Conditions: COVID-19
Keywords: COVID-19 Anticoagulation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 14
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if therapeutic dose anticoagulation (experimental group) improves 30-day mortality in participants with COVID-19 compared to those patients receiving the intermediate dose prophylaxis (control group). Following screening, subjects will be randomized 1:1 to intermediate dose prophylaxis or therapeutic dose anticoagulation treatment arms.Treatment will continue for 28 days, followed by a 6 month follow-up period.

Detailed description:

Arms:
arm 1: Subjects will receive one of the following interventions, at their physician's discretion:

* Enoxaparin 0.5 mg/kg subcutaneously every 12 hours if creatinine clearance greater than or equal to 30 ml/min
* Enoxaparin 0.5 mg/kg subcutaneously every 24 hours if creatinine clearance less than 30 mL/min
* If patient develops acute kidney injury: unfractionated heparin 7,500 units subcutaneously every 8 hours.
* Fondaparinux (if history of heparin-inducted thrombocytopenia \[HIT\]) 2.5 mg daily subcutaneously arm 2: Subjects will receive one of the following interventions, at their physician's discretion:

* Unfractionated heparin (UFH) to target anti-Xa level 0.3 -0.7 IU/mL or activated partial thromboplastin time (aPTT) (according to institutional protocol).
* Enoxaparin 1 mg/kg subcutaneously every 12 hours
* Argatroban (if heparin-induced thrombocytopenia \[HIT\]), dosed according to institutional protocol.
* Fondaparinux (if HIT and creatinine clearance greater than or equal to 50 ml/min) dosed by weight:

  * ≥100 kg: 10 mg daily
  * \<100 kg but ≥50 kg: 7.5 mg daily
  * \<50 kg: 5 mg daily

Interventions: intervention 1: Enoxaparin sodium intervention 2: Unfractionated heparin intervention 3: Fondapariniux intervention 4: Argatroban
Intervention descriptions: intervention 1: Intermediate Dose Prophylaxis Arm:

0.5 mg/kg subcutaneously every 12 hours if creatinine clearance greater than or equal to 30 ml/min --OR-- 0.5 mg/kg subcutaneously every 24 hours if creatinine clearance less than 30 ml/min

Therapeutic Dose Anticoagulation Arm:

1 mg/kg subcutaneously every 12 hours intervention 2: Intermediate Dose Prophylaxis Arm:

7,500 units subcutaneously every 8 hours

Therapeutic Dose Anticoagulation Arm:

Dosed to target anti-Xa level 0.3 - 0.7 IU/mL or activated partial thromboplastin time (aPTT), according to institutional protocol intervention 3: Intermediate Dose Prophylaxis Arm:

2.5 mg daily subcutaneously

Therapeutic Dose Anticoagulation Arm:

Dose by weight:

* If greater than or equal to 100 kg: 10 mg daily
* If less than 100 kg but greater than or equal to 50 kg: 7.5 mg daily
* If less than 50 kg: 5 mg daily intervention 4: Therapeutic Dose Anticoagulation Arm:

Dosed according to institutional protocol

Protocol document:
Prot_SAP_000.pdf: 
Title: InterMediate ProphylACtic versus Treatment Dose Anticoagulation in Critically Ill Patients with 
COVID-19: A Prospective Randomized Study (The IMPACT Trial) 
NCT04406389 
Initial IRB Approval Date: 05 June 2020 
Amendment History 
•
Original Protocol Date: 03 JUN 2020
•
Amendment #1: 08 JUL 2020
•
Amendment #2: 03 DEC 2021


 
 
  
Page # i 
 
 
TITLE:  InterMediate ProphylACtic versus Treatment Dose Anticoagulation in Critically Ill Patients 
with COVID-19: A Prospective Randomized Study (The IMPACT Trial) 
 
IRB Protocol #: 20-04021936 
Version Date: 03 December 2021 
 
Principal Investigator: 
 
Maria T DeSancho, M.D., M.Sc. 
Weill Cornell Medicine Center for Blood Disorders 
428 East 72nd Street, Suite 300 
New York, NY 10021 
Tel: 646-962-2065 
Fax: 646-962-1604 
Mtd2002@med.cornell.edu 
 
Co-Investigators: 
 
 
 
 
Eun-Ju Lee, M.D. 
 
 
 
 
Dana Zappetti, M.D.  
Eul7001@med.cornell.edu   
 
 
 
Daz9001@med.cornell.edu  
 
Lindsay Lief, M.D. 
 
 
 
 
Jeffrey Laurence, M.D. 
Liw9021@med.cornell.edu   
 
 
 
jlaurenc@med.cornell.edu  
  
 
Edward Schenck, M.D. 
 
 
 
 
Andy Huang, M.D. 
ejs9005@med.cornell.edu  
 
 
 
 
anh9107@nyp.org 
 
 
 
 
 
 
 


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Table of Contents 
CONFIDENTIALITY STATEMENT .................................................................................. VII 
LIST OF ABBREVIATIONS............................................................................................. VIII 
1. PROTOCOL SUMMARY ................................................................................................ 1 
1.1 
Schema .................................................................................................................... 3 
1.2 
Study Objectives and End Points ........................................................................ 3 
1.2.1  Primary Objectives ......................................................................................... 3 
1.2.2  Secondary Objectives .................................................................................... 3 
1.2.4 
Primary Endpoints .......................................................................................... 3 
1.2.5 
Secondary Endpoints ..................................................................................... 3 
2. BACKGROUND .............................................................................................................. 4 
2.1 
Disease .................................................................................................................... 4 
2.2 
Investigational Agent ............................................................................................ 5 
2.3 
Rationale ................................................................................................................. 6 
2.4 
 Risk/Benefit Assessment..................................................................................... 6 
2.4.1 
Known Potential Risks ................................................................................... 6 
2.4.2 
Known Potential Benefits .............................................................................. 6 
2.4.3 
Assessment of Potential Risks and Benefits .............................................. 6 
2.5 
Correlative Studies Background ......................................................................... 7 
3. STUDY DESIGN.............................................................................................................. 7 
3.1 
Overall Design ........................................................................................................ 7 
3.2 
Scientific Rationale for Study Design ................................................................. 8 
3.3 
Justification for Dose ............................................................................................ 8 
3.4 
End of Study Definition ......................................................................................... 8 
4. SUBJECT SELECTION .................................................................................................. 8 
4.1 
Study Population ................................................................................................... 8 
4.2 
Inclusion Criteria .................................................................................................... 8 
4.3 
Exclusion Criteria .................................................................................................. 9 
4.4 
Lifestyle Considerations ....................................................................................... 9 
4.5 
Screen Failures ...................................................................................................... 9 
5. REGISTRATION PROCEDURES ................................................................................ 10 
5.1 
Subject Registration (WCM only) ...................................................................... 10 
6. STUDY PROCEDURES ................................................................................................ 10 
6.1 
Schedule of Assessments .................................................................................. 10 
6.1.1 
Screening and Randomization .................................................................... 12 
6.1.1.1 
Screening (within 48 hours of treatment initiation) .............................. 12 


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6.1.1.2 
 Randomization (prior to treatment initiation) ....................................... 12 
6.1.2 
Treatment Phase ........................................................................................... 12 
6.1.2.1 
Visit 1 (Day 1) ............................................................................................. 12 
6.1.2.2 
Visits 2 through 5 (Day 7, Day 14, Day 21, Day 28) ............................... 13 
6.1.3 
Follow-up Phase ............................................................................................ 13 
6.1.3.1 
Visit 6 (30 Days Post-Treatment) ............................................................. 13 
6.1.3.2 
Visit 7 (60 Days Post-Treatment) ............................................................. 14 
6.1.3.3 Visit 8 (6 Months Post-Treatment) ............................................................... 14 
7. STUDY INTERVENTION .............................................................................................. 15 
7.1 
Study Intervention Description .......................................................................... 15 
7.2 
Availability ............................................................................................................ 15 
7.3 
Acquisition and Accountability.......................................................................... 15 
7.4 
Formulation, Appearance, Packaging, and Labeling ...................................... 15 
7.5 
Product Storage and Stability ............................................................................ 16 
7.6 
Preparation ........................................................................................................... 16 
7.7 
Dosing and Administration ................................................................................ 16 
7.7.1 
Dosing Delays/Dose Modifications ............................................................. 17 
7.8 
General Concomitant Medication and Supportive Care Guidelines ............. 17 
7.9 
Duration of Therapy and Criteria for Removal from Study ............................ 17 
7.10 Duration of Follow Up ........................................................................................... 18 
7.11 Measures to Minimize Bias: Randomization...................................................... 18 
8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .............................................................................. 19 
8.1 
Discontinuation of Study Intervention .............................................................. 19 
8.2 
Participant Discontinuation/Withdrawal from the Study ................................ 19 
9. CORRELATIVE/SPECIAL STUDIES ........................................................................... 20 
10.  MEASUREMENT OF EFFECT .................................................................................. 20 
10.1 Response Criteria .................................................................................................. 20 
10.2 Duration of Response ........................................................................................... 20 
10.3 Progression-Free Survival ................................................................................... 20 
10.4 Other Response Parameters ................................................................................ 20 
11. DATA REPORTING / REGULATORY CONSIDERATIONS .................................... 21 
11.1 Data Collection....................................................................................................... 21 
11.1.1 REDCap ............................................................................................................ 21 
11.2 Regulatory Considerations .................................................................................. 21 
11.2.1 Institutional Review Board/Ethics Committee Approval ........................... 21 
11.2.2 Ethical Conduct of the Study ........................................................................ 22 
11.2.3 Informed Consent ........................................................................................... 22 
11.2.4 Compliance with Trial Registration and Results Posting Requirements 22 


