clinical−therapeutic staging proposal. J Heart and Lung Trans. 2020. 
https://doi.org/10.1016/j.healun.2020.03.012. 
Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in 
severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18:1094–
1099. https://doi.org/10.1111/jth.14817. 
University of Washington (UW) Medicine Pharmacy Services. Anticoagulation Services. 
Rivaroxaban drug interaction potential. Modified on 23 April 2020. 
https://depts.washington.edu/anticoag/home/content/rivaroxaban-drug-interaction-potential. 
US Center for Disease Control and Prevention (CDC). 2020. Coronavirus disease 2019. 
www.cdc.gov Accessed 26 May 2020.  
Wang D, Hu, Bo, Hu Chang, et al. Clinical characteristics of 138 hospitalized patients with 2019 
novel coronavirus–infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-1069. 


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doi:10.1001/jama.2020.1585. Published online February 7, 2020. Corrected on February 20, 
2020. 
Wang T, Chen R, Liu C. Attention should be paid to venous thromboembolism prophylaxis in 
the management of COVID-19. www.thelancet.com/haematology Vol 7 May 2020 
https://doi.org/10.1016/ S2352-3026(20)30109-5. 
White House Press Release (WHPR). https://www.whitehouse.gov/presidential-
actions/proclamation-declaring-national-emergency-concerning-novel-coronavirus-disease-
covid-19-outbreak. 2020 Mar 13. 
Wichmann D, Sperhake J-P, Lütgehetmann M, et al. Autopsy findings and venous 
thromboembolism in patients with COVID-19. Ann Intern Med. 2003. doi:10.7326/M20-2003. 
Williams RD, Markus AF, Yang C, et al. Seek Cover: Development and validation of a 
personalized risk calculator for COVID-19 outcomes in an international network. medRxiv May 
29, 2020. https://doi.org/10.1101/2020.05.26.20112649. 
World Health Organization (WHOa). News Release. Statement on the second meeting of the 
International Health Regulations (2005) Emergency Committee regarding the outbreak of novel 
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WHO(b) News Release. Shortage of personal protective equipment endangering health workers 
worldwide. 2020 Mar 03. 
WHO(c). Clinical management of severe acute respiratory infection when novel coronavirus 
(2019-nCoV) infection is suspected: interim guidance, 28 January 2020. World Health 
Organization. https://apps.who.int/iris/handle/10665/330893. 
WHO(d) Working Group on the Clinical Characterization and Management of COVID-19 
infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet 
Infect Dis 2020. Published Online June 12, 2020 https://doi.org/10.1016/S1473-3099(20)30483-
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Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and 
death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 
doi:10.1001/jamainternmed.2020.0994. Published online March 13, 2020. Corrected on May 11, 
2020. 
Xarelto® [rivaroxaban] tablets, for oral use, Package Insert, revised Mar 2020 
Zhou F, Yu Ting, Du Ronghui, et al. Clinical course and risk factors for mortality of adult 
inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 
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Zhu N, Zhang D, Wang W, et al. A novel coronavirus from participants with pneumonia in 
China, 2019. N Engl J Med 2020 Feb;382(8):727-7. 


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13. 
Version History 
Version 1 (30 June 2020) and Version 2 (02 July 2020) were in-house versions shared with CRO 
for reviews and prepared prior to FDA review. 
Version 3 (15 July 2020) was submitted to FDA for review. 
Version 4 (01 August 2020) incorporated FDA suggestions and is the version used for initiation 
of the study. 
Amendment 1 (09 September 2020) is the first amendment to the protocol after study start.  
Amendment 2 (27 January 2021) is the second amendment to the protocol after study start. 
13.1. 
Amendment 1 dated 09 Sept 2020 
Rationale for Amendment 1: The protocol required an amendment after study start to address 
emergent and important issues at sites pertaining to screening and enrollment. The requirement 
for screening to occur within 72 hours of symptom onset resulted in many potential participants 
who had symptoms onset before 72 hours being excluded from consideration for enrollment.  In 
addition, the requirement for Day 1 to occur no later than 72 hours after screening did not take 
into account the time required to obtain SARS-CoV-2 test results (for participants not having 
documentation of a prior positive test) nor the time needed to provide study materials to 
participants once randomization had occurred. The time constraints described above restricted 
enrollment severely and the study team decided that both constraints needed to be relaxed to 
enable efficient enrollment. 
Therefore, changes to the Inclusion criteria #3 and #4 (Section 5.5.1) are:  
3. Documented positive SARS-CoV-2 diagnostic testing with a sample collected ≤10 days of 
screening. 
4. Symptomatic for COVID-19 for ≤7 days at time of randomization 
(symptomatic is defined as having at least one of the following symptoms of COVID-19 that 
is of new onset or has worsened from baseline: and include fever, chills, myalgia, arthralgia, 
headache, fatigue, cough, sore throat, nasal congestion, nausea, vomiting, or diarrhea).  
The change to Section 8.1 is:  
 Required procedures must occur ≤5 days prior to the Day 1 visit.  
Because the putative effect of rivaroxaban to prevent thrombotic complications of COVID-19 
would be present during the whole of the treatment period, the expansion of the intervals as 
detailed above are not anticipated to significantly impact the results of the study.  
A complete list of changes from protocol Version 4 to protocol Amendment 1 are shown as 
follows.  
Title page: Added text: Refer to Section 13 for version history and amendment revisions. 
Changed header throughout document from Version 4 to Amendment 1. 
Changed footer throughout document from 01 August to 09 September  
Changed COVID-19 disease to COVID-19 throughout 


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Sponsor signatory page: added: Amendment 1   
List of abbreviations: added: CRO contract research organization 
Section 1 Synopsis and Section 5.1: Added under Interventional groups, randomization, and 
dosing: Randomization will be stratified by site and by number of days since onset of symptoms 
(<6 days vs. ≥6 days). 
Synopsis:  Figure 1: Study Screening Process 
• 
Positive SARS-CoV-2 diagnostic testing ≤ 7 days at screening performed ≤10 days prior 
to screening 
• 
Mild COVID-19 symptoms ≤ 72 hours at screening present ≤7 days at the time of 
randomization ≤ 72 hours  
• 
≤ 72 hours ≤5 days from screening to Day 1 
• 
Have mild COVID-19 symptoms 
If eligibility is confirmed, enroll and randomize (intervention or control) at screening. 
Section 2. Schedule of Activities:  
Changed screening from ≤ 72 hours to ≤5 days 
Deleted X in the Day 35 column to remove clinical status assessment using ordinal scales for 
Gates MRI and WHO from this time point. 
Added: Self-collection of nasal or oropharynx SARS-CoV-2 sample for diagnostic testing3 
Added an (X)1 under screening for Self-collection of nasal SARS-CoV-2 sample for diagnostic 
testing 
SOA footnotes:  
1If there is documentation of results of a positive diagnostic testing within the past 7 days, this test does 
not need to be repeated If there is documented positive SARS-CoV-2 diagnostic testing performed 
with a sample collected ≤10 days prior to screening, the test does not need to be performed. If no 
documentation, the potential participant will be asked to collect a nasal or oropharynx swab sample 
to send for testing. 
2If documentation of a previous positive SARS-CoV-2 test is not available and a test is performed at 
screening, randomization will occur after a positive result is obtained. 
2 3 Participant will be asked to collect a sample per kit instructions. Discontinue collection during 
hospitalization and/or, per physician’s discretion, when two consecutive negative results are available 
at any time during the study. 
Section 3.1.1 SARS-CoV-2 Epidemiology and Disease, changed: As of June September 2020, 
approximately 26 10 million confirmed cases were reported globally, with over 500 859,000 
deaths JHU 2020].  
Section 3.1.2. Therapeutic Approaches for COVID-19, changed: As of JuneSeptember 2020 
Section 3.2.2 COVID-19 progression requiring hospitalization generally occurs from the second 
week of illness ….  
Section 3.2. Table 2 moved text in title to footnote: Safety Analysis Set- On Treatment Plus 2 
Days  
Section 3.2.2.1 new section added: Rationale for a Limit of 7 Days of Mild COVID-19 
Symptoms Prior to Randomization 


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The incubation period from exposure to early manifestations of COVID-19 ranges from 2 to 14 
days. During the first 3 days of illness, COVID-19 symptoms may be non-specific and include 
cough, fever, headache, lethargy, and/or diarrhea. During the next 3-5 days some patients 
develop worsened symptoms but some patients may show signs of recovery. The second week of 
illness, Days 8-12, is when progression to signs and symptoms indicative of a 
hyperinflammatory phase is more likely to occur. These may include dyspnea, abnormal imaging 
of the lungs, respiratory failure, ARDS, and/or cytokine storm syndrome. In a large series of 410 
patients with COVID-19 hospitalized in Italy [Ciceri 2020], the median (IQR) days from 
COVID-19 symptoms onset to hospitalization was 8 days (5-11) days. Approximately 50% of 
these patients were aged >65 years and approximately 60% had one or more comorbidities.  
The primary endpoint of this study is the time to progression of COVID-19 from Scale 2 to Scale 
3 or higher – a situation that would likely require hospitalization of the participant. The data 
from the cited Italian study can inform the choice of the interval between onset of symptoms and 
the expected time of initiation of study drug therapy. Because the interval from onset of 
symptoms to randomization should be no more than 7 days resulting in the worst-case scenario 
of an interval of around 9 days from onset of symptoms to first dose of study treatment 
(assuming two days for shipment of IP and supplies). Nine days falls within the IQR reported by 
Ciceri, et al [Ciceri 2020]. 
Section 4 Objectives and Endpoints Table 3: 
 Added Objectives and to the title of Table 3. Modified first secondary endpoint: Time to 
disease resolution, defined as BOTH viral clearance (two consecutive negative diagnostic 
tests) and symptoms resolution (new onset COVID-19 symptoms resolved, and pre-existing 
symptoms returned to baseline*) with viral clearance through Day 28 
Section 5.4. Pre-Screening for the Study 
Persons with positive SARS-CoV-2 diagnostic test who have not exhibited symptoms and are at 
high risk for COVID-19 disease progression may enroll in the pre-screening phase provided that 
they are willing to be contacted by the study team and are interested in enrolling in the COVID-
19 treatment trial if they become symptomatic.  
The purpose of pre-screening is to facilitate enrollment of participants with mild COVID-19 
into the study as soon as they become symptomatic. Persons who are in the high risk category 
for COVID-19 progression and are asymptomatic may enroll in the pre-screening phase 
provided that they are willing to be contacted by the study team and are interested in enrolling 
in the COVID-19 treatment trial if they become symptomatic. They must have a confirmed 
positive SARS-CoV-2 diagnostic testing within the past 7 days at Day 1 of pre-screening. 
Participants who do not yet have a documented positive SARS-CoV-2 diagnostic test may have 
the testing done at the pre-screening eligibility check visit provided that they have had a high 
risk exposure to SARS-CoV-2 within the past 14 days.  
High risk exposure is defined as: 
1. being an immediate household contact of a confirmed COVID-19 case and/or  
2. having occupational exposure to a confirmed COVID-19 case (for example, healthcare 
worker or first responder). 
Section 5.4 Figure 2  


