Conditions: Sars-CoV2 COVID
Keywords: COVID-19 Anticoagulation Heparin Coronavirus Thrombosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 257
Healthy volunteers: no

Brief summary:
The aim of this study is to test the hypothesis that prophylaxis of severe COVID-19 patients with treatment dose LMWH leads to better thromboembolic-free outcomes and associated complications during hospitalization than prophylaxis with institutional standard of care with prophylactic to intermediate-doses of UFH or LMWH

Detailed description:
There are clinical data to support the observation that hospitalized acutely ill medical patients with severe viral pneumonitis/Acute Respiratory Distress Syndrome (ARDS), such as those with influenza H1N1 infection, have an over 23-fold increased risk for venous thromboembolism (VTE) - especially pulmonary embolism (PE) - with an overall 44% incidence of VTE in ARDS associated with H1N1 pneumonia. Multicenter studies from China report that key markers of inflammation and/or coagulopathy are associated with morbidity and increased mortality in COVID-19 patients. Elevated D-dimer levels (that are sometime greater than 4 or 6 times the upper limit of normal \[ULN\]) are strongly associated with mortality in patients with severe COVID-19 illness. Recent data also shows that mortality among COVID-19 patients is markedly higher in patients with elevated Troponin-T (TnT) levels than in patients with normal TnT levels. Recently a cohort of 81 patients retrospectively evaluated diagnosed with severe COVID-19 pneumonia and reported a lower extremity VTE incidence of 25% (20/81) and a mortality of 40% (8/20) in the presence of VTE. Reported a case of bilateral pulmonary embolism in a 75 year old woman diagnosed with severe COVID-19, in the absence of predisposing risk factors and a negative lower extremity US. Lastly the investigated use of Tissue Plasminogen Activator (tPA) in the treatment of COVID-19 associated ARDS and reported promising, but transient, results in terms of pulmonary function improvement. It appears that either the SARS-CoV2 infection itself induces a hypercoagulable state, possibly by hypofibrinolytic mechanisms, or the cytokine storm in COVID-19 patients with severe disease induces a prothrombotic state, which leads to clinical deterioration, hypoxia and hemodynamic instability secondary to thromboembolic phenomena and potentially cardiac ischemia. Preliminary data from Northwell Health System, which has one of the largest populations of hospitalized COVID-19 patients in the US, reveals a positivity rate for deep vein thrombosis (DVT) of 40% of those COVID-19 patients screened by Doppler compression ultrasonography of the lower extremities.

Heparin has been shown to have anti-inflammatory and immunomodulatory properties in addition to its anticoagulation effect, which could play a beneficial role in sepsis. In addition, there is in vitro evidence that the large negatively charged sulfated glycosaminoglycans of unfractionated heparin may act as an alternate ligand for the SARS-CoV2 receptor irrespective of ACE2. Whether this in vitro evidence supports the role of a protective or deleterious mechanism in COVID-19 infection is not known. However, an early report with empiric use of treatment dose unfractionated heparin (UFH) in ARDS from a different viral family, influenza H1N1, revealed that H1N1 ARDS patients under systemic anticoagulation had 33-fold fewer VTE events than those treated given prophylactic doses of UFH/low-molecular weight heparin (LMWH) thromboprophylaxis. Very recent evidence suggests that therapy with prophylactic to intermediate doses of the LMWH enoxaparin (30mg to 60mg QD) in severe hospitalized COVID-19 patents with a SIC score ≥ 4 or D-dimer (Dd) \> 6 X ULN improves outcomes and prognosis. All-cause mortality at 28 days was reduced from 64.2% to 40.0% in those patients with a SIC score ≥ 4 (p=0.029), and from 52.4% to 32.8% in those patients with an elevated Dd \> 6 x ULN (P=0.017). Notably, Klok and colleagues investigated 184 ICU patients infected with COVID-19 and reported a 13% mortality rate, a relatively high incidence of CTPA- or ultrasonography-confirmed VTE rate (27%), and arterial thrombotic events (3.7%) despite the use of standard dose thromboprophylaxis. Postulated mechanisms for the improved prognosis with the use of treatment doses of LMWH in the sick COVID-19 population include the decrease in the risk of microthrombi, especially in the pulmonary vasculature, which can lead to hypoxemia, pulmonary vasoconstriction and right ventricular dysfunction as well as the decrease in the risk of progression to disseminated intravascular coagulopathy as a contributor to the high mortality seen in these patients.

The optimal dose of heparin (either LMWH or UFH) in hospitalized COVID-19 patients is unknown, as patients on conventional prophylactic dose heparin (UFH or LMWH) as supported by international guidance statements on hospitalized COVID-19 patients appear to remain at risk for thromboembolic events. There is data to support improved efficacy with treatment doses of twice daily enoxaparin versus once-daily weight-adjusted enoxaparin for the management of VTE, especially with large thrombus burden. There is also long-standing data to support that treatment-dose heparin can reduce major cardiovascular events. Our current standard of care in our 24 hospital Northwell Health System, which has a very large hospitalized COVID-19 patient population, is to use Lovenox 40mg SQ QD for patients with a BMI \< 30 and Creatinine Clearance (CrCl) \> 15ml/min, Lovenox 40mg SQ BID for patients with a BMI \> 30 and CrCl \> 15ml/min, and UFH 5000U SQ BID or TID in patients with a CrCl \< 15ml/min and BMI \< 30 and UFH 7500U SQ BID or TID with a CrCl \< 15ml/min and BMI \> 30. Large healthcare institutions in the US and elsewhere have protocols for in-patient thromboprophylaxis ranging from prophylactic-to-intermediate dose UFH or LMWH for the management of patients with COVID-19 associated coagulopathy. The aim of this study is to test the hypothesis that prophylaxis of severe COVID-19 patients with treatment dose LMWH leads to better thromboembolic-free outcomes and associated complications during hospitalization than prophylaxis with institutional standard of care with prophylactic to intermediate-doses of UFH or LMWH.

Arms:
arm 1: Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and \< 30ml/min) during the course of their hospitalization. arm 2: Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.