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11.2.5 Record Retention ............................................................................................ 23 
12. STATISTICAL CONSIDERATIONS ........................................................................... 23 
12.1 
Study Design/Endpoints: ................................................................................ 23 
12.1.1 
Primary Endpoint: Death at 30 days (primary) ...................................... 23 
12.1.2 
Secondary Endpoint: Length of ICU stay. .............................................. 23 
12.1.3 Secondary Endpoint: Compositive endpoint of: ........................................ 23 
12.1.4 
Secondary Endpoint: Safety Outcomes of major bleeding and 
clinically 23 
12.2 Sample Size/Accrual Rate .................................................................................... 24 
12.3 Stratification Factors ............................................................................................ 24 
12.4 Analysis of Endpoints ........................................................................................... 25 
12.4.1 
Analysis of Primary Endpoints ................................................................ 25 
12.4.2 
Analysis of Secondary Endpoints ........................................................... 25 
12.5 Interim Analysis ..................................................................................................... 26 
12.6 Reporting and Exclusions .................................................................................... 26 
12.6.1 
Evaluation of Toxicity ............................................................................... 26 
12.6.2 
Evaluation of Response ............................................................................ 26 
13. ADVERSE EVENT REPORTING REQUIREMENTS ................................................ 26 
13.1 Adverse Event Definition ...................................................................................... 26 
13.1.1 
Investigational Agent or Device Risks (Expected Adverse Events) ... 26 
13.1.2 
Adverse Event Characteristics and Related Attributions .................... 27 
13.1.3 
Recording of Adverse Events .................................................................. 27 
13.1.4 
Reporting of AE to WCM IRB ................................................................... 27 
13.1.5 
Reporting Events to Participants ............................................................ 27 
13.1.6 
Events of Special Interest ......................................................................... 27 
13.1.7 
Reporting of Pregnancy ............................................................................ 27 
13.2 Definition of SAE ................................................................................................... 27 
13.2.1 
Reporting of SAE to IRB ........................................................................... 28 
13.2.2 
Reporting of SAE to FDA .......................................................................... 28 
13.3 AE/SAE Follow Up ................................................................................................. 28 
13.4 Time Period and Frequency for Event Assessment and Follow Up ............... 28 
14. UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS29 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSO) ....................................................................................................................... 29 
14.1.2 
Unanticipated Problem Reporting ........................................................... 29 
15. DATA AND SAFETY MONITORING PLAN (DSMP) ................................................ 30 
16. REFERENCES ............................................................................................................ 31 
APPENDIX A ..................................................................................................................... 32 


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APPENDIX B ..................................................................................................................... 33 
APPENDIX C ..................................................................................................................... 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Statement of Compliance 
 
 
The trial will be carried out in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR 
Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the Institutional Review Board (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.  In addition, all changes to the 
consent form will be IRB-approved; a determination will be made regarding whether a new 
consent needs to be obtained from participants who provided consent, using a previously 
approved consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from WCM, unless disclosure on ClinicalTrials.gov is federally required. 
 
 
 
 
 
 
 
 
 
 
 
 


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List of Abbreviations 
 
 
AE 
Adverse Event 
AC 
Anticoagulation 
ALT 
Alanine Aminotransferase 
APTT 
Activated Partial Thromboplastin Time 
ASH 
American Society of Hematology 
AST 
Aspartate Aminotransferase 
Bi-PAP 
Bilevel Positive Airway Pressure 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CRRT 
Continuous Renal Replacement Therapy 
CTSC 
Clinical Translational Science Center  
DIC 
Disseminated Intravascular Coagulation 
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
DVT 
Deep Venous Thrombosis 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HIT 
Heparin-Induced Thrombocytopenia 
HUD 
Humanitarian Use Device  
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
IDE 
Investigational Device Exemption  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISTH 
International Society of Thrombosis and Haemostasis 
KDIGO 
Kidney Disease Improving Global Outcomes 
LDH 
Lactate Dehydrogenase 
LMWH 
Low-Molecular-Weight Heparin 
PHI 
Protected Health Information 
PI 
Principal Investigator 


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PT 
Prothrombin Time 
REDCap 
Research Electronic Data Capture 
RNA 
Ribonucleic Acid 
RT-PCR 
Reverse Transcriptase Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
UFH 
Unfractionated Heparin 
UIRTSO 
Unanticipated Problem Involving Risks to Subjects or Others 
VTE 
Venous Thromboembolism 
VWF 
Von Willebrand Factor 
WCM 
Weill Cornell Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol # 20-04021936 
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Page # 1 
 
1. Protocol Summary 
 
Full Title:  
 
 
 
InterMediate ProphylACtic versus Treatment Dose Anticoagulation 
in Critically Ill Patients with COVID-19: A Prospective Randomized 
Study (The IMPACT Trial) 
Short Title: 
 
 
 
The IMPACT Trial 
Clinical Phase: 
 
 
IV 
Principal Investigator:  
Maria T. DeSancho, M.D., M.Sc. 
Study Description:   
The purpose of this study is to determine if therapeutic dose 
anticoagulation (experimental group) improves 30-day mortality in 
participants with COVID-19 compared to those receiving the 
intermediate dose prophylaxis (control group). Following 
screening, subjects will be randomized 1:1 to intermediate dose 
prophylaxis or therapeutic anticoagulation treatment arms. 
Treatment will continue for 28 days with longer-term follow-up 
through 6 months.   
Sample Size: 
 
N=186; 93 patients per cohort 
Enrollment: 
 
The study will enroll 186 subjects and screen up to 300 subjects 
Study Population: 
 
Adult patients with documented COVID-19 infection 
Enrollment Period:  
6 months 
 Intervention Description: Intermediate Dose Prophylaxis 
• 
Enoxaparin 0.5 mg/kg subcutaneously every 12 hours if 
CrCl >30 ml/min 
• 
Enoxaparin 0.5 mg/kg subcutaneously every 24 hours if 
CrCl less than 30 mL/min  
• 
If patient develops acute kidney injury (defined by KDIGO 
guidelines): unfractionated heparin 7,500 units 
subcutaneously every 8 hours. 
• 
Fondaparinux (if history of HIT) 2.5 mg daily 
subcutaneously 
 
 
Therapeutic Anticoagulation 
• 
Unfractionated heparin (UFH) to target anti-Xa level 0.3 – 
0.7 IU/mL or aPTT (according to institutional protocol). 
• 
Enoxaparin 1 mg/kg subcutaneously every 12 hours 
• 
Argatroban (if heparin-induced thrombocytopenia [HIT]), 
dosed according to institutional protocol. 
• 
Fondaparinux (if HIT and CrCl ≥50 ml/min) dosed by 
weight: 
o ≥100 kg: 10 mg daily 
o <100 kg but ≥50 kg: 7.5 mg daily 
o <50 kg: 5 mg daily 
Primary Objective: 
To determine if therapeutic anticoagulation improves 30-day 
mortality in COVID-19 positive patients compared to intermediate 
dose prophylaxis. 
 


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Secondary Objectives: 
1. To assess if therapeutic anticoagulation reduces the length of 
ICU stay. 
2. To determine if therapeutic anticoagulation reduces the number 
of documented venous thromboembolism (VTE), arterial 
thrombosis (stroke, myocardial infarction, other) and micro 
thrombosis.  
3. To evaluate if therapeutic anticoagulation leads to increase 
major and clinically relevant non-major bleeding events as defined 
by the International Society of Thrombosis and Haemostasis 
(ISTH) criteria. 
 
Primary Endpoints: 
Efficacy Outcomes 
Death at 30 days 
Secondary Endpoints: 
 
 
1-   Length of ICU stay 
2-   Objectively documented pulmonary embolism (PE), proximal 
deep vein thrombosis (DVT) of the upper or lower extremities, 
thrombosis of the dialysis, continuous renal replacement 
(CRRT) filters; micro-thrombosis (skin biopsy), arterial 
thrombosis (stroke, myocardial infarction, limb ischemia) 
3-   Major bleeding, (as per ISTH guidelines), and clinically 
relevant non-major bleeding events. 
 
 
 
 
 
 


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1.1 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2 Study Objectives and End Points 
 
 
1.2.1  Primary Objectives  
 
1. To determine if therapeutic anticoagulation improves 30-day mortality in COVID-
19 positive patients compared to intermediate dose prophylaxis. 
 
1.2.2  Secondary Objectives  
 
1. To assess if therapeutic anticoagulation reduced the length of ICU stay. 
2. To determine if therapeutic anticoagulation reduces the number of documented 
venous thromboembolism (VTE), arterial thrombosis (stroke, myocardial infarction 
other) and micro thrombosis. 
3. To evaluate if therapeutic anticoagulation leads to increase major and clinically 
relevant non-major bleeding events as defined by the International Society of 
Thrombosis and Haemostasis (ISTH) criteria. 
 
