Clinical trial NCT04650087
Conditions: Covid19
Sponsor: Thomas L. Ortel
Start date: 2021-02-15; Completion date: 2022-09-23
Enrollment: 1291 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A multicenter, adaptive, randomized platform trial evaluating the efficacy and safety of antithrombotic strategies in patients with COVID-19 following hospital discharge

Detailed description:
This study is an adaptive, prospective, randomized platform trial designed to compare the effectiveness and safety of antithrombotic therapy with no antithrombotic therapy after hospitalization for 48 hours or longer for COVID-19. For Stage 1 of this study, participants will be randomized to either prophylactic anticoagulation or matching placebo for 30 days, and then followed for an additional 60 days after the completion of treatment (total duration of follow-up, 90 days).

The primary objective is to determine the most effective and safe antithrombotic strategy to prevent the composite outcome of symptomatic deep vein thrombosis, pulmonary embolism, other venous thromboembolism, ischemic stroke, myocardial infarction, other arterial thromboembolism, and all-cause mortality by 30 days following discharge from the hospital.

Biobanking of samples for future biomarker and mechanistic studies will be available for centers able to participate and collect samples from eligible participants. Samples will be collected at the time of enrollment and after the completion of 30 days of therapy

Arms: arm 1: Drug: Apixaban 2.5 MG Participants will be given study medication at the time of discharge from the hospital. Participants will take Apixaban 2.5 MG twice a day, once in the morning and once in the evening, for 30 days. Participants will be contacted (electronic or telephone) 2 days after starting the study medication and contact will continue up to day 90 after starting study treatment. Follow up will be through electronic and/or telephone contact depending on the participant's preference, compliance, and medication adherence. Participants will be queried for any clinically relevant endpoints, especially major bleeding or a need to seek healthcare attention for any reason. Follow-up will occur from the time of discharge and through the 30 day study period, with contacts 2 days, 10 days, 20 days, and 30 days after discharge. Two additional study contacts will take place 45 days and 90 days after discharge. arm 2: Drug: Placebo Participants will be given study medication at the time of discharge from the hospital. Participants will take the Placebo twice a day, once in the morning and once in the evening, for 30 days. Participants will be contacted (electronic or telephone) 2 days after starting the study medication and contact will continue up to day 90 after starting study treatment. Follow up will be through electronic and/or telephone contact depending on the participant's preference, compliance, and medication adherence. Participants will be queried for any clinically relevant endpoints, especially major bleeding or a need to seek healthcare attention for any reason. Follow-up will occur from the time of discharge and through the 30 day study period, with contacts 2 days, 10 days, 20 days, and 30 days after discharge. Two additional study contacts will take place 45 days and 90 days after discharge.
Interventions: intervention 1: Apixaban 2.5 MG intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will take Apixaban 2.5 MG twice a day, once in the morning and once in the evening for 30 days. Participants will be contacted (electronic or telephone) 2 days after starting the study medication and will continue up to day 90 after starting study treatment. Followup will occur from the time of discharge through the 30 day study period with contacts at 2 days, 10 days, 20 days and 30 days after discharge. Two additional study contacts will take place 45 days and 90 days after discharge. intervention 2: Participants will take placebo twice a day, once in the morning and once in the evening for 30 days. Participants will be contacted (electronic or telephone) 2 days after starting the study medication and will continue up to day 90 after starting study treatment. Followup will occur from the time of discharge through the 30 day study period with contacts at 2 days, 10 days, 20 days and 30 days after discharge. Two additional study contacts will take place 45 days and 90 days after discharge.

Protocol documents:
Prot_000.pdf: 
Study number: 20203331 
Page i 
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COVID-19 Thrombosis Prevention Trials: Post-hospital Thromboprophylaxis 
Short Title: COVID-19 Post-hospital Thrombosis Prevention Study 
 
 
A multicenter, adaptive, prospective, randomized trial evaluating the efficacy and safety 
of antithrombotic strategies in patients with COVID-19 following hospital discharge 
 
 
 
 
 
 
 
ClinicalTrials.gov Number: NCT04650087 
 
Sponsors: 
National Institute of Neurological Disorders (NINDS), National Heart Lung and Blood 
Institute (NHLBI), National Institutes of Health (NIH), Biomedical Advanced Research and 
Development Authority (BARDA), Operation Warp Speed (OWS), and the U.S. Department 
of Health & Human Services (HHS) 
 
Version Number: 5 
 
20 APR 2022


Study number: 20203331 
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Version: 5, Date:20APR2022 
 
 
Protocol Development Committee Leadership 
 
Study Chair: 
Thomas L. Ortel, MD, PhD 
Professor of Medicine and Pathology 
Chief, Division of Hematology 
Duke University Medical Center 
Durham, NC 27710 
Tel. 919-681-6049 
Fax. 919-681-6160 
E-mail: thomas.ortel@duke.edu 
Study Co-Chair: 
Alison Morris, MD, MS 
Professor of Medicine, Immunology, and Clinical and 
Translational Research 
Division Chief, Pulmonary, Allergy and Critical Care Medicine 
Director, Center for Medicine and the Microbiome 
Vice Chair for Clinical Research, Department of Medicine 
UPMC Chair in Translational Pulmonary and Critical Care 
Medicine 
E-mail: morrisa@upmc.edu 
Principal Investigator: 
Tracy Y. Wang, MD MHS MSc 
Professor of Medicine 
Duke Clinical Research Institute Member 
Duke University Medical Center  
Durham, NC 27710 
Tel. 919-668-8907 
E-mail: tracy.wang@duke.edu 
Study Biostatisticians: 
Abdus S. Wahed, PhD 
Professor of Biostatistics 
University of Pittsburgh, Graduate School of Public Health 
Pittsburgh, PA 
E-mail: WahedA@edc.pitt.edu 
Kevin J. Anstrom, PhD 
Professor of Biostatistics and Bioinformatics 
Duke University Medical Center 
Durham, NC 27710 
Tel. 919-668-8902 
E-mail: kevin.anstrom@duke.edu 
Eric Leifer, PhD 
NHLBI 
leifere@nhlbi.nih.gov 
Research 
Communication Center 
Jerry A. Krishnan, MD, PhD 
Professor of Medicine and Public Health 
Associate Vice Chancellor for Population Health Sciences 
University of Illinois at Chicago 
1220 S. Wood Street, 3rd Floor 
Chicago, IL 60608 
Tel 312-413-0637 
E-mail: jakris@uic.edu 


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NHLBI Representative: 
Andrei Kindzelski, MD, PhD 
kindzelski@nhlbi.nih.gov 
HHS Representative: 
David Douglas 
David.Douglas@hhs.gov 
IND 
153000 
ClinicalTrials.gov 
Identifier 
NCT04650087 


Study number: 20203331 
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Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as 
applicable, any other applicable US government research regulations, and institutional research 
policies and procedures. The International Conference on Harmonization (“ICH”) Guideline for 
Good Clinical Practice (“GCP”) (sometimes referred to as “ICH-GCP” or “E6”) will be applied 
only to the extent that it is compatible with FDA and DHHS regulations. The Principal 
Investigator will assure that no deviation from, or changes to, the protocol will take place without 
prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All 
personnel involved in the conduct of this study have completed Human Subjects Protection 
Training. 
 
The signature below provides the necessary assurance that this study will be conducted 
according to all stipulations of the protocol including statements regarding confidentiality, and 
according to local legal and regulatory requirements, US federal regulations, and ICH E6(R2) 
GCP guidelines. 
 
Site Investigator Signature: 
 
 
Signed:  _________________________________________Date:   
                                 
Name and Title 
 
 


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STATEMENT OF COMPLIANCE ............................................................................................. IV 
MASTER PROTOCOL SUMMARY ........................................................................................... 9 
1. 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE.......12 
1.1 
BACKGROUND INFORMATION, SIGNIFICANCE AND RELEVANT LITERATURE ....................... 12 
1.1.1 Thromboprophylactic therapy: rationale and potential risks .................................... 14 
2. STUDY DESIGN ............................................................................................................... 15 
2.1 
OVERALL STUDY DESIGN ............................................................................................. 15 
2.2 
RANDOMIZATION ......................................................................................................... 15 
2.3 
STUDY INTERVENTIONS ............................................................................................... 16 
2.4 
BIOREPOSITORY ......................................................................................................... 16 
3. OBJECTIVES AND PURPOSE ........................................................................................ 16 
4. STUDY DESIGN AND ENDPOINTS ................................................................................. 17 
4.1 
DESCRIPTION OF STUDY DESIGN: STAGE 1 ................................................................... 18 
4.2 
STUDY ENDPOINTS FOR STAGE I .................................................................................. 19 
4.2.1 Primary Study Endpoints........................................................................................ 19 
4.2.2 Key Secondary and Exploratory Endpoints ............................................................ 19 
4.2.3 Safety Endpoints for Stage 1 ................................................................................. 19 
4.2.4 Adjudication of outcome events ............................................................................. 19 
5. STUDY ENROLLMENT .................................................................................................... 20 
5.1 
INCLUSION CRITERIA ................................................................................................... 20 
5.2 
EXCLUSION CRITERIA .................................................................................................. 20 
5.3 
VULNERABLE SUBJECTS .............................................................................................. 20 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION ......................................................... 21 
5.5 
DURATION OF STUDY PARTICIPATION ........................................................................... 22 
5.6 
PARTICIPANT WITHDRAWAL OR TERMINATION ............................................................... 22 
5.6.1 Reasons for Withdrawal or Termination .................................................................22 
5.6.2 Premature Termination or Suspension of Study ..................................................... 22 
5.7 
STUDY AGENTS ........................................................................................................... 23 
5.8 
DURATION OF THERAPY ............................................................................................... 23 
6. STUDY PROCEDURES AND SCHEDULE ....................................................................... 23 
6.1 
STUDY SCHEDULE ....................................................................................................... 23 
6.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................... 24 
6.2.1 Study encounters ................................................................................................... 24 
6.3 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES .................................... 25 
6.4 
EXPEDITED CRITICAL AND MAJOR EVENT REPORTING .................................................... 25 
6.5 
DATA AND SAFETY MONITORING PLAN AND STUDY HALTING RULES ................................ 25 
7. STATISTICAL CONSIDERATIONS .................................................................................. 25 
7.1 
STATISTICAL AND ANALYTICAL PLANS (SAP) ................................................................. 25 
7.2 
POWER AND SAMPLE SIZE CALCULATIONS .................................................................... 26 
7.3 
PRIMARY OUTCOME ANALYSIS ..................................................................................... 26 
7.4 
SECONDARY AND EXPLORATORY ENDPOINTS ANALYSES ............................................... 27 


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7.5 
TABULATION OF INDIVIDUAL RESPONSE DATA ............................................................... 27 
7.6 
SUB-GROUP ANALYSES ............................................................................................... 27 
7.6.1 Safety Analyses ..................................................................................................... 28 
7.6.2 Adherence and Retention Analyses ....................................................................... 28 
7.6.3 Baseline Descriptive Statistics ............................................................................... 28 
7.6.4 Planned Interim Analysis, Futility, and Efficacy ...................................................... 28 
7.6.5 Safety Review ........................................................................................................ 29 
7.6.6 Subgroup Analyses based on Anti-Platelet Use, WHO Severity Score, and Other 
Pre-specified Characteristics ............................................................................................. 30 
7.6.7 Analyses of Duration of Treatment ......................................................................... 30 
8. MEASURES TO MINIMIZE BIAS ......................................................................................... 30 
8.1 
ENROLLMENT/RANDOMIZATION .................................................................................... 30 
9. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ..................31 
10. QUALITY ASSURANCE AND QUALITY CONTROL...................................................... 31 
11. ETHICS/PROTECTION OF HUMAN SUBJECTS ........................................................... 31 
11.1 
ETHICAL STANDARD .................................................................................................... 31 
11.2 
INSTITUTIONAL REVIEW BOARD .................................................................................... 31 
11.3 
INFORMED CONSENT PROCESS .................................................................................... 31 
11.3.1 Consent/Assent and Other Informational Documents Provided to Participants ......31 
11.3.2 Consent Procedures and Documentation ............................................................... 32 
11.4 
POSTING OF CLINICAL TRIAL CONSENT FORM................................................................ 32 
11.5 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................... 32 
12. DATA HANDLING AND RECORD KEEPING ................................................................. 33 
12.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................. 33 
12.2 
STUDY RECORDS RETENTION ...................................................................................... 33 
12.3 
PROTOCOL DEVIATIONS............................................................................................... 34 
12.4 
PUBLICATION AND DATA SHARING POLICY ..................................................................... 34 
13. STUDY FINANCES ......................................................................................................... 35 
13.1 
FUNDING SOURCE ....................................................................................................... 35 
13.2 
COSTS TO THE PARTICIPANT ........................................................................................ 35 
14. CONFLICT OF INTEREST POLICY ................................................................................ 35 
15. REFERENCES ................................................................................................................ 35 
APPENDIX 1: CRITERIA FOR ADDITION AND REPLACEMENT OF ARMS ..........................38 
APPENDIX 2: DEFINITION AND DETERMINATION OF OUTCOMES .................................... 39 
A2.1 
APPROACH TO ASCERTAINMENT AND VERIFICATION OF OUTCOMES .................................39 
A2.2 
OUTCOME DEFINITIONS ................................................................................................ 39 
APPENDIX 3: STUDY ARMS A AND B FOR STAGE 1 ........................................................... 41 
A3.1 POTENTIAL RISKS & BENEFITS .......................................................................................... 41 
A3.1.1 Known Potential Risks ............................................................................................ 41 
A3.1.2 Known Potential Benefits ....................................................................................... 42 
A3.2 
STUDY ENROLLMENT ................................................................................................... 42


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A3.2.1 Inclusion Criteria for Stage 1, Arms A and B ....................................................... 42 
A3.2.2 Exclusion Criteria ................................................................................................ 42 
A3.3 SAFETY ANALYSES ....................................................................................................... 42 
A3.4 TREATMENT REGIMEN: ARM A ....................................................................................... 43 
A3.5 TREATMENT REGIMEN: ARM B ....................................................................................... 43 
A3.6 STATISTICAL ANALYSES ................................................................................................ 43 
13.3 
LABORATORY TEST ABNORMALITIES .......................................................................... 47 
13.4 
OTHER SAFETY CONSIDERATIONS ............................................................................. 47 
APPENDIX 4. BIOSPECIMENS .............................................................................................. 48 
APPENDIX 5. ADDITION OF NEW KEY SECONDARY AND EXPLORATORY 
OURCOMES ........................................................................................................................... 49 
APPENDIX 6. PROTOCOL SUMMARY OF CHANGES ......................................................... 51 
 
 


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List of Abbreviations 
 
 
ACTIV 
Accelerating COVID-19 Therapeutic Interventions and Vaccines 
AE 
Adverse Event 
COVID-19 
Coronavirus Disease 
CRF 
Case Report Form 
CRNMB 
Clinically Relevant non-Major Bleeding 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DIC 
Disseminated intravascular coagulation 
DOAC 
Direct oral anticoagulant 
DSMB 
Data and Safety Monitoring Board 
DVT 
Deep Venous Thrombosis 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
IRB 
Institutional Review Board 
ISTH 
International Society on Thrombosis and Haemostasis 
ITT 
Intent to Treat 
LAR 
Legally Authorized Representative 
LMWH 
Low Molecular Weight Heparin 
MOP 
Manual of Procedures 
NIH 
National Institutes of Health 
PE 
Pulmonary Embolism 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
VTE 
Venous thromboembolism 
WHO 
World Health Organization 


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Master Protocol Summary 
 
Title 
COVID-19 Thrombosis Prevention Trials: Post-hospital 
Thromboprophylaxis 
A multicenter, adaptive, prospective, randomized trial evaluating the 
efficacy and safety of antithrombotic strategies in patients with COVID- 
19 following hospital discharge 
Short Title 
COVID-19 Post-hospital Thrombosis Prevention Study 
Brief Summary 
This study is an adaptive, prospective, randomized trial designed to 
compare the effectiveness and safety of antithrombotic therapy with 
no antithrombotic therapy after hospitalization for 48 hours or longer 
for COVID-19. For Stage 1 of this study, participants will be 
randomized to either prophylactic anticoagulation or no anticoagulant 
therapy for 30 days, and then followed for an additional 60 days after 
the completion of treatment (total duration of follow-up, approximately 
90 days). 
Biobanking of samples for future biomarker and mechanistic studies 
will be available for centers able to participate and collect samples 
from eligible participants. Samples will be collected at the time of 
enrollment and after the completion of 30 days of therapy 
Objectives 
1. Primary Objective: To determine the most effective and safe 
antithrombotic strategy to prevent the composite outcome of 
symptomatic deep vein thrombosis, pulmonary embolism, other 
venous thromboembolism, ischemic stroke, myocardial infarction, 
other arterial thromboembolism, and all-cause mortality by 30 days 
following discharge from the hospital. 
2. Secondary Objectives: To determine the most effective and safe 
antithrombotic strategy on (1) the endpoint of venous 
thromboembolism (inclusive of symptomatic deep vein thrombosis, 
pulmonary embolism, other venous thromboembolism) by 30 days 
in the study population; (2) the endpoint of arterial 
thromboembolism (inclusive of ischemic stroke, myocardial 
infarction, other arterial thromboembolism) by 30 days in the study 
population; and (3) the composite primary outcome by 45 and 90 
days following discharge from the hospital 
3. To establish a repository of biospecimens collected at the time of 
enrollment and after completion of therapy. 
Methodology 
Adaptive, prospective, randomized controlled trial 


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Endpoint 
Primary Endpoint: First occurrence of any of the components of the 
composite endpoint of symptomatic deep vein thrombosis, pulmonary 
embolism, other venous thromboembolism, ischemic stroke, 
myocardial infarction, other arterial thromboembolism, and all-cause 
mortality by 30 days post-discharge from the hospital 
Secondary Endpoints: (1) Venous thromboembolism (inclusive of 
symptomatic DVT of the upper or lower extremities, symptomatic 
and/or clinically relevant PE, and other symptomatic venous 
thrombosis, including cerebral sinus and splanchnic vein thrombosis) 
by 30 days post-discharge from the hospital; (2) Arterial 
thromboembolism (inclusive of symptomatic ischemic stroke, 
myocardial infarction, and other symptomatic arterial thromboembolic 
events) by 30 days post-discharge from the hospital; and (3) the 
composite primary endpoint by 45 days and 90 days post-discharge 
from the hospital 
Primary Safety Endpoints: Major bleeding, as defined by the ISTH; 
clinically-relevant non-major bleeding 
Study Duration 
At least one year 
Participant Duration 
Approximately 90 days from randomization 
Duration of assigned 
treatment strategy 
30 days for the primary outcome in Stage 1. 
Population 
Adults ≥ 18 years of age with COVID-19 who are hospitalized for 48 
hours or longer and who are ready for discharge from the hospital 
Key exclusion 
criteria 
1. Clinical requirement for anticoagulant therapy (therapeutic dose or 
prophylactic dose) 
2. Contraindication to anticoagulant therapy 
3. Anticipated life-expectancy < 90 days 
Study Sites 
Up to 400 sites 
Number of 
participants 
The estimated sample size (for Stage 1) is 2,660 participants per 
Study Arm based on an estimated baseline rate of the primary 
endpoint of ~4%. 


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Description of Study 
Agents (Stage 1) 
Stage 1 is a two-arm trial incorporating: 
1. Prophylactic dose anticoagulant therapy 
2. Matching placebo 
Participants will be enrolled prior to discharge from the hospital, 
randomized as close to time of discharge as possible, and will begin 
the study medication (either prophylactic anticoagulation or matching 
placebo) upon discharge from the hospital for a total of 30 days. Study 
participants will be stratified based on: (1) whether or not they are 
taking an antiplatelet agent (e.g., aspirin, clopidogrel); and (2) on their 
WHO ordinal scale score dichotomized (below five vs. five or above). 
Subsequent stages may investigate alternative antithrombotic 
strategies or focus on selected high-risk patient subsets. 
Key Procedures 
See arm-specific Appendices 
Statistical Analysis 
A frequentist approach has been used for the sample size 
calculations. Interim analyses will be used to guide decisions about 
stopping based on efficacy and futility. The primary analyses will be 
based on intention-to-treat approaches. 


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1. Introduction, Background Information and Scientific Rationale 
 
1.1 
Background Information, Significance and Relevant Literature 
In December 2019, an outbreak of pneumonia of unknown cause was first observed in Wuhan, the 
capital of Hubei province in China. By early January, a novel coronavirus was isolated from these 
patients, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and initial 
descriptive clinical reports of the pandemic designated coronavirus disease 2019 (COVID-2019) by 
the World Health Organization (WHO) began to appear shortly afterwards (1). The disease has 
spread explosively, and, by early July 2020, about 7 months from the initial reports, more than 11 
million people worldwide had been confirmed to have a COVID-19 infection, with more than 
530,000 deaths. In addition to the healthcare problems associated with this coronavirus, it has 
resulted in worldwide disruption of everyday life as measures have been introduced to interfere with 
the rapid spread of the virus and treat those patients with the infection. 
 
The clinical manifestations associated with COVID-19 range from asymptomatic infections through 
severe pneumonia and death. A significant inflammatory response is frequently seen in patients 
who require hospitalization, associated with dramatic elevations in inflammatory biomarkers such as 
the ESR and CRP, as well as proinflammatory cytokines such as IL6 and others. This robust 
inflammatory response is also associated with elevated fibrinogen levels, as well as increased 
levels of D-dimers, even at initial presentation to the hospital (2). Notably, elevated D-dimer levels 
were associated with increased mortality (2, 3), although it was also noted that these patients were 
not developing hemorrhagic complications as might be seen with disseminated intravascular 
coagulopathy (DIC) (4, 5). 
 