Interventions: intervention 1: Enoxaparin intervention 2: Prophylactic/Intermediate Dose Enoxaparin
Intervention descriptions: intervention 1: Full Dose LMWH anticoagulation therapy intervention 2: Prophylactic/Intermediate Dose LMWH or UFH therapy

Protocol document:
Prot_SAP_003.pdf: 
Official Title: Systemic Anticoagulation with Full Dose Low Molecular Weight Heparin (LMWH) Vs. 
Prophylactic or Intermediate Dose LMWH in High Risk COVID-19 Patients (HEP-COVID Trial) 
NCT04401293 
Protocol Version: 3/23/2021 


1 
 
Systemic Anticoagulation with Full Dose Low Molecular Weight Heparin (LMWH) Vs. Prophylactic or 
Intermediate Dose LMWH in High Risk COVID-19 Patients (HEP-COVID Trial) 
Northwell Health HRPP: 20-0340 
IND Exempt: PIND #150026 
PROTOCOL VERSION: March 23rd, 2021 
 
 
 
 
 
 
Proprietary and Confidential 


2 
 
 
TABLE OF CONTENTS 
 
INVESTIGATOR AGREEMENT................................................................................................... 
TABLE OF CONTENTS ................................................................................................................ 2 
1. INTRODUCTION ...................................................................................................................... 8 
1.1. Background .............................................................................................................................. 9 
1.1.1. Pharmaceutical and Therapeutic Background .................................................................... 10 
1.2. Study Rationale ...................................................................................................................... 11 
2. STUDY OBJECTIVES AND HYPOTHESIS .......................................................................... 11 
2.1. Study Objectives .................................................................................................................... 11 
2.1.1. Primary Objectives .............................................................................................................. 11 
2.1.2. Secondary Objectives .......................................................................................................... 11 
2.2. Hypothesis .............................................................................................................................. 12 
2.3. Study Endpoints ..................................................................................................................... 12 
2.3.1. Primary Efficacy Endpoint .................................................................................................. 12 
2.3.2. Secondary Efficacy Endpoints ............................................................................................ 13 
3. STUDY DESIGN ...................................................................................................................... 14 
3.1. Overall Design ....................................................................................................................... 14 
3.1.1. Study Duration… ................................................................................................................ 15 
3.1.2. Duration of Study Participation .......................................................................................... 15 
4. STUDY POPULATION ........................................................................................................... 15 
4.1. Eligibility Criteria .................................................................................................................. 15 
4.1.1. Inclusion Criteria ................................................................................................................ 15 
4.1.1.1. Inclusion Criteria for Study Subjects ............................................................................... 15 
4.1.2. Exclusion Criteria ............................................................................................................... 16 
3 


4.1.2.1. Rationale for Selected Exclusion Criteria ........................................................................ 16 
5. STUDY TREATMENTS .......................................................................................................... 17 
5.1. Assigning Subjects to Treatments .......................................................................................... 17 
5.1.1. Stratification ........................................................................................................................ 17 
5.1.2. Randomization .................................................................................................................... 17 
5.2. Study Drugs (Commercial Supply) ....................................................................................... 19 
5.2.1. Description .......................................................................................................................... 19 
5.2.2. Preparation .......................................................................................................................... 19 
5.2.3. Administration .................................................................................................................... 19 
5.2.4. Storage ................................................................................................................................ 19 
5.2.5. Pregnancy ........................................................................................................................... 20 
5.2.6. Contraception… .................................................................................................................. 20 
5.2.7. Adverse Reactions .............................................................................................................. 20 
5.3. Drug Dispensation Documentation ........................................................................................ 20 
5.4. Guidelines for Delay, Reduction and/or Discontinuation of Study Medications ................... 20 
5.5. Prior and Concomitant Medications ....................................................................................... 20 
5.6. Method of Assessing Treatment Compliance ........................................................................ 21 
5.7. Subject Withdrawal/Discontinuation ..................................................................................... 21 
5.7.1. Subject Replacement ........................................................................................................... 21 
6. STUDY PROCEDURES .......................................................................................................... 22 
6.1. Screening ................................................................................................................................ 22 
6.2. Enrollment .............................................................................................................................. 22 
6.3. Treatment Period. ................................................................................................................... 22 
6.4. Follow-up ............................................................................................................................... 22 
7. EFFICACY ASSESSMENTS .................................................................................................. 22 
4 
8. SAFETY EVALUATION AND REPORTING ....................................................................... 23 


8.1. Assessment of Safety Endpoints ............................................................................................ 23 
8.2. Adverse Events (AE) and Serious Adverse Events (SAE) .................................................... 23 
8.2.1. Definition of Adverse Event (AE) ...................................................................................... 23 
8.2.2. Definition of Serious Adverse Event (SAE) ....................................................................... 23 
8.2.3. Classification of Adverse Events (AE)… ......................................................................... 24 
8.2.3.1. Severity of Event ........................................................................................................... 24 
8.2.3.2. Relationship to Study Intervention. ............................................................................... 24 
8.2.3.3. Expectedness .................................................................................................................. 25 
8.2.4. Time Period and Frequency for Event Assessment and Follow-up… ............................. 25 
8.2.5. Adverse Event Reporting… .............................................................................................. 25 
8.2.6. Serious Adverse Event Reporting ..................................................................................... 26 
8.2.7. Reporting Events to Participants ....................................................................................... 26 
8.2.8. Events of Special Interest .................................................................................................. 26 
8.2.9. Reporting of Pregnancy .................................................................................................... 26 
8.3. Unanticipated Problems (UP) .............................................................................................. 26 
8.3.1. Definition of Unanticipated Problem (UP). ...................................................................... 26 
8.3.2. Unanticipated Problem (UP) Reporting ............................................................................ 26 
8.4. Other Safety ......................................................................................................................... 28 
8.4.1. Clinical Laboratory Evaluations ....................................................................................... 27 
8.4.2. Vital Signs ........................................................................................................................ 29 
8.4.3. Physical Examination. ...................................................................................................... 29 
8.4.4. Other Examinations .......................................................................................................... 29 
9. STATISTICAL METHODS ................................................................................................... 30 
9.1. General Statistical Considerations ....................................................................................... 30 
5 
9.2. Analysis Sets ........................................................................................................................ 30 
9.3. Efficacy Analyses ................................................................................................................. 32 