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Fulfill key eligibility criteria 
• 
Age ≥18 yrs old 
• 
At high risk for severe COVID-19 disease 
• 
Positive SARS-CoV-2 test ≤57 days at day 1 of pre-screening 
• 
No COVID-19 symptoms 
• 
Laboratory tests obtained and reviewed 
• 
Willing to be contacted by study team 
• 
Interested in participating in study 
Box below: Day 1 to Day 7 Day 10 
Last box: Exit pre-screening if no symptoms at Day 10 after diagnosis or Day 10 of pre-
screening, if no symptoms at Day 7 after diagnosis or Day 7 of pre-screening, whichever comes 
first. 
Section 5.4.1. Pre-Screening Inclusion Criteria  
COVID-19 disease characteristics 
3. Documented SARS-CoV-2 positive diagnostic test of ≤5 days at time of informed consent 
Documented positive SARS-CoV-2 diagnostic testing with sample collected ≤7 days at Day 1 of 
pre-screening  
No COVID-19 symptoms (defined as no fever, chills, myalgia, arthralgia, headache,… 
Section 5.4.2, Table 4: Pre-screening Schedule of Activities  
Eligibility check  
(≤24 72 hrs) 
Added a row at end of table 
No AEs will be collected  
Added: Note that no data during the pre-screening stage will be recorded in the database or in a 
case report form. 
Footnote:  
1If there is documentation of results within the past 5 days of a positive diagnostic test, this test does not need to be 
repeated. 
2Participant will exit the pre-screening phase if he/she remains asymptomatic at day 7 after diagnosis or day 7 of the 
pre-screening phase, whichever comes first. 
1If documented positive SARS-CoV-2 testing is not available at the eligibility check visit, testing may be 
performed provided that the potential participant has had a high risk exposure to SARS-CoV-2, defined as being 
an immediate household contact of a confirmed COVID-19 case and/or having occupational exposure to a 
confirmed COVID-19 case (for example, healthcare worker or first responder). 
2Participant will exit the pre-screening phase if he/she remains asymptomatic at day 10 after diagnosis or day 10 
of the pre-screening phase, whichever comes first. 


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Section 5.5.1 Inclusion and Exclusion Criteria 
COVID-19 Characteristics 
3. Documented positive SARS-CoV-2 diagnostic testing with a sample collected ≤10 days of 
screening. 
4. Symptomatic for COVID-19 for ≤72 hours days at time of screening randomization 
(symptomatic is defined as having at least two one of the following symptoms of COVID-19 
that is of new onset or has worsened from baseline, and include fever, chills, myalgia, 
arthralgia, headache, fatigue, cough, sore throat, nasal congestion, anosmia, ageusia, nausea, 
vomiting, or diarrhea.  
Must have at least one symptom other than anosmia or ageusia.  
Section 5.5.2 Exclusion Criteria under Medical Conditions or history 
3. Hypoxemia (oxygen saturation<94% in ambient air or oxygen saturation below pre-COVID-
19 level oxygen saturation [if known] for people with known COPD) at Day 1 
6.11. Hospitalization  
If a participant clinically worsens, such as requiring hospitalization, it is expected that standard 
clinical care will be provided. and participation in another study intervention trial will be 
permitted. Hospitalized participants may continue to receive study intervention if maintained 
on the originally randomized study-intervention regimen.   
The treating physician will be contacted by the study investigator or designee, to get approval for 
continuing study encounters to the extent possible, in the hospital setting.  
Section 7.1 Discontinuation of Study Intervention: 
Study intervention will be discontinued for the following reasons: 
Hospitalization, at the discretion of the in-patient provider: hospitalized participants may 
continue to receive study intervention if maintained on the originally randomized Study 
Intervention regimen) Hospitalization, if the in-patient provider decides continuation of 
study treatment is contraindicated.   
Section 7.2 Withdrawal from the Study: Added bullet:The participant progressed to moderate 
or severe COVID-19 (or worse) prior to initiation of IP dosing on Day 1 
Section 8 Study Encounters: edited:  Participants will be instructed to seek clinical care should 
they manifest any signs or symptoms of COVID-19 disease progression requiring medical 
intervention and notify their the treating physician about trial participation. 
Section 8.1 Screening Process and Procedures: edited: 
The following procedures must occur ≤5 days prior to 72 hours of the Day 1 visit.  
The study staff conducting the Screening visit will: 


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Collect laboratory documentation of positive SARS-CoV-2 diagnostic test performed ≤7 days of 
screening. Collect documented positive SARS-CoV-2 diagnostic testing performed with a 
sample collected ≤10 days of screening. If no such document is available, SARS-CoV-2 
diagnostic testing will be performed at screening. 
Enrolled eligible participants and randomized to a study group.  
Collect information on AEs in eligible participants. 
If eligible, participants will receive supplies and study IP, delivered to the participant at home, or 
if deemed necessarily it may be picked up at study site or other methods may be used as 
appropriate.  
Eligible participants who meet all criteria will be enrolled and randomized to a study group 
and will receive supplies and study IP, delivered to the participant at home, or if deemed 
necessary, it may be picked up at study site or other methods may be used as appropriate.  
Eligible participants will receive the following: 
 Nasal Diagnostic test kit, with user instructions 
Section 9.1:  Day 1 (first day of study) 
 Assess the Gates MRI and WHO ordinal scales and confirm that participant continues 
to meet criteria for Scale 2 of Gates MRI COVID-19 Ordinal Scale (Table 7) 
 Collect information on AEs (note that AEs will be collected from the time the 
participant signs the informed consent). 
Deleted bullet: Collect information on bleeding events and severity 
Section 9.4 Efficacy Assessments 
Edited: The primary efficacy endpoint is the proportion of participants who progress to moderate 
or severe disease category or higher (Gates MRI ordinal scale ≥3). 
The proportion of participants who progress to moderate or severe category or higher (Gates 
MRI ordinal scale ≥3) will be assessed at study visits indicated in the SoA. 
Section 9.4.1 Nasal Sampling: edited: Nasal sampling for SARS-CoV-2 diagnostic test will 
follow study instruction document from the testing laboratory. Nasal sampling collection will be 
discontinued during hospitalization and/or when two consecutive negative results are available at 
any time during the study. 
Nasal sampling for SARS-CoV-2 diagnostic testing will follow study instruction document 
from the testing laboratory. Nasal sampling collection will be discontinued during 
hospitalization and/or, per physician’s discretion, when two consecutive negative results are 
available at any time during the study. 
Section 9.6 Table 6 title: COVID-19 Signs and Symptoms to be Recorded in the CRF/eCRF 
Section 10.2 Primary Hypothesis: Prophylactic treatment Treatment with 
Section 10.5: All AEs will be followed until resolution, stabilization, lost to follow-up, or until 
the end of the study (Day 35). All SAEs will be followed until resolution, stabilization, or the 
participant is lost to follow-up, until the end of the study (Day 35). 


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Section 10.5.5.  All SAEs, regardless of whether related or not to the IP, will be followed until 
resolution, stabilization, or the participant is lost to follow-up, until the end of the study (Day 
35).All SAEs, regardless of whether related or not to the IP, will be followed until resolution, 
stabilization, lost to follow-up, or until the end of the study (Day 35). 
Section 12 References: added Ciceri F, Castagna A, Rovee-Querini P, De Cobelli F, et al. Early 
predictors of clinical outcomes of COVID-19 outbreak in Milan, Italy. Clin Immunol 
2020;217:108509 https://doi.org/10.1016/j.clim.2020.108509 
Minor typographical errors and formatting errors were corrected throughout the document. 


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13.2. 
Amendment 2 dated 27 January 2021 
Rationale for Amendment 2 
The pace and trajectory of study enrollment suggests that the targeted number of total study 
participants (600) will be enrolled by the time of the proposed data cut for the second interim 
analysis that was previously planned. The majority of study participants would have completed 
the study by the time the IDMC meeting would take place. Therefore, any decision stemming 
from the proposed second interim analysis would unlikely affect the study conduct. 
Therefore, based on these circumstances the protocol is amended to reduce the number of interim 
analyses from 3 to 1 interim analysis and to remove the sample size re-estimation. Additional 
changes included modify the first interim analysis from an evaluation of futility and efficacy to 
be only for futility, and to remove any additional pre-specified interim analyses. 
A complete list of changes is provided below. 
List of Changes 
Header: Changed from Amendment 1 to Amendment 2 
Footer: Changed from 09 September 2020 to 27 Jan January 2021.  
Title page: Approval Date: Version 4, Amendment 2 1, 27 January 2021 09 September 2020 
Signature page: Changed from Amendment 1 to Amendment 2 
Synopsis 
Safety and efficacy monitoring: The IDMC will also review unblinded efficacy data at a pre-
specified interim analysis analyses. 
Analysis: The primary analysis will occur after all participants complete Day 35. There will be 1 
interim analysis to assess futility. The interim analysis will occur after the first approximately 
200 participants complete Day 28.  
There will be up to 3 interim analyses to assess the appropriateness of the planned sample size 
and efficacy. The first interim analysis will occur after the first approximately 200 participants 
complete Day 28. At the first interim analysis, a sample size re-assessment will be performed. If 
the final sample size is not adjusted, the first interim analysis for efficacy will also occur at this 
time and the second interim analysis will occur when approximately 400 participants complete 
Day 28. If the final sample size is adjusted at the first interim analysis, the first and second 
interim analyses for efficacy will occur when approximately one-third and two-thirds of the 
adjusted total number of participants complete Day 28, respectively. 


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If the trial does not cross the pre-specified boundaries to declare early efficacy or futility at the 
interim analysis analyses, a final efficacy and safety analysis will occur after all participants 
complete Day 35.  
Section 10.1 Sample Size Determination 
Efficacy 
The total number of participants planned to be enrolled is approximately 600 (300 per group). If 
the true control rate for progression to moderate or severe category or greater is at least 30%, 294 
participants per group will result in 80% power when the true Study Intervention effect is 35%. 
This sample size assumes a drop-out rate of 10% and a 1-sided Type I error rate of 2.5%. 
To account for two planned interim efficacy analyses without adversely affecting the statistical 
power, the sample size was increased to 300 per group. 
Because the statistical power relies heavily on the observed control event rate, the final target 
sample size will be assessed using the observed control event rate and overall drop-out rate as a 
blinded sample size reassessment after approximately 200 participants have completed Day 28 of 
follow-up (see Section 10.6 for interim analyses).  
Section 10.3.1 Assigning Shared Controls 
 The primary comparison will utilize eligible participants in the SOC control arm with all 
control formulations. 
Section 10.5 Statistical Methods 
The statistical analysis plan will be developed and finalized before database lock and will 
describe the detailed analytical plans and procedures for the interim and final analyses, 
performing sample size reassessments, interim and final analyses, and accounting for missing 
data.  
Section 10.6 Interim Analysis Analyses 
There will be 1 up to 3 prespecified interim analyses analysis to assess futility the 
appropriateness of the planned sample size and efficacy. If the trial does not cross the pre-
specified boundaries to declare early efficacy or futility at the interim analysis analyses, a final 
efficacy and safety analysis will occur after all participants complete the study Day 35 of follow-
up.  
A group sequential design strategy will be used to assess futility efficacy at each at the interim 
analysis. The first and second analyses interim analysis will occur after approximately 200 and 
400 participants have completed Day 28 of follow-up.  
The first interim analysis will occur after the first approximately 200 participants complete Day 
28. At the first interim analysis, a sample size re-assessment will be performed. The procedure 
for this blinded sample size reassessment will be detailed in the statistical analysis plan. In brief, 
the unblinded study statistician will assess the control event rate and drop-out rate, and 
recalculate the sample size required to detect treatment effects of 35%, 40%, 45% and 50% with 
80% statistical power using a 2.5% one-sided type I error rate. Based on this assessment, the 


Bill & Melinda Gates Medical Research Institute 
Gates MRI – COD-01-T01-01 Version 4, Amendment 2 
CONFIDENTIAL 
27 January 2021 
65 
IDMC will make recommendations to the Sponsor for the final target sample size. This will be 
done with proper firewalls to maintain blinding of the information as it relates to the final target 
sample size.  
If the final sample size is not adjusted, the first interim analysis for efficacy will also occur at 
this time and the second interim analysis will occur when approximately 400 participants 
complete Day 28. If the final sample size is adjusted at the first interim analysis, the first and 
second interim analyses for efficacy will occur when approximately one-third and two-thirds of 
the adjusted total number of participants complete Day 28. 
 