 
1.2.4 Primary Endpoints 
 
Efficacy Outcomes: 
1. Death at 30 days 
1.2.5 Secondary Endpoints 
 
Safety Outcomes: 
1. Length of ICU Stay 
2. Objectively documented pulmonary embolism (PE), proximal deep vein 
thrombosis (DVT) of the upper or lower extremities, thrombosis of the 
Patient is eligible 
 
Consent is signed  
Randomization 
Intermediate Dose AC  
(standard of care) 
Therapeutic AC 
(experimental) 
  Screening          
 
 
 
Treatment 
 
 
  
 
Follow-Up 
 
6 Month Observation 
Period 
 Day 1    Day 7    Day 14    Day 21    Day 28 


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dialysis, continuous renal replacement (CRRT) filters, micro-thrombosis (skin 
biopsy), or arterial thrombosis (stroke, myocardial infarction, limb ischemia) 
3. Major bleeding, defined (as per ISTH guidelines) as acute clinically overt 
bleeding associated with one or more of the following: 
a. A decrease in hemoglobin of 2 g/dL or more; 
b. A transfusion of 2 or more units of packed red cells; 
c. Bleeding that occurs in at least one of the following critical sites: 
i. Intracranial 
ii. Intra-spinal 
iii. Intraocular (within the corpus of the eye; thus, a conjunctival 
bleed is not an intraocular bleed) 
iv. Pericardial 
v. Intra-articular 
vi. Intramuscular with compartment syndrome 
vii. Retroperitoneal 
d. Bleeding that is fatal; 
e. Bleeding that necessitates surgical intervention. 
OR Clinically relevant non-major bleeding event, defined as acute clinically 
overt bleeding that does not meet the criteria for major and consists of; 
f. Any bleeding compromising hemodynamics; 
g. Spontaneous hematoma larger than 25cm2, or 100cm2 if there was a 
traumatic cause; 
h. Intramuscular hematoma documented by ultrasonography; 
i. 
Epistaxis or gingival bleeding requiring tamponade or other medical 
intervention or bleeding from venipuncture for >5 minutes; 
j. 
Hematuria that was macroscopic and was spontaneous or lasted for 
more than 24 hours after invasive procedures; 
k. Hemoptysis, hematemesis, or spontaneous rectal bleeding requiring 
endoscopy or other medical intervention; 
l. 
Clinically relevant bleeding defined as the composite of major and 
clinically relevant non-major bleeding; 
m. Permanent early discontinuation of the anticoagulant due to safety 
reasons 
 
2. Background 
 
2.1 Disease 
 
The SARS-COV-2 (COVID-19) pandemic has had an unprecedented effect on our 
healthcare system and led to the death of over 164,939 people worldwide. Within the United 
States, New York State and specifically New York City has the highest number of COVID-19 
infected patients. Why the pandemic carries a relatively high mortality rate across the world 
remains unclear, but there is growing evidence that COVID-19 triggers a hypercoagulable 


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state causing mostly microvascular thrombosis. A retrospective study in China showed that 
critically ill patients with markedly elevated D-Dimers who were on heparin or low-molecular 
weight heparin (LMWH) prophylactic-dose had lower mortality compared to those who did 
not receive pharmacologic thromboprophylaxis. At our own institution, pulmonary micro 
thrombi have been observed on autopsies and numerous skin biopsies of retiform purpura 
lesions on these patients have revealed thrombotic vasculopathies. In some countries, the 
dose of heparin or LMWH is being escalated to a therapeutic dose. Whether therapeutic-
dose anticoagulation improves outcomes in these critically ill COVID-19 patients has not 
been studied. 
 
2.2 Investigational Agent 
 
 
All of the drugs described in this protocol are FDA approved for the intended indications and 
can be obtained through a prescription.  
 
Enoxaparin (Lovenox®) is an anticoagulant medication approved by the FDA for the 
prophylaxis and treatment of deep vein thrombosis and pulmonary embolism. Enoxaparin is 
available as an injectable and is delivered subcutaneously. For this study, subjects 
randomized to the intermediate dose prophylaxis arm will receive Enoxaparin 0.5 mg/kg 
subcutaneously every 12 hours if their creatinine clearance is > 30 ml/min. Subjects with 
creatinine clearance of < 30 ml/min will receive Enoxaparin 0.5 mg/kg subcutaneously every 
24 hours. Subjects randomized to the therapeutic anticoagulation arm will receive 
Enoxaparin 1 mg/kg subcutaneously every 12 hours if their creatinine clearance is > 30 
ml/min and 1 mg/kg subcutaneously every 24 hours if creatinine clearance of < 30 ml/min.  
 
Heparin sodium (unfractionated heparin) is an anticoagulant indicated for the prophylaxis 
and treatment of venous thromboembolism. For this study, subjects on the intermediate 
dose prophylaxis arm who develop acute kidney injury, as defined by the KDIGO guidelines, 
may receive unfractionated heparin 7,500 units subcutaneously every 8 hours. Subjects on 
the therapeutic anticoagulation arm may receive unfractionated heparin intravenous 
continuous infusion to target anti-Xa level of 0.3 – 0.7 IU/mL or therapeutic range aPTT, 
according to institutional guidelines. 
 
Argatroban is a synthetic direct thrombin inhibitor that is approved for the prophylaxis and 
treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT). 
Subjects randomized to the therapeutic anticoagulation arm with a history of HIT may 
receive argatroban dosed according to institutional protocol. 
 
Fondaparinux (Arixtra®) is a synthetic and specific inhibitor of Factor X (Xa) indicated for the 
prophylaxis and treatment of deep vein thrombosis or acute pulmonary embolism. Subjects 
randomized to the intermediate dose prophylaxis arm with a history of HIT will receive 
fondaparinux 2.5 daily subcutaneously. Subjects randomized to the therapeutic 
anticoagulation arm with a history of HIT and creatinine clearance of ≥50 ml/min may 
receive fondaparinux dosed according to weight: if ≥100 kg, 10 mg daily subcutaneously; if 
<100 kg but ≥50 kg, 7.5 mg daily subcutaneously; if <50 kg, 5 mg daily subcutaneously. 
 
More information about these agents may be obtained through their package inserts; see 
Appendix A for further details. 
 


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The researchers are requesting an IND exemption for this study as it involves off-label use 
of FDA-approved medications and will not be applying for a label change. 
 
2.3 Rationale 
 
Venous thromboembolism is a common complication in critically ill patients. Recent 
publications have demonstrated that the risk of thrombosis (venous, arterial and 
microthrombosis) in ICU patients with COVID-19 is 31% in a study from Holland despite 
prophylactic anticoagulation and 25% (venous thrombosis) in a study from China (without 
prophylactic anticoagulation). In a prospective cohort study from France, there were sixty-
four clinically relevant thrombotic complications diagnosed in 150 patients with COVID-19 
ARDS during their ICU stay, mainly pulmonary embolisms (25 patients, 16.7%). Based on 
above published data, we will compare 2 doses of parenteral anticoagulation (intermediate 
and therapeutic dose) in critically ill patients with COVID-19 infection. 
 
In this study, intermediate dose prophylaxis will be considered the standard of care arm 
based on experience from the ICU at Weill Cornell Medicine and published data on standard 
prophylactic dose anticoagulation. The therapeutic anticoagulation arm will be considered 
experimental. 
 
The D-dimer entry criteria of greater than or equal to 6 times the upper limit or normal was 
chosen based on published data from Cui et al. D-Dimers are checked on a daily basis as it 
is being done now in the ICU at WCM. 
 
2.4  Risk/Benefit Assessment  
 
 
 
2.4.1 Known Potential Risks 
 
Enoxaparin, heparin, argatroban and fondaparinux are FDA approved parenteral 
anticoagulants used to prevent and treat VTE. The main side effect of 
anticoagulation is bleeding, therefore close monitoring of anticoagulation is 
required. 
 
Further risks and known side effects of the various anticoagulants being used in 
this protocol may be found in the package inserts, located in Appendix A. 
 
 
2.4.2 Known Potential Benefits  
 
Critically ill patients with COVID-19 have an increased risk of death, but some 
studies have shown evidence that this risk has been decreased with the use of 
parenteral anticoagulation. We believe there will be a lower risk of VTE and other 
thrombotic events with the use of intermediate dose prophylaxis and therapeutic 
dose anticoagulation. 
 
2.4.3 Assessment of Potential Risks and Benefits 
 
Hospitalized patients typically receive standard-dose prophylactic anticoagulation 
to prevent the risk of developing thrombosis throughout their admission. From 


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April 5, 2020 patients who have required ICU-level care for treatment of COVID-
19 in our hospital have been receiving intermediate dose prophylactic 
anticoagulation due to the observation of higher thrombosis risk noted in critically 
ill COVID-19 infected patients. Therapeutic dose anticoagulation may be 
warranted providing that the benefits outweigh the bleeding risk. We hope that 
this study will provide evidence that higher dose (therapeutic) anticoagulation is 
more efficacious and as safe as intermediate dose prophylaxis for prevention of 
thrombosis in critically ill patients with COVID-19 infection. 
 
2.5 Correlative Studies Background 
 
Additional blood will be collected for correlative studies to further assess the 
pathophysiology of thrombosis in these patients including: thrombin generation assay, 
plasmin generation, platelet activation assay, clot lysis time, annexin2. 
 