9.3.1. Summary of Baseline Demographic and Clinical Data .................................................... 32 
9.3.2. Comparability of Randomized Subjects and Historical Controls ..................................... 32 
9.3.3. Primary Efficacy Analyses ................................................................................................ 32 
9.3.3.1. Analysis of Primary Clinical Endpoint .......................................................................... 32 
9.3.4. Secondary Analysis ........................................................................................................... 34 
9.3.5. Interim Analysis ................................................................................................................ 34 
9.3.6. Missing Data ..................................................................................................................... 34 
9.3.7. Sample Size and Power Calculation. ................................................................................. 35 
9.3.8. Secondary Efficacy Analyses ............................................................................................. 35 
9.4. Biomarker Analysis ............................................................................................................... 35 
9.5. Safety Analyses ..................................................................................................................... 35 
9.6. Data Safety Monitoring Board (DSMB) ............................................................................... 35 
9.7. Executive Committee ............................................................................................................ 35 
10. DATA INTEGRITY AND QUALITY ASSURANCE ......................................................... 36 
10.1. Monitoring and Inspections ................................................................................................. 36 
10.2. Data Collection. ................................................................................................................... 37 
10.3. Data Management ................................................................................................................ 37 
10.4. Electronic Systems ............................................................................................................... 37 
10.5. Study Documentation ........................................................................................................... 37 
10.5.1. Case Report Form (CRF) Requirements ........................................................................... 37 
10.5.2. Record Keeping and Storage............................................................................................. 37 
10.6. Operational Procedures ........................................................................................................ 38 
11. PUBLICATION POLICY ...................................................................................................... 39 
6 
11.1. Publication and Public Disclosure of Clinical Trial Information. ....................................... 39 
12. ETHICS AND ADMINISTRATIVE INFORMATION ........................................................ 39 
12.1. Good Clinical Practice Statement ........................................................................................ 39 


12.2. Confidentiality ..................................................................................................................... 40 
12.3. Informed Consent ................................................................................................................ 40 
12.4. Regulatory Compliance........................................................................................................ 43 
12.5. Protocol Deviations .............................................................................................................. 43 
12.6. New Information Affecting the Conduct of the Study ......................................................... 43 
12.7. Protocol Amendments .......................................................................................................... 44 
12.8. Study Termination................................................................................................................ 44 
13. REFERENCES ....................................................................................................................... 46 
14. APPENDICES ........................................................................................................................ 48 
14.1. Appendix A. Northwell Health System Guidance ............................................................... 48 
14.2. Appendix B. ISTH SIC Score .............................................................................................. 49 
14.3. Appendix C. Duplex Doppler Screen .................................................................................. 50 
14.4. Appendix D. Quick SOFA Score ......................................................................................... 51 
14.5. Appendix E. IMPROVE VTE Score ................................................................................... 52 
14.6. Appendix F. Study Flow Chart and Events Schedule .......................................................... 53 
14.7. Appendix G. DSMB Charter (Includes Interim Analysis Plan) ........................................... 54 
14.8. Appendix H. DataMart Data Elements ................................................................................ 55 
14.9. Appendix I. BRMS User Manual ......................................................................................... 56 
15. Appendix J. External Agreement Contract .......................................................................... 57 
15.1 Appendix K. Investigational Drug Service - SOP ............................................................... 58 
15.2 Appendix L. Patient Drug Accountability Log .................................................................... 59 


7 


8 
 
PROTOCOL SYNOPSIS 
 
1. INTRODUCTION 
 
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection was first reported in Wuhan, China, on 31 
December 2019. The World Health Organization (WHO) declared the outbreak a global health 
emergency on 30 January 2020. The infection can be transmitted by direct interpersonal contact, 
fomites, respiratory secretions, and direct viral shedding into the air via normal respiration. 
SARS-CoV-2 has been isolated from both feces and urine. 
 
From the beginning of the month to April 15, 2020 New York State has reported over 203,377 
cases of SARS-CoV-2 infection and 10,834 deaths. New York City has reported over 107,263 
cases of SARS-CoV-2 infection and 10,367 deaths 
 
Recent data is emerging of a very high incidence of thromboembolic complications, especially 
venous thromboembolic (VTE) complications, in hospitalized COVID-19 patients, especially the 
sick hospitalized patients in Intensive Care Units (ICU) with respiratory failure. Although 
hospital and antithrombotic guidelines advocate for routine VTE risk assessment and use of 
standard thromboprohylaxis, recent reports also suggest the failure to prevent thromboembolic 
events in these patients using standard or routine thromboprohylaxis strategies, likely due to the 
prothrombotic state seen in these patients. Previous data suggests a mortality advantage in using 
empiric treatment dose anticoagulant therapy with heparin in patients with severe viral 
pneumonia. 
 
To date, there is no data to inform the optimal dose of heparin thromboprophyalxis in the sick, 
hospitalized, and likely prothrombotic COVID-19 population. Multiple international 
antithrombotic societies have advocated high quality data to inform this critical clinical question, 
and to definitively answer the question of whether empiric treatment dose heparin therapy 
confers a net clinical benefit to reduce major thromboembolic events and associated mortality in 
this population. 


9 
 
 
1.1. Background 
 
COVID-19 patients have been noted to have significantly elevated markers of hypercoagulability 
including d-dimer (Dd), fibrinogen levels, FVIII levels, short activated partial thromboplastin time (aPTT) 
and Sepsis-Induced Coagulopathy (SIC) scores with an increase in venous thromboembolic disease as 
well as cardiac injury, for which potential causes may include atherothrombosis, demand ischemia or 
microthrombosis. The mechanism underlying morbidity related to thrombosis in COVID-19 patients 
remains unclear [1]. 
 
There are clinical data to support the observation that hospitalized acutely ill medical patients with severe 
viral pneumonitis/Acute Respiratory Distress Syndrome (ARDS), such as those with influenza H1N1 
infection, have an over 23-fold increased risk for venous thromboembolism (VTE) - especially pulmonary 
embolism (PE) - with an overall 44% incidence of VTE in ARDS associated with H1N1 pneumonia [2]. 
Multicenter studies from China report that key markers of inflammation and/or coagulopathy are 
associated with morbidity and increased mortality in COVID-19 patients. Elevated D-dimer levels (that 
are sometime greater than 4 or 6 times the upper limit of normal [ULN]) are strongly associated with 
mortality in patients with severe COVID-19 illness [3,4]. Recent data also shows that mortality among 
COVID-19 patients is markedly higher in patients with elevated TnT levels than in patients with normal 
TnT levels [5]. Recently, Cui and colleagues retrospectively evaluated a cohort of 81 patients diagnosed 
with severe COVID-19 pneumonia and reported a lower extremity VTE incidence of 25% (20/81) and a 
mortality of 40% (8/20) in the presence of VTE [6]. Danzi et al reported a case of bilateral pulmonary 
embolism in a 75 year old woman diagnosed with severe COVID-19, in the absence of predisposing risk 
factors and a negative lower extremity US [7]. Lastly Wang et al investigated the use of Tissue 
Plasminogen Activator (tPA) in the treatment of COVID-19 associated ARDS and reported promising, 
but transient, results in terms of pulmonary function improvement [8]. It appears that either the SARS- 
CoV2 infection itself induces a hypercoagulable state, possibly by hypofibrinolytic mechanisms, or the 
cytokine storm in COVID-19 patients with severe disease induces a prothrombotic state, which leads to 
clinical deterioration, hypoxia and hemodynamic instability secondary to thromboembolic phenomena 
and potentially cardiac ischemia [9]. Preliminary data from Northwell Health System, which has one of 
the largest populations of hospitalized COVID-19 patients in the US, reveals a positivity rate for deep 
vein thrombosis (DVT) of 40% of those COVID-19 patients screened by Doppler compression 
ultrasonography of the lower extremities (internal Northwell data). 
 