Section 11.1 Independent Data Monitoring Committee  
The purpose of the IDMC is to monitor the study for safety and efficacy. The IDMC will also 
review any sample size re-assessment analyses and recommend sample size changes as 
appropriate.  
The IDMC will also review unblinded efficacy data at a pre-specified interim analysis analyses.  
 

SAP_001.pdf: 
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Adaptive Platform Trial 
Bill & Melinda Gates Medical Research Institute 
Statistical Analysis Plan: Gates MRI - COD-01-T01-01 
 23 February 2021
 
 
 
 
Confidential 
Page 2 of 39 
1 TABLE OF CONTENTS 
1 
TABLE OF CONTENTS .........................................................................................................2 
LIST OF TABLES ...........................................................................................................................3 
2. 
SIGNATURE PAGE ................................................................................................................4 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................................5 
4. 
INTRODUCTION ....................................................................................................................7 
5 
TRIAL OBJECTIVES ..............................................................................................................7 
6 
STUDY DESIGN CONSIDERATIONS ..................................................................................8 
6.1 
Study Design ........................................................................................................................8 
6.2 
Efficacy Measures ..............................................................................................................10 
6.3 
Safety Measures .................................................................................................................10 
7 
STUDY POPULATIONS .......................................................................................................10 
7.1 
Analysis Populations ..........................................................................................................10 
7.2 
Assigning Shared Controls across Multiple Intervention-specific Analysis 
Populations ......................................................................................................................11 
8 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL .........14 
9 
OVERALL STATISTICAL CONSIDERATIONS ................................................................14 
9.1 
Determination of Sample Size ...........................................................................................14 
9.1.1 
Efficacy ........................................................................................................................14 
9.1.2 
Safety ...........................................................................................................................14 
9.2 
General Conventions ..........................................................................................................14 
9.3 
Baseline definition .............................................................................................................15 
9.4 
Stratification Factor ...........................................................................................................15 
9.5 
Handling of Missing Data ..................................................................................................15 
9.6 
Pooling Strategy for Study Sites ........................................................................................15 
9.7 
Visit Windows/Unscheduled Visits ...................................................................................15 
10 STATISTICAL ANALYSIS METHODS ..............................................................................15 
10.1 
Subject Disposition ............................................................................................................15 
10.2 
Demographics and Baseline Characteristics ......................................................................16 
10.3 
Treatment Compliance and Exposure ................................................................................17 
11 EFFICACY PARAMETERS..................................................................................................18 
11.1 
Primary Analysis ................................................................................................................19 
11.1.1 
Estimand ......................................................................................................................19 
11.1.2 
Sensitivity Analyses .....................................................................................................21 
11.1.3 
Subgroup Analysis .......................................................................................................21 
11.2 
Secondary Analysis ............................................................................................................22 
11.2.1 
Estimand ......................................................................................................................22 
11.2.2 
Disease Resolution .......................................................................................................23 
11.2.2.1 
Time to Disease Resolution (Symptoms Resolution) ............................................23 
11.2.2.2 
Time to Disease Resolution (Symptoms Resolution and Viral Clearance) ...........24 


Adaptive Platform Trial 
Bill & Melinda Gates Medical Research Institute 
Statistical Analysis Plan: Gates MRI - COD-01-T01-01 
 23 February 2021
 
 
 
 
Confidential 
Page 3 of 39 
11.2.2.3 
Subgroup Analysis .................................................................................................24 
11.2.3 
Proportion of Participants with Disease Resolution ....................................................24 
11.2.4 
Disease Progression of COVID-19 ..............................................................................25 
11.2.5 
Gates MRI Scale Scores ...............................................................................................25 
11.2.6 
WHO Ordinal Scale Scores .........................................................................................25 
11.2.7 
Incidence of Hospitalization ........................................................................................26 
11.2.8 
Number of Days of Hospitalization .............................................................................26 
11.3 
Exploratory Analysis .........................................................................................................26 
11.3.1 
SARS-CoV-2 Diagnostic Test .....................................................................................26 
11.3.2 
Cycle Threshold Value of SARS CoV-2 Test. ............................................................26 
11.4 
Independent Data Monitoring Committee .........................................................................27 
11.5 
Group Sequential Design ...................................................................................................27 
11.5.1 
Interim Analyses ..........................................................................................................27 
11.5.1.1 
Stopping Probabilities Under Various Hypothetical References ...........................28 
12 SAFETY AND TOLERABILITY ..........................................................................................29 
12.1 
Adverse Events ..................................................................................................................29 
13 OTHER RELEVANT DATA ANALYSES/SUMMARIES ..................................................30 
13.1 
Medical History .................................................................................................................30 
13.2 
Prior and Concomitant Medications ..................................................................................31 
14 REFERENCES .......................................................................................................................32 
15 APPENDICES ........................................................................................................................33 
 
LIST OF TABLES 
Table 1: Study objectives and associated endpoints. .......................................................................8 
Table 2: Analysis populations ........................................................................................................11 
Table 3: Censoring rules for time to disease resolution. ................................................................23 
Table 4: Example scenarios for time to time to disease resolution. ...............................................23 
Table 5: Gates MRI Ordinal Scale Clinical Endpoint Definitions ................................................25 
Table 6: WHO Ordinal Scale for Assessment of Clinical Status of COVID-19 Patients ..............25 
Table 7: Example of Alpha and Binding Beta Boundaries ............................................................28 
 
 
 


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Adaptive Platform Trial 
Bill & Melinda Gates Medical Research Institute 
Statistical Analysis Plan: Gates MRI - COD-01-T01-01 
 23 February 2021
 
 
 
 
Confidential 
Page 5 of 39 
3. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AESI 
adverse event of special interest 
ANOVA 
analysis of variance 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haezszel 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
Ct 
Cycle threshold 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
Gates MRI 
Bill & Melinda Gates Medical Research Institute 
IDMC 
independent data monitoring committee 
IEC 
Independent Ethics Committee 
IP 
investigational product 
ITT 
intention to treat 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intention to treat 
PCR 
polymerase chain reaction 
PI 
principal investigator 
PO 
orally 
PP 
per protocol 
PT 
preferred term 
SAE 
serious adverse event 


Adaptive Platform Trial 
Bill & Melinda Gates Medical Research Institute 
Statistical Analysis Plan: Gates MRI - COD-01-T01-01 
 23 February 2021
 
 
 
 
Confidential 
Page 6 of 39 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
standard deviation 
SE 
standard error  
SoA 
schedule of activities 
SOC 
system organ class 
WHO 
World Health Organization 
 
 


Adaptive Platform Trial 
Bill & Melinda Gates Medical Research Institute 
Statistical Analysis Plan: Gates MRI - COD-01-T01-01 
 23 February 2021
 
 
 
 
Confidential 
Page 7 of 39 
4. INTRODUCTION 
The purpose of this statistical analysis plan is to describe the framework for the reporting, 
summarization and statistical analysis methodology of the safety and efficacy parameters 
measured for the Gates Medical Research Institute (MRI) study COD-01-T01-01. It is based on 
Protocol Gates MRI - COD-01-T01-01 Version 4, Amendment 2, 27 January 2021. This study is 
performed as part of an adaptive, randomized platform core protocol for treatment of early and 
mildly symptomatic individuals in out-patient settings with severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection. Additional statistical analysis plans will be developed 
for future protocols and interventions that will be added to the core protocol.  
On January 28 and February 3, 2021, the Independent Data Monitoring Committee (IDMC) met 
to review the available safety and efficacy data to (1) perform the monthly safety review of 
accumulating data; and (2) evaluate the results of the first prespecified interim analysis for 
futility. Based on the review of the data, the IDMC determined on February 3, 2021, that the 
futility boundary was crossed and recommended that the clinical study be stopped. The final 
statistical analysis plan was amended to reflect changes to the planned analysis following early 
termination of the study.  
As of February 4, 2021, the following changes were made in the study conduct: 
• all randomization is ceased and no new study participants are enrolled.  
• current participants must discontinue dosing of all study drug and discard their study 
drug.  
• participants should remain in active, masked follow up and continue their study visits 
until Day 35 if they have had at least one dose of study drug.  
o Participants who have not reached Day 21 will continue safety follow up only 
until Day 35. These participants will be monitored for AEs, bleeding events and 
concomitant medication. These participants will not have further assessments for 
Gates MRI and WHO ordinal scale, symptoms, and nasal swabs for polymerase 
chain reaction (PCR) test. 
o Participants who have reached Day 21 but not Day 35 of study will continue 
safety and efficacy follow up until Day 35. These participants will be monitored 
for AEs, bleeding events, concomitant medication, Gates MRI and WHO ordinal 
scales, and symptoms. These participants will not have further nasal swabs for 
PCR test. 
• participants who have not yet taken any study drug will discontinue the study early. 
To address potential for substantial under-estimation of the treatment effect, efficacy analyses 
will be performed on a final efficacy analysis population as described in Section 7.1. Safety 
analyses will be performed on the Safety analysis population.  
5 TRIAL OBJECTIVES 
The following objectives and associated endpoints are part of this study.  


Adaptive Platform Trial 
Bill & Melinda Gates Medical Research Institute 
Statistical Analysis Plan: Gates MRI - COD-01-T01-01 
 23 February 2021
 
 
 
 
Confidential 
Page 8 of 39 
Table 1: Study objectives and associated endpoints.  
Objectives 
Endpoints  
Primary 
To characterize safety of study 
intervention 
 
Through Day 35 
• 
Frequencies of grade 3 adverse events (AEs) and grade 4 AEs 
• 
AEs resulting in study intervention discontinuation 
• 
All SAEs 
To assess efficacy of study 
intervention  
• 
Proportion of participants who progress to moderate or severe disease 
category or higher (Gates MRI ordinal scale ≥3) through Day 28 
Secondary  
To assess clinical efficacy of 
study intervention  
• 
Time to disease resolution, defined as symptoms resolution only (new 
onset COVID-19 symptoms resolved, and pre-existing symptoms returned 
to baseline*) through Day 28 
• 
Time to disease resolution, defined as both viral clearance (two 
consecutive negative diagnostic tests) and symptoms resolution (new 
onset COVID-19 symptoms resolved, and pre-existing symptoms returned 
to baseline*) through Day 28. 
• 
Proportion of participants who progress to moderate or severe disease 
category or higher (Gates MRI ordinal scale ≥3) at Days 8, 14 and 21 
• 
Proportion of participants who achieve disease resolution, defined as 
symptoms resolution only, at Days 8, 14, 21 and 28 
• 
Proportion of participants who achieve disease resolution, defined as both 
viral clearance and symptoms resolution, at Days 8, 14, 21 and 28 
• 
Gates MRI scale score at Days 8, 14, 21 and 28 
• 
World Health Organization (WHO) ordinal scale score at Days 8, 14, 21 
and 28 
• 
Incidence and number of days of hospitalization at Days 8, 14, 21 and 28  
Exploratory  
To assess virological efficacy  
• 
Quantity (and change from baseline) of SARS CoV-2 virus at Days 8, 14, 
21 and 28  
To assess viral sequence 
• 
Phylogenetic relationships of SARS-CoV-2 viruses sequenced from 
positive nasal swab samples 
*Baseline refers to health status prior to contracting new onset COVID-19 symptoms. 
6 STUDY DESIGN CONSIDERATIONS 
6.1 
Study Design 
This is an adaptive, randomized platform trial for treatment of early and mildly symptomatic 
individuals in out-patient settings with SARS-CoV-2 infection. The protocol will enroll people at 
high risk for COVID-19 progression based on age, BMI and comorbidity. The primary outcome 
through 28 days after the first intervention dose is focused on safety and efficacy (time to disease 
resolution or progression of disease).  
Primary purpose: To assess the safety and clinical efficacy of a rivaroxaban with a primary 
endpoint of reduction in proportion of participants who progress to moderate or severe disease 
category or higher (Gates MRI ordinal scale ≥3) through Day 28. 