Prothrombotic manifestations of COVID-19 
Subsequently, multiple reports have appeared documenting an increased incidence of venous 
thromboembolism (VTE) in COVID-19 positive patients, particularly those who required care in an 
ICU setting (6, 7). The cumulative frequency of symptomatic VTE was 25% by 21 days in one study 
(7), and these events occurred in some patients despite the use of VTE prophylaxis. Using 
surveillance ultrasound imaging, a second study reported a frequency approaching 70% of patients 
with severe COVID-19, but almost a quarter of these patients had superficial venous thrombosis 
(8). In contrast, other studies have found a lower frequency of radiographically-confirmed VTE 
(7.6% in critically ill patients) and bleeding rates that were not insignificant (5.6% in critically ill 
patients) (5). Arterial events, including ischemic stroke, MI, and peripheral arterial thromboembolism 
have also been reported, although they appear to occur less frequently than VTE (9, 10). 
 
Several studies have suggested that for hospitalized patients with COVID-19, prophylactic dose 
anticoagulant therapy may be insufficient (6, 7). In addition, a recent retrospective cohort study 
reported that systemic therapeutic anticoagulation was associated with improved survival, although 
this study did not specifically look at patients with thromboembolic events (11). A separate, 
prospective randomized trial that is part of the NIH-supported ACTIV-4 program will investigate the 
dose of anticoagulant therapy in the inpatient population. 
 
There are also an increasing number of reports describing patients with COVID-19 who develop 
thromboembolic events in the outpatient setting. Two recent studies described patients with COVID- 
19 being evaluated for progressive respiratory symptoms in the Emergency Department, finding PE 
by CT angiography in 18% to 23% of patients (12, 13). Previously undiagnosed DVT and PE have 
also been identified by autopsy in patients dying at home or in a nursing home (14), and a case 
report described an asymptomatic individual with COVID-19 who presented with sudden death due 


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to massive PE (15). Whether VTE rates are increased in non-hospitalized patients with COVID-19 
is unknown, however. 
 
Similarly, limited data exist concerning the risk of thromboembolic complications for patients with 
COVID-19 in the post-discharge/convalescence setting. One study noted that out of 1,368 patients 
discharged following a hospitalization related to COVID-19, 61 patients (4.4%) were re-admitted, 10 
for a thrombotic event in venous or arterial territory (16). 
 
Extended thromboprophylaxis following hospitalization in non-COVID-19 patients 
Multiple studies have documented that a recent hospitalization is associated with an increased risk 
for VTE in the post-discharge setting. This increased risk for PE and DVT remains markedly 
elevated for at least the first month after hospital discharge (17). Although several trials have 
investigated whether an extended course of thromboprophylaxis with an anticoagulant can 
decrease this increased risk for VTE, none have shown a substantial improvement in the VTE rate 
(Table 1). There are unique aspects to each of the studies that may have contributed to the 
observed outcomes, however. 
 
Table 1. Clinical trials investigating thromboprophylaxis in patients hospitalized for acute medical 
illness.* 
Clinical Trial 
Arms 
Efficacy 
outcome(s) 
Event rate for 
anticoagulant 
Event rate for 
placebo 
Comparisons† 
(95% CI) 
EXCLAIM (18) 
(1) Enoxaparin vs. 
(2) Placebo 
Symptomatic 
VTE at 28 d 
0.2% 
1.0% 
-0.75 (-1.19 to - 
0.32) 
ADOPT (19) 
(1) Apixaban 
(extended course) 
vs. (2) Enoxaparin 
(short course) 
Total VTE‡ or 
VTE-related 
death 
2.71% 
3.06% 
0.87 (0.62-1.23) 
MAGELLAN (20) 
(1) Rivaroxaban 
vs. (2) Placebo 
Symptomatic 
non-fatal VTE at 
35 d 
-or- 
CV death, MI, or 
ischemic CVA at 
35 d 
0.6% 
1.8% 
0.7% 
1.6% 
0.82 (0.47-1.43) 
1.11 (0.79-1.55) 
APEX (21) 
(1) Betrixaban vs. 
(2) Placebo 
Symptomatic 
VTE by 42 d 
0.9% 
1.5% 
0.64 (0.42-0.98) 
MARINER (22) 
(1) Rivaroxaban 
vs. (2) Placebo 
VTE + VTE- 
related death 
-or- 
VTE, MI, CVA, 
or CV death 
0.83% 
1.56% 
1.10% 
2.00% 
0.76 (0.52-1.09 
0.78 (0.60-1.02) 
* 
Efficacy outcomes reported in this table could be either primary or secondary outcomes, chosen to most closely 
reflect the study design developed in this protocol. Both MAGELLAN and APEX included an initial anticoagulant for 
10 ± 4 days received by all patients, followed by anticoagulant vs. placebo for an additional ~25 days. ADOPT 
compared apixaban 2.5 mg twice daily for 30 days to enoxaparin 40 mg once daily for 6-14 days. 
†     EXCLAIM, absolute risk differences; ADOPT, MAGELLAN and APEX, relative risk; MARINER, hazard ratio. 
‡     Total VTE includes symptomatic VTE and asymptomatic VTE, determined by screening ultrasounds of study 
  
participants. 
 
 
EXCLAIM studied acutely ill medical patients ≥40 years of age with recently reduced mobility, 
treated with enoxaparin for 10 days followed by an additional 28 days of enoxaparin or placebo 
(18). The protocol was modified after interim analyses suggested lower than expected VTE rates to 
enroll only individuals at higher risk (age >75 yrs; history of VTE; active or previous cancer). The 
trial showed a decrease in the incidence of VTE, but primarily restricted to women, patients >75 


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years of age, and with level 1 immobility (18). MAGELLAN also treated patients with an initial 10 
days of enoxaparin, and then randomized to rivaroxaban or placebo for an additional 25 days of 
therapy (20). Rivaroxaban reduced the risk of the primary outcome, symptomatic DVT/PE and 
asymptomatic DVT, but not of symptomatic VTE alone (20). APEX included a similar design with an 
initial 10 days of anticoagulant, followed by betrixaban or placebo for an additional 25–32 days (21). 
There was no significant difference between betrixaban and placebo for the primary outcome, 
symptomatic and asymptomatic DVT, although there was a decrease in symptomatic VTE (Table 
1). MARINER compared 45 days of rivaroxaban to placebo in medically ill patients at an increased 
risk for VTE on the basis of a modified IMPROVE score of ≥4 (22). The decrease in symptomatic 
VTE and VTE-related death was not significant (Table 1) 
 
Recent guidelines recommend against the routine use of extended thromboprophylaxis in medical 
patients following hospital discharge (23), although it is recognized that selected high-risk patients 
may warrant this approach. The COVID-19 post-discharge patient population, however, potentially 
represents such a novel high-risk group that might benefit from extended thromboprophylaxis. In 
particular, the noted increased risk that these patients exhibit for thromboembolic events while 
hospitalized (5-7), the autopsy data indicating a significant amount of thrombus affecting smaller 
vessels (14, 24), and the observations that this hospitalized patient population exhibits additional 
risk factors for VTE (e.g., older age, obesity) all support a study on post-discharge 
thromboprophylaxis in this patient population. 
 
 
1.1.1 Thromboprophylactic therapy: rationale and potential risks 
For Stage 1 of this adaptive-design trial, we will investigate whether thromboprophylaxis with 
prophylactic-dose anticoagulant therapy (apixaban 2.5 mg twice daily) can significantly decrease 
the risk for thromboembolic complications in patients with COVID-19 who are discharged from the 
hospital compared to matching placebo. Details of this study are provided in Appendix 3. In Stage 
1, concomitant aspirin therapy (or other single-agent antiplatelet therapy) is not a contraindication 
for participation, and participants will be stratified based on whether they need to be treated with a 
single antiplatelet agent and WHO severity score (<5 vs. >= 5). The primary outcome will be a 
composite endpoint of venous thromboembolism, stroke, myocardial infarction, peripheral arterial 
thromboembolism, and all-cause death. 
 
Potential risks associated with participation in this trial include bleeding complications, and patients 
with a clinical contraindication to anticoagulant therapy (e.g., gastroduodenal ulcer, major surgery 
within 14 days, ischemic stroke, intracranial bleed or surgery within 3 months, known hemorrhagic 
diathesis) or thrombocytopenia (platelet count <50,000/mcL) would be excluded from participation 
in the randomized study. Bleeding rates associated with the trials presented in Table 1 are shown in 
Table 2 below. 


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Table 2. Bleeding rates in clinical trials investigating thromboprophylaxis in patients hospitalized for 
acute medical illness.* 
Clinical Trial 
Arms 
Safety 
outcome(s) 
Event rate for 
anticoagulant 
Event rate for 
placebo 
Comparisons† 
(95% CI) 
EXCLAIM (18) 
(1) Enoxaparin vs. 
(2) Placebo 
Major bleeding 
0.8% 
0.3% 
0.51 (0.12-0.89) 
ADOPT (19) 
(1) Apixaban 
(extended course) 
vs. (2) Enoxaparin 
(short course) 
Major bleeding 
0.47% 
0.19% 
2.58 (1.02-7.24) 
MAGELLAN (20) 
(1) Rivaroxaban 
vs. (2) Placebo 
Major bleeding 
at 35 d 
-or- 
Clinically 
relevant 
bleeding at 35 d 
1.1% 
4.1% 
0.4% 
1.7% 
2.9 (1.60-5.15) 
2.5 (1.85-3.25) 
APEX (21) 
(1) Betrixaban vs. 
(2) Placebo 
Major bleeding 
-or- 
Major or 
clinically 
relevant non- 
major bleeding 
0.7% 
3.1% 
0.6% 
1.6% 
1.19 (0.67-2.12) 
1.97 (1.44-2.68) 
MARINER (22) 
(1) Rivaroxaban 
vs. (2) Placebo 
Major bleeding 
-or- 
Nonmajor 
clinically 
relevant 
bleeding 
0.28% 
1.42% 
0.15% 
0.85% 
1.88 (0.84-4.23) 
1.66 (1.17-2.35) 
* 
MAGELLAN and APEX included an initial anticoagulant for 10 ± 4 days received by all patients, followed by 
anticoagulant vs. placebo for an additional ~25 days. ADOPT compared apixaban 2.5 mg twice daily for 30 days to 
enoxaparin 40 mg once daily for 6-14 days. 
†     EXCLAIM, absolute risk differences; ADOPT, MAGELLAN and APEX, relative risk; MARINER, hazard ratio. 
 
 
 
2. Study Design 
 
2.1 
Overall Study Design 
This trial is an adaptive design protocol intended to determine the optimal antithrombotic strategy to 
prevent thromboembolic complications in patients hospitalized with COVID19 following discharge 
from the hospital.  The first Stage is a randomized, double-blind, placebo-controlled study 
comparing a prophylactic dose anticoagulant (apixaban 2.5 mg twice daily; venous 
thromboembolism prophylaxis dose) with matching placebo (Figure 1). 
 
Subsequent Stages of this adaptive protocol will incorporate new data as it becomes available in 
this rapidly evolving clinical and research environment.  Each Stage will be developed as a 
separate, detailed Appendix to the Master Protocol. Each Stage will use concurrent control arm 
data, and no data (from either treatment arm) collected in earlier Stages will be used in subsequent 
Stages. A full Statistical Analysis Plan will be developed for each Stage, and each new Stage will 
be submitted with the Statistical Analysis Plan for review by the FDA before implementation. 
 
2.2 
Randomization 
Randomization will be performed for study participants as close to the time of hospital discharge as 
possible. Hospitalized patients may be screened and approached about the study up to 72 hours 
prior to hospital discharge, but final enrollment and randomization should occur as close to the time 


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of discharge as possible. In Stage 1, participants will be randomized in a 1:1 ratio using an online 
randomization system to either Arm A (apixaban 2.5 mg twice daily); or Arm B (matching placebo). 
The randomization scheme will be determined by the study phase and its associated group of 
intervention arms. Randomization for Stage 1 will be stratified by (1) concomitant use of a single 
antiplatelet agent (yes/no), and (2) a maximal score of 5 or greater vs. a score of less than 5 by the 
WHO Ordinal Index (Table 3). 
 
 
Table 3. WHO ordinal scale for clinical improvement (https://www.who.int/blueprint/priority- 
diseases/key-action/COVID- 
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf) 
 
Patient State 
Score Descriptor 
Uninfected 
0 
No clinical or virological evidence of infection 
Ambulatory 
1 
No limitation of activities 
2 
Symptomatic: Limitation of activities 
Hospitalized: Mild 
disease 
3 
Hospitalized; no oxygen therapy 
4 
Hospitalized; oxygen by mask or nasal prongs* 
Hospitalized: Severe 
disease 
5 
*Non-invasive ventilation or high-flow oxygen 
6 
Intubation & Mechanical ventilation 
7 
Ventilation and additional organ support – pressors, RRT, ECMO 
Death 
8 
Death 
*chronic CPAP or BiPAP use for sleep apnea excluded 
 
2.3 
Study Interventions 
This master protocol study will open by comparing a prophylactic anticoagulant therapy in Arm A, 
and matching placebo in Arm B, as described in Appendix 3. 
 
2.4 
Biorepository 
A biorepository will be established to biobank samples for further studies of biomarkers of 
thrombotic risk and inflammation. Centers capable of collecting, processing, and shipping samples 
may opt in for collecting and biobanking these samples from eligible participants. As an alternative 
to collecting samples by phlebotomy, sites/participants may be able to send biobank samples 
through dry blood spots for both Day 0 and Day 30. There will be a nested design to the 
biobanking strategy, so that sites can participate based on level of expertise, staffing, and interest. 
The initial samples proposed for the biorepository are listed in Appendix 4. 
Biorepository specimens may change during different stages of this adaptive design protocol. 
 
 
3. Objectives and Purpose 
The overarching objective of this adaptive research trial design is to iteratively learn which 
antithrombotic strategy is best for the prevention of thromboembolic complications in patients with 
COVID-19 who have been hospitalized for two or more days and are being discharged from the 
hospital, during the post-discharge/convalescence phase of the illness. At each Stage of the trial, 
the goal is to determine the superior approach that should be considered standard care for this 
patient population. Subsequent stages will introduce alternative strategies and/or designs that will 
be compared to this new standard of care in an iterative fashion. This process will continue until 
there are no new strategies that replace the standard of care. 


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The primary outcome for Stage 1 will be a composite endpoint of venous thromboembolic events, 
including new, symptomatic proximal or distal deep vein thrombosis affecting the upper and/or 
lower extremities, pulmonary embolism, or thrombosis of other veins (e.g., cerebral sinus veins, 
splanchnic veins); arterial thromboembolic events, including new ischemic stroke, myocardial 
infarction, mesenteric or peripheral arterial thromboembolism; and all-cause mortality for up to 30 
days after randomization. This primary outcome is expected to be similar across all stages of this 
study, although it is possible that changes could be introduced on the basis of results accrued 
during the study. 
 
Primary Objective: In COVID-19 patients who have been hospitalized, the primary objective of this 
master trial is to determine the optimal antithrombotic strategy to minimize the composite endpoint 
of venous and arterial thromboembolic outcomes, and all-cause mortality. Stage 1 of this trial will 
compare the effects of treatment beginning at the time of discharge from the hospital with either (i) 
anticoagulation at a prophylactic dose, or (ii) no anticoagulation on the primary outcome for up to 30 
days after randomization. See Appendix 3 for details of Stage 1. Randomization is expected to 
occur on the day of discharge. 
 
Secondary Objectives: 
 
Secondary Objective 1:  To compare the effects of treatment beginning at the time of discharge 
from the hospital with either Arm A or Arm B on the incidence of the composite outcome at 45 days 
and at 90 days after randomization. 
 
Secondary Objective 2: To compare the effects of treatment beginning at the time of discharge 
from the hospital with either Arm A or Arm B on the incidence of new, symptomatic VTE (inclusive 
of DVT, PE, or  other venous thrombosis) for up to 30 days after randomization. 
 
Secondary Objective 3: To compare the effects of treatment beginning at the time of discharge 
from the hospital with either Arm A or Arm B on the incidence of new, symptomatic ATE (inclusive 
of ischemic stroke, MI, or peripheral arterial thromboembolism) for up to 30 days after 
randomization. 
 
Exploratory Objectives: 
 
Exploratory Objective 1:  To compare the effects of treatment beginning at the time of discharge 
from the hospital with either Arm A or Arm B on the incidence of all-cause rehospitalization for up to 
90 days after randomization. 
 
Exploratory Objective 2: To compare the effects of treatment beginning at the time of discharge 
from the hospital with either Arm A or Arm B on the incidence of all-cause mortality for up to 30 
days after randomization. 
 
 
4. Study Design and Endpoints 
Stage 1 of the protocol is described in Appendix 3. Subsequent stages will incorporate 
recommendations from the DSMB based on the accrued in-trial data at prespecified timepoints or at 
selected milestones of participants accrued into the study. Adaptive changes may impact the 
treatment arms (e.g., modifications to the antithrombotic agent or regimen, duration of therapy), 
patient eligibility (e.g., identification of unique patient characteristics associated with a higher or 


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lower risk of the primary outcome), endpoints (e.g., addition of alternative endpoints), or any 
combination of these variables. 
 
4.1 
Description of Study Design: Stage 1 
The Stage 1 study is a randomized trial of COVID-19 positive patients who have been hospitalized 
and are ready for discharge from the hospital. All inclusion and exclusion criteria (Sections 5.1 and 
5.2, below) must be met prior to enrollment and randomization. In Stage 1, participants will be 
randomized to either Arm A (apixaban 2.5 mg twice daily), or Arm B (matching placebo) (Figure 1). 
Potential study participants will be identified through review of inpatient census data at each site. 
 
 
Figure 1. COVID-19 Post-Discharge Clinical Trial Stage 1. Participants will be enrolled in the Study prior to discharge 
from the hospital and randomized to one of two Arms (this general design may change with adaptations during the course 
of the study). Screening and enrollment will occur prior to discharge from the hospital, with randomization occurring as 
close to discharge as possible (randomization identified as the encircled “R”, occurring immediately prior to discharge, 
identified by the vertical dashed line). Follow-up encounters for the primary outcome will occur on Days 2, 10, 20, and 30. 
Two additional follow-up encounters will occur for secondary outcomes on Days 45 and 90. The Day 45 follow-up 
encounter will also be included to ensure the 2nd biorepository specimens have been collected for those participating in 
this part of the study. 
 
 
The initial follow-up encounter, which will be conducted by the Call Center via the participant’s 
preferred method (electronic or phone call), will occur within 2 days following discharge from the 
hospital, to confirm study medication adherence and perform an initial assessment of outcomes. 
Subsequent encounters, which will also be conducted by the Call Center electronically or by phone, 
will occur at 10, 20, and 30 days after enrollment. With each encounter, assessments of medication 
adherence and outcomes will be performed. Two additional encounters will occur after completion 
of the primary outcome, at 45 and 90 days after enrollment, to determine if there is an increased 
risk for thromboembolic complications following hospital discharge that extends for a longer period 
of time than 30 days and to facilitate/confirm collection of the 2nd set of biorepository specimens. All 
contacts will be scripted to ensure that all information is uniformly collected. 


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4.2 
Study Endpoints for Stage I 
 
4.2.1 Primary Study Endpoints 
At approximately day 30 from randomization, a binary composite endpoint of venous and arterial 
thrombotic complications—including new, symptomatic proximal, or distal DVT of the upper or lower 
extremities, PE, and new thrombosis of other veins (including cerebral sinus and splanchnic veins), 
ischemic stroke, myocardial infarction, other arterial thromboembolism (e.g., mesenteric or acute 
limb ischemia), and all-cause mortality will be the primary study endpoint. 
 
4.2.2 Key Secondary and Exploratory Endpoints 
 
Key secondary endpoints include the following. 
1. The composite endpoint for the primary outcome at day 45 following randomization 
2. The composite endpoint for the primary outcome at day 90 following randomization 
3. Composite endpoint of venous thromboembolic events, including symptomatic DVT of the upper or 
lower extremities, symptomatic and/or clinically relevant PE, and other symptomatic venous 
thrombosis, including cerebral sinus and splanchnic vein thrombosis at day 30 
4. Composite endpoint of arterial thromboembolic events, including symptomatic ischemic stroke, 
myocardial infarction, and other symptomatic arterial thromboembolic events at day 30 
Secondary endpoints will be formally tested using a fallback approach only if the primary endpoint 
was statistically significant at the two-sided 5% level. 
 
 
Exploratory endpoints include the following. 
 