Heparin has been shown to have anti-inflammatory and immunomodulatory properties in addition to its 
anticoagulation effect, which could play a beneficial role in sepsis [10]. In addition, there is in vitro 
evidence that the large negatively charged sulfated glycosaminoglycans of unfractionated heparin may act 
as an alternate ligand for the SARS-CoV2 receptor irrespective of ACE2 [4]. Whether this in vitro 
evidence supports the role of a protective or deleterious mechanism in COVID-19 infection is not known. 
However, an early report with empiric use of treatment dose unfractionated heparin (UFH) in ARDS from 
a different viral family, influenza H1N1, revealed that H1N1 ARDS patients under systemic 
anticoagulation had 33-fold fewer VTE events than those treated given prophylactic doses of UFH/low- 
molecular weight heparin (LMWH) thromboprophylaxis [2]. Very recent evidence suggests that therapy 
with prophylactic to intermediate doses of the LMWH enoxaparin (30mg to 60mg QD) in severe 
hospitalized COVID-19 patents with a sepsis-induced coagulopathy (SIC) score ≥ 4 or D-dimer (Dd) > 4 
or even > 6 X ULN improves outcomes and prognosis [4]. All-cause mortality at 28 days was reduced 
from 64.2% to 40.0% in those patients with a SIC score ≥ 4 (p=0.029), and from 52.4% to 32.8% in those 
patients with an elevated Dd > 6 x ULN (P=0.017) (4). Notably, Klok and colleagues investigated 184 
ICU patients infected with COVID-19 and reported a 13% mortality rate, a relatively high incidence of 
CTPA- or ultrasonography-confirmed VTE rate (27%), and arterial thrombotic events (3.7%) despite the 
use of standard dose thromboprophylaxis [11]. Postulated mechanisms for the improved prognosis with 


10 
 
the use of treatment doses of LMWH in the sick COVID-19 population include the decrease in the risk of 
microthrombi, especially in the pulmonary vasculature, which can lead to hypoxemia, pulmonary 
vasoconstriction and right ventricular dysfunction as well as the decrease in the risk of progression to 
disseminated intravascular coagulopathy as a contributor to the high mortality seen in these patients [12]. 
 
 
 
1.1.1. Pharmaceutical and Therapeutic Background 
 
The optimal dose of heparin (either LMWH or UFH) in hospitalized COVID-19 patients is unknown, as 
patients on conventional prophylactic dose heparin (UFH or LMWH) as supported by international 
guidance statements on hospitalized COVID-19 patients appear to remain at risk for thromboembolic 
events [13]. There is data to support improved efficacy with treatment doses of twice daily enoxaparin 
versus once-daily weight-adjusted enoxaparin for the management of VTE, especially with large 
thrombus burden [14]. There is also long-standing data to support that treatment-dose heparin can reduce 
major cardiovascular events [15]. Our current standard of care in our 24 hospital Northwell Health 
System, which has a very large hospitalized COVID-19 patient population, is to use Lovenox 40mg SQ 
QD for patients with a BMI < 30 and Creatinine Clearance (CrCl) > 15ml/min, Lovenox 40mg SQ BID 
for patients with a BMI > 30 and CrCl > 15ml/min, and UFH 5000U SQ BID or TID in patients with a 
CrCl < 15ml/min and BMI < 30 and UFH 7500U SQ BID or TID with a CrCl < 15ml/min and BMI > 30. 
(Appendix A). Large healthcare institutions in the US and elsewhere have protocols for in-patient 
thromboprophylaxis ranging from prophylactic-to-intermediate dose UFH or LMWH for the management 
of patients with COVID-19 associated coagulopathy [16]). The aim of this study is to test the hypothesis 
that prophylaxis of severe COVID-19 patients with treatment dose LMWH leads to better 
thromboembolic-free outcomes and associated complications during hospitalization than prophylaxis with 
institutional standard of care with prophylactic to intermediate-doses of UFH or LMWH. 
 
 
 
 
 
. 


11 
 
1.2. Study Rationale 
 
 
2. STUDY OBJECTIVES AND HYPOTHESIS 
 
2.1. Study Objectives 
Our hypothesis is that sick hospitalized COVID-19 patients receiving therapeutic doses of heparin 
(LMWH) during hospitalization will show a reduction of the primary and secondary endpoints that 
are associated with a prothrombotic state within 30 days of their hospital admission. 
 
2.1.1. Primary Objective 
The overall objective of the study is to evaluate the clinical efficacy of therapeutic low molecular 
weight heparin (LMWH) versus prophylactic/intermediate doses of UFH or LMWH as per local 
institutional protocols in reducing the composite of arterial thromboembolic events (including 
myocardial infarction, stroke, systemic embolism), venous thromboembolism (including 
symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic 
proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause 
mortality at Day 30 ± 2 days. 
 
 
2.1.2. Secondary Objectives 
To evaluate the safety of such an approach by assessing the risk of major bleeding 
defined using the International Society of Thrombosis and Haemostasis (ISTH) criteria 
at Day 30 ± 2 days. 


12 
 
 
 
2.2. Hypothesis 
 
Patients receiving therapeutic doses of heparin (LMWH) patients will show a reduction of the 
primary and secondary endpoints that are associated with a prothrombotic state within 30 ± 2 days of 
their hospital admission. 
 
2.3. Study Endpoints 
 
2.3.1. Primary Efficacy Endpoints 
Primary Clinical Endpoint: The composite of arterial thromboembolic events (including myocardial 
infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein 
thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower 
extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Day 30 ± 2 days. 
 