Adaptive Platform Trial 
Bill & Melinda Gates Medical Research Institute 
Statistical Analysis Plan: Gates MRI - COD-01-T01-01 
 23 February 2021
 
 
 
 
Confidential 
Page 9 of 39 
Interventional model: Participants will be randomized 1:1 to either the rivaroxaban or the 
placebo group, in parallel for the duration of the study. Randomization will be stratified by site 
and by number of days since onset of symptoms at time of randomization.  
Intervention groups:  
Study intervention group: rivaroxaban, 10 mg (1 tablet) orally daily for 21 days. 
Control group: placebo-equivalent (multi-vitamin supplement) 1 tablet orally daily for 21 days  
Masking: Every effort will be made to mask the assigned treatment groups. Participants and 
study staff evaluating them will not be told of the assigned treatment groups. The laboratories 
performing the SARS-CoV-2 diagnostic testing will be blinded. Sponsor will be blinded 
throughout the study conduct. 
Study visits: Every effort will be made to conduct the study protocol visits virtually with the 
study participants. A web-based video conferencing tool will be employed to allow for virtual 
(remote) interactions to take place between the study staff and the participant, for screening and 
all study visits.    
Safety and efficacy monitoring: An Independent Data Monitoring Committee (IDMC) will be 
convened for this study for safety and efficacy monitoring with expertise in COVID-19 or 
respiratory viruses and emerging epidemics as well as biostatistics. 
Changes in randomization strata: The protocol required an amendment after study start to 
address emergent and important issues at sites pertaining to screening and enrollment. The 
protocol amendment 1 modified the stratification factor of number of days since onset of 
symptoms at time of randomization by changing from <3 days vs. ≥3 days to <6 days vs. ≥6 
days. Eight participants (1.3%) out of the total planned 600 participants randomized were 
enrolled under original protocol Gates MRI-COD-01-T01-01 Version 4 dated 01 August 2020 
(randomized strata: <3 days vs. ≥3 days).  Combining data from the original protocol and 
amendment 1 for the pre-specified analyses preserves the double-blind nature of the treatment 
comparison contrast in the same way a patient-level meta-analysis does. Because participants 
were randomly assigned under both protocols, one can expect participants within each treatment 
arm to be comparable at baseline under each of the original and amendment 1 protocols. 
Analyses where participants are analyzed according to the stratum to which they were 
randomized under the original protocol or protocol amendment 1 are statistically the most 
appropriate (resulting in 4 total stratification levels); however, the number of participants 
randomized under the original protocol (randomized strata: <3 days vs. ≥3 days) is relatively 
very small [8 (1.3%) out of the total planned 600 participants].  Further, since the number of 
participants randomized to the ≥3 days stratum is extremely small (2 participants) statistical 
modelling using a randomization factor with 4 stratification levels may not be possible. Because 
of this, and the fact that it is unlikely that knowledge of the protocol version will meaningfully 
impact investigators and participants e.g., with respect to participant management, follow-up or 
endpoint reporting, it is proposed that participants randomized under the original protocol are 
mapped under the new strata <6 days vs. ≥6 days and analyzed accordingly. Specifically, the 6 


Adaptive Platform Trial 
Bill & Melinda Gates Medical Research Institute 
Statistical Analysis Plan: Gates MRI - COD-01-T01-01 
 23 February 2021
 
 
 
 
Confidential 
Page 10 of 39 
participants that were randomized to the <3 days strata will be assigned to the <6 days stratum 
and the 2 participants that were randomized to the ≥3 days stratum will be assigned to the <6 
days vs ≥6 days according to the actual number of days since symptom onset at the time of 
randomization.  As participants are not concurrently recruited for the two versions of the 
protocol and assignment to protocol version was not at random, analyses will be performed and 
reported separately for the original and amendment 1 protocols when possible to assess the 
similarity of the results.  
6.2 
Efficacy Measures 
Efficacy measures include the following: 
• Clinical status assessment using ordinal scale for Gates MRI 
• COVID-19 symptoms 
• Nasal sampling for SARS-Cov-2 diagnostic testing 
• Clinical status assessment using ordinal scale for WHO 
6.3 
Safety Measures 
Safety measures include AEs assessment, bleeding events and severity assessment. 
7 STUDY POPULATIONS 
7.1 
Analysis Populations 
An interim analysis was conducted on 28 January, 2021 using the data cut of 8 January, 2021. 
Efficacy interim analyses were produced based on the first 200 randomized participants who 
either had discontinued the study or had completed Day 28 in the ITT population. The interim 
efficacy primary endpoint result will be reported in the CSR using the data cut of 8 January, 
2021.  
IDMC’s recommendation that the clinical study be stopped impacts the efficacy evaluation for 
the  participants who were continuing in the study and had not yet reached Day 21 of the study 
(end of treatment period) as of 4 February, 2021. In order to have meaningful results of the final 
efficacy analyses, efficacy analyses will be performed on a final efficacy analysis set of 
participants who met either one the following criteria: 
• Completed or discontinued the study or progressed prior to 5 February, 2021. 
• Completed Day 21 or later visits as of 5 February, 2021.  
Final analysis will be conducted following database lock.  
• Efficacy analyses will be produced for randomized participants who meet the selection 
criteria described above and also meet the analysis population criteria described below.  
• Safety analyses will be produced for all participants in the database who received at least 
one dose of study intervention. 


Adaptive Platform Trial 
Bill & Melinda Gates Medical Research Institute 
Statistical Analysis Plan: Gates MRI - COD-01-T01-01 
 23 February 2021
 
 
 
 
Confidential 
Page 11 of 39 
Table 2: Analysis populations 
Population 
Description 
ITT Population  
All participants in the ITT population who met the criteria stated above. Participants 
will be analyzed according to the intervention to which they were randomized. 
mITT population 
All participants in the ITT population, who received the study interventiona and 
have mild disease at study entry. Participants will be analyzed according to the 
intervention they actually received.  
PP population 
All participants in the ITT population, who received the study interventions as 
planned, have mild disease at study entry, and did not substantially deviate from the 
protocol procedures. Participants will be analyzed according to the intervention they 
actually received. 
Safety population 
All participants randomly assigned to study intervention, who received the study 
intervention. Participants will be analyzed according to the intervention they actually 
received. 
7.2 
Assigning Shared Controls across Multiple Intervention-specific Analysis Populations  
Each intervention may be initiated and stopped at different time frames, and within different 
sites. Depending on the number of interventions that a participant can be eligible to receive, a 
participant randomized to a control arm may be part of multiple intervention-specific analysis 
populations for the purposes of comparing a single intervention to control. We note the following 
core principles associated with sharing controls across intervention-specific analysis populations: 
• Controls will only be shared across multiple intervention-specific populations when there 
is randomization across those interventions and the control. All participants will only be 
randomized once. 
• A participant who is eligible for multiple interventions at a site will be randomized 
equally to receive 1 of the interventions for which they are eligible vs control. 
Participants randomized to control will be equally likely to receive the matched control of 
each intervention for which they are eligible. If the participant is randomized to control, 
they will be assigned to each of the intervention-specific analysis populations included in 
the randomization. A participant randomized to control will not be assigned to an 
intervention-specific analysis population that was not included in the randomization. 
• Controls will only be shared contemporaneously. A participant can only be used in the 
intervention-specific population(s) that was available and included at the time of their 
randomization.  
• A control does not have to receive the intervention-specific matched control to be eligible 
for an intervention-specific population. For example, a participant randomized 1:1:1 to 
receive 2 available interventions vs control would serve as a control for each of the 
interventions regardless of the matched control assigned. The primary comparison will 
utilize eligible participants in the intervention-specific analysis population randomized to 
control, regardless of the specific intervention-specific matched control that was 
randomized. 


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Adaptive Platform Trial 
Bill & Melinda Gates Medical Research Institute 
Statistical Analysis Plan: Gates MRI - COD-01-T01-01 
 23 February 2021
 
 
 
 
Confidential 
Page 14 of 39 
8 CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL 
Not applicable.  
9 OVERALL STATISTICAL CONSIDERATIONS 
9.1 
Determination of Sample Size 
9.1.1 Efficacy 
The total number of participants planned to be enrolled is approximately 600 (300 per group). If 
the true control rate for progression to moderate or severe category or greater is at least 30%, 
294 participants per group will result in 80% power when the true study intervention effect is 
35% as a relative decrease of rate progression, i.e., a true rivaroxaban rate of progression of 
19.5% is 35% lower than that of a true placebo-control rate of progression of 30%. This sample 
size accounts for a drop-out rate of 10% and a 1-sided Type I error rate of 2.5%. To account for 
one planned interim futility analysis without adversely affecting the statistical power, the sample 
size was increased to 300 per group. 
9.1.2 Safety 
With 300 participants in the rivaroxaban intervention group, there is 80% probability to observe 
at least 1 SAE related to rivaroxaban when the true SAE rate is at least 0.54%. 
9.2 
General Conventions 
Frequency (n) and percentages (%) will be used to summarize categorical variables; mean, 
standard deviation (SD), median, minimum, and maximum will be used to summarize 
continuous variables.  
Decimal precision for summary statistics of continuous variables will be based on the mean 
value. Typically, the mean will contain 1 more decimal place than actual values but the decimal 
precision may vary in order to obtain an organized and understandable table or listing. The 
median will contain the same number of decimal places as the mean, the SD will contain 1 more 
decimal place than the mean, and the minimum and maximum will contain 1 less decimal place 
than the mean. 
Unless otherwise specified, the denominators for percentages will be the number of participants 
in each intervention group with non-missing data for the variable of interest.  
The day of receiving first dose of study intervention is defined as Study Day 1 or Day 1. All 
other study days will be computed relative to Day 1. For events on or after Day 1, study day for a 
particular event or visit will be calculated as Dateevent – DateDay 1 + 1. For events before Day 1, 
study day for a particular event will be calculated as Dateevent  – DateDay 1. Day 0 will not be used.  