1. All-cause mortality at day 30 following discharge from the hospital 
2. All-cause re-hospitalization at day 90 following discharge from the hospital 
 
4.2.3 Safety Endpoints for Stage 1 
Safety endpoints will include (1) major bleeding, as defined by the ISTH, and (2) clinically-relevant, 
non-major bleeding, also as defined by the ISTH. Criteria for major bleeding, and for CRNMB are 
provided below 
 
1. Major bleeding 
a. Fatal bleeding 
b. Bleeding into a critical area or organ (e.g., intracranial, intraspinal, intraocular, 
pericardial, intra-articular, intramuscular with compartment syndrome, 
retroperitoneal) 
c. Bleeding causing a fall in the hemoglobin level of 2 g/dL or more, or leading to 
transfusion of 2 or more units of whole blood or red cells 
2. Clinically-relevant, non-major bleeding 
a. Bleeding requiring medical intervention by a healthcare professional 
b. Bleeding leading to hospitalization or an increase in the level of care 
c. Bleeding prompting a face-to-face (i.e., not just a telephone or electronic 
communication) evaluation 
 
4.2.4 Adjudication of outcome events 
All patient-reported events will be investigated by the Clinical Coordinating Center, including 
obtaining information from healthcare facilities where the patient received treatment. An 


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independent, central adjudication committee (ICAC) will review and adjudicate events in a blinded 
manner without knowledge of treatment allocation. During the study period, the ICAC will adjudicate 
all suspected occurrences of venous or arterial thromboembolic events, ischemic stroke, acute 
myocardial infarction, deaths, and re-hospitalization. The ICAC will also review all suspected 
episodes of bleeding that require medical attention and categorize adjudicated bleeding as major, 
clinically-relevant non-major, or minor bleeding. The Committee will be provided with all relevant 
documentation related to the events. The criteria and definitions of the study outcomes, as well as 
the procedures followed by the Committee, will be described in an adjudication manual which will 
be provided to the ICAC members prior to the first meeting. 
 
 
5. Study Enrollment 
 
5.1 
Inclusion Criteria 
The inclusion criteria for Stage 1 of this adaptive protocol are listed below and in Appendix 3. 
Potential study participants will be identified during hospitalization and reviewed for 
inclusion/exclusion criteria. Per the adaptive trial design strategy, these criteria may change after 
the first and subsequent analyses of in-trial accrued data. 
• 
Age ≥ 18 years 
• 
COVID-19 positive test (PCR, antigen, or point of care test diagnosing a current infection) 
within 2 weeks of hospital admit date 
• 
Hospitalized for COVID-19 infection for 48 or more hours 
 
5.2 
Exclusion Criteria 
The exclusion criteria for Stage 1 of this adaptive protocol are listed below and, with additional 
details, in Appendix 3. These are potentially subject to change based on the adaptive trial design 
and analyses of in-trial accrued data. 
• 
Existing indication for anticoagulation, either therapeutic or prophylactic dose 
• 
Contraindication to antithrombotic therapy, such as 
o Ischemic stroke, intracranial bleed, or neurosurgery within 3 months 
o Known bleeding within the last 30 days requiring emergency room presentation or 
hospitalization 
o Known major surgery within 14 days (at least 1 hour and/or requires general 
anesthesia) 
o Inherited or active acquired bleeding disorder 
• 
Platelet count < 50,000/mcL 
• 
Hemoglobin < 8 gm/dL 
• 
Pregnancy 
• 
Prison inmate 
• 
Life expectancy less than 90 days 
• 
Unwilling or unable to provide informed consent / unwilling or unable to complete the study 
protocol 
• 
Other criteria related to stage-specific appendices developed as adaptations to the trial. (i.e. 
Stage 1 is in appendix 3) 
 
5.3 
Vulnerable Subjects 
As noted in the Exclusion Criteria, this study will not enroll children < 18 years of age, pregnant 
women, or prisoners. 


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5.4 
Strategies for Recruitment and Retention 
The Protocol Implementation Committee (PIC) will respond to the evolving landscape of the 
pandemic by leveraging the network of networks already established within ACTIV-4, including all 
sites participating within the networks. As is currently evident, the pace of the pandemic varies 
across different areas within the United States, based on propagation patterns, local social 
distancing rules, and compliance with those rules. In addition, the PIC will also be monitoring the 
course of the pandemic across the world to identify regions where the number of potential study 
subjects would make rapid recruitment feasible. By monitoring the evolution of the infection, the PIC 
will place sites on hold when disease activity wanes in their geographic areas and activate new 
sites when the local rate of new COVID-19 cases exceeds a threshold making recruitment feasible. 
 
Screening and enrollment will occur within the hospital setting, targeting patients being considered 
for discharge within 72 hours. Providers managing these patients will be made aware of the study, 
and the research team at each site will review the list of inpatients to identify potentially eligible 
patients for the study. Study participants will be provided with study drug at the time of discharge 
from the hospital, with detailed instructions for taking the medication. At those sites with the 
capability to process and store biospecimens, those patients who agree to participate will be asked 
to provide samples for preparation of plasma, serum, and genomic DNA, as described below. 
 
The local study team will collect relevant contact information for the participant, participant’s spouse 
or partner, one contact individual who is not related to the participant to maintain contact, and the 
participant’s Primary Care Physician. The local study team will inform the participant about the Call 
Center’s role and, if possible, put the phone number in the participant’s phone so they recognize the 
caller later. The participant will be asked to sign a Release of Records form for the PCP or other 
hospital. This form will have an expiration date 150 days after randomization. 
 
One encounter with the study participant will occur at one to three days after discharge, to confirm 
medication compliance and collect information concerning any early outcome events. Five 
additional encounters for confirming compliance with the protocol and collecting outcome 
information will occur at 10 days, 20 days, 30 days, 45 days, and 90 days from initiation of the 
study. These visits may be set up to be electronic only (e-mail or text) or by telephone, depending 
on which approach works best for the individual study participant. The study is completed within 
approximately 90 days of hospital discharge. 
 
Site investigators will be educated about the importance of retention of subjects in the study and will 
be informed about the steps that will be taken to prevent missing data. Study participants will be 
educated about the importance of their completion of the study and the different options available 
for them to accomplish this objective. Study participants who discontinue treatment with the study 
medication will continue to be followed by the study team unless the participant requests to be 
withdrawn from the study. Regular web-based and/or phone-based contacts during the course of 
study participation are designed to maintain ongoing interaction and support retention in the study. 
 
Enrollment and retention of economically-disadvantaged individuals. The overall success of this 
study is critically dependent on the ability of all patients who meet inclusion/exclusion criteria to 
participate in the study. Populations historically affected by health disparities, including non- 
Hispanic Blacks and Hispanics, have been shown in several studies to be disproportionally affected 
by and hospitalized with COVID-19 (25, 26). These populations are also disproportionally affected 
by economic disparities, which can lead to difficulties with obtaining costly outpatient medications, 
leading to non-compliance. Consequently, the first stage of this study will provide the anticoagulant 
and the matching placebo to eliminate this potential reason for not participating in the study. This 


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approach will ensure that this study is relevant to the entire range of patients hospitalized with 
COVID-19. 
 
5.5 
Duration of Study Participation 
Study participation lasts from the time the participant is enrolled into the study until 90 days from 
hospital discharge. 
 
Total Number of Participants 
Sample size calculations for Stage 1 are described in Section 7. Initial power calculations using 
conservative event rates from post-hospital extended duration VTE prophylaxis trials in medically ill 
patients selected for increased risk suggest that 2,660 participants per arm will be required to 
determine if thromboprophylaxis with an anticoagulant is superior to no anticoagulant 
thromboprophylaxis. There will be interim monitoring to enable early stopping for futility, efficacy, or 
safety. 
 
5.6 
Participant Withdrawal or Termination 
 
5.6.1 Reasons for Withdrawal or Termination 
Study participants are free to withdraw from participation in the study at any time upon written 
request. The site PI will notify the Clinical Coordinating Center of all withdrawals from the study. 
Study participants who withdraw consent will not have additional information collected after they 
withdraw from the study. 
 
A site investigator may discontinue study drug for a study participant on the basis of either: 
• 
Any clinical adverse event, laboratory abnormality, or other medical condition or situation 
occurs such that continued study drug treatment would not be in the best interest of the 
patient. 
• 
The participant meets an exclusion criterion, either newly developed or not previously 
recognized (e.g., new thrombocytopenia, renal insufficiency), that precludes further study 
medication continuation. 
 
Study participants may choose to withdraw from participation in the study at any time. 
 
As noted above, study participants who discontinue taking the study drug prior to completing 30 
days of therapy will continue to be followed as study participants, unless they also request to be 
withdrawn from the study. 
 
5.6.2 Premature Termination or Suspension of Study 
All deaths, SAEs, and related clinical events within the study period will be reviewed by the DSMB. 
The decision to stop or suspend the study will be made by the DSMB after considering the totality of 
the data and the benefit-risk of continuing the study. These decisions could lead to an adaptive 
change in the protocol, with one arm of the study being discontinued or modified/changed to an 
alternative approach. 
 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed and satisfy the IRB, the DSMB, and the sponsor. 


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5.7 
Study Agents 
Study agents for Stage 1 (described in more detail in Appendix 3) include: 
1) Prophylactic anticoagulant, defined as a dose intended for the prevention of VTE; and 
2) Matching placebo 
Subsequent adaptations of this study may focus on modifications to the antithrombotic strategy, 
specific subsets of patients identified as being higher-risk for thrombotic complications, or other 
changes, as outlined in Figure 1. 
 
5.8 
Duration of Therapy 
Duration of the thromboprophylaxis period will be 30 days, beginning at the time of discharge from 
the hospital. Primary outcome will be assessed by approximately 30 days after randomization. 
Study participants will be followed for an additional 60 days after discontinuation of 
thromboprophylaxis (total duration of study participation = approximately 90 days). 
 
Study agents for subsequent stages will be determined based on the adaptive design of the trial. 
 
6. Study Procedures and Schedule 
 
6.1 
Study Schedule 
 
Activity 
Baseline 
screening 
Enrollment 
(~Days -3 to 
0) 
Randomization 
(Day 0) 
Day 
2 
Day 
10 
Day 
20 
Day 
30 
Day 
45 
Day 
90 
Eligibility 
Assessment 
Medical history 
X 
SARS-Cov 2 test 
positive 
X 
Creatinine/eGFR 
X 
CBC 
X 
Enrollment & 
Randomization 
Informed consent 
X 
Baseline data 
collection 
X 
D-dimer 
X 
Pregnancy testing 
(if necessary) 
X 
Randomization 
X 
Study Drug 
Administration 
Study drug 
provided 
X 
Patient education 
X 
X 
X 
X 
X 
Confirmation of 
study drug taken 
X 
X 
X 
X 
Study Procedures 
Confirm study 
drug adherence 
X 
X 
X 
X 
Outcome 
assessment 
X 
X 
X 
X 
X 
X 
AE assessment 
and reporting 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
Assessments 


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Biorepository 
samples 
(substudy, 
optional) 
X 
X* 
*Second biorespository sample should be collected between Days 30 and 45, after the patient has 
discontinued study drug.     
 
6.2 
Laboratory Procedures/Evaluations 
All study participants will have either (1) clinical/standard of care D-dimer results or (2) a study 
D-dimer drawn within 72 hours prior to randomization.  Hgb, Creatinine, and Platelet Count can 
be within 72 hours prior to study enrollment. The creatinine is used in the calculation of the 
eGFR, and a eGFR <30 mL/min/1.73 m2 is an exclusion criterion (see Stage 1 exclusion criteria 
in Appendix 3).   Include the LFT, LDH and Albumin if completed during the participant’s hospital 
stay.  These results (LFT, LDH, and Albumin) can be the most recent if not drawn within 72-hour 
of hospital discharge.  
In addition, participants who consent to the biorepository substudy will be given the option of 
providing a blood sample by phlebotomy or independently mailing in a dry blood spot sample at 
two time points: 
1) On Day 0, prior to initiation of the study drug 
2) Between Days 30 and 45, after the patient has discontinued the study drug. 
 
The proposed samples to be collected for the biorepository during Stage 1 of the study are 
reviewed in Appendix 4. Samples collected for the biorepository may change to accommodate 
the adaptive design of the study in response to changes in trial design. 
 
6.2.1 Study encounters 
Baseline screening and enrollment (occurs ~Day –3 up to Day 0) 
1. Inclusion/exclusion criteria reviewed—including a pregnancy test, if necessary—and 
eligibility for the trial determined. Prior urine or serum pregnancy test results accepted as 
long as they are obtained within the hospitalization.  Abstinence does not count as a 
reason not to obtain a pregnancy test. 
2. Patient enrolled into the study and informed consent obtained 
3. Patient provided with information concerning the study, contact information, etc. 
4. Occurs during last few days of hospitalization 
 
Encounter 1:  Randomization (Day 0) 
1. Patient randomized to study drug 
2. Information concerning the study, contact information, etc., reviewed with the patient 
3. Clinical/standard of care D-dimer results or a study D-dimer drawn within 72 hours prior to 
randomization  
4. Randomization expected to occur on day of discharge from the hospital 
 
Encounter 2:  First follow-up (Day 2) 
1. First post-discharge encounter 
2. Confirm taking study medication, review for any outcome events, adverse events 
 
Encounter 3:  Day 10 
1. Second post-discharge encounter 
2. Confirm taking study medication, review for any outcome events, adverse events 
 
Encounter 4:  Day 20 
1. Third post-discharge encounter 
2. Confirm taking study medication, review for any outcome events, adverse events 
 
 


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Encounter 5:  Day 30 
1. Fourth post-discharge encounter 
2. Confirm taking study medication, review for any outcome events, adverse events 
3. Participant will stop taking the study medication on Day 30 
4. Events occurring up to this encounter will be included in the primary outcome 
5. Make and confirm arrangements for second biorepository encounter 
 
Encounter 6:  Day 45 
1. Fifth post-discharge encounter 
2. Review for any outcome events, adverse events 
3. Confirm second biorepository encounter has occurred 
 
Encounter 7:  Day 90 encounter 
1. Sixth and last post-discharge check-in 
2. Review for any outcome events, adverse events 
3. Follow-up ends after the Day 90 encounter 
 
6.3 
Concomitant Medications, Treatments, and Procedures 
Concomitant medications taken during study participation will be recorded on the case report forms 
(CRFs). Concomitant medications to be recorded are: 
1. Antiplatelet therapies (e.g., aspirin, clopidogrel) 
2. Anticoagulant medications that may be prescribed to the participant after randomization and 
discharge from the hospital (e.g., a new prescription introduced by an outpatient provider, 
without notification of the study team, in response to a clinical concern about thrombosis risk 
or symptoms) 
3. Other therapies that may impact arm-specific appendices 
 
6.4 
Expedited Critical and Major Event Reporting 
All efficacy and safety outcome events will be assessed and documented in the patients’ study 
records. Events meeting the DSMB-specified severe criteria will be reported within 1 business day 
of Safety being notified. These events include major bleeding (fatal bleeding or symptomatic 
bleeding in a critical area or organ), including intracranial hemorrhage. 
 
The ACTIV-4c trial will have a common policy for reporting adverse events to ensure that all events 
are assessed quickly and are submitted to the DSMB, IRB(s), and other groups as needed (e.g., 
FDA), following each group’s reporting guidelines and timelines. Sites are required to follow their 
local guidelines for adverse event and unanticipated problem reporting. 
 
6.5 
Data and Safety Monitoring Plan and Study Halting Rules 
The ACTIV-4 will have a single Data and Safety Monitoring Plan with a single Data and Safety 
Monitoring Committee to review all research carried out within the master protocol. 
 
7.  Statistical Considerations 
 
7.1 
Statistical and Analytical Plans (SAP) 
This section provides an overview of the design and main analyses for the key endpoints. A 
separate SAP will be constructed for the DSMB review process. Additionally, a final SAP will be 
formalized and agreed upon by the study team prior to the completion of the study and before 
database lock for each stage. The final SAP will include additional details about the statistical 
analyses, including analysis of specified populations, plans for addressing missing data, and 
planned sensitivity analyses. 
 
7.2 
Power and Sample Size Calculations 


Study number: 20203331 
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The primary analysis for this randomized trial will be an intention-to-treat comparison of a composite 
endpoint (CE) of venous thromboembolic events, including new, symptomatic proximal or distal 
deep vein thrombosis affecting the upper and/or lower extremities, pulmonary embolism, or 
thrombosis of other veins (e.g., cerebral sinus veins, splanchnic veins); arterial thromboembolic 
events, including new ischemic stroke, myocardial infarction, mesenteric or peripheral arterial 
thromboembolism; and all-cause mortality for up to 30 days after randomization across the 
intervention arms. This binary primary endpoint was used to power the study. 
 
The MARINER trial (21) reported a 2% event rate for a combined outcome of VTE, MI, CVA, or CV 
deaths in the placebo group. These rates are expected to be higher in COVID-19 patients who are 
discharged from the hospital. Recent information from patients discharged alive from the University 
of Pittsburgh Medical Center suggests that the 30-day mortality rate in this population could be as 
high as 4%. To be conservative, 4% was used as the expected CE rate of events for the no 
anticoagulant arm. An effect size of 35% percent risk reduction (risk ratio = 0.65) in the 
anticoagulant group compared to no anticoagulant group was used to calculate the expected 
sample size for the study. 
 
The analysis will use a group-sequential two-sample two-sided Z-test for proportions with pooled 
standard deviation to test the primary hypothesis at overall significance level alpha = 0.05. Four 
equally spaced interim analyses and one final analysis will use O’Brien-Fleming alpha spending 
boundaries for decision-making (27, 28). In order to ensure an 80% power to detect a CE rate 
reduction of 35% through anticoagulation use, the study needs to enroll at least 2,530 participants 
per arm. Since the primary outcome is observed within 30 days of follow-up, the loss to follow-up 
and withdrawal of consent rates should be low, and it is estimated that CE will be missing on a 
maximum of 5% of the participants. Therefore, the sample size required for this study will be 
approximately 2,660 per arm. The sample size has been calculated using 2,000 simulations in 
PASS 13 [PASS 13 Power Analysis and Sample Size Software (2014). NCSS, LLC. Kaysville, 
Utah, USA, ncss.com/software/pass]. 
 
7.3 
Primary Outcome Analysis 
The ITT principle will be used for the treatment comparisons of trial outcomes such that subjects 
randomized to the treatment arms will be included in the analysis. Trial follow up will begin at the 
time of randomization. In other words, Day 0 is the day of randomization. 
 
As a primary approach, the primary endpoint will be compared between two arms using a two- 
sample Z-statistic for proportion (standardized difference between proportion having CE in 
anticoagulant arm and matching placebo arm, positive difference favoring anticoagulant arm). More 
explicitly, denoting 𝑝𝑝𝑝𝑝, 𝑝𝑝𝑝𝑝𝐴𝐴𝐴𝐴and 𝑝𝑝𝑝𝑝𝑃𝑃𝑃𝑃 the estimated proportion of CE in the whole sample, anticoagulant 
and placebo group respectively, the null hypothesis of no difference in the proportions will be tested 
using the test statistic 
 
𝑍𝑍= (𝑝𝑝𝑃𝑃−𝑝𝑝𝐴𝐴)/𝑆𝑆𝑆𝑆(𝑝𝑝𝑃𝑃−𝑝𝑝𝐴𝐴), 
where 𝑆𝑆𝑆𝑆(𝑝𝑝𝑃𝑃−𝑝𝑝𝐴𝐴) will be estimated by pulling over the two groups, that is 
𝑆𝑆𝑆𝑆(𝑝𝑝𝑃𝑃−𝑝𝑝𝐴𝐴) = √ቂ𝑝𝑝(1 −𝑝𝑝) ቀ
1
𝑛𝑛𝑃𝑃 +
1
𝑛𝑛𝐴𝐴ቁቃ, 
where 𝑛𝑛𝑃𝑃  and 𝑛𝑛𝐴𝐴 are the sample sizes for the placebo and anticoagulant groups, respectively. 
 
For Stage 1, the CE rates will also be modeled using a log-binomial regression model with 
treatment arm as the independent variable and adjusting for trial stratification variables (i.e., 
antiplatelet use; WHO ordinal scale score). Secondary analyses of this endpoint will include 


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adjustment for D-dimer levels, patient characteristics, and demographic factors, including race and 
ethnicity. The matching placebo arm will serve as the “reference group” in this model, and analysis 
will involve testing whether the coefficient for each active treatment group relative to the reference 
group is equal to 0, or equivalently, whether the adjusted relative risk for anti-coagulant arm is equal 
to 1. The adjusted relative risk and the related confidence interval will be provided. 
 
In addition, unadjusted event rates for each treatment group, and relative risk and the absolute risk 
differences with confidence intervals, will be calculated and presented. Kaplan-Meier cumulative 
incidence curves will also be presented to allow visualization of the patterns of time to first events. 
As a sensitivity analysis, a modified intention-to-treat analysis, excluding all randomized participants 
who fail to initiate treatment, will be conducted. 
 
 
7.4 
Secondary and Exploratory Endpoints Analyses 
 
There are four secondary outcomes that are of interest in this trial. We will use a fallback method to 
control for type I error (see page 30 of the Food and Drug Administration guidance on multiple endpoints 
in clinical trials; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/multiple-
endpoints-clinical-trials-guidance-industry ).  More specifically, these secondary outcomes will only be 
formally tested if the primary hypothesis was rejected at level alpha=0.05. The ordering of the secondary 
endpoints is as follows:  
1) Primary endpoint at 45 days (CE45) 
2) Primary endpoint at 90 days (CE90) 
3) Venous events at 30 days (CEVTE30) 
4) Arterial events at 30 days (CEATE30) 
Using a fallback method the 0.05 type I error rate would be split as follows – 0.035, 0.005, 0.005, and 
0.005.  If CE45 was statistically significant then CE90 would be tested at 0.04 = 0.035 + 0.005.  On the 
other hand, if CE45 was NOT statistically significant then CE90 would be tested at 0.005.  The process 
would continue until all 4 secondary endpoints were tested. 
 
Statistical methods for testing the secondary endpoints listed above will follow exactly the same 
procedures used for the primary endpoint described in Section 4.2 above. Except that for the CEVTE30 
and CEATE30 events, an additional sensitivity analysis will be conducted by combining death from any 
causes to each one of the events separately.   
 