1. Any arterial thromboembolic event defined by: 
a. Documented thromboembolic stroke by imaging (Head CT, Brain MRI) defined as a new focal 
neurologic defect lasting at least 24 hours that is not due to a readily identifiable non-vascular cause 
b. Documented peripheral arterial thromboembolism by imaging (CT scan, arteriography, arterial 
Doppler of extremities) 
c. Documented acute myocardial infarction defined by 2 of the 3 following conditions: 1) an 
appropriate clinical condition such as new EKG changes, 2) elevation of CK-MB or Troponin-T or I 
≥ 2 X ULN (if CK-MB or troponin unavailable then total CK ≥ 2 X ULN), 3) new significant (≥0.04 
seconds) Q waves in ≥ two contiguous leads 
 
2. Any new venous thromboembolic event (symptomatic DVT or asymptomatic proximal DVT 
found by screening ultrasonography or as an incidental finding of PE on CT scan) including DVT of 
upper or lower extremities, PE, splanchnic vein thrombosis, cerebral vein thrombosis defined by: 
a. One or more new filing defects with venography, CT venography, or MR venography 
b. A new perfusion defect of at least 75% of a segment with a local normal ventilation result (high 
probability) on ventilation/perfusion scan (V/Q scan) 
c. A non-compressible venous segment on compression ultrasonography, or in patients with a history 
of previous DVT, either a new non-compressible segment or a substantial increase (4mm or more) in 
the diameter of the vein during full compression in a previously abnormal segment on 
ultrasonography 
d. In the absence of an imaging test in a hemodynamically unstable patient, evidence of right 
ventricular dysfunction by transthoracic or trans esophageal echocardiogram (ESC Criteria) 
 
3. All-cause mortality 


13 
 
Principal Safety-endpoint: Major bleeding using ISTH criteria at 30 ± 2 days. 
 
1. Documented major bleeding using ISTH criteria defined by: 
a. A decrease in hemoglobin of 2g/dl or more within 24 hours 
b. A transfusion of 2 or more units of packed red blood cells 
c. Critical site bleeding (including intracranial, intraocular, intra-articular, retroperitoneal, 
intramuscular with component syndrome, pericardial) 
d. Bleeding that is fatal 
e. Bleeding that necessitates surgical intervention 
 
 
 
2.3.2. Secondary Efficacy Endpoint 
The composite of arterial thromboembolic events (including myocardial infarction, stroke, systemic 
embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the 
upper or lower extremity, asymptomatic proximal and distal DVT of the lower extremity, non-fatal 
pulmonary embolism (PE), and all-cause mortality at Hospital Day 10 + 4 
 
Progression to Acute Respiratory Distress Syndrome (ARDS), new-onset atrial fibrillation (AF), 
acute kidney injury (AKI), non-fatal cardiac arrest, need for intubation, need for Extracorporeal 
Membrane Oxygenation (ECMO), re-hospitalization at Day 30 ± 2 days. 


14 
 
 
3. STUDY DESIGN 
 
3.1. Overall Design 
 
Prospective Open-label Randomized Trial using an Active Control Group, with patients stratified by 
ICU stay or Non-ICU stay 


15 
 
 
 
3.1.1. Study Duration 
The study is expected to last for up to twelve months. 
 
3.1.2. Duration of Study Participation 
An individual subject will complete the study in about 30 ± 2 days, from screening at Day -1 or 1 to 
follow-up visit on Day 30 ±2 days. If a participant is unable to return to the site for Day 30±2 
assessment, safety will be assessed via Telemedicine or telephone contact. 
 
4. STUDY POPULATION 
 
4.1. Eligibility Criteria 
 
4.1.1. Inclusion Criteria 
 
 
4.1.1.1. Inclusion Criteria for Study Subjects 
1. Subject (or legally authorized representative) provides written informed consent prior to 
initiation of any study procedures. 
2. Understands and agrees to comply with planned study procedures. 
3. Male or non-pregnant female adult ≥18 years of age at time of enrollment. 
4. Subject consents to randomization within 72 hours of hospital admission or transfer from 
another facility within 72 hours of index presentation. 
5. Subjects with a positive COVID-19 diagnosis by nasal swab or serologic testing 
6. Hospitalized with a requirement for supplemental oxygen 
7. Have: 
• Either a D- Dimer > 4.0 X ULN OR 
• Sepsis-induced coagulopathy (SIC) score of ≥4 (Appendix B) 


16 
 
4.1.2. Exclusion Criteria 
1. Indications for therapeutic anticoagulation 
 
2. Absolute contraindication to anticoagulation including: 
 
a. active bleeding, 
b. recent (within 1 month) history of bleed, 
c. dual (but not single) antiplatelet therapy, 
d. active gastrointestinal and intracranial cancer, 
e. a history of bronchiectasis or pulmonary cavitation, 
f. Hepatic failure with a baseline INR > 1.5, 
g. CrCl < 15ml/min, 
h. a platelet count < 25,000, 
i. a history of heparin-induced thrombocytopenia (HIT) within the past 100 days or in the 
presence of circulating antibodies. 
j. contraindications to enoxaparin including a hypersensitivity to enoxaparin sodium, 
hypersensitivity to heparin or pork products, hypersensitivity to benzyl alcohol 
k. pregnant females 
l. inability to give or designate to give informed consent 
m. participation in another blinded trial of investigational drug therapy for COVID-19 
(Applies to both Study Subjects and Randomized Subjects) 
 
4.1.2.1. Rationale for Selected Exclusion Criteria 
LMWH has a well-established risk of clinically important bleeding, including major and fatal 
bleeding, with therapeutic doses of drug increasing this risk. The clinical exclusionary criteria as 
established by previous randomized trials of anticoagulant therapy in patients with thrombotic 
disorders and as used by the Hep-COVID trial represent well-established high clinical bleed risk 
factors. Pregnant women will be excluded due to uncertain characterization of the risk of VTE 
when hospitalized with COVID-19 with unlikely net clinical benefit from an aggressive 
thromboprophylactic strategy. 


17 
 
5. STUDY TREATMENTS 
 
5.1. Assigning Randomized Subjects to Treatments 
5.1.1. Stratification 
Prior to randomization, subjects will be stratified according to whether they are in a designated 
ICU unit or not. 
 