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9.3 
Baseline definition 
Unless otherwise specified, Baseline is defined as the last non-missing assessment (scheduled or 
unscheduled) prior to the first dose. In the case where the last non-missing assessment and the 
first dose coincide (i.e., assessments on Day 1), that assessment will be considered 
pre-intervention (Baseline).  
9.4 
Stratification Factor 
The variable associated with the stratification factor of number of days since onset of symptoms 
at time of randomization [original protocol (<3 days or ≥3 days); protocol amendment 1 (<6 days 
or ≥6 days)] will be defined according to data from the IVRS/IWRS.  If there are any participants 
who are identified as being miss-stratified (i.e. randomized to the incorrect strata), a sensitivity 
analysis of the primary analysis will be carried out using the derived stratification variable for 
number of days since onset of symptoms at time of randomization. As discussed in section 6 
participants enrolled under the original strata will be analyzed under the derived stratification 
variable for number of days since onset of symptoms at time of randomization (<6 days or ≥6 
days). 
9.5 
Handling of Missing Data 
Missing and partial dates of prior and concomitant medications and adverse events will be 
imputed to determine the relationship between the start date of the event and the first dose date 
of study drug. The imputation rules provided in Appendices 2 and 3.  
Statistical methods to address missing data for efficacy endpoints are provided in Section 11. 
9.6 
Pooling Strategy for Study Sites 
Randomization will be stratified by site. Generally, all sites will be pooled by intervention for 
analysis purposes. Summaries by site will be included for relevant endpoints. Details are 
provided in the relevant sections. 
9.7 
Visit Windows/Unscheduled Visits 
Visit windowing in general will not be applied. Unscheduled visits will not be included in 
by-visit summaries or analysis, but may contribute to the Baseline value and worst post-baseline 
assessments. In the case of a retest (same visit number assigned), the latest available test result as 
provided in the data transfer for that visit/time point will be used for by-visit summaries. 
10 STATISTICAL ANALYSIS METHODS 
10.1 Subject Disposition 
All participants who provide informed consent will be accounted for in this study.  


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The number of participants screened, number of screening failures, and the number of 
participants randomized will be summarized for all screened participants per site and overall.  
The following disposition and withdrawals (including reasons for intervention and study 
discontinuation as provided on the eCRF) will be summarized by intervention group: 
• The number of participants who are randomized 
 The number of participants who are randomized and not treated 
 The number of participants who are randomized and treated 
• The number of participants who completed the intervention period 
• The number of participants who discontinued study intervention 
• The number of participants who completed the study 
• The number of participants who discontinued the study 
In addition, number and percentage of participants in each analysis population, reason(s) for 
exclusion from each analysis population and critical and major protocol deviations will be 
summarized and listed for the randomized analysis population.  
10.2 Demographics and Baseline Characteristics 
Demographic data and other baseline characteristics will be summarized using descriptive 
statistics only, for the ITT,  and Safety population. The denominators for percentages will be the 
number of participants in each intervention group with non-missing data available for the 
variable of interest.  
Explicitly the following characteristics will be summarized: 
• Age (years) 
• Age groups (<65 years, ≥65 years; and 18 to <35 years, 35 to <50 years, 50 to <65 years, 
65 to <75 years, ≥75 years) 
• Sex (Male, female) 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Mixed Race, Other, Unknown) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2)  
• BMI groups (<35 kg/m2, ≥35 kg/m2) 
BMI (kg/m2) will be calculated using the following formula: 


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𝐵𝐵𝐵𝐵𝐵𝐵= 
𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘)
ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡 (𝑚𝑚) × ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡 (𝑚𝑚) 
• Presence of comorbidities factors at randomization 
 Age (<65 years, ≥65 years) 
 Presence of chronic pulmonary disease, COPD, pulmonary hypertension (Yes, No) 
 Diabetes mellitus (type 1 or type 2) requiring medication or insulin (Yes, No) 
 Hypertension, requiring at least 1 oral medication for intervention (Yes, No) 
 Immunocompromised status due to disease (Yes, No) 
 Immunocompromised status due to medication (Yes, No) 
 Chronic disease associated with high risk for severe COVID-19 (Yes, No) 
 BMI groups (<35 kg/m2, ≥35 kg/m2) 
• Number of days since onset of symptoms at time of randomization [continuous and 
categorical: original protocol (<3 days or ≥3 days); protocol amendment 1 (<6 days or ≥6 
days); and across both protocol versions (<6 days or ≥6 days)] 
• Number of days since onset of symptoms at time of Day 1 [continuous and categorical: 
(<6 days or ≥6 days), where this is calculated as date of Day 1 – date of onset of 
symptoms + 1. 
• SARS-CoV-2 diagnostic test at Day 1 (Positive, Negative) 
• Gates MRI and WHO clinical assessment status at Day 1 (applicable categories) 
• Oxygen saturation at Day 1 
• COVID-19 signs and symptoms, participants with at least 2 symptoms, 3 symptoms, 
4 symptoms, etc. at Day 1. Categories will not be mutually exclusive (i.e., patients having 
at least 3 symptoms will also be summarized in the at least 2 symptoms category).  
• COVID-19 signs and symptoms at Day 1: each symptom (Yes, No) 
• Alcohol and non-medical illicit drugs use in the last month (Yes, No) 
10.3 Treatment Compliance and Exposure 
Treatment compliance and exposure will be summarized for the Safety population. 
Treatment compliance information for study drug will be collected through counts of remaining 
tablets in the bottle at the EOT or discontinuation of study drug. Compliance is computed as the 
number expected to be taken at time of EOT or discontinuation of study drug minus number 
remained +1 (as there is an extra tablet in a bottle) relative to the number expected to be taken 
will be summarized. The frequency and percentage of participants in each of the following 
categories will be presented: <50%, ≥50% and <75%, ≥75% and <100%, and >100% by study 
intervention group.  


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Any days that participants administered a dose of study drug will be tabulated for number of days 
exposure to study drug. Number of days exposure will be summarized as both continuous and 
categorical variables by study intervention group. For categorical presentation, the frequency and 
percentage of participants in each of the following categories will be presented: ≤7 days, 8 to 
≤14 days, 15 to ≤24 days. 
11 EFFICACY PARAMETERS 
The primary efficacy endpoint is the proportion of participants who progress to moderate or 
severe disease category or higher (Gates MRI ordinal scale ≥3) at any day through Day 28. 
Secondary efficacy endpoints include: 
• Time to disease resolution, defined as symptoms resolution only (new onset COVID-19 
symptoms resolved, and pre-existing symptoms returned to baseline) through Day 28  
• Time to disease resolution, defined as both viral clearance (two consecutive negative 
diagnostic tests) and symptoms resolution (new onset COVID-19 symptoms resolved, 
and pre-existing symptoms returned to baseline*) through Day 28 
• Proportion of participants who progress to moderate or severe disease category or higher 
(Gates MRI ordinal scale ≥3) at Days 8, 14, and 21 
• Proportion of participants who achieve disease resolution, defined as symptoms 
resolution only, at Days 8, 14, 21 and 28 
• Proportion of participants who achieve disease resolution, defined as both viral clearance 
and symptoms clearance, at Days 8, 14, 21 and 28 
• Gates MRI scale score at Days 8, 14, 21, and 28 
• WHO ordinal scale score at Days 8, 14, 21, and 28 
• Incidence of hospitalization through Days 8, 14, 21, and 28 
• Number of days of hospitalization through Days 8, 14, 21, and 28 
Exploratory endpoints include: 
• Quantity (and change from baseline) of SARS-CoV-2 virus at Days 8, 14, 21 and 28 
• Phylogenetic relationships of SARS-CoV-2 viruses sequenced from positive nasal swab 
samples 


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11.1 Primary Analysis 
11.1.1 Estimand 
The treatment policy estimand with respect to the primary efficacy objective is defined by the 
following: 
Population: Participants in the ITT population.  
Patient-level outcome: Binary outcome of progression to moderate or severe disease category or 
higher (Gates MRI ordinal scale ≥3) at any day through Day 28. 
Intercurrent events: The following intercurrent events to be taken into account: 
1. If a death occurs on or prior to Day 28, the participant will be considered as having 
progression to moderate or severe category (Gates MRI ordinal scale ≥3) through Day 28. 
2. If hospitalization occurs on or prior to Day 28, the participant will be considered as 
having progression to moderate or severe category (Gates MRI ordinal scale ≥3) through 
Day 28. 
3. If a participant is lost to follow-up on or prior to Day 28, the last observed Gates MRI 
ordinal scale status evaluation will be carried forward onward to Day 28. 
4. If a participant discontinues the study prior to initiation of IP dosing on Day 1 (for any 
reason: lost to follow-up, progression to moderate or severe COVID-19, withdrawal of 
consent) and no Gates MRI ordinal scale assessment is available, the participant will be 
considered as having progression to moderate or severe category (Gates MRI ordinal 
scale ≥3) through Day 28. 
Participants who discontinue study intervention will be followed at least until end of study, Day 
35. 
Population-level summary measure: Proportion of participants who progress to moderate or 
severe disease category or higher (Gates MRI ordinal scale ≥3) at any day through Day 28. 
The primary efficacy analysis will be conducted in the ITT population. Participants randomized 
to rivaroxaban will be compared to participants randomized to placebo. For the primary efficacy 
analysis, the following primary hypothesis will be tested: Prophylactic treatment with 
rivaroxaban will reduce progression to moderate or severe disease category or greater (Gates 
MRI ordinal scale ≥3) relative to placebo in high risk participants with mild COVID-19. 
The proportion of participants who have progression of COVID-19 at any time up to and 
including Day 28 and the corresponding 2-sided 95% CI, computed using the Mid-p method, 
will be summarized for the study intervention and control. The absolute difference in the risk of 
progression of COVID-19 and the corresponding 2-sided 95% CI will be assessed using the 