 
7.5 
Tabulation of Individual Response Data 
The composite outcome evaluated will be tabulated and broken down by component (e.g., death, 
pulmonary embolus, symptomatic DVT, myocardial infarction, etc.). Note that all clinical endpoint 
events that occur during the 30-day treatment period will be collected regardless of whether a 
patient discontinues therapy or experiences an initial clinical event. As a result, some participants 
may experience more than one component of the primary endpoint. Event rates and relative risks 
and the absolute risk difference between treatment groups will be calculated with their confidence 
intervals for each of the defined secondary endpoints. 
 
7.6 
Sub-group Analyses 
A select number of subgroup analyses will be performed based on pre-specified baseline factors 
that potentially modify the effect of treatment. The main subgroup analyses will be done for 
antiplatelet use and no antiplatelet use groups, and for severity of illness during hospitalization, 
based on the WHO ordinal scale score (score < 5, vs. ≥ 5). Additional subgroup analysis are 
described in section 7.6.6. When outcomes are rare within subgroups, the categories may be 


 
Study number: 20203331 
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Page 28 
amalgamated (e.g., White vs. Others, US vs. Other countries). The rate of the 30-day primary 
composite outcome and the safety outcomes will be compared by assigned treatment within pre- 
defined subgroups. In addition, an assessment of whether there is evidence that each subgroup 
variable modifies treatment effectiveness will be performed by creating a log-binomial regression 
model including the subgroup variable, treatment assignment, and the interaction between the 
subgroup variable and treatment assignment, and evaluating the magnitude of the interaction term. 
 
7.6.1 Safety Analyses 
The rates of safety outcomes listed in section 2.3 (e.g., ISTH major bleeding and the rate of ISTH 
clinically relevant non-major bleeding (CRNMB)) during the 30-day treatment period and during the 
additional 60-day safety follow up period between the two arms will be compared. The proportion of 
patients in each assigned treatment group who experience each safety event, the relative risk, and 
the absolute risk difference will be calculated from the observed data, and confidence intervals will 
be calculated. Analyses of the bleeding outcomes that occur during the full 90-day follow-up period 
(i.e., 30-day treatment period plus the 60-day safety follow-up) will also be conducted as part of the 
trial safety analyses 
 
7.6.2 Adherence and Retention Analyses 
Receipt of planned therapy will be recorded on electronic case report forms. The proportion of 
patients evaluated with less than 30-days of follow-up (the primary outcome assessment time) will 
be tabulated. Every effort will be made to re-contact patients who are unreachable. Due to the short 
timeline of trial participation, there should be excellent patient retention. A thorough evaluation of 
missing data patterns will be undertaken. Baseline characteristics of patients with missing primary 
outcome data will be compared to those with complete data; factors associated with missing 
primary outcome data will be identified using logistic regression. Missing follow-up data will not be 
imputed for the analysis of the primary hypothesis unless critical issues are identified. 
 
7.6.3 Baseline Descriptive Statistics 
A limited number of demographic, clinical history, symptom, and biomarker variables will be 
collected for each patient at baseline. The distribution of each variable will be examined. All 
variables will be summarized using appropriate central tendency (mean/median) and spread 
measures (standard deviation, 25th and 75th percentiles, or range) for continuous variables and 
frequency and percent for categorical variables. Baseline characteristics will be examined with 
respect to assigned treatment group to verify randomization balance. 
 
7.6.4 Planned Interim Analysis, Futility, and Efficacy 
An independent data safety and monitoring board (DSMB) will review all interim analyses prepared 
by an unmasked statistician. The trial design planned for 4 interim analyses and a final analysis at 
equally-spaced information points. At each interim analysis cumulative primary outcome data, and 
potentially the secondary analyses, will be presented to the DSMB. Based on the data, a decision to 
stop or continue the trial will be taken following the O’Brien-Fleming Rule. If the Z-statistic crosses 
the lower boundary, the trial will be stopped for futility while if the Z-statistic crosses the upper 
boundary, the trial will be stopped declaring anticoagulant to be effective in preventing CE. In either 
case, Stage 1 of the trial will end and secondary analyses, including subgroup analyses will be 
critical for driving adaptive changes made based on accrued data. Eligibility criteria, efficacy, and 
safety endpoints will be analyzed at predefined intervals to guide the design of subsequent stages 
to allow efficient use of data and resources to inform the adaptations in trial design. 


 
Study number: 20203331 
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Page 29 
Assessments of futility will be conducted at all interim looks, whereas efficacy will only be assessed 
starting at the third interim analysis (after 60% of the information accumulated; Table 4). For the 
efficacy and futility, O’Brien-Fleming analog alpha-spending function and Hwang-Shih-DeCani beta- 
spending function will be utilized to create the non-binding boundaries. Table 4 and Figure 2 
provide specific efficacy and futility boundaries at each interim analysis.. 
 
Table 4: Stopping Boundaries for Efficacy and Futility based on Z-statistic above. 
Look 
Information 
proportion 
Efficacy Boundary 
Futility Boundary 
1 
20% 
NA 
0.1383 
2 
40% 
NA 
-0.5933 
3 
60% 
-2.6686 
-1.1439 
4 
80% 
-2.2887 
-1.5918 
Final 
100% 
-2.0307 
-2.0307 
 
 
 
 
 
Group-Sequential Plot 
 
 
 
 
1 
 
 
 
 
 
0 
 
 
Z Value 
 
 
Z: Crossed Efficacy 
Z: Crossed Futility 
Efficacy Boundary 
-1 
Futility Boundary 
 
 
 
 
-2 
 
 
 
 
0 
10000 
20000 
30000 
40000 
50000 
 
-3 
Information 
 
Figure 2: Stopping Boundaries for Efficacy and Futility based on the Z-statistic described above 
 
 
7.6.5 Safety Review 
Safety monitoring will be continuous. In addition to examining the rate of ISTH major bleeding and 
the rate of ISTH clinically relevant non-major bleeding (CRNMB) in each of the treatment arms, 
monitoring will include unacceptable toxicity, defined as major bleeding, including hospitalization, 
and all-cause mortality. Prior studies have shown that the rate of major bleeding will be very low. 
The degree of evidence about differences in risk of unacceptable toxicity from accruing data will be 
addressed on a regular and pre-determined basis (e.g. every 3 months) and will be shared with the 


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DSMB. Unadjusted safety event rates for each assigned treatment group, and relative risks and the 
absolute risk differences with 95% confidence intervals, will be calculated and presented to the 
DSMB for each of the specified safety outcomes. Additionally, participants with safety events will be 
categorized in comparison to those without the safety events using a logistic regression to identify if 
the safety event was associated with any particular participant characteristics to identify high-risk 
groups, which will potentially inform DSMB of changing the inclusion criteria. 
 
If safety issues arise, the DSMB will use their clinical and statistical judgement to assess the 
potential risks relative to the potential benefits. The DSMB may also examine the safety and 
efficacy data in subgroups known to be high risk for bleeding such as those with older age and/or 
higher BMI. The DSMB will use all available information to make recommendations to the NHLBI. 
The DSMB can recommend that the Post-discharge COVID-19 trial should continue as proposed, 
that one treatment arm or more may be dropped, that the trial protocol should be modified, or that 
the trial should be terminated early for safety reasons. At any of the safety reviews, the DSMB can 
request further statistical evaluation of the safety data to make a decision. Only the DSMB and 
those individuals invited to the DSMB closed-session are permitted to examine outcomes by 
assigned treatment group. The DSMB will evaluate the rates of the primary endpoint and the safety 
endpoints by assigned treatment groups overall and within pre-specified subgroups. 
 
7.6.6 Subgroup Analyses based on Anti-Platelet Use, WHO Severity Score, and Other Pre- 
specified Characteristics 
Beyond its primary aim, a major interest of the trial is to address the effect of anticoagulant 
separately within antiplatelet users and non-users. The primary analysis will be repeated within 
each of these subgroups. The pre-specified subgroups include 
• 
WHO severity score (below five vs. five or above) 
• 
Antiplatelet use and no antiplatelet use groups 
• 
D-dimer, 
• 
BMI, 
• 
age, 
• 
sex, 
• 
race/ethnicity, and 
• 
country of enrollment. 
 
7.6.7 Analyses of Duration of Treatment 
The optimal length of treatment is not well-understood in this clinical setting. Hence, the analyses 
will examine the timing of clinical thrombotic events and safety hemorrhagic events based on the 
accruing data. Kaplan-Meier curves will be created to assess the time to the first thrombotic event 
and the time to the first hemorrhagic event, and Nelson-Aalen cumulative hazard curves will be 
used to assess the cumulative number of events. 
 
8.  Measures to Minimize Bias 
 
8.1 
Enrollment/Randomization 
 
Enrollment 
 
1. Hospitalized patients confirmed COVID-19 positive are screened daily for inclusion/exclusion 
criteria. Any patient who meets all inclusion criteria and no exclusion criteria will be approached 
for enrollment. 


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2. Patients remain in the intention-to-treat group. 
Randomization 
 
Randomization assignments are performed for patients at baseline visit. Randomization will be 
done with equal probability across the arms for which the participant is eligible. For Stage 1, 
randomization stratification will be done by anti-platelet use (yes/no) and WHO severity score (<5 / 
>=5). 
 
The randomization scheme will be determined by the study Stage and its associated group of 
intervention arms. Randomization should obviate the need for additional adjustment factors, but if 
pre-specified demographic or clinical characteristics are unbalanced with respect to treatment 
group, an adjustment will be considered during the analyses phase; these characteristics include 
but are not limited to age, sex, race, ethnicity, BMI, and, potentially, country. 
 
9. Source Documents and Access to Source Data/Documents 
ACTIV-4 will have uniform policies describing what source documents are, how to make 
corrections, and who can access them. 
 
10. Quality Assurance and Quality Control 
ACTIV-4 will have common policies for quality assurance at the data entry level and site monitoring. 
 
11. Ethics/Protection of Human Subjects 
 
11.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR 
Part 56, and/or the ICH E6. 
 
11.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study. All changes to 
the consent form will be IRB approved; a determination will be made regarding whether previously 
consented participants need to be re-consented. 
 
11.3 Informed Consent Process 
 
11.3.1 Consent/Assent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant, and written documentation of informed consent is required prior to starting intervention / 
administering study product. 
 
A written consent will be sought from every participant via a face-to-face consenting process or 
remotely by using a REDCap based e-consent option pending IRB approval of this protocol. 


Study number: 20203331 
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11.3.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Informed consent will be 
obtained following institutional COVID-19 policy to protect study staff. 
 
An extensive discussion of risks and possible benefits of participation will be provided to the 
participants and their families. Consent forms will be IRB-approved and the participant will be asked 
to read and review the document. The investigator will explain the research study to the participant 
and answer any questions that may arise. Participants will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their surrogates or think about it prior to agreeing to 
participate. The participant will sign the consent document prior to any procedures being done 
specifically for the study. The participants may withdraw consent at any time throughout the course 
of the trial. A copy of the signed informed consent document will be provided to participants. The 
rights and welfare of the participants will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. 
 
 
11.4 Posting of Clinical Trial Consent Form 
The informed consent form will be posted on the study website after the clinical trial is closed to 
recruitment, and no later than 60 days after the last study visit by any subject, as required by the 
protocol. 
 
11.5 Participant and Data Confidentiality 
ACTIV-4 has adopted uniform policies for protecting the privacy of participants and maintaining 
confidentiality. 
 
Information about study participants will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
 
• 
What protected health information (PHI) will be collected from participants in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For participants that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e., that the subject is alive) at 
the end of their scheduled study period. 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. 
No information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor. 


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The study monitor, other authorized representatives of the sponsor, and representatives of the IRB 
or pharmaceutical company supplying study product may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records (office, 
clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by local IRB and Institutional regulations. 
 
Participant identifying information will be collected via electronic survey, and will be stored in secure 
encrypted servers at the University of Pittsburgh. All data will be streamed via secure API to the 
project clinical trial management system. Identifiers are required in both of these locations to enable 
electronic outreach to participants for the purpose of self-reported data collection. The participant’s 
name, mobile phone number, address, and contact information will only be housed on a temporary 
basis to allow for follow-up during the course of the trial. These data will be maintained until 
database lock at the end of the trial, at which point they will be destroyed, unless the participant has 
agreed to be contacted for future research. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the University of Pittsburgh Data Coordinating Center. This will 
not include the participant’s contact or identifying information. Rather, individual participants and 
their research data in the central database will be identified by a unique study identification number. 
The study data entry and study management systems used by clinical sites will be secured and 
password protected. At the end of the study, all study databases will be de-identified and archived 
at the NIH designated data repository. 
 
 
12. Data Handling and Record Keeping 
 
12.1 Data Collection and Management Responsibilities 
 
Initial data collection is the responsibility of the clinical trial staff under the supervision of the site PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported. Follow up data will be collected electronically from the participant’s self-report 
and by study staff via telephone. Responsibility for the accuracy, completeness, and timeliness of 
data collected by telephone is under the supervision of the Coordinating Center investigators who 
are responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained 
for recording data for each participant enrolled in the study. Data recorded in the eCRF derived 
from source documents should be consistent with the source documents or the discrepancies 
should be explained and captured in a progress note and maintained in the Coordinating Center’s 
official electronic study record. 
 
12.2 Study Records Retention 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final 
reporting/publication, or 2 years after the last approval of a marketing application is approved for the 
drug for the indication for which it is being investigated or 2 years after the investigation is 


 
Study number: 20203331 
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Page 34 
discontinued and FDA is notified if no application is to be filed or if the application has not been 
approved for such indication. No records will be destroyed without the written consent of the 
sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
 
12.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, 
the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
 
It is the responsibility of the site PI/study staff to use continuous vigilance to identify and report 
deviations. 
 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. Further details about the handling 
of protocol deviations will be included in the MOP. 
 
12.4 Publication and Data Sharing Policy 
This study will comply with the NIH Public Access Policy, which ensures that the public has access 
to the published results of NIH funded research. It requires scientists to submit final peer-reviewed 
journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication. 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a 
clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial as 
any research project that prospectively assigns human subjects to intervention or concurrent 
comparison or control groups to study the cause-and-effect relationship between a medical 
intervention and a health outcome. Medical interventions include drugs, surgical procedures, 
devices, behavioral treatments, process-of-care changes, and the like. Health outcomes include 
any biomedical or health-related measures obtained in patients or participants, including 
pharmacokinetic measures and adverse events. The ICMJE policy, and the Section 801 of the Food 
and Drug Administration Amendments Act of 2007, requires that all clinical trials be registered in a 
public trials registry such as ClinicalTrials.gov, which is sponsored by the National Library of 
Medicine. Other biomedical journals are considering adopting similar policies. For interventional 
clinical trials performed under NIH IC grants and cooperative agreements, it is the grantee’s 
responsibility to register the trial in an acceptable registry, so the research results may be 
considered for publication in ICMJE member journals. The ICMJE does not review specific studies 
to determine whether registration is necessary; instead, the committee recommends that 
researchers who have questions about the need to register err on the side of registration or consult 
the editorial office of the journal in which they wish to publish. 
FDAAA mandates that a "responsible party" (i.e., the sponsor or designated principal investigator) 
register and report results of certain "applicable clinical trials": 
• 
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I 
investigations of a product subject to FDA regulation; 
• 
Trials of Devices: Controlled trials with health outcomes of a product subject to FDA 
regulation (other than small feasibility studies) and pediatric post-market surveillance 
studies. 


 
Study number: 20203331 
Version: 4, Date: 26OCT2021 
 
Page 35 
• 
NIH grantees must take specific steps to ensure compliance with NIH implementation of 
FDAAA. 
 
 
13. Study Finances 
 
13.1 Funding Source 
National Institutes of Health 
 
13.2 Costs to the Participant 
There will be no costs incurred related to the study medication, which will be provided by the study, 
or the baseline D-dimer blood test, if it was not drawn as part of the participants standard of care, 
which will also be covered by the study. There will also be no costs related to participation in the 
optional biorepository. Participant health insurance may be billed for the costs of medical care 
during this study since these expenses would have happened even if the participant was not in the 
study, if their insurance does not cover these costs or participants do not have insurance, these 
costs will be participant responsibility. 
 
14. Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a 
role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the trial. 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by the Conflict of Interest Management Unit (CIMU) with a Committee-sanctioned conflict 
management plan that has been reviewed and approved by the study sponsor prior to participation 
in this study. All investigators will follow the applicable conflict of interest policies. 
 
 


 
 
 
15. References 
References 
 
1. 
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 
2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. 
2. 
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor 
prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844-7. 
3. 
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of 
adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 
2020;395(10229):1054-62. 
4. 
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of 
Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708-20. 
5. 
Al-Samkari H, Karp Leaf RS, Dzik WH, Carlson JC, Fogerty AE, Waheed A, et al. COVID 
and Coagulation: Bleeding and Thrombotic Manifestations of SARS-CoV2 Infection. Blood. 2020. 
6. 
Klok FA, Kruip M, van der Meer NJM, Arbous MS, Gommers D, Kant KM, et al. Incidence of 
thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145-7. 
7. 
Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Muller MCA, et al. 
Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 
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Llitjos JF, Leclerc M, Chochois C, Monsallier JM, Ramakers M, Auvray M, et al. High 
incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb 
Haemost. 2020;18(7):1743-6. 
9. 
Varatharaj A, Thomas N, Ellul MA, Davies NWS, Pollak TA, Tenorio EL, et al. Neurological 
and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. 
Lancet Psychiatry. 2020. 
10. 
Lodigiani C, Iapichino G, Carenzo L, Cecconi M, Ferrazzi P, Sebastian T, et al. Venous and 
arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in 
Milan, Italy. Thromb Res. 2020;191:9-14. 
11. 
Paranjpe I, Fuster V, Lala A, Russak AJ, Glicksberg BS, Levin MA, et al. Association of 
Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With 
COVID-19. J Am Coll Cardiol. 2020;76(1):122-4. 
12. 
Gervaise A, Bouzad C, Peroux E, Helissey C. Acute pulmonary embolism in non- 
hospitalized COVID-19 patients referred to CTPA by emergency department. Eur Radiol. 2020. 
13. 
Bompard F, Monnier H, Saab I, Tordjman M, Abdoul H, Fournier L, et al. Pulmonary 
embolism in patients with Covid-19 pneumonia. Eur Respir J. 2020. 
14. 
Edler C, Schroder AS, Aepfelbacher M, Fitzek A, Heinemann A, Heinrich F, et al. Dying with 
SARS-CoV-2 infection-an autopsy study of the first consecutive 80 cases in Hamburg, Germany. Int 
J Legal Med. 2020;134(4):1275-84. 
15. 
Polat V, Bostanci GI. Sudden death due to acute pulmonary embolism in a young woman 
with COVID-19. J Thromb Thrombolysis. 2020;50(1):239-41. 
16. 
Parra LM, Cantero M, Morras I, Vallejo A, Diego I, Jimenez-Tejero E, et al. Hospital 
readmissions of discharged patients with COVID-19. medRxiv. 2020. 
17. 
Amin AN, Varker H, Princic N, Lin J, Thompson S, Johnston S. Duration of venous 
thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med. 
2012;7(3):231-8. 
18. 
Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, et al. Extended- 
duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced 
mobility: a randomized trial. Ann Intern Med. 2010;153(1):8-18. 
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Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, et al. Apixaban 
versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 
2011;365(23):2167-77. 
20. 
Cohen AT, Spiro TE, Buller HR, Haskell L, Hu D, Hull R, et al. Rivaroxaban for 
thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368(6):513-23. 
21. 
Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, et al. Extended 
Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med. 
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Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, et al. Rivaroxaban 
for Thromboprophylaxis after Hospitalization for Medical Illness. N Engl J Med. 2018;379(12):1118- 
27. 
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Schunemann HJ, Cushman M, Burnett AE, Kahn SR, Beyer-Westendorf J, Spencer FA, et 
al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: 
prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv. 2018;2(22):3198-225. 
24. 
Fox SE, Akmatbekov A, Harbert JL, Li G, Quincy Brown J, Vander Heide RS. Pulmonary 
and cardiac pathology in African American patients with COVID-19: an autopsy series from New 
Orleans. Lancet Respir Med. 2020. 
25. 
Garg S, Kim L, Whitaker M, O'Halloran A, Cummings C, Holstein R, et al. Hospitalization 
Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 
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64. 


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26. 
Wadhera RK, Wadhera P, Gaba P, Figueroa JF, Joynt Maddox KE, Yeh RW, et al. Variation 
in COVID-19 Hospitalizations and Deaths Across New York City Boroughs. JAMA. 2020. 
27. 
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 
1979;35(3):549-56. 
28. 
Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error 
probability spending functions. Stat Med. 1990;9(12):1439-45. 
29. 
Wijeysundera DN, Austin PC, Hux JE, Beattie WS, Laupacis A. Bayesian statistical 
inference enhances the interpretation of contemporary randomized controlled trials. J Clin 
Epidemiol. 2009;62(1):13-21 e5. 


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Appendix 1: Criteria for Addition and Replacement of Arms 
 
This master protocol trial design is built as a process, with the possibility of multiple interventions 
being investigated. In subsequent stages, this trial may incorporate 2 or more interventions, and the 
number of interventions may evolve as the science evolves and as data accrues during the course 
of the trial. 