 
 
5.1.2. Randomization 
This study is a randomized, controlled trial using open-label active controls to evaluate the 
efficacy and safety of treatment dose LMWH versus prophylactic/intermediate dose LMWH in 
sick hospitalized adult patients diagnosed with COVID-19 during their hospitalization. The study 
is a multi-site trial that will be conducted both in hospitals within the Northwell Health system in 
New York as well as other health systems in United States. The study will compare the following 
two active treatment arms that patients received during their hospitalization: 
 
 
Arm 0: Treatment Arm 
 
• Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min at randomization 
• Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and < 30ml/min at randomization 
 
Arm 1: Prophylactic/Intermediate Dose Arm 
 
Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. 
Regimens allowed are: 
• UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 
IU BID/TID) 
• Enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 
0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged) 
• Dalteparin 2500IU or 5000 IU QD 
 
 
Randomization into Arms 0 and 1 will be carried out using a balanced 1:1 design 
 
 
The Biostatistics Unit will develop and implement the randomization procedure using the 
Biostatistics Randomization Management System (BRMS). The Biostatistics Randomization 
Management System (BRMS) is a secure, HIPAA-compliant, web-based application that allows 
investigators to randomize subjects into randomized clinical trials (RCTs) using their personal 
computer. The BRMS allows for multi-center, stratified, and single/double blinded RCTs, using 
permuted blocks. Randomization notifications (respectful of blinding status) are automatically 
sent to the PI and other authorized personnel. Due to the pragmatic nature of this study “open- 
label multicenter randomized active control trial with pseudo-blinding” mechanisms at the time 
of randomization the study subject and corresponding Site PIs will be blinded (unaware of 
specific treatment arm the patient is assigned to i.e. Arm 0 or Arm 1). The study pharmacists as 
well as data extractors and designated randomization personnel (i.e. research coordinators and/or 
research nurses performing the randomization process) will be un-blinded (aware of specific 


18 
 
treatment arm the patient is assigned to i.e. Arm 0 or Arm 1). BRMS also includes a feature that 
allows for medically indicated breaking of the blind, with requirement for justification without 
violating the protocol. BRMS includes an audit trail of all transactions (Appendix I) 
 
A site research coordinator or designee will notify site pharmacist(s) of a newly enrolled subject, the 
status of informed consent, and other pertinent information such as patient name, date of birth, 
subject number, and location. Upon randomization by the investigator or designee, the Biostatistics 
Randomization Management System (BRMS) will automatically notify research pharmacist of the 
assigned treatment arm. The pharmacist will determine the drug dose for Arm 0, based on section 
5.1.2, and for Arm 1, based on local standard of care including guidance found in (Appendix A). 
The pharmacist will enter the drug order using an order entry system on behalf of the investigator. 


19 
 
 
5.2. Study Drugs (commercial supply) 
Enoxaparin injection in commercially available pre-filled syringes and vials 
Unfractionated heparin injection, in commercially available vials 
 
 
5.2.1. Description 
Enoxaparin injection and unfractionated heparin are anticoagulant medications approved for use to 
prevent thromboembolic complications. Both medications as per protocol are approved for use in 
hospitalized patients. 
 
 
5.2.2. Preparation 
Enoxaparin injection is available as a 300 mG/ 3mLvial as well as pre-filled syringes in 40mg, 
60mg, 80mg, 100mg, 120mg, or 150mg. Unfractionated heparin injection is available in multi-dose 
vials. The pharmacists will calculate and prepare doses based on local standard of care including 
guidance found in Appendix A and dispense the doses in a blinded manner, if possible. 
 
 
15.2.3 
Administration 
 
Enoxaparin injection will be administered at a dose of 1mg/kg SQ BID for CrCl ≥ 30ml/min 
(0.5mg/kg SQ BID for CrCl ≥ 15ml/min and < 30ml/min) or as per local institutional protocols for 
prophylactic or intermediate-dose use. UFH will be administered as per local institutional protocols 
for prophylactic or intermediate dose use. Patients will have study drug administered for the 
duration of their hospitalization. 
 
CrCl will be calculated using Cockcroft-Gault equation. 
If height is not obtainable to calculate CrCl, then the use of estimated GFR is acceptable to calculate 
LMWH and UFH doses, although discouraged 
 
 
15.2.4 Storage 
 
Enoxaparin and unfractionated heparin injections can be stored at room temperature. 


20 
 
 
15.2.5 Pregnancy 
Pregnant females are excluded from the present study. 
 
15.2.6 Contraception 
Women of childbearing age must agree to use contraception for the duration of study treatment 
prior to providing consent. 
 
15.2.7 
Adverse Reactions 
Heparin (UFH or LMWH) including enoxaparin is usually well tolerated; most adverse 
reactions have been mild and transient. Some common adverse reactions include: anemia, 
thrombocytopenia, elevation of serum aminotransferase, diarrhea, nausea, fever, edema, 
peripheral edema, dyspnea, bleeding gums, nosebleeds, prolonged bleeding from cuts, 
confusion and injection site pain. There is an unlikely risk of serious allergic reactions with 
Enoxaparin. In some cases, there have been reports of spinal/epidural hematomas in patients 
receiving neuraxial anesthesia or undergoing spinal puncture. 
 
5.3. Drug Dispensation Documentation 
 
Pharmacy will dispense the dose(s) as per local pharmacy site procedure and maintain a subject- 
specific dispensing record (Appendix L). All records will be made available for inspection by 
regulatory agencies, and kept on file onsite as per local institutional policy (Appendix K). 
 
 
5.4. Guidelines for Delay, Reduction and/or Discontinuation of Study Medications 
 
Dose modification for an individual subject is not permitted unless the following ensues. 
Modification of study medication is allowed in Arm 0 (treatment arm with enoxaparin) if the 
CrCl falls < 15ml/min. In that instance conversion to dose adjusted IV UFH is acceptable during 
the time that the CrCl remains < 15ml/min. If the patient cannot be placed on UFH IV (difficult 
to obtain frequent aPTT draws, etc), an acceptable alternative is the use of UFH SQ using the 
fixed-dose weight-adjusted FIDO regimen, 333U/kg SQ, followed by 250U/kg Q12 hours, 
without the need to obtain aPTT monitoring. The investigator is then encouraged to convert back 
to treatment dose enoxaparin as per protocol once the CrCl ≥ 15ml/min. Modification is allowed 
in Arm 1 (prophylactic group) if the CrCl falls < 15ml/min to use UFH up to 22,500 U daily (i.e. 
UFH 5000u SQ BID or TID or 7500IU SQ BID or TID). The investigator is then encouraged to 
convert back to prophylactic/intermediate dose enoxaparin as per protocol once the CrCl ≥ 
15ml/min if a subject requires permanent discontinuation of study medication they will be 
withdrawn from the study and standard of care treatment will be initiated. 
 