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stratified Miettinen and Nurminen method [Miettinen, 1985] with the Cochran-Mantel-Haenszel 
(CMH) weights [Lu, 2008], stratified by number of days since onset of symptoms at time of 
randomization (<6 days or ≥6 days). The point estimates and variance estimated for each stratum 
𝑗𝑗 using the Miettinen and Nurminen method are defined as  
𝑑𝑑̂𝑗𝑗= 𝑝𝑝̂1𝑗𝑗−𝑝𝑝̂2𝑗𝑗 
where 𝑝𝑝̂1𝑗𝑗 and 𝑝𝑝̂2𝑗𝑗 are the proportions of participants in rivaroxaban and placebo group who had 
progression of COVID-19 through Day 28, respectively, and   
𝑉𝑉𝑉𝑉𝑉𝑉
෪𝑗𝑗(𝛿𝛿) = (
𝑛𝑛𝑗𝑗
𝑛𝑛𝑗𝑗−1)(
𝑝𝑝෤1𝑗𝑗(𝛿𝛿) ቀ1 −𝑝𝑝෤1𝑗𝑗(𝛿𝛿)ቁ
𝑛𝑛1𝑗𝑗
+
𝑝𝑝෤2𝑗𝑗(𝛿𝛿) ቀ1 −𝑝𝑝෤2𝑗𝑗(𝛿𝛿)ቁ
𝑛𝑛2𝑗𝑗
)   
where 𝑛𝑛𝑗𝑗= 𝑛𝑛1𝑗𝑗+ 𝑛𝑛2𝑗𝑗, and 𝑝𝑝෤1𝑗𝑗(𝛿𝛿) and 𝑝𝑝෤2𝑗𝑗(𝛿𝛿) are the maximum likelihood estimates of 
rivaroxaban and placebo proportions under the restriction that the risk difference is 𝛿𝛿. For the 
hypothesis specified, 𝛿𝛿= 0. The maximum likelihood estimates of 𝑝𝑝1𝑗𝑗 and 𝑝𝑝2𝑗𝑗, subject to the 
constraint that the risk difference is 𝛿𝛿, are computed as 
𝑝𝑝෤1𝑗𝑗(𝛿𝛿) = 2𝑢𝑢 cos(𝑤𝑤) −𝑏𝑏/3𝑎𝑎   and   𝑝𝑝෤2𝑗𝑗(𝛿𝛿) = 𝑝𝑝෤1𝑗𝑗(𝛿𝛿) +  𝛿𝛿 
where 
𝑤𝑤= (𝜋𝜋+ cos−1(𝑣𝑣/𝑢𝑢3))/3 
𝑢𝑢= 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠(𝑣𝑣)ඥ𝑏𝑏2/(3𝑎𝑎)2 −𝑐𝑐/3𝑎𝑎 
𝑣𝑣= 𝑏𝑏3/(3𝑎𝑎)3 −𝑏𝑏𝑏𝑏/6𝑎𝑎2 + 𝑑𝑑/2𝑎𝑎  
𝑎𝑎= 1 + 𝜃𝜃 
𝑏𝑏= −(1 + 𝜃𝜃+ 𝑝𝑝̂1𝑗𝑗+ 𝜃𝜃𝑝𝑝̂2𝑗𝑗+ 𝛿𝛿(𝜃𝜃+ 2)) 
𝑐𝑐= 𝛿𝛿2 + 𝛿𝛿൫2𝑝𝑝̂1𝑗𝑗+ 𝜃𝜃+ 1൯+ 𝑝𝑝̂1𝑗𝑗+  𝜃𝜃𝑝𝑝̂2𝑗𝑗 
𝑑𝑑= −𝑝𝑝̂1𝑗𝑗𝛿𝛿(1 + 𝛿𝛿) 
𝜃𝜃= 𝑛𝑛2𝑗𝑗/𝑛𝑛1𝑗𝑗 
The CMH weights will be used to combine the point estimates and variance estimates that are 
calculated within each stratum using the Miettinen and Nurminen method.  
𝑑𝑑̂ = ෍𝑤𝑤𝑗𝑗
𝑗𝑗
𝑑𝑑̂𝑗𝑗 
𝑉𝑉𝑉𝑉𝑉𝑉
෪(𝛿𝛿) = ෍𝑤𝑤𝑗𝑗
2
𝑗𝑗
𝑉𝑉𝑉𝑉𝑉𝑉
෪𝑗𝑗(𝛿𝛿) 
where CMH weights, 𝑤𝑤𝑗𝑗, are defined as 


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𝑤𝑤𝑗𝑗= 𝑊𝑊𝑗𝑗/ ෍𝑊𝑊𝑘𝑘
𝑘𝑘
 
where  
𝑊𝑊𝑗𝑗= ቆ1
𝑛𝑛1𝑗𝑗
+ 1
𝑛𝑛2𝑗𝑗
ቇ
−1
 
A score-based test statistic for the null hypothesis is that the risk difference equals δ can be 
expressed as 
𝑍𝑍(𝛿𝛿) = (𝑑𝑑̂ −𝛿𝛿)/ට𝑉𝑉𝑉𝑉𝑉𝑉
෪(𝛿𝛿) 
The 95% confidence interval for the risk difference consists of all values of δ for which the score 
test statistic 𝑍𝑍൫𝛿𝛿̂𝐿𝐿൯= 𝑧𝑧1−𝛼𝛼/2 and 𝑍𝑍൫𝛿𝛿̂𝑈𝑈൯= −𝑧𝑧1−𝛼𝛼/2, where 𝑧𝑧1−𝛼𝛼/2 is the (1 −𝛼𝛼/2) percentile of 
the standard normal distribution, and 𝛿𝛿̂𝐿𝐿denotes the lower limit and 𝛿𝛿̂𝑈𝑈 denotes the upper limit. 
For participants who are lost to follow-up prior to Day 28, the last disease status evaluation will 
be used as last observation carried forward to Day 28 to address the missing visit data in the 
primary analysis.   
11.1.2 Sensitivity Analyses 
To assess the robustness of the primary results, analyses will be repeated for the primary analysis 
using the mITT and PP populations.  
Sensitivity analysis will be performed according to their derived actual strata instead of the 
randomized strata. 
In case any participants use any prohibited concomitant use of medication prior to treatment 
discontinuation and day 28, they will be flagged as significant protocol deviations and excluded 
from the per-protocol efficacy analyses. 
11.1.3 Subgroup Analysis 
In order to assess the consistency of treatment benefit with respect to the primary efficacy 
endpoint, forest plots and summary tables will be provided for the following subgroups: 
• Race (White, Black, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Sex (Male, Female) 
• Number of days since onset of symptoms at time of randomization (<6 days or ≥6 days)  


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• Comorbidities and risks consist of the following:  
 Age (<65 years, ≥65 years) 
 Presence of chronic pulmonary disease, COPD, pulmonary hypertension (Yes, No) 
 Diabetes mellitus (type 1 or type 2) requiring medication or insulin (Yes, No) 
 Hypertension, requiring at least 1 oral medication for intervention (Yes, No) 
 Immunocompromised status due to disease or medication (Yes, No) 
 Chronic disease associated with high risk for severe COVID-19 (Yes, No) 
 BMI groups (<35 kg/m2, ≥35 kg/m2) 
11.2 Secondary Analysis 
Secondary analyses will be conducted in the ITT population. Sensitivity analyses of secondary 
analyses will be performed using the mITT and PP populations, to assess the robustness of the 
secondary results. 
11.2.1 Estimand 
The treatment policy estimand with respect to the secondary efficacy objective is defined for the 
key secondary endpoints by the following: 
Population: Participants in the ITT population. 
Patient-level outcome: Time to disease resolution through day 28. 
Intercurrent events: The following intercurrent events to be taken into account: 
1. If a death occurs prior to Day 28, the participant will be considered as not having disease 
resolution through Day 28 (i.e., censored at Day 28).  
2. If a participant is lost to follow-up prior to Day 28, the participant will be considered as 
not having disease resolution and will be censored at the time of lost to follow-up. 
3. If a participant discontinues the study [for any reason: lost to follow-up, progression to 
moderate or severe COVID-19 (or worse), withdrawal of consent] prior to initiation of IP 
dosing on Day 1 and no symptoms resolution assessment is available, the participant will 
be considered as not having disease resolution and will be censored on Day 1. 
Participants who discontinue study intervention will be followed at least until end of study, Day 
35. 
Population-level summary measure: Median time to disease resolution. 


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11.2.2 Disease Resolution 
11.2.2.1 Time to Disease Resolution (Symptoms Resolution) 
Disease resolution is defined as symptoms resolution (new onset coronavirus disease 2019 
(COVID-19) symptoms resolved, and pre-existing symptoms returned to baseline) through Day 
28. For the time to disease resolution analysis, the following hypothesis will be tested: 
prophylactic treatment with rivaroxaban will increase the rate of time to disease resolution 
relative to placebo in high risk participants with mild COVID-19.  
Time to disease resolution is defined as the time from first dose to the date of symptoms 
resolution (as determined by the investigator: has the participant’s COVID-19 signs and/or 
symptoms resolved or returned to baseline). The following rules (Table 3) will be used to define 
time to disease resolution:  
Table 3: Censoring rules for time to disease resolution.  
Situation 
Outcome 
Date of event/censoring 
Death for any reason 
Censored 
Day 28 
Discontinued prior to Day 28 without disease resolution 
Censored 
Date of last disease resolution assessment 
No disease resolution through Day 28 
Censored 
Day 28 
Randomized, treated but no post-baseline assessments available 
Censored 
Day 1 
Disease resolution through Day 28 
Event 
Initial date of last sequence of consecutive disease resolution. 
Discontinued prior to Day 28 with disease resolution at last 
assessment 
Event 
Initial date of last sequence of consecutive disease resolution. 
Randomized, not treated 
Censored 
Date of randomization 
*sequence = a series of one or more disease resolutions with no progression. 
Example scenarios are included in Table 4 for reference. 
Table 4: Example scenarios for time to time to disease resolution.  
Time point 
Day 
1 
Day  
4 
Day  
6 
Day 
8 
Day 
10 
Day 
12 
Day 
14 
Day 
18 
Day 
21 
Day 
24 
Day 
28 
 
Endpoint 
Participant 1 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
No DR, censored at Day 28 
Participant 2 
N 
Y 
N 
N 
N 
N 
Died 
 
 
 
 
No DR, censored at Day 28 
Participant 3 
N 
Y 
Y 
N 
N 
N 
Disc. 
 
 
 
 
No DR, censored at Day 12 
Participant 4 
N 
Y 
N 
N 
N 
Y 
Y 
Y 
Y 
Y 
N 
DR at Day 12* 
Participant 5 
N 
Y 
Y 
N 
N 
Y 
Y 
Y 
Disc. 
 
 
DR at Day 12 
Participant 6 
N 
N 
Y 
Y 
N 
N 
Y 
Y 
Y 
Y 
Y 
DR at Day 14 
Participant 7 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
Y 
DR at Day 28 
Participant 8 
N 
N 
N 
N 
N 
Y 
Y 
Y 
Y 
N 
N 
No DR, censored at Day 28**  
Participant 9 
N 
Y 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
DR at Day 4  
Participant 10 
N 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
No DR, censored at Day 1 
Participant 11 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
DR at Day 1 
Participant 12 
N 
Y 
N 
N 
N 
Y 
Y 
N 
Disc. 
 
 
No DR, censored at Day 18 
* Due to consecutive days with disease resolution and followed by a day with no disease resolution as the last assessment. 
**Due to consecutive days with no disease resolution occur after days with disease resolution. 
DR = disease resolution. N=no; Y=yes. NA=Not available.  
For time to disease resolution, a stratified 1-sided log-rank test, stratified by number of days 
since onset of symptoms at time of randomization (<6 days or ≥6 days), will be used to compare 
between the study intervention and control. The Kaplan-Meier method will be used to obtain the 
estimates of medians with the associated 2-sided 95% CIs of time to disease resolution, 


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computed using Brookmeyer and Crowley method. A stratified Cox proportional hazards model, 
stratified by number of days since onset of symptoms at time of randomization (<6 days or ≥6 
days) will be used to estimate the hazard ratio and the corresponding 2-sided 95% CI associated 
with the rate of disease resolution for the study intervention relative to control.  
Due to anticipated heterogeneity in the rate of disease resolution, pre-specified baseline 
variables, including age and BMI will be included in the model to increase precision. Including 
time-dependent variables, i.e., log(time)-by-variables interactions, to the model to fit a stratified 
Cox non-proportional hazards model to assess the proportional hazards assumption. If the 
coefficients for the time-dependent variables are not statistically different from zero based on a 
chi-square test with 1 degree of freedom would suggest that proportional hazards assumption is 
adequate for all variables included in the model. 
11.2.2.2 Time to Disease Resolution (Symptoms Resolution and Viral Clearance) 
Time to disease resolution that is defined as both viral clearance (two consecutive negative 
diagnostic tests) and symptoms resolution (new onset COVID-19 symptoms resolved, and 
pre-existing symptoms returned to baseline) through Day 28 will be analyzed as similarly to that 
described for time to disease resolution that is defined as symptoms resolution. Participants who 
have completed Day 21 visit but not Day 35 visit and did not have two consecutive negative tests 
at the time of study stop will be censored at the time of their last visit. 
11.2.2.3 Subgroup Analysis 
Analysis of key secondary endpoints will be repeated for the subgroups as specified in Section 
11.1.3. Forest plots will be provided.  
11.2.3 Proportion of Participants with Disease Resolution 
The proportions of participants who achieve disease resolution defined as symptom resolution at 
Days 8, 14, 21, and 28 will be summarized for the study intervention and control. The 2-sided 
95% CI for the proportion will be computed using the Mid-p method. The absolute difference in 
the proportion and the corresponding 2-sided 95% CI of participants achieving disease resolution 
defined as symptom resolution at any time up to and including Days 8, 14, 21, and 28 between 
the study intervention and control will be assessed using the stratified Miettinen and Nurminen 
method, stratified by number of days of symptoms at time of randomization (<6 days or ≥6 
days). 
In addition, the proportions of participants who achieve disease resolution defined as symptom 
resolution and viral clearance (2 consecutive negative diagnostic tests) at any time up to and 
including Days 8, 14, 21, and 28 will be summarized and analyzed as similar to that described 
for the proportions of participants who achieve disease resolution defined as symptom resolution 
only. 