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Appendix 2: Definition and Determination of Outcomes 
 
A2.1 
Approach to ascertainment and verification of outcomes 
Patients will be enrolled and randomized in the inpatient setting, prior to discharge from the hospital 
(see Figure 1 in the main protocol). A total of six follow-up contacts would be made during the 
course of the study, at study days 2, 10, 20, 30, 45, and 90. Although one or more of these 
encounters may occur as part of an in-person study visit, we anticipate that most of these 
encounters will occur via remote telephone monitoring. All patient reported events will be 
investigated by the Central Coordinating Center, including obtaining information from healthcare 
facilities where patients received treatment and/or were admitted to the hospital. An independent 
central adjudication committee (ICAC) will review and adjudicate events in a blinded manner 
without awareness of treatment allocation. During the study period, the ICAC will adjudicate all 
suspected occurrences of venous or arterial thromboembolic events, acute myocardial infarction, 
acute ischemic stroke, and all-cause mortality. The ICAC will also review all reported episodes of 
bleeding that require medical attention and categorize these events as meeting criteria for major, 
non-major clinically relevant, or minor bleeding. The ICAC will also review all reported 
hospitalization events. The ICAC will be provided with all relevant documentation related to these 
events. The criteria and definitions of the study outcomes as well as the procedures followed by the 
Committee will be described in an adjudication manual which will be provided to the ICAC members 
prior to the first meeting. 
 
A2.2 
Outcome definitions 
The primary study outcome is a composite endpoint of venous and/or arterial thromboembolic 
events, including new, symptomatic proximal or distal DVT of the upper or lower extremities, 
symptomatic PE, other venous thrombotic events, ischemic stroke, myocardial infarction, and 
mesenteric or peripheral arterial thromboses, and all-cause mortality up to 30 days after discharge 
from the hospital. These endpoints are individually defined below. 
 
Deep vein thrombosis 
Deep vein thrombosis will be diagnosed by venous ultrasound or point-of-care ultrasound (POCUS) 
or other imaging modality, performed for clinical indications and documented in a note. A positive 
ultrasound test is defined by a non-compressible or partially non-compressible venous segment in 
an upper or lower extremity. Deep vein thrombosis may be either proximal (e.g., femoral vein) or 
distal (e.g., deep veins of the calf), but thrombosis of a superficial vein only does not meet criteria 
for a DVT. 
 
Pulmonary embolism 
Pulmonary embolism will be confirmed by chest CT using a PE protocol (CTPA), ventilation- 
perfusion scan (V/Q), or digital subtraction angiography (DSA), performed for clinical indications. A 
positive CTPA is defined as a central contrast filling defect or complete occlusion up to the 
subsegmental level of the pulmonary arteries. A positive V/Q is defined as at least two large 
mismatched segmental perfusion defects or the arithmetic equivalent of moderate or large and 
moderate defects (revised PIOPED). A positive DSA is defined as a filling defect or a cut-off of a 
vessel of >2.5 mm. Source for criteria: http://isth.breakthrough.healthcare/. 
 
Other venous thrombotic events 
Other venous thrombotic events include cerebral sinus venous thrombosis, splanchnic venous 
thrombosis, or renal vein thrombosis, all confirmed by appropriate imaging studies (e.g., CT 
angiography, MR venography) performed for clinical indications. 


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Ischemic stroke 
Ischemic stroke will be confirmed by head CT or MRI performed for the development of new 
symptoms (e.g., acute hemiplegia). A transient ischemic attack is not considered an outcome for 
this study. 
 
Myocardial infarction 
Myocardial infarction is defined according to the universal definition of MI, which excludes 
myocardial injury. MI must include rise and fall of cardiac troponin above the 99th percentile with 
ECG changes consistent with ischemia, plus: new/presumed new wall-motion abnormalities or 
other imaging evidence of MI; potentially ischemic symptoms; and/or abnormal coronary 
angiography. 
 
Arterial thromboembolism 
Arterial thromboembolism may involve a visceral organ (e.g., spleen, kidney) or limb and must be 
confirmed by appropriate imaging studies (e.g., CT angiography). 
 
All-cause mortality 
Death due to any cause. 
 
Secondary study outcomes will include venous thromboembolism (inclusive of deep vein 
thrombosis, pulmonary embolism, and other venous thrombotic events) and arterial 
thromboembolism (inclusive of ischemic stroke, MI, and other arterial thromboembolic events) up to 
30 days after discharge from the hospital, as well as the primary composite endpoint, up to 45 days 
and 90 days after discharge from the hospital. 
 
Hospital re-admission 
Re-admission to the hospital due to any cause. 
 
Safety endpoints 
Safety endpoints will include (1) major bleeding and (2) clinically-relevant non-major bleeding, both 
as defined by the International Society on Thrombosis and Haemostasis (ISTH). 
 
Major bleeding 
Bleeding events that are characterized as: (1) fatal bleeding; (2) bleeding into a critical area or 
organ (e.g., intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with 
compartment syndrome, retroperitoneal); or (3) bleeding causing a fall in the hemoglobin level of 2 
g/dL or more, or leading to transfusion of 2 or more units of whole blood or red cells. 
 
Clinically-relevant, non-major bleeding 
Bleeding events that are characterized as: (1) bleeding requiring medical intervention by a 
healthcare professional; (2) bleeding leading to hospitalization or an increase in the level of care; or 
(3) bleeding prompting a face-to-face (i.e., not just a telephone or electronic communication) 
evaluation. 


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Appendix 3: Study Arms A and B for Stage 1 
Stage 1 of this study will compare prophylactic-dose anticoagulant therapy (Arm A) to matching 
placebo (Arm B) on the composite endpoint of venous thromboembolism, ischemic stroke, 
myocardial infarction, peripheral arterial thromboembolism, or all-cause mortality. The anticoagulant 
therapy will be apixaban, 2.5 mg every 12 hours. The general design of the trial is provided below. 
 
 
Figure 3. Stage 1 Post-Discharge Clinical Trial. Patients will be enrolled in the Study prior to discharge from the 
hospital and randomized to either apixaban 2.5 mg every 12 hours or matching placebo. Screening and enrollment will 
occur prior to discharge from the hospital, with randomization occurring as close to discharge as possible (randomization 
identified as the encircled “R”, occurring immediately prior to discharge, identified by the vertical dashed line). Follow-up 
encounters for the primary outcome will occur on Days 2+3, 10+6, 20+6, and 30+10. Two additional follow-up encounters 
will occur for secondary outcomes on Days 45+14 and 90+14. 
 
 
 
The trial is a prospective, randomized, double-blind, placebo-controlled trial that compares an 
extended prophylactic anticoagulant regimen to matching placebo. Participants randomized to Arm 
A will receive apixaban 2.5 mg orally twice a day for 30 days. Participants randomized to Arm B will 
receive a matching placebo. Follow-up encounters occur as shown in Figure 3. 
 
This trial design will investigate whether prophylactic anticoagulation with apixaban is superior to 
matching placebo in this setting. 
 
 
A3.1 Potential Risks & Benefits 
 
A3.1.1 Known Potential Risks 
Participants who use anticoagulant therapy are at an increased risk for developing hemorrhagic 
complications, although this risk is low in patients who are receiving a prophylactic dose of 
anticoagulant therapy. 


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A3.1.2 Known Potential Benefits 
Several studies have demonstrated the importance of prophylactic anticoagulant therapy in patients 
with COVID-19 who are hospitalized. Although the data are currently limited, there are concerns 
that the increased thrombotic risk exhibited by these patients persists into the convalescent phase 
following discharge from the hospital. We hypothesize that the frequency of these post-discharge 
thromboembolic complications will be decreased with the use of a prophylactic anticoagulant. 
 
A3.2 
Study Enrollment for Stage 1, Arms A and B 
 
A3.2.1 Inclusion Criteria 
Inclusion criteria for Stage 1 of the protocol: 
1. Age ≥ 18 years 
2. COVID-19 positive test (PCR, antigen, or point of care test diagnosing a current infection) 
within 2 weeks of hospital admit date. 
3. Hospitalized for COVID-19 infection for 48 or more hours 
 
A3.2.2 Exclusion Criteria 
Exclusion criteria for Stage 1 of the protocol: 
1. Existing indication for anticoagulation, either therapeutic or prophylactic dose 
2. Contraindication to antithrombotic therapy, such as 
a) ischemic stroke, intracranial bleed, or neurosurgery within 3 months 
b) Known bleeding within the last 30 days requiring emergency room presentation of 
hospitalization 
c) Known major surgery with 14 days (at least 1 hour and/or requires general 
anesthesia) 
d) Inherited or acquired active bleeding disorder 
3. Platelet count < 50,000/mcL 
4. Hemoglobin < 8 gm/dL 
5. Renal insufficiency (eGFR < 30 mL/min/1.73 m2) 
6. Pregnancy 
7. Prison inmate 
8. Life expectancy less than 90 days 
9. Unwilling or unable to provide informed consent/unwilling or unable to complete the study 
protocol 
10. Dual antiplatelet therapy that cannot be discontinued 
11. Concomitant need for strong inducers/inhibitors of p-gp and CYP3A4 
 
Note that the additional exclusion criteria for dual antiplatelet therapy, and for strong 
inducers/inhibitors of p-gp and CYP3A4, is specific to Stage 1, since Arm A is an anticoagulant, and 
the anticoagulant being studied in Stage 1 is a direct oral anticoagulant. 
 
A3.3 Safety Analyses 
The rates of bleeding and thrombotic events will be summarized for each arm. For Stage 1, the 
rates of bleeding in Arm A, the “Anticoagulant” arm, will be directly compared to the rates of 
bleeding in Arm B, the “No anticoagulant” arm. If the rate of major or clinically relevant non-major 
bleeding in the anticoagulant arm exceeds the rate of bleeding in the no anticoagulant arm by more 
than 5%, this will trigger a review by the DSMB for a risk-benefit analysis of this approach. 


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A3.4 Treatment Regimen: Arm A 
1. Prophylactic anticoagulant therapy 
• 
Apixaban 2.5 mg twice daily for 30 days. 
 
Apixaban was selected because of its documented efficacy and safety records, current 
usage in millions of patients, and ease of use. The prophylactic dose of apixaban (2.5 mg 
twice daily) was chosen because bleeding complications have been observed in patients 
with COVID-19 following hospital discharge and because a significant subset of the study 
participants will also be on an antiplatelet agent. 
 
A3.5 Treatment Regimen: Arm B 
1. No anticoagulant therapy 
• 
Matching placebo. 
 
A3.6 Statistical Analyses 
The anticoagulant arm (Arm A) will be compared to the matching placebo (Arm B) for efficacy on 
the primary outcome and the secondary endpoints, as described in Section 7 of the Master 
Protocol. 
 
 
A3.7 Adverse Events 
DEFINITIONS 
ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of investigational product, whether or not considered related to 
the investigational product. 
 
A non-serious adverse event is an AE not classified as serious. 
 
SERIOUS ADVERSE EVENTS 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• 
results in death 
• 
is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below) 
• 
results in persistent or significant disability/incapacity 


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• 
is a congenital anomaly/birth defect 
• 
is an important medical event (defined as a medical event(s) that may not be immediately life- 
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) 
• 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE. 
 
Although pregnancy and potential drug-induced liver injury (DILI), are not always serious by 
regulatory definition, however, these events must be reported within the SAEs timeline. 
 
Any component of a serious study endpoint that is considered related or not related to study 
therapy should be reported as an SAE (e.g., death is an endpoint, if death occurred due to 
anaphylaxis, anaphylaxis must be reported). 
 
NOTE: The following hospitalizations are not considered SAEs: 
 
− 
a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event) 
− 
elective surgery, planned prior to signing consent 
− 
admissions as per protocol for a planned medical/surgical procedure 
− routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
− Medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases. 
− Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason). 
− 
Admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols) 
 
Adverse Event and Serious Adverse Event Collection Period 
All non-serious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period through the 90-day visit or check-in and 
for a minimum of 30 days following the last dose of study treatment if the participant 
prematurely stops study drug. 
Serious adverse events will be collected from informed consent through the 90-day visit or 
check-in. If the participant prematurely stops study drug, the collection  will occur through a 
minimum of 30 days following discontinuation of dosing. 
Following the subject’s written consent to participate in the study, SAEs, whether related or 
not related to study drug, are collected, including those thought to be associated with protocol- 
specified procedures. 
 


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Event Reporting 
 
Non-serious AEs should be reported as SAEs if they become serious. 
Non-serious AEs are to be provided to BMS in aggregate via the final study report as specified in the 
agreement or, if a regulatory requirement [eg, IND US trial] as part of an annual reporting requirement. 
Serious adverse events that occur following the participant’s written consent to participate in the 
study through 30 days of discontinuation of dosing must be reported to BMS Worldwide Safety, 
whether or not the subject started study drug and whether related or not related to study drug. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure (e.g., a 
follow-up skin biopsy). 
 
Participants can record events within an electronic patient portal. Participants can call to report an 
event. In addition, the Research Communication Center (RCC) is responsible for performing periodic 
assessments with the participants for adverse events. 
 
If the RCC notes an unplanned medical contact by the participant (physician visit, emergency room 
(ER), Urgent care or hospitalization), the RCC will escalate to a pharmacist. The pharmacist will 
complete the Pharmacist Escalation Form within the EDC. Medical records will be obtained for 
hospitalizations, ER visits or if the pharmacist is unsure of potential endpoint or safety event. The 
coordinating center medical coordinator coordinates retrieval and upload of source documents for 
appropriate capture of the event(s) within the EDC. The coordinating center medical coordinator will 
provide the Pharmacist Escalation Form and received source documents to the coordinating center 
Core Medical Monitor.  
 
The Core Medical Monitor will review the source documents to determine the event and will complete 
the AE/SAE form in the EDC including seriousness and causality to study drug prior for notification to 
DCRI Safety Surveillance. 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to DCRI 
Safety Surveillance. 
 
The Core Medical Monitors should report any SAE occurring after these aforementioned time 
periods, which is believed to be related to study drug or protocol- specified procedure.  
An SAE report should be completed for any event where doubt exists regarding its 
seriousness. 
If the Core Medical Monitor believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a complication of a 
study procedure), the relationship should be specified in the narrative section of the AE/SAE Form 
in the EDC. 


 
St u d y n u m b er : 2 0 2 0 3 3 3 1 
V er si o n: 5 , D at e: 2 0 A P R 2 0 2 2  
 
P a g e 4
 
U p o n r e c ei pt b y D C RI S af et y, D C RI S af et y will r e p ort t o B M S wit hi n 1 b u si n e s s d a y of b e c o mi n g 
a w ar e of t h e e v e nt t h at i s d et er mi n e d t o b e a n S A E. S A E s will b e r e c or d e d o n eit h er CI O M S or 
M e d W at c h f or m. T h e B M S Pr ot o c ol n u m b er will b e i n cl u d e d o n t h e c o v er s h e et wit h t h e S A E 
f or m tr a n s mi s si o n. 
 
T h e S p o n s or I n v e sti g at or d e si g n e e will r e c o n cil e t h e cli ni c al d at a b a s e S A E c a s e s ( c a s e l e v el 
o nl y ) tr a n s mitt e d t o B M S Gl o b al P h ar m a c o vi gil a n c e (W orl d wi d e. S af et y @ b m s. c o m ). 
 T h e D C RI S af et y will r e q u e st fr o m B M S G P V & E, 
a e p b u si n e s s pr o c e s s @ b m s. c o m  t h e S A E r e c o n cili ati o n r e p ort a n d i n cl u d e t h e 
B M S pr ot o c ol n u m b er e v er y 3 m o nt h s a n d pri or t o d at a b a s e l o c k or fi n al d at a 
s u m m ar y  
 G P V & E will s e n d t h e D C RI S af et y t h e r e p ort t o v erif y a n d c o nfir m all 
S A E s h a v e b e e n tr a n s mitt e d t o B M S  G P V & E.  
 T h e d at a el e m e nt s li st e d o n t h e G P V & E r e c o n cili ati o n r e p ort will b e u s e d  f or 
c a s e i d e ntifi c ati o n p ur p o s e s. If D C RI S af et y d et er mi n e s a c a s e w a s n ot 
tr a n s mitt e d t o B M S G P V & E, t h e c a s e s h o ul d b e s e nt i m m e di at el y t o B M S 
(W orl d wi d e. S af et y @ b m s. c o m ). 
I n a d diti o n t o t h e S p o n s or I n v e sti g at or’ s r e s p o n si bilit y t o r e p ort e v e nt s t o t h eir l o c al h e alt h a ut h oriti e s 
( H A), s u s p e ct e d s eri o u s a d v er s e r e a cti o n s ( w h et h er e x p e ct e d or u n e x p e ct e d) s h all b e r e p ort e d b y 
B M S t o t h e r el e v a nt c o m p et e nt h e alt h a ut h oriti e s i n all c o n c er n e d c o u ntri e s a c c or di n g t o l o c al 
r e g ul ati o n s ( eit h er a s e x p e dit e d a n d/ or i n a g gr e g at e r e p ort s). 
I n a c c or d a n c e wit h l o c al r e g ul ati o n s, B M S will n otif y s p o n s or i n v e sti g at or s of all r e p ort e d S A E s 
t h at ar e s u s p e ct e d (r el at e d t o t h e i n v e sti g ati o n al pr o d u ct) a n d u n e x p e ct e d (i e, n ot pr e vi o u sl y 
d e s cri b e d i n t h e I B). A n e v e nt m e eti n g t h e s e crit eri a i s t er m e d a S u s p e ct e d, U n e x p e ct e d S eri o u s 
A d v er s e R e a cti o n ( S U S A R). S p o n s or i n v e sti g at or n otifi c ati o n of t h e s e e v e nt s will b e i n t h e f or m 
of eit h er a S U S A R R e p ort or a S e mi -A n n u al S U S A R  R e p ort.  
 O t h er i m p ort a nt fi n di n g s w hi c h m a y b e r e p ort e d b y B M S a s a n E x p e dit e d S af et y R e p ort 
( E S R) i n cl u d e: i n cr e a s e d fr e q u e n c y of a cli ni c all y si g nifi c a nt e x p e ct e d S A E, a n S A E 
c o n si d er e d a s s o ci at e d wit h st u d y pr o c e d ur e s t h at c o ul d m o dif y t h e c o n d u ct of t h e st u d y, 
l a c k of effi c a c y t h at p o s e s si g nifi c a nt h a z ar d t o st u d y p arti ci p a nt s, cli ni c all y si g nifi c a nt 
s af et y fi n di n g fr o m a n o n cli ni c al ( e. g., a ni m al) st u d y, i m p ort a nt s af et y r e c o m m e n d ati o n s 
fr o m a st u d y d at a m o nit ori n g c o m mitt e e, or s p o n s or or B M S d e ci si o n t o e n d or t e m p or aril y 
h alt a cli ni c al st u d y f or s af et y  r e a s o ns.  


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 Upon receiving an ESR from BMS, the Sponsor Investigator must review and retain the 
ESR with the IB. Where required by local regulations or when there is a central IRB/IEC 
for the study, the Sponsor will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. The 
investigator should also comply with the IRB/IEC procedures for reporting any other 
safety information. 
 
Follow-up 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 1 business day to BMS by DCRI 
Safety Surveillance using the same procedure used for transmitting the initial SAE report. 
 
All SAEs should be followed to resolution or stabilization. 
 
Causal Assessment 
 
The causal relationship to study drug is determined by a physician and should be used to assess all 
serious adverse events (SAE). The casual relationship can be one of the following: 
 
• 
Related: There is a reasonable causal relationship between study drug administration and 
the AE. 
• 
Not related: There is not a reasonable causal relationship between study drug administration 
and the AE. 
 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.) 
 
 


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13.3 Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported to BMS as such. 
 
The following laboratory abnormalities should be documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy. 
 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value). 
 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half-lives after product administration, the investigational product will be 
permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for 
participant). 
 
The Core Medical Monitor must immediately notify DCRI Safety Surveillance of the pregnancy via 
the BMS Pregnancy Surveillance Form in accordance with SAE reporting procedures. 
 
DCRI Safety Surveillance will perform due diligence follow-up using the BMS Pregnancy 
Form, which the Core Medical Monitor must complete. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the BMS Pregnancy 
Surveillance Form if known within the study participation period.  If pregnancy outcome is not 
known at the time of the participant’s last visit of the study, BMS will follow up regarding pregnancy 
and neonatal outcome. A BMS Pregnancy Surveillance Form may be provided upon request. Any 
associated AE or SAE should be reported with the EDC. 
 
13.4 Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, 
X-rays, and any other potential safety assessments, whether or not these procedures are required 
by the protocol, should also be recorded as a non-serious or serious AE, as appropriate, and 
reported accordingly. 


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Appendix 4. Biospecimens 
 
Biospecimens will be collected at two time points during the study, at the time of enrollment, and 
following completion of the antithrombotic therapy being studied (shortly after Day 30 for Stage 1). 
Samples that would collected for the biorepository would collect citrated plasma (2 tubes), serum, 
and a sample for genomic DNA or dried blood spot samples. 
 
At sites capable of sample collection and processing, additional samples sent by the site teams 
may include: Pax gene DNA; Pax gene RNA; Platelets; and Cryopreserved PBMS. 