 
 
5.5. Prior and Concomitant Medications 
 
Concomitant use of hepatotoxic medications, immunosuppressive therapy and/or investigational 
study drugs for the treatment of COVID-19 with the exception of blinded investigational 
therapies for COVID-19 are permitted as per usual standard of care. Any other treatment 
administered from the first dose of study drug to the final study assessment will be considered 
concomitant medication and recorded per subject. 


21 
 
5.6. Method of Assessing Treatment Compliance 
Study drugs will be administered per protocol while subjects are hospitalized. Medication records 
will be made available for inspection by the sponsor and/or regulatory agencies, and kept on file 
onsite as per local institutional policy. 
 
 
5.7. Subject Withdrawal/Discontinuation 
 
A subject has the right to withdraw from the study at any time. The investigator and/or sponsor 
have the right to withdraw a subject from the study if it is no longer in the best interest of the 
subject to continue, or if the subject’s continuation in the study places the scientific outcome of 
the study at risk. 
 
5.7.1. Subject Replacement 
Due to the large target enrollment and short treatment duration of this study, withdrawn subjects 
will not be replaced. 


22 
 
 
6 
STUDY PROCEDURES (applied to concurrent randomized subjects only) 
 
6.1. Screening 
 
Upon admission, the research coordinator will be notified about potentially eligible patients who 
require screening. The lab parameters required to determine eligibility are part of standard of care 
and will be available to the research coordinator shortly after admission. There will be an up to a 72 
hour window from admission or transfer from another facility within 72 hours of index presentation. 
by which to randomize patients into the trial. 
 
6.2 Enrollment 
 
Upon meeting the inclusion/exclusion criteria including consent, the research coordinator will 
officially enroll the subject and implement the randomization procedure. 
 
6.3 Treatment Period 
 
Treatment with study medication enoxaparin will be for the duration of hospitalization. 
 
In the post-hospital discharge period, patients will receive post-hospitalization 
thromboprophylaxis as per local institutional protocols. The use of extended 
thromboprophylaxis for approximately 30 days’ post-hospital discharge is strongly encouraged 
but not mandatory. Northwell Health institutional protocols mandate thromboprophylaxis with 
either enoxaparin 40mg SQ QD or rivaroxaban 10mg PO QD for up to 39 days at the discretion 
of the investigator (Appendix A). However, other antithrombotic therapy, including low dose 
apixaban 2.5mg PO BID and low dose aspirin, is permitted, although discouraged. 
 
No additional research procedures are indicated. 
 
6.4 Follow-up 
 
Subjects will be followed at Hospital Day 10 + 4, and for Day 30 ± 2. 
 
7 
EFFICACY ASSESSMENTS 
 
At Hospital Day 10 + 4 or sooner at the time of hospital discharge, there will be a lower extremity 
Duplex screening compression ultrasonography using standardized screening methods. 
Confirmatory lower extremity ultrasound of symptomatic DVT or asymptomatic screening of lower 
extremity DVT is recommended using full duplex Doppler compression ultrasonography of the 
entire extremity venous system. Where resource constraints or local institutional policies preclude 
use of full ultrasound, point-of-care ultrasound using two-region compression can be substituted and 
has shown reasonable accuracy (Appendix C). There will also be an assessment of the primary 
efficacy, principal safety, and secondary outcomes 
 
At Day 30 ± 2, there will be an assessment of the primary efficacy, principal safety, and secondary 
outcomes via a face-to-face or telephonic visit. 


23 
 
8 
SAFETY EVALUATION AND REPORTING 
 
8.1 Assessment of Safety Endpoints 
Subject safety will be assessed continuously while hospitalized as per standard of care for 
hospitalized patients. Upon discharge, subject safety will be assessed at a follow up visit on Day 
30 ±2. Subjects unable to return will be assessed via Telemedicine or by telephone. 
 
8.2 Adverse Events and Serious Adverse Events 
 
8.2.1 Definition of Adverse Event (AE) 
Adverse event (AE) is defined as any untoward medical occurrence associated with the use 
of an intervention in humans, whether or not considered intervention-related. 
 
8.2.2. Definition of Serious Adverse Event (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: death, a life- 
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 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 participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. 


24 
 
 
8.2.3. Classification of Adverse Event 
 
8.2.3.1. Severity of Event 
The following guidelines will be used to describe severity of Adverse Events (AE): 
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities. 
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.2.3.2. Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the categories 
below. In a clinical trial, the study product must always be suspect. 
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study intervention, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 


25 
 
 
 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
 
8.2.3.3. Expectedness 
The DSMB will be responsible for determining whether an adverse event (AE) is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study intervention. 
 
8.2.4. 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, or upon review by a study monitor. 
 
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 if it meets reporting 
criteria. 
 
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. 
 
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 will be 
recorded. Events will be followed for outcome information until resolution or stabilization. 
 
8.2.5. Adverse Event Reporting 
Adverse events (AEs) will be reported immediately to the PI and the Co-Investigators. It will 
also be reported to all members of the research team, and to the local IRB if it meets the local 
IRB’s reporting requirements. The PI and Co-Investigators will be notified of Adverse events 
(AEs) occurring at high frequency during study duration. 


26 
 
8.2.6. Serious Adverse Event Reporting 
 
The study clinician will immediately report any serious adverse event (SAE), whether or not considered 
study intervention related, including those listed in the protocol and must include an assessment of 
whether there is a reasonable possibility that the study intervention caused the event. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation of 
the event will be recorded. 
 
The Principal Investigator (PI) will be responsible for notifying the Food and Drug Administration (FDA) 
of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case 
later than 7 calendar days after initial receipt of the information. 


27 
 
 
8.2.7. Reporting Events to Participants 
Participants will not be informed of AEs and SAEs unless the AE or SAE happened to them. 
 
8.2.8. Events of Special Interest 
SAEs of special interest will include hypersensitivity reactions, including Steven Johnson’s 
syndrome, evidence of hepatic toxicity with transaminase elevations greater than 6 times the 
upper limit of normal, the onset of heparin-induced thrombocytopenia, and bone marrow 
toxicity. 
 
 
8.2.9. Reporting of Pregnancy 
N/A 
 
8.3. Unanticipated Problems 
 
8.3.1. Definition of Unanticipated Problems (UP) 
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. 
 
8.3.2. Unanticipated Problem Reporting 
The investigator or study team member who becomes aware will report unanticipated problems 
(UPs) to the reviewing Institutional Review Board (IRB) and to the Principal Investigator (PI). 
The UP report will include the following information: 


28 
 
 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
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 UP; 
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
 
• 
UPs that are serious adverse events (SAEs) will be reported within 5 business days of the 
investigator becoming aware of the event. 
• 
Any other UP will be reported within 5 business days of the investigator becoming aware 
of the problem. 
 