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11.2.4 Disease Progression of COVID-19 
The proportion of participants who progress to moderate or severe disease category or higher 
(Gates MRI ordinal scale ≥3) at any time up to and including Days 8, 12, and 21 will be 
summarized and analyzed for the study intervention and control as similar to that described for 
proportion of participants who progress to moderate or severe disease category or higher through 
Day 28. 
11.2.5 Gates MRI Scale Scores 
Table 5: Gates MRI Ordinal Scale Clinical Endpoint Definitions 
Scale 
Category 
Endpoint definition 
1 
Asymptomatic/symptoms 
similar to pre-COVID-19 status 
• 
No symptoms and signs AND 
• 
No limitation of daily activities 
2 
Mild 
• 
Symptomatic AND 
• 
No shortness of breath AND 
• 
No hypoxemia (O2 saturation ≥94% in ambient air)  
3 
Moderate or severe 
• 
Symptomatic AND 
• 
Shortness of breath* OR tachypnea (respiratory rate  
≥20 min)* OR hypoxemia (<94% in ambient air)* 
4 
Critically ill 
• 
 Symptomatic AND 
• 
Receiving high flow oxygen OR non-invasive mechanical 
ventilation 
5 
Critically ill with invasive 
mechanical ventilation or extra 
pulmonary complication 
• 
Symptomatic AND 
• 
Receiving invasive mechanical ventilation OR Life threatening 
or debilitating extra pulmonary complications 
6 
Critically ill with Extra-
Corporeal Membrane 
Oxygenation (ECMO) 
• 
Symptomatic AND 
• 
Receiving ECMO  
7 
Death 
• 
Death 
*For known COPD participants, moderate or severe category requires worsening of shortness of breath or medical or oxygen 
saturation from pre-COVID-19 status.  
The distributions of the Gates MRI ordinal scale scores (defined as in Table 5) will be 
summarized by day and treatment group. Stacked bar plots presenting the proportion of 
participants in each category of Gates MRI ordinal scale at Days 8, 14, 21, and 28 for each 
treatment group will be provided. 
11.2.6 WHO Ordinal Scale Scores 
Table 6: WHO Ordinal Scale for Assessment of Clinical Status of COVID-19 Patients 
Participant Status 
Descriptor 
Scale 
Uninfected 
Uninfected; no viral RNA detected 
0 
Ambulatory mild disease 
Asymptomatic; viral RNA detected 
1 
Symptomatic; independent 
2 
Symptomatic; assistance needed 
3 
Hospitalized moderate 
disease 
Hospitalized; no oxygen therapy* 
4 
Hospitalized; oxygen by mask or nasal prongs 
5 


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Hospitalized severe disease 
Hospitalized; oxygen by NIV or high flow 
6 
Intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 
≥200 
7 
Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or 
vasopressors 
8 
Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or 
ECMO 
9 
Dead 
Dead 
10 
WHO clinical progression scale; WHO Working group [WHO(c), 2020] 
ECMO=extracorporeal membrane oxygenation;  FiO2=fraction of inspired oxygen; 
NIV=non-invasive ventilation; pO2=partial pressure of oxygen; RNA = ribonucleic acid; SpO2=oxygen saturation.  
*If hospitalized for isolation only, record status as for ambulatory patient. 
WHO ordinal scale scores (as defined in Table 6) will be summarized and analyzed for overall 
burden of disease and disease severity as similar to that described for Gates MRI scale scores. 
For the purposes of evaluating the disease severity using the proportional odds model, the 
log-odds of the cumulative probability of the WHO ordinal scale score ≤3 is modeled. 
11.2.7 Incidence of Hospitalization 
The proportion of hospitalized participants at any time up to and including Days 8, 14, 21, and 
28 will be summarized for the study intervention and control with the corresponding 2-sided 
95% CIs computed using the Mid-p method. The risk ratios and the corresponding 2-sided score 
95% CIs associated with the incidence of hospitalization for the study intervention relative to 
control at any time up to and including Days 8, 14, 21, and 28 will be assessed using the 
stratified CMH method, stratified by number of days of symptoms at time of randomization (<6 
days or ≥6 days). 
11.2.8 Number of Days of Hospitalization 
Number of days of hospitalization will be summarized using descriptive statistics by treatment 
group and number of days of symptoms at time of randomization (<6 days or ≥6 days). 
11.3 Exploratory Analysis 
11.3.1 SARS-CoV-2 Diagnostic Test 
Proportion of participants having negative or positive SAR-CoV-2 diagnostic test will be 
summarized by treatment group and days since onset of symptoms at time of randomization (<6 
days or ≥6 days) at Days 1, 4, 8, 14, 21, and 28. For computing percentages, the denominator 
will be the number of participants with a test outcome available or indicated as not done in CRF 
for a specific group and visit. 
11.3.2 Cycle Threshold Value of SARS CoV-2 Test.  
Cycle threshold value (Ct) is the number of cycles in an RT-PCR assay needed to amplify viral 
RNA to reach detectable level. Low Ct value represents the number of cycles in an RT-PCR 
assay needed to amplify viral RNA to reach a detectable level; with lower Ct values reflective of 


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higher viral levels. Ct will be summarized using descriptive statistics by treatment group and 
number of days since onset of symptoms at time of randomization (<6 days or ≥6 days) at Days 
1, 4, 8, 14, 21, and 28. 
Viral sequencing may be used to assess the phylogenetic relationships between SARS-CoV-2 
viruses obtained from positive nasal swab samples. Phylogenetic trees will be generated to 
determine whether participants were part of a transmission cluster. The aforementioned analyses 
may be performed upon availability of SARS CoV-2 viral load data.  
11.4 Independent Data Monitoring Committee 
The purpose of the IDMC is to monitor the study for safety and efficacy. The IDMC may request 
additional information, or a pause in recruitment and dosing, while safety data are being 
evaluated. 
The IDMC will operate according to a charter and the structure, participants, meeting 
information and other details will be provided in the charter. The charter will be available prior 
to study start.  
The IDMC will meet monthly or ad hoc, if necessary, to review safety data, and may request 
additional information, or a pause, while safety data are being evaluated. All procedures 
associated with this review will be documented. 
The IDMC will review the pausing guidelines that are put in place to address medical events 
necessitating a pause in enrollment and in participant dosing, and trigger IDMC reviews. 
Therefore, these guidelines are in effect during the active enrollment and dosing period. Any of 
the below conditions, if identified either by the study staff, investigator, the Sponsor or the 
IDMC, will trigger a pause of the enrollment and pause of administration of study intervention 
until the IDMC has reviewed the safety data and made a recommendation on how to proceed: 
1. One report of anaphylaxis with or without bronchospasm within 4 hours of taking study 
intervention indicative of an immediate hypersensitivity reaction to the study intervention. 
2. One report of major bleeding judged as related to study intervention by the investigator. 
This sponsor will set up a proper firewall to ensure that those blinded are insulated from 
knowledge of unblinded interim results. Participants and study staff evaluating them will not be 
aware of the assigned treatment groups. The laboratories performing the SARS-CoV-2 
diagnostic testing will be blinded. Sponsor will be blinded throughout the study conduct. 
11.5 Group Sequential Design 
11.5.1 Interim Analyses 
An interim analysis will only include participants who have been lost to follow-up or who have 
completed 28 days of follow-up at the time of the data cut. A 2-stage  group sequential design 


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will be used to assess futility at the interim analysis using a Hwang-Shih-DeCani beta spending 
function at 33% of the information.  If the trial does not cross the pre-specified boundaries to 
declare futility at the interim analysis, a final efficacy and safety analysis will occur after all 
participants complete the study Day 35 of follow-up. The predefined gamma parameter used will 
be -4 for futility, which is similar to the boundaries from the O’Brien-Fleming method (O’Brien, 
1979). The lower bound for futility will be binding. 
Table 7 displays the Hwang-Shih-DeCani boundary information for the group sequential design 
with an interim analysis for futility after approximately 200 participants complete Day 28  and a 
final analysis for efficacy and safety after  600 participants completed Day 35.  The actual 
boundaries used will be based on the Hwang-Shih-DeCani spending functions that reflect the 
actual number of participants (i.e., the actual proportion of the information) included at the time 
of the interim analysis.  
Table 7: Example of Alpha and Binding Beta Boundaries 
Boundary Information (p-Value Scale) [EAST 6 (Version 6.5)]  
Binding Beta Boundary 
Stage 
Information Level 
Boundary p-values 
Proportion 
Number of Participants 
Alpha 
Binding Beta  
Interim 1 
0.3333 
200 
NA 
0.7550 
Final 
1.0000 
600 
0.0250 
0.0250 
If the test statistic of the interim analysis for the primary endpoint crosses the pre-specified 
binding futility boundary to declare futility, the study will stop enrollment, but will continue 
following those enrolled participants until study completion.  The study will not be evaluated for 
efficacy at the interim analysis.   
11.5.1.1 
Stopping Probabilities Under Various Hypothetical References 
The study design allows early stopping for futility probabilities under various hypothetical 
“harm” or “equal” scenarios; examples are included below using EAST 6 (Version 6.5) (number 
of simulations=10,000, seed=6547): 
• “harm” scenario 1: If the true rivaroxaban rate of progression is 35% and the true control 
rate is 30%, the probability of stopping early for futility is 50.2%  at the interim analysis.  
• “harm” scenario 2: If the true rivaroxaban rate of progression is 19.5% and the true 
control rate is 15%, the probability of stopping early for futility is 51.6%  at the interim 
analysis. 
• “equal” scenario 1: If the true rivaroxaban rate of progression is 30% and the true control 
rate is 30%, the probability of stopping early for futility is 25.5% at the interim analysis.  
• “equal” scenario 2: If the true rivaroxaban rate of progression is 15% and the true control 
rate is 15%, the probability of stopping early for futility is 23.0% at the interim analysis. 