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Appendix 5.  Addition of New Key Secondary and Exploratory Outcomes 
 
A5.1 
Rationale for new Secondary and Exploratory Outcomes 
Health-related quality of life data has been collected on participants in ACTIV 4c by use of the 
EuroQol 5 Dimension 5 Level (EQ-5D-5L) survey, administered at three timepoints following 
randomization into the study:  Day 2 (within the first few days of starting study drug), Day 30 (time 
of completion of study drug), and Day 90 (60 days after completion of study drug).  The EQ-5D 
survey consists of five questions that cover the following domains:  mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression.  The response to each question is collected as 
a 5-level ordinal scale, spanning scores of 1 (no problems, or best outcome), 2 (slight problems), 3 
(moderate problems), 4 (severe problems) and 5 (extreme problems, or worst outcome).  The 
rationale for collecting these quality of life data was driven by early reports describing a significant 
subset of patients with COVID-19 who had a prolonged course with persistent symptoms of 
fatigue, dyspnea, and other problems, lasting for months and longer after the acute illness. 
An analysis of the EQ-5D data was not included in the Master Protocol, since study leadership 
had not anticipated that anticoagulant therapy would have a significant impact on quality of life.  A 
post-hoc analysis of EQ-5D data collected in ACTIV 4a, however, comparing prophylactic-dose 
with therapeutic-dose anticoagulation in hospitalized patients with COVID-19 in the non-ICU 
setting, observed that patients randomized to therapeutic anticoagulation had less moderate-to-
extreme impairment scores in four of the five EQ-5D domains at 90 days after hospital discharge.  
This difference was statistically significant in the self-care domain, with an improvement from 8.4% 
to 2.9% of participants having moderate-to-extreme impairment scores with therapeutic 
anticoagulation, for an odds ratio (adjusted for age, co-morbidities and pre-hospitalization status) 
of 0.26 (95% CI, 0.08-0.83) and a p-value of 0.016 (J. Hochman and M. Sholzberg, personal 
communication).  This preliminary observation that anticoagulant therapy could impact quality of 
life in patients with COVID-19 resulted in the decision by the ACTIV 4c leadership team to include 
an analysis of the collected EQ-5D data in two new secondary objectives and one new exploratory 
objective.  
 
A5.2 
New Secondary Objectives 
Secondary Objective 1:  To compare the effects of treatment at 30 days after randomization for 
the composite endpoint of QOL and mortality.   
Secondary Objective 2:  To compare the effects of treatment at 90 days after randomization for 
the composite endpoint of QOL and mortality. 
The existing three secondary objectives in the Master Protocol will now become Secondary 
Objectives 3, 4, and 5 
 
A5.3 
New Exploratory Objective 
Exploratory Objective 3: To compare the effects of treatment beginning at the time of discharge 
from the hospital with either Arm A or Arm B on the individual domains of EQ5D and the EQ5D 
visual analog scale for 30 and 90 days after randomization. 
The existing two exploratory objectives in the Master Protocol will remain as Exploratory 
Objectives 1 and 2. 
 
A5.4 
New Key Secondary Endpoints 
The two new key secondary endpoints are:  
1. The composite endpoint of EQ5D index score and mortality at day 30 following randomization 


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2. The composite endpoint of EQ5D index score and mortality at day 90 following randomization 
The existing four key secondary endpoints in the Master Protocol will now become key secondary 
endpoints 3 through 6 
 
A5.5 
Secondary and Exploratory Endpoints Analyses 
Six secondary outcomes are of interest in this trial. We will use a fallback method to control for 
type I error. Statistical methods for testing the QOL&M30 and QOL&M90 endpoints will be based 
on a proportional odds model. The covariates in the model will include the participant’s age 
(restricted cubic spline with 3 knots), sex, D-dimer (normal or abnormal), BMI (restricted cubic 
spline with 3 knots), antiplatelet usage (yes/no - at enrollment), WHO severity score (<five vs. 
≥five), and the randomized treatment. The results of these models will be summarized using an 
odds ratio and associated 95% confidence interval. 
Secondary analyses of the QOL&M30 and QOL&M90 endpoints will use a multiple imputation 
approach. 20 datasets will be imputed using predictive mean matching and the above covariates 
plus the Day 2 and Day 90 EQ5D index scores.  The model estimates will be combined using 
Rubin’s rules to obtain the estimated odds ratio and 95% confidence interval. 
More specifically, these secondary outcomes will only be formally tested if the primary hypothesis 
was rejected at level alpha=0.05.  If the study stops without the CE30 test statistic crossing the 
‘efficacy boundary’ or ‘futility boundary’ (i.e. not enough primary endpoint events), the key 
secondary endpoints will be evaluated and summarized using point estimates and associated 95% 
confidence intervals (without p-values). 
The ordering of the secondary endpoints is as follows:  
1) Composite endpoint of mortality and EQ5D index at Day 30 (QOL&M30) 
2) Composite endpoint of mortality and EQ5D index at Day 90 (QOL&M90) 
3) Primary endpoint at 45 days (CE45) 
4) Primary endpoint at 90 days (CE90) 
5) Venous events at 30 days (CEVTE30) 
6) Arterial events at 30 days (CEATE30) 
Using a fallback method the 0.05 type I error rate would be split as follows – 0.025, 0.005, 0.005, 
0.005, 0.005, and 0.005. If QOL&M30 was statistically significant then QOL&M90 would be tested 
at 0.03 = 0.025 + 0.005. On the other hand, if QOL&M30 was NOT statistically significant then 
QOL&M90 would be tested at 0.005. The process would continue until all 6 secondary endpoints 
were tested.  If the study does not accumulate enough CE30 events, it is expected that there 
would be limited information for secondary endpoints 3-6. 
Statistical methods for testing the secondary endpoints 3-6 listed above will follow exactly the 
same procedures used for the primary endpoint described in Section 4.2 in the Master Protocol. 
Additional details concerning the analysis of the new key secondary and exploratory endpoints are 
included in the Statistical Analysis Plan. 
 
 


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Appendix 6. Protocol Summary of Changes 
 
Summary of Changes protocol version 4.0 to 5.0 
 
Protocol 
Section 
Section Name 
 
 
 
Title 
Page 
N/A 
Previous 
Version 4.0, 20OCT2021 
Update 
Version 5.0, 20APR2022 
Rationale 
Update version 
A5 
Addition of New 
Key Secondary 
and Exploratory 
Outcomes 
Previous 
NA 
 
Update 
All Appendix 5 is new. 
 
 

SAP_001.pdf: 
SAP Version 2.0  
 
 
 
 
 
 
 
            Post-Hospital Study 
 
 
1 
CONFIDENTIAL 
 
 
Protocol: ACTIV-4C (Post-Discharge) 
COVID-19 Thrombosis Prevention Trials:  Post-hospital Thromboprophylaxis 
 
STATISTICAL ANALYSIS PLAN (SAP)  
for Stage I Study of Apixaban vs. Placebo 
 
 
Protocol Version: 5.0  
Protocol Version Date: April 20, 2022  
 
SAP Version Number: 2.0 
SAP Version Date: April 19, 2022 
 
 
 
 
Thomas L. Ortel, MD, PhD 
Professor of Medicine and Pathology 
Chief, Division of Hematology 
Duke University Medical Center 
Durham, NC  27710 
Tel.  919-681-6049 
Fax.  919-681-6160 
E-mail: thomas.ortel@duke.edu  
 
 
 
 
 
 
 
 
 
 
 
 


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SAP Approval Page 
 
Study Title: COVID-19 Thrombosis Prevention Trials:  Post-hospital Thromboprophylaxis 
 
Version: 2.0 
 
Date of Issue: April 19, 2022 
 
Study Sponsor:  
Thomas L. Ortel, MD, PhD 
Professor of Medicine and Pathology 
Chief, Division of Hematology 
Duke University Medical Center 
Durham, NC  27710 
Tel.  919-681-6049 
Fax.  919-681-6160 
E-mail: thomas.ortel@duke.edu 
 
 
We, the undersigned, have read and approve of this SAP and agree on its content. 
 
 
______________________________________________ 
Sponsor Representative and ACTIV4C Protocol Chair – Thomas L. Ortel, MD, PhD 
 
 
_______________________________________________ 
ACTIV-4C Principal Investigator – Tracy Wang, MD MHS MSc 
 
 
_______________________________________________ 
ACTIV-4C Protocol Statistician – Abdus S. Wahed, PhD 
 
 
_____________________________________________ 
ACTIV-4C Protocol Statistician – Kevin J. Anstrom, PhD 
 
 
_______________________________________________ 
ACTIV-4C NHLBI Statistician – Eric Leifer, PhD 
 
 
_______________________________________________ 
ACTIV-4C Protocol Co-Chair – Alison Morris, MD, MS 
 
 


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TABLE OF CONTENTS 
List of Abbreviations .................................................................................................................................................. 4 
1.0 
Study and Document Overview ......................................................... 5 
2.0 
Study Objectives ................................................................................ 5 
3.0 
Study Endpoints ................................................................................. 7 
3.1 
Primary Study Endpoints .................................................................... 7 
3.2 
Key Secondary and Exploratory Endpoints ........................................ 7 
3.3 
Safety Endpoints .............................................................................. 10 
3.4 
Adjudication of Outcome Events ..................................................... 11 
3.5 
Power and Sample Size .................................................................... 11 
3.6 
Randomization Scheme ................................................................... 12 
3.7 
Interim Analyses and Data Monitoring ............................................ 12 
3.7.1 
Interim Safety Analyses ................................................................... 12 
3.7.2 
Interim Analyses for Futility and Efficacy Review ............................ 13 
3.8 
Data Sources .................................................................................... 14 
3.9 
Software Package ............................................................................. 14 
3.10 
Verification of Results ...................................................................... 15 
3.11 
Subject Disposition .......................................................................... 15 
3.12 
Populations for Analyses .................................................................. 15 
4.0 
Statistical Analyses ........................................................................... 16 
4.1 
Descriptive Statistics ........................................................................ 16 
4.2 
Analysis of the Primary Efficacy Endpoint........................................ 16 
4.3 
Analysis of the Secondary Efficacy Endpoint(s) ............................... 17 
4.4 
Safety Analyses ................................................................................ 18 
4.5 
Exploratory Endpoints and Analyses ................................................ 18 
4.6 
Sub-Group Analyses ......................................................................... 19 
4.7 
References ....................................................................................... 20 
4.8 
Appendices....................................................................................... 21 
 
 
 


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LIST OF ABBREVIATIONS 
 
ACTIV 
Accelerating COVID-19 Therapeutic Interventions and Vaccines 
CRNMB 
Clinically Relevant non-Major Bleeding 
CE 
Composite Endpoint 
CEx 
Composite Endpoint at Day x 
CEATE30 
Composite Arterial Endpoint at Day 30 
CEVTE30 
Composite Venus Endpoint at Day 30 
CI 
Confidence Interval 
COVID-19 
Coronavirus disease 2019 
DSMB 
Data and Safety Monitoring Board 
DVT 
Deep Venous Thrombosis 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
ICU 
Intensive Care Unit 
ISTH 
International Society on Thrombosis and Haemostasis 
ITT 
Intent to Treat 
LAR 
Legally Authorized Representative 
LMWH 
Low Molecular Weight Heparin 
mITT 
Modified ITT 
NIH 
National Institutes of Health 
PE 
Pulmonary Embolism 
PI 
Principal Investigator 
QOL&M30 
Composite endpoint of EQ5D and Mortality at Day 30 
QOL&M90 
Composite endpoint of EQ5D and Mortality at Day 90 
SAE 
Serious Adverse Event 
SARS-CoV2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SAP 
Statistical Analysis Plan 
VTE 
Venous thromboembolism 
WHO 
World Health Organization 
 
 
 


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1.0 
STUDY AND DOCUMENT OVERVIEW 
 
ACTIV-4C study is an adaptive, prospective, randomized trial designed to compare the effectiveness and 
safety of antithrombotic therapy with no antithrombotic therapy after hospitalization for 48 hours or 
longer for Coronavirus disease 2019 (COVID-19) resulting from severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2). For Stage 1 of this study, participants will be randomized to either 
prophylactic anticoagulation or placebo for 30 days, and then followed for an additional 60 days after 
the completion of treatment (total duration of follow-up, approximately 90 days). 
 
This document describes the planned statistical analyses that will be conducted during (interim) and at 
the completion of stage 1 of the study. Once the initial unblinded data review has occurred, only the 
blinded statistics team members will be allowed to modify the SAP (see Appendix 1 for the list of 
blinded and unblinded statisticians). The initial interim review is expected to occur when 20% of the 
information fraction is accumulated.  
 
The study population corresponds to adults at least 18 years of age with COVID-19 who are hospitalized 
for 48 hours or longer and who are ready for discharge from the hospital. Patients both with and 
without intensive care unit (ICU) stay will be included in the study population. Key exclusion criteria are 
a clinical requirement for anticoagulant therapy (therapeutic dose or prophylactic dose), 
contraindication to anticoagulant therapy, and anticipated life expectancy < 90 days. 
 
Enrollment into this first stage of the ACTIV-4C study began in February 2021. 
 
The study period is 90 days, with follow-up assessments on days 2, 10, 20, 30, 45, and 90 days from 
randomization. The initial follow-up encounter, which will be conducted by the Call Center via the 
participant’s preferred method (electronic or phone call), will occur within 2 days following discharge 
from the hospital, to confirm study medication adherence and perform an initial assessment of 
outcomes. Subsequent encounters, which will also be conducted by the Call Center electronically or by 
phone, will occur at 10, 20, and 30 days after enrollment. With each encounter, assessments of 
medication adherence and outcomes will be performed. Two additional encounters will occur after 
completion of the primary outcome, at 45 and 90 days after enrollment, to determine if there is an 
increased risk for thromboembolic complications following hospital discharge that extends for a longer 
period than 30 days and to facilitate/confirm collection of the 2nd set of biorepository specimens.  
 
This first stage of the ACTIV-4C trial uses a group-sequential design where interim analyses are planned 
to assess the efficacy and futility of the treatments with the potential for early stopping. Proper 
statistical approaches are used to control type I error at the interim and final analyses. Safety 
monitoring will be performed throughout the trial and will be periodically reported by the Data and 
Safety Monitoring Board (DSMB) established for ACTIV-4C which will have oversight responsibility for 
the study.  
 
2.0 
STUDY OBJECTIVES  
 
Primary Objective: 


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• 
The primary objective of this first stage of the ACTIV-4C trial is to compare the effects of 
treatment beginning at the time of discharge from the hospital with either (i) anticoagulation at 
a prophylactic dose, or (ii) placebo (no anticoagulation) for up to 30 days after randomization on 
the composite endpoint of venous and arterial thromboembolic outcomes, and all-cause 
mortality. 
  
Secondary Objectives: 
• 
Secondary Objective 1:  To compare the effects of treatment at 30 days after randomization for 
the composite endpoint of QOL and mortality.   
• 
Secondary Objective 2:  To compare the effects of treatment at 90 days after randomization for 
the composite endpoint of QOL and mortality.   
• 
Secondary Objective 3:  To compare the effects of treatment beginning at the time of discharge 
from the hospital with either Arm A or Arm B on the incidence of the composite outcome at 45 
days and at 90 days after randomization. 
• 
Secondary Objective 4:  To compare the effects of treatment beginning at the time of discharge 
from the hospital with either Arm A or Arm B on the incidence of new, symptomatic VTE 
(inclusive of Deep Venous Thrombosis (DVT), PE, or other venous thrombosis) for up to 30 days 
after randomization. 
• 
Secondary Objective 5:  To compare the effects of treatment beginning at the time of discharge 
from the hospital with either Arm A or Arm B on the incidence of new, symptomatic ATE 
(inclusive of ischemic stroke, MI, or peripheral arterial thromboembolism) for up to 30 days 
after randomization. 
Exploratory Objectives: 
• 
Exploratory Objective 1:  To compare the effects of treatment beginning at the time of discharge 
from the hospital with either Arm A or Arm B on the incidence of all-cause rehospitalization for 
up to 90 days after randomization. 
• 
Exploratory Objective 2:  To compare the effects of treatment beginning at the time of discharge 
from the hospital with either Arm A or Arm B on the incidence of all-cause mortality for up to 30 
days after randomization. 
• 
Exploratory Objective 3: To compare the effects of treatment beginning at the time of discharge 
from the hospital with either Arm A or Arm B on the individual domains of EQ5D and the EQ5D 
visual analog scale for 30 and 90 days after randomization. 
 
 


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3.0 
STUDY ENDPOINTS  
3.1 
PRIMARY STUDY ENDPOINTS 
At approximately day 30 from randomization, a binary composite endpoint of venous and arterial 
thrombotic complications—including new, symptomatic proximal, or distal DVT of the upper or lower 
extremities, PE, and new thrombosis of other veins (including cerebral sinus and splanchnic veins), 
ischemic stroke, myocardial infarction, other arterial thromboembolism (e.g., mesenteric or acute limb 
ischemia), and all-cause mortality will be the primary study endpoint. 
3.2 
KEY SECONDARY AND EXPLORATORY ENDPOINTS  
Key secondary endpoints include the following. 
1. The composite endpoint of EQ5D index score and mortality at day 30 following randomization 
2. The composite endpoint of EQ5D index score and mortality at day 90 following randomization 
3. The composite endpoint for the primary outcome at day 45 following randomization 
4. The composite endpoint for the primary outcome at day 90 following randomization 
5. Composite endpoint of venous thromboembolic events, including symptomatic DVT of the upper or lower 
extremities, symptomatic and/or clinically relevant PE, and other symptomatic venous thrombosis, 
including cerebral sinus and splanchnic vein thrombosis at day 30 
6. Composite endpoint of arterial thromboembolic events, including symptomatic ischemic stroke, 
myocardial infarction, and other symptomatic arterial thromboembolic events at day 30 
 
Secondary endpoints will be formally tested using a fallback approach (see Section 4.3) only if the 
primary endpoint was statistically significant at the two-sided 5% level. 
 
Exploratory endpoints include the following. 
 
1. All-cause mortality at day 30 following discharge from the hospital 
2. All-cause re-hospitalization at day 90 following discharge from the hospital 
 
Table 1. Summary of important questions of interest and related estimands 
 
Row Question of 
Interest 
Objective 
Description / 
Study 
Population 
Endpoint 
Intercurrent 
Events/Strategy 
to handle 
Population 
Summary 
Estimands 
1 
Does Apixaban 
reduce the rate 
of venous and 
arterial 
thromboembolic 
outcomes, and 
all-cause 
mortality during 
30 days after 
discharge? 
Primary 
Objective of 
the Study / 
All 
Randomized 
Participants  
Composite endpoint 
(CE) of venous and 
arterial thrombotic 
complications—
including new, 
symptomatic proximal, 
or distal DVT of the 
upper or lower 
extremities, PE, and 
new thrombosis of 
other veins (including 
cerebral sinus and 
The only inter-
current event 
will be patient 
drop-out. The 
drop-out is 
expected to be 
less than 5% and 
un-related to 
treatment and 
their data up to 
the time of 
drop-out will be 
The 
difference in 
the 
proportion of 
CE between 
the Apixaban 
arm and the 
placebo arm. 
A negative 
value will 
favor the 


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splanchnic veins), 
ischemic stroke, 
myocardial infarction, 
other arterial 
thromboembolism 
(e.g., mesenteric or 
acute limb ischemia), 
and all-cause mortality 
by day 30 
used in the 
event 
determination* 
Apixaban 
arm. 
2 
Does Apixaban 
improve the 
composite of 
QOL and 
mortality at 30 
days after 
discharge? 
Key 
Secondary 
Objective of 
the Study / 
All 
Randomized 
Participants 
Composite endpoint of 
mortality and EQ5D 
index at Day 30.  All 
mortality events will be 
considered worse than 
any possible EQ5D 
response [QOL&M30] 
The expected 
rate of missing 
data for the 
EQ5D endpoint 
is expected to be 
approximately 
20%.  The odds 
ratio will be 
estimated using 
maximum 
likelihood 
methods which 
yield valid 
estimators 
under the MAR 
(or MCAR) 
assumptions. 
The odds 
ratio from a 
proportional 
odds model 
with the 
EQ5D index 
and mortality 
endpoint as 
the response 
variable. 
Values 
greater than 
1.0 will favor 
the Apixaban 
arm. 
3 
Does Apixaban 
improve the 
composite of 
QOL and 
mortality at 90 
days after 
discharge? 
Key 
Secondary 
Objective of 
the Study / 
All 
Randomized 
Participants 
Composite endpoint of 
mortality and EQ5D 
index at Day 90.  All 
mortality events will be 
considered worse than 
any possible EQ5D 
response [QOL&M90] 
The expected 
rate of missing 
data for the 
EQ5D endpoint 
is expected to be 
approximately 
20%.  The odds 
ratio will be 
estimated using 
maximum 
likelihood 
methods which 
yield valid 
estimators 
under the MAR 
(or MCAR) 
assumptions. 
The odds 
ratio from a 
proportional 
odds model 
with the 
EQ5D index 
and mortality 
endpoint as 
the response 
variable. 
Values 
greater than 
1.0 will favor 
the Apixaban 
arm. 
4 
Does Apixaban 
reduce the rate 
of venous 
Key 
Secondary 
Objective of 
Composite endpoint of 
venous 
thromboembolic 
Inter-current 
events will be 
death and 
The 
difference in 
the 