 
3. Study Design 
 
3.1 Overall Design 
 
Prospective phase IV, open-label randomized control trial comparing two different doses of 
parenteral anticoagulation (Intermediate vs. therapeutic dose) in critically ill patients with 
COVID-19 infection. The purpose of the study is to determine if therapeutic dose 
anticoagulation improves 30-day mortality in COVID-19 positive patients compared to 
intermediate dose prophylaxis. Patients will be randomized 1:1 to either intermediate dose 
prophylaxis (standard of care arm) or therapeutic-dose anticoagulation (experimental arm). 
Each arm will enroll 93 patients, for a total of 186 patients Treatment on both arms will be for 
28 days continuously. Patients will enter the study at the time of hospital admission. Patients 
will be recruited by their treating physician in the hospital or by the principal investigator.  
 
Intermediate dose prophylaxis: 
• 
If CrCl >30 ml/min, Enoxaparin 0.5 mg/kg SC every 12 hours 
• 
If CrCl less than 30 ml/min, Enoxaparin 0.5 mg/kg SC every 24 hours 
• 
If patient develops acute kidney injury (defined by KDIGO guidelines): unfractionated 
heparin 7,500 units SC every 8 hours 
• 
If patient has a history of HIT, Fondaparinux 2.5 mg daily subcutaneously 
 
For patients receiving Enoxaparin, adjust dose based on anti-Xa activity 4 hours after 3rd 
dose; goal of 0.4 – 0.6 IU/mL for intermediate prophylactic dose. 
 
Therapeutic anticoagulation: 
Full dose parenteral anticoagulation per institutional protocol: 
• 
Enoxaparin 1 mg/kg SC every 12 hours If CrCl equal or more than 30 mL/min to 
target peak anti-Xa level 4 hours after the 3rd dose; goal 0.6 - 1.0 IU/mL 
• 
Enoxaparin 1 mg/Kg SC every 24 hours If CrCl less than 30 mL/min to target peak 
anti-Xa level 4 hours after the 3rd dose; goal 0.6 - 1.0 IU/m 
• 
If patient develops acute kidney injury (defined by KDIGO guidelines): Unfractionated 
heparin (UFH) to target anti-Xa level 0.3 – 0.7 IU/mL or aPTT (according to 
institutional protocol) 


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• 
If patient has a history of HIT or develops HIT: 
o Fondaparinux (if CrCl ≥50 ml/min). 
▪ 
If patient weight is ≥100 kg, 10 mg daily 
▪ 
If patient weight is <100kg but ≥50 kg, 7.5 mg daily 
▪ 
If patient weight is <50 kg, 5 mg daily 
o Or Argatroban if CrCl <50 ml/min), dosed according to institutional protocol. 
 
Therapeutic dose adjusted per NYP Infonet protocols. 
 
3.2 Scientific Rationale for Study Design 
 
The risk of thrombosis in ICU patients with COVID-19 is 31% in a study from Holland despite 
prophylactic anticoagulation and 25% in a study from China (without prophylactic 
anticoagulation) and 43% in a French study despite prophylactic anticoagulation. Therefore 
we will compare 2 doses of parenteral anticoagulation (intermediate and therapeutic dose) 
in critically ill patients with COVID-19 infection. 
 
3.3 Justification for Dose  
 
We will compare an intermediate dose (high prophylactic-dose) vs. therapeutic dose 
anticoagulation in COVID-19 critically ill patients because significant risk of thrombosis was 
still observed with the standard prophylactic dose of anticoagulation. 
 
3.4 End of Study Definition 
 
A participant is considered to have completed the study if he or she has completed all 
phases of the study including the last visit or the last scheduled procedure shown in the 
Schedule of Assessments (SoA), Section 6.1. The end of the study is defined as 
completion of the last visit or procedure shown in the SoA in the trial globally. 
 
4. Subject Selection 
 
4.1 Study Population 
 
 
Adult subjects with COVID-19 infection will be eligible for this study. 
 
4.2 Inclusion Criteria 
1. Age > 18 years old 
2. COVID-19 positive on RT-PCR nasopharyngeal swab, or suspected COVID-19 infection 
with detectable SARS-CoV-2 IgG or IgM. 
 
NOTE: COVID-19 will be defined according to the World Health Organization (WHO) 
case definition for a “confirmed case”, which is a positive laboratory test for SARS-CoV-
2, irrespective of clinical signs and symptoms. WHO reference laboratories currently use 
reverse transcription polymerase chain reaction (RT-PCR) tests to detect the presence 
of SARS-CoV-2 viral RNA.  


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3. ICU patient or non-ICU patient on invasive mechanical ventilation, BiPAP, 100% non-
rebreather mask, or high-flow O2, or supplemental O2 of at least 4 liters per minute nasal 
cannula. 
4. D dimer > 700 ng/mL (3 times the upper limit of normal) 
4.3 Exclusion Criteria  
 
1. Objectively documented deep vein thrombosis or pulmonary embolism. 
2. Patients in whom there is very high suspicion for pulmonary embolism and are on full-
dose anticoagulation as per the treating physician. 
3. Platelets <30,000 not due to disseminated intravascular coagulation (DIC), based on 
ISTH criteria and ASH FAQ (Appendix B). 
4. Active bleeding that poses a contraindication to therapeutic anticoagulation in the 
opinion of the investigator. 
5. History of bleeding diathesis (e.g., hemophilia, severe von Willebrand Disease, severe 
thrombocytopathy) 
6. History of intracranial hemorrhage in the last 90 days 
7. History of ischemic stroke in the past 2 weeks 
8. Major neurosurgical procedure in the past 30 days 
9. Cardiothoracic surgery in the past 30 days 
10. Intra-abdominal surgery in the past 30 days 
11. Intracranial malignancy  
12. Patients who require therapeutic anticoagulation for other reasons like atrial fibrillation, 
deep venous thrombosis, pulmonary embolism, or antiphospholipid syndrome. 
4.4 Lifestyle Considerations 
 
Not applicable 
 
4.5 Screen Failures  
 
Screen failures are defined as participants who consent to participate in the clinical trial but 
are not subsequently randomly assigned to the study intervention or entered in the study. A 
minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because 
of a D-dimer level of <1400 ng/mL may be rescreened. Rescreened participants should be 
assigned the same participant number as for the initial screening. 
 
 
 


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5. Registration Procedures 
 
5.1 Subject Registration (WCM only) 
 
Subjects will be registered within the WRG-CT as per the standard operating procedure 
for Subject Registration.  
 
 
 
6. Study Procedures 
 
6.1 Schedule of Assessments 
See Table 1. Schedule of trial events.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1. Schedule of trial events 
 
Screening 
(within 48 
hours of 
treatment 
initiation) 
Randomization 
 
Treatment 
 
Follow-Up 
Day 1 
Day 7 
Day 14 
Day 21 
Day 28 
30 days post-
treatment 
(+/- 2 days) 
60 days 
post-
treatment 
(+/- 2 days) 
6 months 
post-
treatment 
(+/- 7 days) 
Treatment6 
 
 
X------------------------------------------------------> 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History1 
X 
 
 
 
 
 
 
 
 
 
Treatment 
Initiation 
 
 
X 
 
 
 
 
 
 
 
Vital Signs2 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/ diff, 
platelets 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
PT, aPTT  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
D-Dimer 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Fibrinogen 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry3 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII/VWF4 
 
X 
 
 
 
 
X 
 
X 
X 
Activated Protein C 
Resistance 
 
X 
 
 
 
 
X 
 
X 
X 
Lupus 
Anticoagulant 
aPTT lupus 
insensitive 
 
X 
 
 
 
 
 
 
X 
X 
Anticardiolipin  
 
X 
 
 
 
 
 
 
X 
X 
Anti-B2 
Glyocprotein-1 
 
X 
 
 
 
 
 
 
X 
X 
Correlative 
Samples5 
 
X 
 
 
 
 
 
 
X 
X 
Vital Status 
 
 
 
 
 
 
 
X 
X 
X 
Adverse Event 
Evaluation 
X 
X 
X------------------------------------------------------------------------------------------------------------------------> 
Concomitant 
Medications 
X 
X 
X------------------------------------------------------------------------------------------------------------------------> 
1. Including information on symptoms of VTE, site and confirmatory tests, arterial thrombosis or microvascular thrombosis, type of 
anticoagulant/antiplatelet treatment and other treatment. 
2. Body weight, blood pressure, heart rate, O2 saturation, mechanical ventilation, Bi-PAP, high flow O2, 100% non-rebreather mask (as applicable). 
3. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, potassium, total protein, SGOT [AST], SGPT 
[ALT], sodium  
4. VWF (von Willebrand Factor) 
5. Two 3mL blue sodium citrate tubes. Randomization sample will be drawn prior to initiation of study treatment. 
6. Treatment will be given every day for Day 1-Day 28; see section 7.7 for specific dosing schedules. 