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12 SAFETY AND TOLERABILITY 
Safety analyses will be conducted in the safety population. Safety outcomes will include: 
• Grade 3 AEs 
• Grade 4 AEs 
• AEs resulting in study intervention discontinuation 
• SAEs 
• AESIs (including major bleeding and severe hypersensitivity to rivaroxaban) 
12.1 Adverse Events 
AEs will be coded using MedDRA version 22.1 or higher. AE severity will be graded as Grade 1 
(Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Potentially Life-threatening), or Grade 5 
(Death) as referencing to the specific toxicity grading by Division of Acquired 
Immunodeficiency Syndrome (DAIDS) AE Grading Table [DAIDS 2017].  
AEs starting on or after first day of study intervention will be considered as treatment-emergent. 
Only AEs within the reporting window will be included within the relevant category in summary 
tables. All AEs will be listed, regardless of if it was reported within the applicable reporting 
window.  
An AE overview table containing the frequency and percent of participants in each of the 
following categories (summarized by intervention group) and also the 95% CI (calculated for a 
single proportion using the Mid-p method): 
• Any AE 
• Related AEs  
• Grade 3 AEs 
• Grade 4 AEs 
• AEs resulting in study intervention discontinuation  
• SAEs 
• AEs with outcome of death 
• AESIs (including major bleeding and severe hypersensitivity to rivaroxaban) 
Additionally, the following will be summarized by SOC and PT for each intervention group: 
• Incidence of AEs 
• Incidence of related AEs  


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• Incidence of Grade 3 AEs 
• Incidence of Grade 4 AEs 
• Incidence of AEs resulting in study intervention discontinuation  
• Incidence of SAEs 
• Incidence of AEs with outcome of death 
• Incidence of AESIs 
Summaries of SOC and PT will be sorted alphabetically by SOC and by decreasing frequency of 
PT in the intervention group. If a participant has more than 1 AE at a given level (e.g., SOC and 
PT), the participant will only be counted once within that level.  
Missing severities and relationship will not be regarded as ‘worst case’. 
Incidences of Grade 3 AEs, Grade 4 AEs, and AEs resulting in study intervention discontinuation 
will be summarized by subgroups.  
• Race (white, black, other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Sex (male, female) 
• Number of days since onset of symptoms at time of randomization (<6 days or ≥6 days) 
• Presence of comorbidities/risks  
 Age (<65 years, ≥65 years) 
 Presence of chronic pulmonary disease, COPD, pulmonary hypertension (Yes, No) 
 Diabetes mellitus (type 1 or type 2) requiring medication or insulin (Yes, No) 
 Hypertension, requiring at least 1 oral medication for intervention (Yes, No) 
 Immunocompromised status due to disease or medication (Yes, No) 
 Chronic disease associated with high risk for severe COVID-19 (Yes, No) 
 BMI groups (<35 kg/m2, ≥35 kg/m2) 
13 OTHER RELEVANT DATA ANALYSES/SUMMARIES 
13.1 Medical History 
Medical history will be coded using MedDRA version 22.1 or higher. Medical history will be 
summarized by SOC and PT by intervention group for the Safety population and listed for the 
randomized population. Summaries of SOC and PT will be sorted alphabetically by SOC and by 
descending frequency of PT in the rivaroxaban group. If a participant has more than 1 medical 


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history even at a given level (e.g., SOC and PT), the participant will only be counted once within 
that level. A listing of medical history will also be presented.  
No imputation of partial or missing dates will be performed for medical history and study days 
will not be presented for these cases. 
13.2 Prior and Concomitant Medications 
Medications will be coded using the WHO Drug Global Mar2019 or later version. A prior 
medication is defined as a medication with a stop date before the first dose date. A concomitant 
medication is defined as a medication with a stop date on or after the first dose date, thus a 
medication that is ongoing at the time of a participant receiving study intervention is considered 
concomitant. Partial and missing dates for concomitant medications will be imputed using the 
guidance in Appendix 2. The recorded partial/missing dates will be displayed in the listings and 
study days will not be presented for these cases. 
Medications will be summarized by ATC level 3 and preferred name by intervention group for 
the Safety population. Summaries of ATC levels 3 and preferred name will be sorted 
alphabetically by ATC level 3 and by decreasing frequency of preferred name in the rivaroxaban 
group. If a participant has more than 1 medication at a given level, the participant will only be 
counted once at that level.  Separate summaries for prior and concomitant medications will be 
provided. 
 
 


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14 REFERENCES 
1. Lu, K, Cochran-Mantel-Haenszel Weighted Miettinen & Nurminen Method for Confidence 
Intervals of the Difference in Binomial Proportions from Stratified 2×2 Samples, American 
Statistical Association, Alexandria, VA: ASA Proceedings of the Joint Statistical Meetings, 
2008;3888-93. 
2. Miettinen O, Nurminen M. Comparative analysis of two rates.1985;4(2):213-226. 
https://doi.org/10.1002/sim.4780040211. 
3. O’Brien, PC, Fleming, TR. A Multiple Testing Procedure for Clinical Trials. Biometrics. 
1979;35:549-56. 
4. WHO(c). Clinical management of severe acute respiratory infection when novel coronavirus 
(2019-nCoV) infection is suspected: interim guidance, 28 January 2020. World Health 
Organization. https://apps.who.int/iris/handle/10665/330893. 
5. East 6 (Version 6.5). Statistical software for the design, simulation and monitoring clinical 
trials. Cytel Inc., Cambridge MA. 
6. Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes 
of Health US Department of Health and Human Services (DAIDS) Regulatory Support 
Center. 2017. Table for grading the severity of adult and pediatric adverse events. Corrected 
version 2.1. https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. 
 
 


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15 APPENDICES 
Appendix 1 
 
Schedule of Assessments and Procedures 
Visits 
Screening  
(≤5 days of 
Day 1) 
Day 
1 
Day 
4 
Day 
6 
Day 
8 
Day 
10 
Day 
12 
Day 
14 
Day 
18 
Day 
21 
Day 
24 
Day 
28 
Day 
35 
Obtain consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, past and 
current medical history 
including known 
pregnancy/lactation status, 
and medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Lab-confirmed SARS-CoV-2 
positive diagnostic testing1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention dose 
(Day 1 Day 21) and record 
adherence to dosing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinical status assessment 
using ordinal scales for Gates 
MRI and WHO 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
COVID-19 signs and 
symptoms, temperature, 
oxygen saturation  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bleeding events and severity 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Self-collection of nasal or 
oropharynx SARS-CoV-2 
sample for diagnostic testing3 
(X)1 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Note that visits will preferably take place remotely. 
SARS-CoV-2= Severe acute respiratory syndrome coronavirus 2 
Gates MRI= Bill & Melinda Gates Medical Research Institute 
WHO = World Health Organization 
1 If there is documented positive SARS-CoV-2 diagnostic testing performed with a sample collected ≤10 days prior to 
screening, the test does not need to be performed. If no documentation, the potential participant will be asked to collect a nasal 
or oropharynx swab sample to send for testing. 
2 If documentation of a previous positive SARS-CoV-2 test is not available and a test is performed at screening, randomization 
will occur after a positive result is obtained. 
 3 Participant will be asked to collect a sample per kit instructions. Discontinue collection during hospitalization and/or per 
physician’s discretion when two consecutive negative results are available at any time during the study.  
Note that an unscheduled visit may be required. Additional collection of a nasal swab sample may be performed based on the 
clinical judgement of the PI. 
   
 
 


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Appendix 2 
 
Prior and Concomitant Medications Date Imputation 
Imputation Rules for Partial Dates (D=day, M=month, Y=year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start Date 
D only 
M and Y same as M and Y of date of 
treatment 
Date of treatment 
 
 
M and/or Y not the same as date of 
treatment 
First day of month 
 
M and D 
Y same as Y of date of treatment 
Date of treatment 
 
 
Y not the same as date of treatment 
Jan 01 of Y 
 
M, D, and Y 
Non-date completely missing 
Day prior to date of treatment 
Stop Date 
D only 
M and Y same as M and Y of date of 
discontinuation/completion of study 
Date of discontinuation/ 
completion of study  
 
 
M and/or Y not the same as date of 
discontinuation/completion of study 
Last day of month 
 
M and D 
Y same as Y of date of 
discontinuation/completion of study 
Date of discontinuation/ 
completion of study 
 
 
Y not the same as date of 
discontinuation/completion of study 
Dec 31 of Y 
 
M, D, and Y 
None – date completely missing and 
NOT ongoing 
Date of discontinuation/ 
completion of study 
 
 


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Appendix 3 
 
Adverse Events Dates Imputation 
Date 
Situation 
Imputation Rule 
AE Start Date 
Only month and year are known and 
month is prior to first dose date  
Use the first day of the month 
Only month and year are known and 
month is the same as first dose date 
Use the first dose date 
Only month and year are known and 
month is after first dose date 
Use the first day of the month 
Only year is known and year is after first 
dose date 
Use Jan 1 of that year 
AE End Date 
Only month and year are known and 
month is prior to last dose date  
Use the last day of the month 
Only month and year are known and 
month is the same as last dose date 
Use the last dose date 
Only month and year are known and 
month is after last dose date 
Use the first day of the month 
Only year is known and year is before 
last dose date 
Use Dec 31 of that year 
The estimated stop date is before a 
complete or imputed AE start date 
Use the last day of the month of 
the AE start date 
AE = adverse event 
Note: The imputation of end date must be later than start date. 
 
 


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Appendix 4 
 
SAS Code 


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Appendix 5 
 
Document History 
DOCUMENT HISTORY 
Document 
Date 
Original SAP (Version 1.1): 
14 Dec 2020 
Amendment 1 (Version 1.2) 
27 Jan 2021 
Amendment 2 (Version 2.0) 
11 Feb 2021 
Changes in Version 1.2: 
Following protocol Version 4, Amendment 2, the SAP was revised to match the protocol 
changes as follows: 
• 
The second interim analysis is removed from the group sequential design. The first 
interim analysis will be used to assess futility and the final analysis will be used to assess 
efficacy and safety. 
• 
The Hwang-Shih-DeCani spending function is re-computed for a group sequential design 
that plans for one interim analysis to assess futility and a final analysis to assess efficacy 
and safety. 
• Re-computing the stopping probabilities under various hypothetical references based on 
the revised group sequential design. 
Changes in Version 2.0: 
The Gates MRI-COD-01-T01 was discontinued early on February 4, 2021 based on the 
recommendation of the IDMC after reviewing the interim data on January 28 and February 3, 
2021. Changes to efficacy analyses to account for participants who discontinued study 
intervention due to study discontinuation.  
• Define final efficacy population for final efficacy analyses 
• Omit sensitivity analyses #1 through #3 for the primary endpoint 
• Omit summary tables of subgroup analyses for the key secondary endpoints 
• Omit sensitivity analysis of applying different censoring rule for time to event analysis 
of the key secondary endpoints 
• Omit proportional odds model for COVID-19 clinical status measured by Gates MRI 
ordinal scale 
• Omit MMRM analysis of Gates MRI ordinal scale 


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• Omit ANCOVA of overall burden of disease based on Gates MRI ordinal scale 
• Omit ANCOVA of maximum post-baseline Gates MRI score 
• Omit proportional odds model for COVID-19 clinical status measured by WHO ordinal 
scale 
• Omit MMRM analysis of WHO ordinal scale 
• Omit ANCOVA of overall burden of disease based on WHO ordinal scale 
• Omit ANCOVA of maxium post-baseline WHO score 
• Omit negative binomial model for number of days of hospitalization 
• Omit linear mixed effects model for cycle threshold values of SAR CoV-2 diagnostic 
test