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thromboembolic 
outcomes during 
30 days after 
discharge? 
the Study / 
All 
Randomized 
Participants 
events, including 
symptomatic DVT of 
the upper or lower 
extremities, 
symptomatic and/or 
clinically relevant PE, 
and other symptomatic 
venous thrombosis, 
including cerebral sinus 
and splanchnic vein 
thrombosis at day 30 
[CEVTE30] 
patient drop-
out. Patients 
who died 
without an 
intercurrent 
event will be 
censored. The 
drop-out is 
expected to be 
less than 5% and 
un-related to 
treatment and 
their data up to 
the time of 
drop-out will be 
used in the 
event 
determination* 
proportion of 
CEVTE30 
between the 
Apixaban 
arm and the 
placebo arm. 
A negative 
value will 
favor the 
Apixaban 
arm. 
5 
Does Apixaban 
reduce the rate 
of arterial 
thromboembolic 
outcomes during 
30 days after 
discharge? 
Key 
Secondary 
Objective of 
the Study / 
All 
Randomized 
Participants 
Composite endpoint of 
arterial 
thromboembolic 
events, including 
symptomatic ischemic 
stroke, myocardial 
infarction, and other 
symptomatic arterial 
thromboembolic 
events at day 30 
[CEATE30] 
Inter-current 
events will be 
death and 
patient drop-
out. Patients 
who died 
without an 
intercurrent 
event will be 
censored. The 
drop-out is 
expected to be 
less than 5% and 
un-related to 
treatment and a 
complete-case 
analysis will be 
employed* 
The 
difference in 
the 
proportion of 
CEATE30 
between the 
Apixaban 
arm and the 
placebo arm. 
A negative 
value will 
favor the 
Apixaban 
arm. 
6 
Does Apixaban 
reduce the rate 
of venous and 
arterial 
thromboembolic 
outcomes, and 
all-cause 
mortality during 
45 days after 
discharge? 
Key 
Secondary 
Objective of 
the Study / 
All 
Randomized 
Participants 
Composite endpoint of 
venous and arterial 
thrombotic 
complications—
including new, 
symptomatic proximal, 
or distal DVT of the 
upper or lower 
extremities, PE, and 
new thrombosis of 
The only inter-
current event 
will be patient 
drop-out. The 
drop-out is 
expected to be 
less than 5% and 
un-related to 
treatment and 
their data up to 
The 
difference in 
the 
proportion of 
CE45 
between the 
Apixaban 
arm and the 
placebo arm. 
A negative 


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other veins (including 
cerebral sinus and 
splanchnic veins), 
ischemic stroke, 
myocardial infarction, 
other arterial 
thromboembolism 
(e.g., mesenteric or 
acute limb ischemia), 
and all-cause mortality 
by day 45 [CE45] 
the time of 
drop-out will be 
used in the 
event 
determination* 
value will 
favor the 
Apixaban 
arm. 
7 
Does Apixaban 
reduce the rate 
of venous and 
arterial 
thromboembolic 
outcomes, and 
all-cause 
mortality during 
90 days after 
discharge? 
Key 
Secondary 
Objective of 
the Study / 
All 
Randomized 
Participants 
Composite endpoint of 
venous and arterial 
thrombotic 
complications—
including new, 
symptomatic proximal, 
or distal DVT of the 
upper or lower 
extremities, PE, and 
new thrombosis of 
other veins (including 
cerebral sinus and 
splanchnic veins), 
ischemic stroke, 
myocardial infarction, 
other arterial 
thromboembolism 
(e.g., mesenteric or 
acute limb ischemia), 
and all-cause mortality 
by day 90 [CE90] 
The only inter-
current event 
will be patient 
drop-out. The 
drop-out is 
expected to be 
less than 5% and 
un-related to 
treatment and 
their data up to 
the time of 
drop-out will be 
used in the 
event 
determination* 
The 
difference in 
the 
proportion of 
CE90 
between the 
Apixaban 
arm and the 
placebo arm. 
A negative 
value will 
favor the 
Apixaban 
arm. 
*See the sensitivity analysis (Section 4.2) 
3.3 
SAFETY ENDPOINTS  
Safety endpoints will include (1) major bleeding, as defined by the ISTH, and (2) clinically relevant, non-
major bleeding, also as defined by the ISTH. Criteria for major bleeding, and CRNMB are provided below 
 
1. Major bleeding 
a. Fatal bleeding 
b. Bleeding into a critical area or organ (e.g., intracranial, intraspinal, intraocular, 
pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal) 
c. Bleeding causing a fall in the hemoglobin level of 2 g/dL or more, or leading to 
transfusion of 2 or more units of whole blood or red cells 
2. Clinically relevant, non-major bleeding 
a. Bleeding requiring medical intervention by a healthcare professional 


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b. Bleeding leading to hospitalization or an increase in the level of care 
c. Bleeding prompting a face-to-face (i.e., not just a telephone or electronic 
communication) evaluation 
3.4 
ADJUDICATION OF OUTCOME EVENTS 
All patient-reported events will be investigated by the Clinical Coordinating Center, including obtaining 
information from healthcare facilities where the patient received treatment. An independent, central 
adjudication committee (ICAC) will review and adjudicate events in a blinded manner without 
knowledge of treatment allocation. During the study period, the ICAC will adjudicate all suspected 
occurrences of venous or arterial thromboembolic events, ischemic stroke, acute myocardial infarction, 
deaths, and re-hospitalization. The ICAC will also review all suspected episodes of bleeding and 
categorize adjudicated bleeding as major, clinically relevant non-major, or minor bleeding. The 
Committee will be provided with all relevant documentation related to the events. The criteria and 
definitions of the study outcomes, as well as the procedures followed by the Committee, will be 
described in an adjudication manual which will be provided to the ICAC members before the first 
meeting. 
 
 
3.5 
POWER AND SAMPLE SIZE 
 
The primary analysis for this randomized trial will be an intention-to-treat comparison of a composite 
endpoint (CE) of venous thromboembolic events, including new, symptomatic proximal or distal deep 
vein thrombosis affecting the upper and/or lower extremities, pulmonary embolism, or thrombosis of 
other veins (e.g., cerebral sinus veins, splanchnic veins); arterial thromboembolic events, including new 
ischemic stroke, myocardial infarction, mesenteric or peripheral arterial thromboembolism; and all-
cause mortality for up to 30 days after randomization across the intervention arms. This binary primary 
endpoint was used to power the study. 
 
The MARINER trial reported a 2% event rate for a combined outcome of VTE, MI, CVA, or CV deaths in 
the placebo group (Spyropoulos, 2018). These rates are expected to be higher in COVID-19 patients who 
are discharged from the hospital. Recent information from patients discharged alive from the University 
of Pittsburgh Medical Center suggests that the 30-day mortality rate in this population could be as high 
as 4%. To be conservative, 4% was used as the expected CE rate of events for the no anticoagulant arm. 
An effect size of 35% percent risk reduction (risk ratio = 0.65) in the anticoagulant group compared to 
the no anticoagulant group was used to calculate the expected sample size for the study. 
 
The analysis will use a group-sequential two-sample two-sided Z-test for proportions with pooled 
standard deviation to test the primary hypothesis at overall significance two-sided level alpha = 0.05. 
Four equally spaced interim analyses and one final analysis will use O’Brien-Fleming alpha spending 
boundaries for efficacy and the Hwang-Shih-DeCani boundaries for the futility reviews (O'Brien and 
Fleming, 1979; Hwang, Shih, and De Cani, 1990). In order to ensure an 80% power to detect a CE rate 
reduction of 35% through anticoagulation use, the study needs to enroll at least 2,530 participants per 
arm. Since the primary outcome is observed within 30 days of follow-up, the loss to follow-up and 
withdrawal of consent rates should be low, and it is estimated that CE will be missing on a maximum of 
5% of the participants. Therefore, the sample size required for this study will be approximately 2,660 per 


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arm. The sample size has been calculated using 2,000 simulations in PASS 13 [PASS 13 Power Analysis 
and Sample Size bounds Software (2014). NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass]. 
 
The operating characteristics (type I error and power) of the design has been investigated through 
simulations under the bounds established in the interim analysis (Section 3.3 below) and under the 
above assumptions using multiple software packages. The Type I error and Power were both adequate.   
 
3.6 
RANDOMIZATION SCHEME 
 
Randomization will be performed for study participants as close to the time of hospital discharge as 
possible. Hospitalized patients may be screened and approached about the study up to 48 hours before 
hospital discharge, but final enrollment and randomization should occur as close to the time of 
discharge as possible. Participants will be randomized in a 1:1 ratio using an online randomization 
system to either Arm A (apixaban 2.5 mg twice daily), or Arm B (matching placebo). Randomization will 
be stratified by (1) concomitant use of a single antiplatelet agent (yes/no), and (2) a maximal score of 5 
or greater vs. a score of less than 5 by the World Health Organization (WHO) Ordinal Index. 
 
3.7 
INTERIM ANALYSES AND DATA MONITORING 
 
3.7.1 
INTERIM SAFETY ANALYSES 
 
Safety monitoring will be continuous. In addition to examining the rate of ISTH major bleeding and the 
rate of ISTH clinically relevant non-major bleeding (CRNMB) in each of the treatment arms, monitoring 
will include unacceptable toxicity, defined as major bleeding, including hospitalization, and all-cause 
mortality. Prior studies have shown that the rate of major bleeding will be very low. The degree of 
evidence about differences in risk of unacceptable toxicity from accruing data will be addressed on a 
regular and pre-determined basis (e.g. every 3 months or more frequently per DSMB request) and will 
be shared with the DSMB. Unadjusted safety event rates for each assigned treatment group, and 
relative risks, and the absolute risk differences with 95% confidence intervals, will be calculated and 
presented to the DSMB for each of the specified safety outcomes.  
Events will be adjudicated centrally by an adjudication committee. The following events will be 
adjudicated: Hospitalization or Emergency Room/Department visit documented on the related 
Pharmacist form, DVT, PE or major bleeding is checked as event type, and SAE has hospitalization or 
prolonged hospitalization as a reason for seriousness. 
 
Appendix 2 provides a list of tables that are presented to DSMB every month. 
 
Full DSMB report every three months, in addition, will contain the listings of all safety events, including 
the date of onset, relatedness to treatment/unexpectedness, resolution, treatment adjustment, and 
other detailed narratives.  Appendix 3 provides a list of tables and figures provided to DSMB every 3 
months.  
 
Additionally, participants with safety events will be categorized in comparison to those without the 
safety events using a logistic regression to identify if the safety event was associated with any particular 
participant characteristics to identify high-risk groups. 
 


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If safety issues arise, the DSMB will use their clinical and statistical judgment to assess the potential risks 
relative to the potential benefits. The DSMB may also examine the safety and efficacy data in subgroups 
known to be high risk for bleeding such as those with older age and/or higher BMI. The DSMB will use all 
available information to make recommendations to the NHLBI. The DSMB can recommend that the Post-
discharge COVID-19 trial should continue as proposed, that one treatment arm or more may be 
dropped, that the trial protocol should be modified, or that the trial should be terminated early for 
safety reasons. At any of the safety reviews, the DSMB can request a further statistical evaluation of the 
safety data to make a decision. Only the DSMB and those individuals invited to the DSMB closed session 
is permitted to examine outcomes by the assigned treatment group. The DSMB will evaluate the rates of 
the primary endpoint and the safety endpoints by assigned treatment groups overall and within pre-
specified subgroups. 
 
3.7.2 
INTERIM ANALYSES FOR FUTILITY AND EFFICACY REVIEW 
 
The trial design planned for 4 interim analyses and a final analysis at equally-spaced information points. 
At each interim analysis cumulative primary outcome data, and potentially the secondary analyses, will 
be presented to the DSMB. Based on the data, a decision to stop or continue the trial will be taken 
following the O’Brien-Fleming Rule. If the Z-statistic crosses the lower boundary, the trial will be stopped 
for futility while if the Z-statistic crosses the upper boundary, the trial will be stopped declaring 
anticoagulant to be effective in preventing CE. In either case, Stage 1 of the trial will end and secondary 
analyses, including subgroup analyses will be critical for driving adaptive changes made based on 
accrued data. Eligibility criteria, efficacy, and safety endpoints will be analyzed at predefined intervals to 
guide the design of subsequent stages to allow efficient use of data and resources to inform the 
adaptations in trial design. 
 
Assessments of futility will be conducted at all interim looks, whereas efficacy will only be assessed 
starting at the third interim analysis (after 60% of the information accumulated; Table 1). For the 
efficacy and futility, O’Brien-Fleming analog alpha-spending function and Hwang-Shih-DeCani beta-
spending function will be utilized to create the non-binding boundaries. Table 1 and Figure 2 provide 
specific efficacy and futility boundaries at each interim analysis.  
 
Table 1: Stopping Boundaries for Efficacy and Futility based on Z-statistic above. 
Look  
Information 
fraction 
Efficacy Boundary 
Futility Boundary 
1 
20% 
NA 
0.1383 
2 
40% 
NA 
-0.5933 
3 
60% 
-2.6686 
-1.1439 
4 
80% 
-2.2887 
-1.5918 
Final 
100% 
-2.0307 
-2.0307 
     
 
 
 
 


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Figure 2: Stopping Boundaries for Efficacy and Futility based on the Z-statistic described above. 
 
3.8 
DATA SOURCES 
 
Initial data collection is the responsibility of the clinical trial staff under the supervision of the site PI. The 
investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. Follow-up data will be collected electronically from the participant’s self-report and by study 
staff via telephone. Responsibility for the accuracy, completeness, and timeliness of data collected by 
telephone is under the supervision of the Coordinating Center investigators at Duke Clinical Research 
Institute and the University of Illinois-Chicago who are responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data recorded in the eCRF derived from source 
documents should be consistent with the source documents or the discrepancies should be explained 
and captured in a progress note and maintained in the Coordinating Center’s official electronic study 
record. 
Programmed computer edit checks will be run against the database to identify discrepancies and verify 
the reasonableness of the data. Queries to resolve discrepancies will be generated and resolved by the 
sites. Analysis datasets will be created by the Data Coordinating Center for the production of tables, 
figures, and listings. All planned reporting will be based on the analysis datasets, but in the case of 
emergent safety data, some reporting may occur from the raw eCRF data. All programs written to create 
analysis datasets and perform analyses will be validated according to Standard Operating Procedures 
established by the ACTIV4C Data Management and Statistical Analyst teams.  
 
3.9 
SOFTWARE PACKAGE 
 
Group-Sequential Plot
Information
0
10000
20000
30000
40000
50000
-3
-2
-1
0
1
Z Value
Z: Crossed Efficacy
Z: Crossed Futility
Efficacy Boundary
Futility Boundary


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The statistical analyses described in this SAP, as well as the production of tables, listings, and figures, will 
be performed using SAS®, version 9.4 or higher (SAS Institute, Cary, NC) or R software. Additional 
statistical software may be used as needed. 
 
3.10 VERIFICATION OF RESULTS 
 
All tables, listings, and graphs will be verified and reviewed before being considered final. The 
verification process will ensure that the numbers are produced by a statistically valid method and that 
the execution of the computations is correct. Qualified statisticians or statistical programmers employed 
at the Data Coordinating Center who have not been previously involved in the production of the original 
programming will perform the verification procedures. Methods of verification include independent 
programming, prior to issuance of the draft statistical report, of all analysis datasets and comparison to 
data listings. Tables, listings, and figures will be reviewed for accuracy, consistency with this analysis 
plan, consistency within tables/listings/figures, and consistency with the corresponding output. Once 
verification is complete, all documentation of the verification process will be saved.  
 
3.11 SUBJECT DISPOSITION 
 
The disposition of subjects (number randomized, number who received any amount of the randomly 
assigned treatment, number completing study drug administration, number who withdrew consent or 
discontinued from study drug early, and number lost to follow-up, and number who completed the trial) 
will be summarized by treatment group. The number of subjects screened for inclusion and a 
breakdown of reasons for exclusion will be summarized. The timing and reasons for early 
discontinuation of study drug and/or withdrawal from the study will be summarized by treatment 
group. For the calculation of percentages, subjects who die will not be included in the denominators for 
visits/assessments beyond their death. Treatment compliance (e.g., number of subjects with missed 
doses) will be summarized by treatment group. A subject listing of analysis population eligibilities will be 
generated. A listing of all subjects discontinued from the study after enrollment, broken down by site 
and treatment group will be provided. The listing will include the reason for discontinuation, treatment 
group, duration of treatment, and whether or not the blind was broken. Also, for subjects who 
discontinued from the study after enrollment, a listing of adverse events will be provided. Subject-
specific protocol deviations will be summarized by the reason for the deviation, the deviation category, 
treatment group, disease severity, and (separately) site for all subjects. All subject-specific protocol 
deviations and non-subject-specific protocol deviations will be included in listings. 
 
3.12 POPULATIONS FOR ANALYSES 
 
The primary analysis will be based on an intention-to-treat (ITT) population, including all participants 
randomized. Secondary analyses will be based on a modified intention-to-treat (MITT) population 
consisting of all participants who received at least one dose of the study medications. 
 
 


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4.0 
STATISTICAL ANALYSES 
 
4.1 
DESCRIPTIVE STATISTICS 
 
Baseline characteristics representing demographic, clinical history, symptom, and biomarker variables 
will be summarized by treatment arms. The distribution of each variable will be examined. All variables 
will be summarized using appropriate central tendency (mean/median) and spread measures (standard 
deviation, 25th and 75th percentiles, or range) for continuous variables and frequency and percent for 
categorical variables.  
 
4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
 
As a primary approach, the primary endpoint CE30 will be compared between two arms using a two-
sample Z-statistic for proportion (standardized difference between proportion having CE in the 
anticoagulant arm and matching placebo arm, positive difference favoring anticoagulant arm). More 
explicitly, denoting 𝑝𝑝, 𝑝𝑝𝐴𝐴and 𝑝𝑝𝑃𝑃 the estimated proportion of CE30 in the whole sample, anticoagulant 
and placebo group respectively, the null hypothesis of no difference in the proportions will be tested 
using the test statistic  
𝑍𝑍= (𝑝𝑝𝑃𝑃−𝑝𝑝𝐴𝐴)/𝑆𝑆𝑆𝑆(𝑝𝑝𝑃𝑃−𝑝𝑝𝐴𝐴), 
where 𝑆𝑆𝑆𝑆(𝑝𝑝𝑃𝑃−𝑝𝑝𝐴𝐴) will be estimated by pulling over the two groups, that is,   
𝑆𝑆𝑆𝑆(𝑝𝑝𝑃𝑃−𝑝𝑝𝐴𝐴) = √ቂ𝑝𝑝(1 −𝑝𝑝) ቀ
1
𝑛𝑛𝑃𝑃 +
1
𝑛𝑛𝐴𝐴ቁቃ, 
where 𝑛𝑛𝑃𝑃  and 𝑛𝑛𝐴𝐴 are the sample sizes for the placebo and anticoagulant groups, respectively. 
 
The CE30 rates will also be modeled using a log-binomial regression model with treatment arm as the 
independent variable and adjusting for trial stratification variables (i.e., antiplatelet use; WHO ordinal 
scale score). Secondary analyses of this endpoint will include adjustment for D-dimer levels, intensive 
care unit stay, patient characteristics, and demographic factors, including race and ethnicity. The 
matching placebo arm will serve as the “reference group” in this model, and analysis will involve testing 
whether the coefficient for each active treatment group relative to the reference group is equal to 0, or 
equivalently, whether the adjusted relative risk for the anti-coagulant arm is equal to 1. The adjusted 
relative risk and the related confidence interval will be provided. 
 
In addition, unadjusted event rates for each treatment group, and relative risk and the absolute risk 
differences with confidence intervals, will be calculated and presented. Kaplan-Meier cumulative 
incidence curves will also be presented to allow visualization of the patterns of time to first events. As a 
sensitivity analysis, a modified intention-to-treat analysis, excluding all randomized participants who fail 
to initiate treatment, will be conducted.  
 
Patients dropping out of the study prior to day 30 will contribute data up to the time of drop-out. 
 
o Sensitivity Analyses 
 
The primary analysis will be repeated in the MITT analysis population where subjects who did not 
start the medication will be excluded. For all supplemental and sensitivity analyses, p-values will be 


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reported and 95% confidence levels will be used for confidence interval estimates. The tabular and 
graphical summaries described in the previous section will be replicated for the MITT analysis.  
 
The primary analysis will also be repeated using the other subgroups defined in Section 4.6. Each 
subgroup will be considered separately, and the tabular and graphical summaries described in the 
previous section will be replicated for each subgroup. In addition, a forest plot will be generated to 
display the overall treatment difference estimate and CI from each of the within-stratum analyses. 
These analyses will be performed in the ITT and MITT populations.  
 
The primary analysis uses information from participants who dropped out up to the time of the drop-
out. A tipping points sensitivity analysis that systematically and comprehensively varies assumptions 
about the missing outcomes on the two treatment arms will be applied. These analyses will be two-
dimensional and will allow assumptions about the missing outcomes on the two arms to vary 
independently.  These scenarios will include those where dropouts on drug tend to have worse 
outcomes than dropouts on control. The goal is to explore the plausibility of missing data 
assumptions under which the conclusions change, i.e., under which there is no longer evidence of 
efficacy.  
 
Further supplementary analyses of the primary endpoint will include the use of Fisher’s exact test, 
Cochran-Mantel-Haenszel test adjusting for stratification factors. Furthermore, a random intercept 
log-binomial regression of the primary outcome with baseline characteristics including stratification 
factors and a random intercept for the recruitment site will be performed to assess factors associated 
with the primary outcome. 
 
To understand the time course of the primary event CE, we will use Kaplan-Meier curves to estimate 
the cumulative proportion of events over time. Differences between such proportions over time by 
treatment groups will be assessed using log-rank test adjusting for stratification factors and will 
further be investigated using Cox proportional hazard models. In addition to the stratification factors, 
the Cox model will assess other baseline patient characteristics.      
 