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6.1.1 Screening and Randomization 
 
 
6.1.1.1 Screening (within 48 hours of treatment initiation) 
 
• 
Informed Consent 
• 
Medical history, including information on symptoms of VTE, site and 
confirmatory tests, arterial thrombosis or microvascular thrombosis, type 
of anticoagulant/antiplatelet treatment and other treatment. 
• 
Demographics 
• 
Vital Signs (body weight, blood pressure, heart rate, O2 saturation, 
mechanical ventilation, Bi-PAP, high flow O2, 100% non-rebreather mask 
[as applicable]) 
• 
Labwork (results must be available prior to enrollment and randomization) 
o CBC w/ diff, platelets 
o PT, PTT 
o D-dimer 
o Fibrinogen 
o Serum Chemistry (albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium) 
• 
Adverse Event Evaluation 
• 
Concomitant Medications 
 
 
6.1.1.2  Randomization (prior to treatment initiation) 
 
• 
Randomization 
• 
Labwork (results not required for randomization) 
o FVIII, VWF 
o Activated Protein C Resistance 
o Lupus Anticoagulant 
o aPTT lupus insensitive 
o Anticardiolipin 
o Anti-B2 Glycoprotein-1 
o Two 3 mL blue sodium citrate tubes of plasma for correlative studies 
• 
Adverse Event Evaluation 
• 
Concomitant Medications 
 
 
 
 
6.1.2 Treatment Phase 
 
 
 
 
 
Eligible subjects will be randomly assigned to Intermediate Prophylaxis Dose or 
Therapeutic Anticoagulation treatment groups in a 1:1 ratio. Treatment will continue for 
28 days continuously. 
 
 
 
 
6.1.2.1 Visit 1 (Day 1) 
 
• 
Treatment initiation 


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• 
Vital Signs (body weight, blood pressure, heart rate, O2 saturation, 
mechanical ventilation, Bi-PAP, high flow O2, 100% non-rebreather mask 
[as applicable]) 
• 
Labwork 
o CBC w/ diff, platelets 
o PT, PTT 
o D-dimer 
o Fibrinogen 
o Serum Chemistry (albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium) 
o FVIII, VWF 
• 
Activated Protein C ResistanceAdverse Event Evaluation 
• 
Concomitant Medications 
 
 
 
 
6.1.2.2 Visits 2 through 5 (Day 7, Day 14, Day 21, Day 28) 
 
• 
Vital Signs (body weight, blood pressure, heart rate, O2 saturation, 
mechanical ventilation, Bi-PAP, high flow O2, 100% non-rebreather mask 
[as applicable]) 
• 
Labwork 
o CBC w/ diff, platelets 
o PT, PTT 
o D-dimer 
o Fibrinogen 
o Serum Chemistry (albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium) 
• 
Adverse Event Evaluation 
• 
Concomitant Medications 
 
6.1.3 Follow-up Phase 
 
 Following completion of treatment, subjects will enter a 6-month follow-up period. 
 
 
6.1.3.1 Visit 6 (30 Days Post-Treatment) 
 
• 
Vital Signs (body weight, blood pressure, heart rate, O2 saturation, 
mechanical ventilation, Bi-PAP, high flow O2, 100% non-rebreather mask 
[as applicable]) 
• 
Labwork 
o CBC w/ diff, platelets 
o PT, PTT 
o D-dimer 
o Fibrinogen 
o Serum Chemistry (albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium) 
• 
Adverse Event Evaluation 


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• 
Concomitant Medications 
• 
Vital Status 
 
 
6.1.3.2 Visit 7 (60 Days Post-Treatment) 
 
• 
Vital Signs (body weight, blood pressure, heart rate, O2 saturation, 
mechanical ventilation, Bi-PAP, high flow O2, 100% non-rebreather mask 
[as applicable]) 
• 
Labwork 
o CBC w/ diff, platelets 
o PT, aPTT 
o D-dimer 
o Fibrinogen 
o Serum Chemistry (albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium) 
o FVIII, VWF 
o Activated Protein C Resistance 
o Lupus Anticoagulant 
o aPTT lupus insensitive 
o Anticardiolipin 
o Anti-B2 Glycoprotein-1 
o Two 3 mL blue sodium citrate tubes of plasma for correlative studies 
• 
Adverse Event Evaluation 
• 
Concomitant Medications 
• 
Vital Status 
 
 
6.1.3.3 Visit 8 (6 Months Post-Treatment) 
 
• 
Vital Signs (body weight, blood pressure, heart rate, O2 saturation, 
mechanical ventilation, Bi-PAP, high flow O2, 100% non-rebreather mask 
[as applicable]) 
• 
Labwork 
o CBC w/ diff, platelets 
o PT, PTT 
o D-dimer 
o Fibrinogen 
o Serum Chemistry (albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium) 
o FVIII, VWF 
o Activated Protein C Resistance 
o Lupus Anticoagulant 
o aPTT lupus insensitive 
o Anticardiolipin 
o Anti-B2 Glycoprotein-1 
o Two 3 mL blue sodium citrate tubes of plasma for correlative studies 
• 
Adverse Event Evaluation 
• 
Concomitant Medications 


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• 
Vital Status 
 
7. Study Intervention 
 
7.1 Study Intervention Description   
 
Lovenox® (Enoxaparin sodium) is an anticoagulant medication approved by the FDA for 
the prophylaxis and treatment of deep vein thrombosis and pulmonary embolism. 
Enoxaparin is available as an injectable and is delivered subcutaneously. Enoxaparin is 
contraindicated in patients with active major bleeding and a history of immune-mediated 
heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of 
circulating antibodies.  
 
Heparin sodium (unfractionated heparin) is an anticoagulant indicated for the prophylaxis 
and treatment of venous thromboembolism and pulmonary embolism. The use of 
unfractionated heparin is contraindicated in patients with a history of heparin-induced 
thrombocytopenia, patients in an uncontrolled bleeding state except when due to 
disseminated intravascular coagulation, and in patients who cannot have suitable blood 
coagulation tests performed at appropriate intervals. 
 
Argatroban is a synthetic direct thrombin inhibitor that is approved for the prophylaxis or 
treatment of thrombosis in adult patients with heparin-inducted thrombocytopenia (HIT). 
Argatroban is contraindicated in patients with major bleeding. 
 
Fondaparinux (Arixtra®) is a synthetic and specific inhibitor of Factor X (Xa) indicated for 
the prophylaxis and treatment of deep vein thrombosis or acute pulmonary embolism. It 
is supplied as a sterile, preservative-free injectable solution for subcutaneous use. 
 
7.2 Availability 
 
All drugs described in this protocol are FDA approved for the intended indications and 
can be obtained through a prescription. 
 
7.3 Acquisition and Accountability  
 
 
 
All drugs administered while subjects are hospitalized will be documented in the 
electronic medical records system. Any drugs taken at home by the subject will be 
documented in a study-specific drug diary and reviewed with the subject’s treating 
physician at their next clinic visit. 
 
7.4 Formulation, Appearance, Packaging, and Labeling  
 
Lovenox® (Enoxaparin) is a sterile aqueous solution containing enoxaparin sodium, a 
low molecular weight heparin. The pH of the injection is 5.5 to 7.5. Lovenox® is a clear, 
colorless to pale yellow sterile solution that may be administered by intravenous or 
subcutaneous injection only. Lovenox® is manufactured by Sanofi. 
 
Heparin sodium (unfractionated heparin) is available in 0.45% Sodium Chloride Injection 
and 5% Dextrose Injection.  
 


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Argatroban Injection in 0.9% sodium chloride is a clear, colorless to pale yellow solution. 
It is supplied as a single use vial containing 125 mg argatrobain in 125 mL of aqueous 
sodium chloride solution (1 mg/mL). Argatroban Injection is manufactured by Sandoz, 
Inc. 
 
Arixtra® (fondaparinux sodium) is supplied as a sterile, preservative-free injectable 
solution for subcutaneous use. Each single dose, prefilled syringe, affixed with an 
automatic needle protection system, contains 2.5 mg of fondaparinux sodium in 0.5 mL, 
5.0 mg of fondaparinux sodium in 0.4 mL, 7.5 mg of fondaparinux sodium in 0.6 mL or 
10.0 mg of fondaparinux sodium in 0.8 mL of an isotonic solution of sodium chloride and 
water for injection. The final drug product is a clear and colorless to slightly yellow liquid 
with a pH between 5.0 and 8.0. Arixtra® is manufactured by GlaxoSmithKline. 
 
 
7.5 Product Storage and Stability 
 
Lovenox® should be stored at 25°C with excursions permitted to 15°C-30°C (59°F-
86°F). Do not store multiple-dose vials for more than 28 days after the first use. 
 
Heparin sodium should be stored at 20°C to 25°C (68°F-77°F). Avoid excessive heat. Do 
not freeze. 
 
Argatroban vials should be stored in their original cartons at 20°-25° C (68°-77°F). The 
product should be retained in the original carton to protect from light. Do not freeze. 
 
Arixtra® (fondaparinux sodium) should be stored at 25°C (77°F), with excursions 
permitted to 15-30°C (59-86°F). 
 
7.6 Preparation 
 
See Appendix A for package inserts of each drug used in this protocol. 
 
7.7 Dosing and Administration 
 
All subjects will be dosed continuously for 28 days. Specific dosing instructions per drug 
and per arm are as follows: 
 
Intermediate Dose Prophylaxis arm: 
Subjects randomized to the Intermediate Dose Prophylaxis arm will receive one of the 
following treatments: 
• 
If CrCl >30 ml/min, Enoxaparin 0.5 mg/kg subcutaneously every 12 hours 
• 
If CrCl less than 30 ml/min, Enoxaparin 0.5 mg/kg subcutaneously every 24 hours 
• 
If patient develops acute kidney injury (defined by KDIGO guidelines): unfractionated 
heparin 7,5000 units subcutaneously every 8 hours. 
• 
If patient has history of HIT, fondaparinux 2.5 mg daily subcutaneously 
For subjects receiving Enoxaparin, adjust dose based on anti-Xa activity 4 hours after 
the 3rd dose; goal of 0.4 – 0.6 IU/mL. 


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Therapeutic Anticoagulation arm: 
Full dose parenteral anticoagulation per institutional protocol: 
• 
Enoxaparin 1 mg/kg subcutaneously every 12 hours if CrCl >30mL/min.  
• 
Enoxaparin 1 mg/kg subcutaneously daily if CrCl <30 mL/min. 
• 
If AKI develops, Unfractionated heparin (UFH) to target anti-Xa level 0.3 – 0.7 
IU/mL or aPTT (according to institutional protocol). 
• 
Argatroban (if heparin-induced thrombocytopenia [HIT] and CrCl <50 ml/min), 
dosed according to institutional protocol. 
• 
Fondaparinux (if HIT and CrCl ≥50 ml/min), dosed according to patient weight: 
o ≥100 kg: 10 mg daily 
o <100 kg but ≥50 kg: 7.5 mg daily 
o <50 kg: 5 mg daily 
 
Therapeutic dose adjusted per NYP Infonet protocols. 
 
7.7.1 Dosing Delays/Dose Modifications 
 
Dose will be modified according to creatinine clearance; see Section 7.7 for further 
details. 
 
Dose will be delayed or stopped if clinically significant major or non-major bleeding 
occurs. 
 
7.8 General Concomitant Medication and Supportive Care Guidelines 
 
All concomitant medications will be recorded and/or updated on subject medication log 
throughout the course of the study and saved in subject binder, if applicable. 
 
Subjects enrolled on this study are permitted to receive other agents for treatment of 
their COVID-19 disease, including, but not limited to, remdesevir, eculizumab, 
tocilizumab, anakinra, and hydroxychloroquine. Co-enrollment on investigational trials for 
the treatment of COVID-19 is permitted. 
 
7.9 Duration of Therapy and Criteria for Removal from Study 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 
28 days or until one of the following criteria applies: 
 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Subject decides to withdraw from the study, or 
• 
General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator. 
 
 


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In the event of hospital discharge, the decision to continue or discontinue anticoagulation 
therapy will follow institutional guidelines regarding anticoagulation at the time of hospital 
discharge (Appendix C). Anticoagulation treatment may continue beyond Day 28 if the 
investigator and/or treating physician considers it appropriate for the patient’s clinical 
care. 
 
Subjects may discontinue therapy if any of the following events occur: 
• 
Major bleeding, defined (as per ISTH guidelines) as acute clinically overt 
bleeding associated with one or more of the following: 
o A decrease in hemoglobin of 2 g/dL or more; 
o A transfusion of 2 or more units of packed red blood cells; 
o Bleeding that occurs in at least one of the following critical sites: 
▪ Intracranial 
▪ Intra-spinal 
▪ Intraocular (within the corpus of the eye; thus, a conjunctival bleed 
is not an intraocular bleed) 
▪ Pericardial 
▪ Intra-articular 
▪ Intramuscular with compartment syndrome 
▪ Retroperitoneal 
o Bleeding that necessitates surgical intervention 
• 
Clinically relevant non-major bleeding event defined as acute clinically overt 
bleeding that does not meet the criteria for major and consists of: 
o Any bleeding compromising hemodynamics; 
o Spontaneous hematoma larger than 25 cm2, or 100 cm2 if there was a 
traumatic cause; 
o Intramuscular hematoma documented by ultrasonography 
o Epistaxis or gingival bleeding requiring tamponade or other medical 
intervention or bleeding from venipuncture for >5 minutes 
o Hemoptysis, hematemesis or spontaneous rectal bleeding requiring 
endoscopy or other medical intervention; 
o Clinically relevant bleeding defined as the composite of major and 
clinically relevant non-major bleeding 
 
 
 
7.10 Duration of Follow Up 
 
Subjects will be followed for 6 months after discharge from hospital with the intention to 
get complete follow-up, or a minimum of vital status and the occurrence of recurrent 
deep venous thrombosis, pulmonary embolism, or major bleeding.  
 
7.11 Measures to Minimize Bias: Randomization  
 
Blocked randomization will be performed in the study. A series of blocks with random 
block sizes will be generated with a 1:1 allocation ratio to allow for an equal number of 


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Page # 19 
 
patients in the intermediate dose prophylaxis arm and therapeutic anticoagulation 
treatment arm. Patients will not be stratified. The block randomization scheme will be 
provided by a biostatistician not directly involved in the analysis of the study and 
uploaded to the REDCap randomization module. Randomized assignments will be 
generated in REDCap after all eligibility criteria have been met. Blinding is not relevant 
as the study is open-label. 
 
8. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
 
8.1 Discontinuation of Study Intervention 
 
Discontinuation from study intervention does not mean discontinuation from the study, 
and remaining study procedures should be completed as indicated by the study protocol.  
If a clinically significant finding is identified (including, but not limited to changes from 
baseline) after enrollment, the investigator or qualified designee will determine if any 
change in participant management is needed. Any new clinically relevant finding will be 
reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the 
following: 
• 
Reason for study discontinuation 
• 
Adverse events 
• 
Concomitant medications 
• 
Relevant medical history, including: 
o Major and clinically relevant non-major bleeding events 
o Objectively documented pulmonary embolism (PE) 
o Objectively documented and confirmed proximal deep vein thrombosis (DVT) 
of the upper or lower extremities 
o Objectively documented micro-thrombosis (skin biopsy) 
o Objectively documented thrombosis of the dialysis, continuous renal 
replacement (CRRT) filters 
o Objectively documented arterial thrombosis (stroke, myocardial infarction, 
limb ischemia) 
 
8.2 Participant Discontinuation/Withdrawal from the Study 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition 
or situation occurs such that continued participation in the study would not be in the 
best interest of the participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation 


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• 
Participant lost to follow-up after several attempts to contact subject to schedule 
study visit. 
The reason for participant discontinuation or withdrawal from the study will be recorded 
on the Case Report Form (CRF). Subjects who sign the informed consent form and are 
randomized but do not receive the study intervention may be replaced.  Subjects who 
sign the informed consent form, and are randomized and receive the study intervention, 
and subsequently withdraw, or are withdrawn or discontinued from the study, will not be 
replaced. 
 
9. Correlative/Special Studies  
 
For subjects who agree to participate in a research repository, we will collect 5mL of plasma for 
thrombin generation assays and clot lysis at certain time points (see Section 6.1 for more 
details). Samples will be stored in a special freezer located in Dr. Laurence’s laboratory. 
 
 
10.  Measurement of Effect 
 
10.1 Response Criteria 
1. Primary objective: To determine if therapeutic anticoagulation improves 30-day 
mortality in COVID 19 positive patients compared to intermediate dose 
prophylaxis. 
    
      2.   Secondary Objectives 
 
1. To assess if therapeutic anticoagulation reduced the length of ICU stay. 
2. To determine if therapeutic anticoagulation reduces the number of documented 
venous thromboembolism (VTE), arterial thrombosis (stroke, myocardial infarction 
other) and micro thrombosis. 
3. To evaluate if therapeutic anticoagulation leads to increase major and clinically 
relevant non-major bleeding events as defined by the International Society of 
Thrombosis and Haemostasis (ISTH) criteria. 
 
 
10.2 Duration of Response  
 
Duration of response will be evaluated according to evidence of thrombosis or bleeding 
events during the follow up period as defined in 10.1 
 
10.3 Progression-Free Survival  
 
Not applicable. 
 
10.4 Other Response Parameters 
 
Normalization of laboratory values including: D-dimer, prothrombin time (PT), fibrinogen, 
FVIII and VWF and complete blood count 


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11. Data Reporting / Regulatory Considerations 
 
11.1 Data Collection 
 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, 
toxicity, efficacy, and adverse event data for all enrolled subjects.  
 
11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management 
software system that is fully supported by the Weill-Cornell Medical Center 
CTSC.  It is a tool for the creation of customized, secure data management 
systems that include Web-based data-entry forms, reporting tools, and a full 
array of security features including user and group based privileges, 
authentication using institution LDAP system, with a full audit trail of data 
manipulation and export procedures.  REDCap is maintained on CTSC-owned 
servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported 
through a multi-institutional consortium led by the Vanderbilt University CTSA. 
 
The blocked randomization scheme will be incorporated into REDCap and 
assignments will be generated via a randomization module within REDCap. 
 
11.2 Regulatory Considerations 
 
11.2.1 Institutional Review Board/Ethics Committee Approval  
 
As required by local regulations, the Investigator will ensure all legal aspects are covered, 
and approval of the appropriate regulatory bodies obtained, before study initiation.  
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the patients, and any other relevant study documentation will be 
submitted to the appropriate Ethics Committee. Written approval of the study and all 
relevant study information must be obtained before the study center can be initiated or the 
IP is released to the Investigator. Any necessary extensions or renewals of IRB approval 
must be obtained for changes to the study, such as amendments to the protocol, the ICF, 
or other study documentation. The written approval of the IRB together with the approved 
ICF must be filed in the study files.  
The Investigator will report promptly to the IRB any new information that may adversely 
affect the safety of the patients or the conduct of the study. The Investigator will submit 
written summaries of the study status to the IRB as required. On completion of the study, 
the IRB will be notified that the study has ended.  
 