 
4.3 
ANALYSIS OF THE SECONDARY EFFICACY ENDPOINT(S) 
 
Six secondary outcomes are of interest in this trial. We will use a fallback method to control for type I 
error (see page 30 of the Food and Drug Administration guidance on multiple endpoints in clinical trials; 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/multiple-endpoints-
clinical-trials-guidance-industry ).  More specifically, these secondary outcomes will only be formally 
tested if the primary hypothesis was rejected at level alpha=0.05.  If the study stops without the CE30 test 
statistic crossing the ‘efficacy boundary’ or ‘futility boundary’ (i.e. not enough primary endpoint events), 
the key secondary endpoints will be evaluated and summarized using point estimates and associated 95% 
confidence intervals (without p-values). 
 
The ordering of the secondary endpoints is as follows:  
1) Composite endpoint of mortality and EQ5D index at Day 30 (QOL&M30) 
2) Composite endpoint of mortality and EQ5D index at Day 90 (QOL&M90) 
3) Primary endpoint at 45 days (CE45) 


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4) Primary endpoint at 90 days (CE90) 
5) Venous events at 30 days (CEVTE30) 
6) Arterial events at 30 days (CEATE30) 
Using a fallback method the 0.05 type I error rate would be split as follows – 0.025, 0.005, 0.005, 0.005, 
0.005, and 0.005. If QOL&M30 was statistically significant then QOL&M90 would be tested at 0.03 = 0.025 
+ 0.005. On the other hand, if QOL&M30 was NOT statistically significant then QOL&M90 would be tested 
at 0.005. The process would continue until all 6 secondary endpoints were tested.  If the study does not 
accumulate enough CE30 events, it is expected that there would be limited information for secondary 
endpoints 3-6.  
Statistical methods for testing the QOL&M30 and QOL&M90 endpoints will be based on a proportional 
odds model. The covariates in the model will include the participant’s age (restricted cubic spline with 3 
knots), sex, D-dimer (normal or abnormal), BMI (restricted cubic spline with 3 knots), antiplatelet usage 
(yes/no - at enrollment), WHO severity score (<five vs. ≥five), and the randomized treatment. The results 
of these models will be summarized using an odds ratio and associated 95% confidence interval. 
 
Secondary analyses of the QOL&M30 and QOL&M90 endpoints will use a multiple imputation approach. 
20 datasets will be imputed using predictive mean matching and the above covariates plus the Day 2 and 
Day 90 EQ5D index scores.  The model estimates will be combined using Rubin’s rules to obtain the 
estimated odds ratio and 95% confidence interval. 
 
Statistical methods for testing the secondary endpoints 3-6 listed above will follow the same procedures 
used for the primary endpoint described in Section 4.2 above. Except that for the CEVTE30 and CEATE30 
events, an additional sensitivity analysis will be conducted by combining death from any causes to each 
one of the events separately.   
 
 
4.4 
SAFETY ANALYSES 
 
The rates of safety outcomes listed in section 3.0.3 (e.g., ISTH major bleeding and the rate of ISTH 
CRNMB) during the 30-day treatment period and during the additional 60-day safety follow-up period 
between the two arms will be compared. The proportion of patients in each assigned treatment group 
who experience each safety event, the relative risk, and the absolute risk difference will be calculated 
from the observed data, and confidence intervals will be calculated. Analyses of the bleeding outcomes 
that occur during the full 90-day follow-up period (i.e., 30-day treatment period plus the 60-day safety 
follow-up) will also be conducted as part of the trial safety analyses. This analysis will be done for mITT 
population only (participants who had at least one dose of the drugs). 
 
4.5 
EXPLORATORY ENDPOINTS AND ANALYSES 
 
Exploratory endpoints for this trial include the following. 
 
1. 
All-cause mortality at day 30 following discharge from the hospital 
2. 
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For each of the above endpoints, the proportion achieving endpoints and the corresponding 95% 
confidence intervals will be presented by the treatment group using the Wald method and Clopper-
Pearson exact intervals (Clopper and Pearson, 1934). Also, relative risk and the absolute risk differences 
with corresponding 95% confidence intervals will be estimated and presented. 
 
Exploratory Analysis: 
In order to get more insight into the treatment effect estimates, we will further analyze the data using 
Bayesian methods. More specifically, the likelihood of the observed data will be constructed assuming 
the random intercept log-binomial regression model described in Section 4.2. Conditional on the 
random effect for the site (𝛾𝛾), the unadjusted model can be written as 
𝑙𝑙𝑙𝑙𝑙𝑙(𝑝𝑝) = 𝛽𝛽0 + 𝛽𝛽𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡∗𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇+ 𝛾𝛾, 
where  𝑝𝑝 is the probability of CE, 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 is the treatment indicator (1 for treatment, and 0, for placebo), 
𝛽𝛽0is the logit of CE rate in the placebo group, 𝛽𝛽𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡  is the log relative risk (RR) of the treatment 
compared to the placebo. The site random effect 𝛾𝛾will be assumed to follow a normal distribution with 
mean zero and variance 𝜃𝜃. For prior distributions, specifically of the effect of interest  𝛽𝛽𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡, we will 
follow the recommendations provided in Table 1 of the (Wijeysundera et al., 2009), where three types 
of priors were used: (i) flat uninformative - 𝛽𝛽𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡∼𝑁𝑁(0, 100),(ii) Skeptical - 𝛽𝛽𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡∼𝑁𝑁(0, 𝜂𝜂1) , where 
𝜂𝜂1 is such that the probability of achieving a benefit exceeding the assumed, that is, Pr (𝛽𝛽𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡<
ln(0.65)) = 0.05, and (iii) enthusiastic -  𝛽𝛽𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡∼𝑁𝑁(ln (0.65), 𝜂𝜂2) , where 𝜂𝜂2 is such that the probability 
of no benefit Pr (𝛽𝛽𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡> 0) = 0.05. The prior distribution for the intercept 𝛽𝛽0 is assumed non-
informative with mean equal to the logit of the assumed placebo rate and standard deviation 10, and 
the variance component 𝜃𝜃 is assumed to follow a half-normal centered at 0 with standard deviation set 
to a 100 (Gelman, 2006). Prior distributions are assumed to be independent.  
 
Marginal posterior distribution of the parameter 𝛽𝛽𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 is of interest. It will be calculated using the R 
package brms (Bürkner, 2017). Once the posterior distribution is computed, we will estimate two 
posterior quantities to help infer on the treatment effect: a) the probability of any benefit (OR<1, or 
equivalently, 𝛽𝛽𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡< 0), and  b)  the probability of exceeding the effects that were used for sample size 
calculation (RR<0.65 or equivalently, 𝛽𝛽𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡< ln (0.65)). 
 
 
4.6 
SUB-GROUP ANALYSES 
 
The primary analysis will be repeated within each of these subgroups. Interaction test-p-values will be 
obtained using log-binomial regression models.  The pre-specified subgroups include:  
• 
Antiplatelet usage (yes/no - at enrollment) 
• 
WHO severity score (<five vs. ≥five)  
• 
BMI (<30 vs. ≥30) 
• 
D-dimer (normal or abnormal) 
• 
ICU stay,  
• 
Age (<40; 40-64; 65 and older),  
• 
Sex, and 
• 
Race/ethnicity. 
 
 


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4.7 
REFERENCES 
 
Bürkner P (2017). “brms: An R Package for Bayesian Multilevel Models Using Stan.” Journal of Statistical 
Software, 80(1), 1–28 
Clopper, C.; Pearson, E. S. (1934). "The use of confidence or fiducial limits illustrated in the case of the 
binomial". Biometrika. 26 (4): 404–413. doi:10.1093/biomet/26.4.404. 
Gelman, A.(2006). Prior distributions for variance parameters in hierarchical models (comment on article 
by Browne and Draper). Bayesian analysis, 1(3), pp.515-534. 
Hwang IK, Shih WJ, De Cani JS (1990). Group sequential designs using a family of type I error probability 
spending functions. Stat Med.;9(12):1439-45. 
O'Brien PC, Fleming TR (1979). A multiple testing procedure for clinical trials. Biometrics;35(3):549-56. 
Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, et al. Rivaroxaban for 
Thromboprophylaxis after Hospitalization for Medical Illness (2018). N Engl J Med. 379(12):1118-27. 
Wijeysundera DN, Austin PC, Hux JE, Beattie WS, Laupacis A (2009). Bayesian statistical inference 
enhances the interpretation of contemporary randomized controlled trials. J Clin Epidemiol;62(1):13-21 
e5. 
 
 
 
 


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4.8 
APPENDICES 
 
 
Appendix 1. ACTIV4C Roster of Statisticians 
 
Team 
Name 
Email 
Organization 
Attends 
DSMB 
Meetings 
Unblinded 
Statistical Team 
Abdus S. Wahed 
Wahed@pitt.edu 
 
DCC 
X 
 
James Troendle 
james.troendle@nih.gov 
 
NHLBI 
X 
 
Lingyun Lyu 
lil114@pitt.edu 
 
DCC 
 
 
 
 
 
 
Blinded 
Statistical Team 
Kevin Anstrom 
kevin.anstrom@unc.edu 
UNC 
X 
 
 
Jungnam Joo 
jungnam.joo@nih.gov 
NHLBI 
X 
 
Eric Leifer 
leifere@nhlbi.nih.gov 
 
NHLBI 
X 
 
 
 
 
 
 
 
 


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Appendix 2. Abbreviated Monthly DSMB Tables on Safety and Efficacy Outcomes 
A. PROTOCOL SUMMARY 
B. CONSORT CHART 
C. REPORTED SUSPECTED STUDY OUTCOMES 
Table: Suspected Outcome Events among Randomized Subjects by Treatment 
 
All Randomized1 
(N=) 
 
30 Days Follow Up2 
(N=) 
ARM A 
(N=) 
ARM B 
(N=) 
ARM A 
(N=) 
ARM B 
(N=) 
Suspected Study Outcomes, n (%) 
Any Suspected Primary Outcome3 
 
 
 
 
Deep vein thrombosis of upper or 
lower extremities 
 
 
 
 
Pulmonary embolism 
 
 
 
 
Other venous thromboembolism 
 
 
 
 
Ischemic stroke 
 
 
 
 
Myocardial infarction 
 
 
 
 
Other arterial thromboembolism 
 
 
 
 
All-cause mortality 
 
 
 
 
1The number of all randomized participants. 
2The number of 30 days follow up included participants who had 30 days of follow-up or 
withdrawn/dropped-out within 30 days. 
3The primary study endpoint is defined as a composite endpoint of symptomatic deep vein thrombosis of 
upper or lower extremities, pulmonary embolism, other venous thromboembolism, ischemic stroke, 
myocardial infarction, other arterial thromboembolism, and all-cause mortality for up to 30 days after 
initiation of assigned treatment. 
 
 
 


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Figure: Kaplan-Meier Curves for the Time to Suspected Outcome Events 
 
Note: The figure will include numbers at risk and number of events at designated timepoints, and will 
additionally include the KM estimates at days 30, 45, and 90 as inserts.   
 
Table: Suspected Safety Outcome Events among Randomized Subjects by Treatment 
 
All Randomized 
(N=) 
30 Days Follow Up  
(N=) 
 
ARM A (N=) 
ARM B (N=) 
ARM A (N=) 
ARM B (N=) 
Bleeding, n (%) 
 
 
 
 
 
Figure: Kaplan-Meier Curves for the Time to Suspected Safety Outcome Events 
 
 
 


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D. ADJUDICATED STUDY OUTCOMES 
Table: Adjudicated Outcome Events among Randomized Subjects by Treatment 
 
All Randomized1 
(N=) 
 
30 Days Follow Up2 
(N=) 
ARM A 
(N=) 
ARM B 
(N=) 
ARM A 
(N=) 
ARM B 
(N=) 
Study Outcomes, n (%) 
Any Primary Outcome3 
 
 
 
 
Deep vein thrombosis of upper or 
lower extremities 
 
 
 
 
Pulmonary embolism 
 
 
 
 
Other venous thromboembolism 
 
 
 
 
Ischemic stroke 
 
 
 
 
Myocardial infarction 
 
 
 
 
Other arterial thromboembolism 
 
 
 
 
All-cause mortality 
 
 
 
 
1The number of all randomized participants. 
2The number of 30 days follow up included participants who had 30 days of follow-up or 
withdrawn/dropped-out within 30 days. 
3The primary study endpoint is defined as a composite endpoint of symptomatic deep vein thrombosis of 
upper or lower extremities, pulmonary embolism, other venous thromboembolism, ischemic stroke, 
myocardial infarction, other arterial thromboembolism, and all-cause mortality for up to 30 days after 
initiation of assigned treatment. 
 
 
 


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Figure: Kaplan-Meier Curves for the Time to Adjudicated Outcome Events 
 
Table: Adjudicated Safety Outcome Events among Randomized Subjects with 30-day Follow-Up by 
Treatment and adjudicated event data 
 
Arm A 
(N=XX) 
Arm B 
(N=XX) 
Major Bleeding, n (%) 
 
CRNMB, n (%) 
 
 
Minor bleeding, n (%) 
 
 
 
Figure: Kaplan-Meier Curves for the Time to Adjudicated Safety Outcome Events 
 
 
 


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Appendix 3. Detailed Tri-Monthly DSMB Tables on Safety and Efficacy Outcomes 
In addition to the monthly abbreviated reports (Appendix 2), the following reports are made available 
to the DSMB every three months. 
 
A. RECRUITMENT AND RETENTION STATUS 
Figure: Site Activation by Month 
Figure: Randomization by Month 
Table: Numbers Consented and Randomized by Site 
Sites and Networks 
Consented 
Randomized 
Site 1 
 
 
Site 2 
 
 
.. 
 
 
 
Table: Recruitment and Retention among Enrolling Sites 
 
Randomiz
ed 
Discharg
ed 
Drug 
Start 
Activ
e 
Limite
d 
Conta
ct 
Withdra
wn 
Day 30 
Complete 
Day 90 
Comple
te 
All 
Sites 
N 
N 
n 
N 
N 
N 
N 
n 
Site 1 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
Site 2 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
.. 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
  
Table: Visit Completion for Randomized Participants 
 
Randomized Day 2 Day 10 Day 20 Day 30 Day 45 Day 90 
Expected 
 
n 
N 
N 
n 
N 
N 
Total 
N 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
Site 1 
N 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
Site 2 
N 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
.. 
N 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
 
 
 


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B. BASELINE CHARACTERISTICS 
Table: Baseline characteristics of randomized participants 
Randomized Arm A Arm B 
N= 
N= 
N= 
Stratification 
 
 
 
Antiplatelet Use (%) 
 
 
 
Hospitalization Severity (%) 
 
 
 
   Severe 
 
 
 
   Moderate 
 
 
 
Demographics 
 
 
 
Age (median (q1,q3))1 
 
 
 
Biological sex = Female (%) 
 
 
 
Race (%) 
 
 
 
   White 
 
 
 
   Asian 
 
 
 
   Black or African American 
 
 
 
   American Indian or Alaska Native 
 
 
 
   Native Hawaiian or other Pacific Islander 
 
 
 
   Aboriginal or First Nations 
 
 
 
   Middle Eastern or North African 
 
 
 
   More than one race 
 
 
 
   Other race 
 
 
 
   Unknown 
 
 
 
Ethnicity (%) 
 
 
 
   Hispanic or Latino 
 
 
 
   Not Hispanic or Latino 
 
 
 
   Unknown 
 
 
 
Medical History 
 
 
 
Cardiovascular 
 
 
 
   Hypertension (%) 
 
 
 
   Heart Failure 
 
 
 
   Coronary Artery Disease (CAD) 
 
 
 
   Peripheral Arterial Disease (PAD) 
 
 
 
   Cerebrovascular Disease (stroke or TIA) 
 
 
 
   Atrial fibrillation / flutter 
 
 
 
   Deep Vein Thrombosis (DVT) 
 
 
 
   Pulmonary Embolism (PE) 
 
 
 
   Known thrombophilia 
 
 
 
   Lower limb paralysis / paresis 
 
 
 
   History of smoking and/or vaping 
 
 
 
   None of the above 
 
 
 
Metabolic, Renal, or Digestive (%) 
 
 
 


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   Diabetes Type 1 
 
 
 
   Diabetes Type 2 
 
 
 
   Chronic Kidney Disease 
 
 
 
   Liver Disease 
 
 
 
   None of the above 
 
 
 
Respiratory (%) 
 
 
 
   Asthma 
 
 
 
   Chronic Obstructive Pulmonary Disease 
 
 
 
   Interstitial Lung Disease 
 
 
 
   Pulmonary Hypertension 
 
 
 
   History of oxygen use prior to hospitalization 
 
 
 
   None of the above 
 
 
 
Immunosuppressive Disease 
 
 
 
   HIV/AIDS 
 
 
 
   Metastatic Cancer 
 
 
 
   Malignancy, receiving chemotherapy or immunotherapy 
 
 
 
   History of cancer but not currently in treatment 
 
 
 
   Leukemia 
 
 
 
   Lymphoma 
 
 
 
   Solid organ transplant 
 
 
 
   Bone marrow transplant 
 
 
 
   Autoimmune disease 
 
 
 
   None of the above 
 
 
 
History of seizures 
 
 
 
History of alcoholism 
 
 
 
   Current 
 
 
 
   Former 
 
 
 
   Never 
 
 
 
   Unknown 
 
 
 
Baseline Medications 
 
 
 
Hydroxychloroquine / Chloroquine 
 
 
 
Colchicine 
 
 
 
Remdesivir 
 
 
 
IL6 Inhibitors 
 
 
 
Lopinavir / Ritonavir 
 
 
 
Interferon Beta-1a 
 
 
 
Convalescent Plasma 
 
 
 
Dexamethasone 
 
 
 
Azithromycin 
 
 
 
Other steroids (not Dexamethasone) 
 
 
 
Monoclonal Antibody 
 
 
 
Anticoagulants 
 
 
 
   Anti-platelets 
 
 
 


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   IV argatroban continuous infusion 
 
 
 
   IV argatroban continuous infusion 
 
 
 
   IV bivalirudin continuous infusion 
 
 
 
   IV unfractionated heparin infusion 
 
 
 
   Unfractionated heparin subcutaneous 
 
 
 
   Acenocoumarol 
 
 
 
   Apixaban 
 
 
 
   Dabigatran 
 
 
 
   Dalteparin 
 
 
 
   Edoxaban 
 
 
 
   Enoxaparin 
 
 
 
   Fluindione 
 
 
 
   Fondaparinux 
 
 
 
   Nadroparin 
 
 
 
   Phenprocoumon 
 
 
 
   Rivaroxaban 
 
 
 
   Tinzaparin 
 
 
 
   Warfarin 
 
 
 
   Other anticoagulant 
 
 
 
Baseline Measures 
 
 
 
Contact Preference (%) 
 
 
 
   Electronic Participant (ePPT) 
 
 
 
   Telephone Participant (tPPT) 
 
 
 
Weight (kg) (median (q1,q3)) 
 
 
 
BMI (median (q1,q3)) 
 
 
 
Lab work (median (q1,q3)) 
 
 
 
   Albumin (g/dL) 
 
 
 
   Alanine Transaminase (ALT) (U/L) 
 
 
 
   Creatinine (mg/dL) 
 
 
 
   D-Dimer (ug/L FEU) 
 
 
 
   Hemoglobin (g/dL) 
 
 
 
   Lactate Dehydrogenase (LDH) (U/L) 
 
 
 
   Lymphocyte count (/mm3) 
 
 
 
   Neutrophil count (/mm3) 
 
 
 
   Platelets (103/uL) 
 
 
 
   Sodium (mEq/L) 
 
 
 
   Blood Urea Nitrogen (mg/dL) 
 
 
 
   White Blood Cell (WBC) count (109/L) 
 
 
 
   Estimated Glomerular Filtration Rate (eGFR) (mL/min/1.7) 
 
 
 
q1=25th and q3=75th percentiles. 
 
 
 


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C. MEDICATION AND TREATMENT ADHERENCE  
Table: Medication Adherence among Randomized Participants  
1 The number of 30 days follow up include participants who had completed 30 days of follow-up or 
withdrawn/dropped-out within 30 days. 
 
 
Table: Treatment Adherence among Randomized Participants  
 
30 Days Follow Up1 (N=) 
Arm A (N=) 
Arm B (N=) 
Treatment Ever Interrupted, N (%) 
 
 
Number of Interrupted Days 
n (%) 
.. 
 
 
.. 
 
 
.. 
 
 
Treatment Stopped Permanently, N (%) 
 
 
Reasons 
n (%) 
… 
 
 
    1 The number of 30 days follow up include participants who had completed 30 days of follow-up or 
withdrawn/dropped-out within 30 days. 
 
 
 
 
30 Days Follow Up1 (N=) 
Missed Any Pills Since Last Follow Up 
n (%) 
1~4 Pills 
>4 Pills 
ARM A 
(N=) 
ARM B 
(N=) 
ARM A 
(N=) 
ARM B 
(N=) 
ARM A 
(N=) 
ARM B 
(N=) 
Follow Up at Day 10 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
Follow Up at Day 20 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
Follow Up at Day 30 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 
n(%) 


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D. SERIOUS ADVERSE EVENTS LISTINGS: 
All serious adverse events (SAEs) that occurred between the previous DSMB and current DSMB data 
freeze dates are listed by treatment arms. Following information is provided for each SAE. 
PATID:  
Case x of x 
Event Onset Date:  
Expected/Relatedness: Unexpected and Unrelated to Study Medication  
Randomization Date:  
Study Medication Day:  
Reported Event:  
Recovery Status:  
Narrative:  
 
 
 


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E. PROTOCOL DEVIATIONS 
All protocol deviations are listed in this section.