All agreed protocol amendments will be clearly recorded on a protocol amendment form 
and will be signed and dated by the original protocol approving signatories. All protocol 
amendments will be submitted to the relevant institutional IRB for approval before 
implementation, as required by local regulations. The only exception will be when the 


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amendment is necessary to eliminate an immediate hazard to the trial participants. In this 
case, the necessary action will be taken first, with the relevant protocol amendment 
following shortly thereafter.  
Once protocol amendments or consent form modifications are implemented at the lead 
site, Weill Cornell Medicine, updated documents will be provided to participating sites, as 
applicable. Weill Cornell Medicine must approve all consent form changes prior to local 
IRB submission.  
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and approval 
before the beginning of the study. On completion of the study, the regulatory authorities 
will be notified that the study has ended.  
 
11.2.2 Ethical Conduct of the Study  
The Investigators and all parties involved should conduct this study in adherence to the 
ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines and the 
applicable national and local laws and regulatory requirements.  
 
This study will be conducted under a protocol reviewed and approved by the applicable 
ethics committees and investigations will be undertaken by scientifically and medically 
qualified persons, where the benefits of the study are in proportion to the risks. 
 
11.2.3 Informed Consent 
 
The investigator or qualified designee must obtain documented consent according to ICH-
GCP and local regulations, as applicable, from each potential subject or each subject’s 
legally authorized representative prior to participating in the research study. Subjects who 
agree to participate will sign the approved informed consent form and will be provided a 
copy of the signed document. Given the disease state, potential participants may be 
sedated and/or on a ventilator; in such cases, the subject’s legally authorized 
representative will be asked to provide informed consent on behalf of the subject. Subjects 
who enter the study with a legally authorized representative will be re-consented once 
they regain capacity to consent. Subjects who do not speak English may be consented 
using a translated short form in accordance with IRB requirements. 
 
The initial ICF, any subsequent revised written ICF and any written information provided 
to the subject must approved by IRB prior to use. The ICF will adhere to IRB requirements, 
applicable laws and regulations. 
 
11.2.4 Compliance with Trial Registration and Results Posting Requirements  
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to http://www.clinicaltrials.gov. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information. 


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11.2.5 Record Retention 
 
Essential documents are those documents that individually and collectively permit 
evaluation of the study and quality of the data produced.  After completion of the study, all 
documents and data relating to the study will be kept in an orderly manner by the 
Investigator in a secure study file.  Essential documents should be retained for 2 years 
after the final marketing approval in an ICH region or for at least 2 years since the 
discontinuation of clinical development of the IP. In addition, all subjects medical records 
and other source documentation will be kept for the maximum time permitted by the 
hospital, institution, or medical practice.   
 
12. Statistical Considerations 
 
12.1 
Study Design/Endpoints: 
 
Primary Endpoint: 
Efficacy Outcomes 
• 
Death at 30 days 
 
Secondary Endpoints: 
 
Efficacy Outcomes 
1. Length of ICU stay 
2. Objectively documented pulmonary embolism (PE), proximal 
deep vein thrombosis (DVT) of the upper or lower extremities, 
thrombosis of the dialysis, continuous renal replacement 
(CRRT) filters; micro-thrombosis (skin biopsy), arterial 
thrombosis (stroke, myocardial infarction, limb ischemia) 
3. Major bleeding, (as per ISTH guidelines), and clinically 
relevant non-major bleeding events. 
 
12.1.1 Primary Endpoint: Death at 30 days (primary) 
 
12.1.2 Secondary Endpoint: Length of ICU stay. 
 
12.1.3 Secondary Endpoint: Compositive endpoint of: 
• 
Objectively documented pulmonary embolism 
• 
Objectively documented confirmed proximal deep vein thrombosis (DVT) 
of the upper or lower extremities. 
• 
Objectively documented micro-thrombosis (skin biopsy). 
• 
Objectively documented thrombosis of the dialysis, continuous renal 
replacement (CRRT) filters. 
• 
Objectively documented arterial thrombosis (stroke, myocardial infarction, 
limb ischemia). 
 
12.1.4 Secondary Endpoint: Safety Outcomes of major bleeding and clinically  
relevant non-major bleeding events defined as: 
 


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 Major bleeding, defined (as per ISTH guidelines) as acute clinically overt 
bleeding associated with one or more of the following: 
 
 
 
 
 
 
 
 
 
A decrease in hemoglobin of 2 g/dL or more; 
 
 
 
 
A transfusion of 2 or more units of packed red cells; 
 
 
 
 
Bleeding that occurs in at least one of the following critical sites: 
i. Intracranial 
ii. Intra-spinal 
iii. Intraocular (within the corpus of the eye; thus, a conjunctival 
bleed is not an intraocular bleed) 
iv. Pericardial 
v. Intra-articular 
vi. Intramuscular with compartment syndrome 
vii. Retroperitoneal 
 
 
 
 
Bleeding that is fatal; Bleeding that necessitates surgical intervention. 
 
Clinically relevant non-major bleeding event, defined as acute clinically overt 
bleeding that does not meet the criteria for major and consists of; 
 
a) Any bleeding compromising hemodynamics; 
b) Spontaneous hematoma larger than 25cm2, or 100cm2 if there was a 
traumatic cause; 
c) Intramuscular hematoma documented by ultrasonography; 
d) Epistaxis or gingival bleeding requiring tamponade or other medical 
intervention or bleeding from venipuncture for >5 minutes; 
e) Hematuria that was macroscopic and was spontaneous or lasted for more 
than 24 hours after invasive procedures; 
f) Hemoptysis, hematemesis, or spontaneous rectal bleeding requiring 
endoscopy or other medical intervention; 
g) Clinically relevant bleeding defined as the composite of major and clinically 
relevant non-major bleeding;  
h) Permanent early discontinuation of the anticoagulant due to safety reasons. 
 
12.2 Sample Size/Accrual Rate 
 
N=93 subjects per treatment arm (186 total). With approximately 93 patients in each 
treatment arm, a two-sample chi-square test with a 0.05 two-sided significance level will 
have 80% power to detect a difference in the 30-day mortality proportion between 
treatment arms of 12 % or greater. This calculation assumes a 30-day mortality 
proportion of approximately 15 % in the intermediate dose prophylaxis arm. 
 
12.3 Stratification Factors  
None 


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 12.4 Analysis of Endpoints 
 
12.4.1 Analysis of Primary Endpoints 
 
The chi-square test will be used to compare the proportion of patients who die by 
30 days between the two treatment arms. A two-sided 95% confidence interval 
for the difference in the 30-day mortality proportion between the two arms will be 
calculated to assess the precision of the obtained estimate. All other efficacy 
outcome proportions and safety outcome proportions will be compared between 
the two treatment arms by the chi-square test or Fisher’s exact test, as 
appropriate. Two-sided exact Clopper-Pearson 95% confidence intervals will be 
calculated for treatment arm differences, as appropriate.  Participants who are 
discharged prior to day 30 for whom vital status cannot be assessed will be 
censored from the analysis. We expect this to occur only rarely. 
 
12.4.2 Analysis of Secondary Endpoints 
 
 Length of ICU stay:  We will compare the length of stay between arms using 
student’s t-test. The length of time will be the total length of time in the ICU 
during the 30 days.  This can be continuous or non-continuous time (i.e. a 
subject is discharged from ICU and then readmitted to ICU). 
 
 Thrombosis composite endpoint: All participants will be categorized as having 
developed one of the components of the composite endpoint or not through 30 
days.  The endpoint will be analyzed using chi-square test as described for the 
primary endpoint.  We will also graphically display time to event.  We will report 
the proportion of subjects in each diagnosed with each of these components. The 
primary analysis will censor participants who die without known thrombotic event.  
A supporting analysis will consider these deaths as part of the endpoint. 
 
 
 
 Safety Outcomes: All participants will be categorized as having developed a 
major bleeding events or a non-major clinically significant bleeding event and we 
will compare the proportions using chi-square test as described for the primary 
endpoint.  We will also report major and non-major clinically significant bleeding 
event separately by arm. 
 
Note: All secondary endpoint outcome proportions will be compared between the 
two treatment arms by the chi-square test or Fisher’s exact test, as appropriate. 
Two-sided exact Clopper-Pearson 95% confidence intervals will be calculated for 
treatment arm differences, as appropriate. 
 
All p-values will be two-sided with statistical significance evaluated at the 0.05 
alpha level. Ninety-five percent confidence intervals for all parameters of interest 
will be calculated to assess the precision of the obtained estimates. All analyses 
will be performed in R Version 3.6.1 (R Foundation for Statistical Computing, 
Vienna, Austria). Note: The statistical considerations section was written in 
conjunction with the Division of Biostatistics, Department of Population Health 
Sciences. 
 


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12.5 Interim Analysis 
 
We will be perform an interim analysis at one month from the initiation of the study 
 
 12.6 Reporting and Exclusions 
 
12.6.1 Evaluation of Toxicity 
 
All subjects will be evaluable for toxicity from the time of their first treatment in 
either treatment arm. Two-sided exact Clopper-Pearson 95% confidence 
intervals will calculated for all toxicity proportions to assess the precision of the 
obtained estimates. 
 
12.6.2 Evaluation of Response 
 
All subjects included in the study will be assessed for response to treatment according to 
the intention to treat (ITT). 
 
13. Adverse Event Reporting Requirements  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug or device under investigation.  Safety will be monitored by evaluation of adverse 
events reported by subjects or observed by investigators or research staff, as well as by other 
investigations such as clinical laboratory tests, x-rays, computed tomography (CT), 
electrocardiographs, etc. 
 
13.1 Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment about 
causality. An adverse event can arise with any use of the drug (e.g., off-label use, use in 
combination with another drug) and with any route of administration, formulation, or 
dose, including an overdose.  
 
Because this is a trial focusing on a critically ill population where adverse events are 
expected to occur frequently, only AEs meeting the following criteria will be collected and 
reported: 
1. AEs related to bleeding (any major or clinically significant non-major bleeding) or 
thrombotic events (DVT/PE, stroke, myocardial infarction, peripheral embolism, 
skin thrombosis). 
2. Any adverse event that results in interruption or discontinuation of the assigned 
anticoagulant treatment. 
3. Any adverse event that meets the criteria for serious, as defined in Section 13.2. 
 
 
13.1.1 Investigational Agent or Device Risks (Expected Adverse Events) 
 
Expected adverse events for drugs administered as part of this protocol may be found in 


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the package inserts, located in Appendix A. 
 
13.1.2 Adverse Event Characteristics and Related Attributions 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
• 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
13.1.3 Recording of Adverse Events 
 
All adverse events described in section 13.1 will be recorded on a subject specific AE 
log. The AE log will be maintained by the research staff and kept in the subject’s 
research chart.    
 
 
13.1.4 Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting
_Policy.pdf.  
 
13.1.5 Reporting Events to Participants 
 
Participants will be informed of any adverse event related to the anticoagulant treatment 
that represents a new or increased risk from participating in the study. 
 
13.1.6 Events of Special Interest 
Not applicable. 
 
13.1.7 Reporting of Pregnancy 
 
Not applicable. 
 
13.2 Definition of SAE 
 
SAEs include death, life threatening adverse experiences, hospitalization or 
prolongation of hospitalization, disability or incapacitation, overdose, congenital 
anomalies and any other serious events that may jeopardize the subject or require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 


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13.2.1 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:   
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting
_Policy.pdf.  
 
13.2.2 Reporting of SAE to FDA 
 
IND application sponsor must report any suspected adverse reaction or adverse 
reaction to study treatment that is both serious and unexpected. Unexpected fatal 
or life-threatening suspected adverse reactions represent especially important 
safety information and must be reported to FDA as soon as possible but no later 
than 7 calendar days following the sponsor’s initial receipt of the information. 
i. death, 
ii. a life-threatening adverse event,   
iii. in-patient hospitalization or prolongation of existing hospitalization, 
iv. a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, or   
v. a congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or research subject and may 
require medical or surgical intervention to prevent one of the outcomes listed as 
serious 
 
CDER INDs:  
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of xxxx Products  
5901-B Ammendale Road  
Beltsville, MD 20705-1266  
 
 
13.3 AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. 
This requirement indicates that follow-up may be required for some events after the 
subject discontinues participation from the study.  
 
13.4 Time Period and Frequency for Event Assessment and Follow Up 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to 
the attention of study personnel during study visits and interviews of a study participant 
presenting for medical care, or upon review by a study monitor. 
 


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All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate case report form (CRF). Information to be collected includes 
event description, time of onset, clinician’s assessment of severity, relationship to study 
product (assessed only by those with the training and authority to make a diagnosis), 
and time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
 
 
The study team will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the 
last day of study participation.  At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome 
information until resolution or stabilization. 
 
14. Unanticipated Problems Involving Risks to Subjects or Others 
 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSO) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
14.1.2 Unanticipated Problem Reporting 
 
The investigator will report unanticipated problems (UPIRTSOs) to the reviewing 
Institutional Review Board (IRB) and to the Data Coordinating Center (DCC)/lead 
principal investigator (PI). The UPIRTSO report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the 
IRB project number; 


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• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, 
or outcome represents an UPIRTSO;  
• 
A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UPIRTSO. 
 
To satisfy the requirement for prompt reporting, UPIRTSOs will be reported using the 
following timeline:   
 
• 
UPIRTSOs that are serious adverse events (SAEs) will be reported to the IRB 
and to the DCC/study sponsor within <insert timeline in accordance with policy> 
of the investigator becoming aware of the event.  
• 
Any other UPIRTSO will be reported to the IRB and to the DCC/study sponsor 
within <insert timeline in accordance with policy> of the investigator becoming 
aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or 
designee), Food and Drug Administration (FDA), and the Office for Human 
Research Protections (OHRP) within <insert timeline in accordance with policy> 
of the IRB’s receipt of the report of the problem from the investigator. 
 
15. Data and Safety Monitoring Plan (DSMP) 
 
The Weill Cornell Medical College Data Safety Monitoring Board (DSMB) is being requested to 
review safety data and to make recommendations regarding continuation, termination, or 
modification to the study.  
 
During the study, the DSMB will regularly (every 6 months) review all incidences of symptomatic 
DVT and PE, clinically relevant bleeding, and death, including those not yet adjudicated, which 
will result in recommendations to the study team. 
 
An interim analysis will be performed one month after the first patient is enrolled. 
 
 


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16. References 
 
1- Tang N et al. Abnormal coagulation parameters are associated with poor prognosis in 
patients with novel coronavirus pneumonia. J Thromb Haemost 2020 epublished 
2- Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with 
decreased mortality in  
severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 
epublished 
3. Xiong TY, Redwood S, Prendergast B, Chen M.  Coronaviruses and the cardiovascular 
system: acute and  
long-term implications. Eur Heart J. 2020 Mar 18. pii: ehaa231. doi: 10.1093/eurheartj/ehaa231.  
4. Young E.  The anti-inflammatory effects of heparin and related compounds.  Thrombosis 
Research.  
2008; 122(6): 743–752. 
5. Esmon CT. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb 
Haemost. 2014 Apr  
1; 111(4): 625-33 
6.  Poterucha TJ, Libby P, Goldhaber SZ. More than an anticoagulant: Do heparins have direct 
anti-inflammatory  
effects?  Thromb Haemost. 2017 Feb 28; 117(3): 437-444 
7. Hanity JM et al. Failure of chemical thromboprophylaxis in critically ill medical and surgical 
patients with sepsis. J Critical Care. 2017; 37:206-210 
8. Thachil J. The versatile heparin in COVID-19.  J Thromb Haemost 2020 
9. Cui et al. Prevalence of venous thromboembolism in patients with severe coronavirus 
pneumonia. doi: 
10.1111/JTH.14830 
10. Klok FA et al. Incidence of thrombotic complications in COVID-19. Thrombosis Research 
2020 
11. Schulman S, Kearon C on behalf of the subcommittee on control of anticoagulation of the 
Scientiﬁc and Standardization committee of the International Society on Thrombosis and 
Haemostasis. Deﬁnition of major bleeding in clinical investigations of antihemostatic medicinal 
products in non-surgical patients. Scientiﬁc and Standardization Committee Communication. J 
Thromb Haemost 2005; 3: 692–4 
12. Helms J et al. High risk of thrombosis in patients in severe SARS-CoV-2 infection: 
a multicenter prospective cohort study. Intensive Care Med DOI: 10.1007/s00134-020-06062-x 
13.Middeldorp S et al. Incidence of venous thromboembolism in hospitalized patients with 
COVID-19. Preprint 2020 
13. Goyal P et al. Clinical Characteristics of Covid-19 in New York City. NEJM April 17, 2020 
14. Paranjpe I et al. Association of treatment dose anticoagulation with in-Hospital Survival 
Among Hospitalized Patients with COVID-19.  JACC 2020 
 
 
 


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Appendix A 
 
Package insert for each of the drugs used in this protocol is available at the links below: 
 
 
Lovenox® (Enoxaparin sodium): 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020164s085lbl.pdf 
 
Sodium heparin (unfractionated heparin): 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017029s140lbl.pdf 
 
Argatroban Injection: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022485lbl.pdf  
 
ARIXTRA® (fondaparinux sodium): 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021345s010lbl.pdf  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix B 
 
 
Source: Levi, M., Toh, C.H., Thachil, J. and Watson, H.G. (2009), Guidelines for the diagnosis and 
management of disseminated intravascular coagulation. British Journal of Haematology, 145: 24-33. 
doi:10.1111/j.1365-2141.2009.07600.x 
 
 
ASH COVID-19 Resources - Frequently Asked Questions: 
 
COVID-19 and VTE-Anticoagulation 
COVID-19 and Coagulopathy 
COVID-19 and aPL Ab 
COVID-19 and D-dimer 
COVID-19 and Pulmonary Embolism 
 
 
 
 
 
 


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Appendix C 
 
Weill Cornell Medicine/NewYork-Presbyterian: Discharge Thromboprophylaxis for 
Patients with COVID-19 Infection (April 20, 2020)