8.4. Other Safety 
 
8.4.1. Clinical Laboratory Evaluations 
Laboratory values will be obtained by venipuncture and evaluated on the day of 
randomization: 
 
1. PT/INR (standard of care) 
2. Platelet count (standard of care) 
3. Hemoglobin/hematocrit (standard of care) 
4. Serum creatinine (standard of care) 
5. D-dimer (allowed within 72 hours prior to randomization) (standard of care) 
6. C-reactive protein (CRP) (allowed within 72 hours prior to randomization) (standard of care) 
7. Fibrinogen (allowed within 72 hours prior to randomization) (standard of care) 
8. Troponin (allowed within 72 hours prior to randomization) (standard of care) 
9. Protein C antigen/activity and Protein S Antigen/activity (allowed within 72 hours prior to 
randomization) (research purposes) 
10. Antithrombin activity (allowed within 72 hours prior to randomization) (research purposes) 
11. Quick SOFA score (Appendix D) (allowed within 72 hours prior to randomization) 
12. ISTH SIC score (Appendix B) (allowed within 72 hours prior to randomization) 
13. IMPROVE VTE score (Appendix E) (allowed within 72 hours prior to randomization) 
14. Medical History (including comorbid conditions such as congestive heart failure, diabetes 
mellitus, a history of cardiovascular disease including venous thromboembolism and peripheral 
vascular disease, history of atrial fibrillation, known thrombophilia, history of hypertension, a 
history of dyslipidemia, a history of coronary artery disease or congestive heart failure, a history 
of renal or lung disease, a history of liver disease, a history of thyroid disease, a history of cancer, 
a history of autoimmune disease, a history of bleeding diathesis, recent surgery or trauma, tobacco 
use) 
15. Relevant medications (all antiplatelet agents such as aspirin, clopidogrel, ticagrelor, prasugrel, 
vorapaxar, cangrelor; thrombolytic agents such as tPA; steroids; use of chloroquine or 
hydroxychloroquine; 
hormonal 
therapy; 
use 
of 
famotidine, 
immunosuppressant 
or 
immunomodulatory agents, antivirals, non-steroidal anti-inflammatory agents) 
16. Use of IVC filter 


29 
 
17. Mechanical thromboprophylaxis (intermittent pneumatic compression devices, graduated 
compression stockings) 
 
After randomization, the following data will be captured and collected as per trial protocol on 
Hospital Day 10 + 4 or at the time of discharge, whichever comes first: 
 
1. PT/INR (standard of care) 
2. Platelet count (standard of care) 
3. Hemoglobin/hematocrit (standard of care) 
4. Serum creatinine (standard of care) 
5. D-dimer (standard of care) 
6. C-reactive protein (CRP) (research purposes) 
7. Fibrinogen (research purposes) 
8. Troponin (research purposes) 
9. Quick SOFA score (Appendix D) 
10. ISTH SIC score (Appendix B) 
11. IMPROVE VTE score (Appendix E) 
12. Relevant medications (all antiplatelet agents such as aspirin, clopidogrel, ticagrelor, prasugrel, 
vorapaxar, cangrelor; thrombolytic agents such as tPA; steroids; use of chloroquine or 
hydroxychloroquine; hormonal therapy; use of famotidine, immunosuppressant or 
immunomodulatory agents, antivirals, non-steroidal anti-inflammatory agents). 
13. Use of IVC filter 
14. Mechanical thromboprophylaxis (intermittent pneumatic compression devices, graduated 
compression stockings) 
 
8.4.2. Vital Signs 
Vital signs will be collected daily as per the standard of care for hospitalized patients. 
 
8.4.3. Physical Examination 
Changes in clinical severity will be assessed via physical examinations. 
 
8.4.4. Other Examinations 
Lower extremity Duplex screening compression ultrasonography will be done at Hospital Day 
10+4 or sooner at the time of hospital discharge using standardized screening methods. 
 
There will be a 30 ± 2 day face to face or telephonic visit to assess study outcomes including the 
primary efficacy and principal safety outcomes or adverse events 
 
Patients will be on standard medical therapy for COVID 19 as per one’s institutional guidelines 
and policies. Patients participating in another clinical trial of blinded investigational drug 
therapies for COVD-19 will be excluded. The management of adverse events such as heparin-
induced thrombocytopenia, an arterial or venous thromboembolic event, or major or critical site 
bleeding event will be as per usual medical care. There is guidance to suggest that a dose increase 
of LMWH by 25% is acceptable to treat refractory thrombosis despite adequate weight adjusted 
treatment doses of LMWH [17,18]. For patients that need temporary interruption of study 
medication for an invasive procedure or surgery, investigators will follow local established 
guidelines for both doses of enoxaparin. If a patient develops severe renal failure with a CrCl < 
15ml/min during the course of their hospitalization, their study medication will be switched to 
intravenous or subcutaneous unfractionated heparin as per usual care using one’s institutional 
guidelines (Appendix A). 


30 
 
For patients with rising troponins and electrocardiographic changes that reflect standard 
definitions of NSTEMI recommendations will be made to start aspirin regardless of heparin dose. 
 
Other examinations may include nasopharyngeal swabs to analyze virologic clearance per 
standard of care for COVID-19 patients. 
 
Additional SOC examinations performed during the inpatient treatment period will be 
documented in the subject file and reviewed to assess safety. 
 
9 STATISTICAL METHODS 
 
9.1 General Statistical Considerations 
 
The primary clinical objective is to compare the incidence of the primary safety and efficacy 
outcomes, and secondary outcomes at Day 30 ± 2 days between patients receiving full dose LMWH 
treatment and patients receiving prophylactic/intermediate dose UFH or LMWH. A key secondary 
endpoint to compare the incidence of the primary safety and efficacy outcomes, and secondary 
outcomes at Hospital Day 10 + 4. 
9.2 Analysis Sets 
 
Assuming a 40% relative risk reduction in the primary efficacy outcome with LMWH treatment (4) 
and an incidence of the primary efficacy endpoint of 42% in the usual medical care arm (2, 4, 
internal Northwell data), 246 patients will be needed to be enrolled (123 in each arm) to have 80% 
power with a two-sided significance level of 0.05. Assuming a 20% drop out rate, we will need 308 
patients in total. The Intent-To-Treat (ITT) Population will consist of all subjects that were 
randomized. The Safety (SAF) Population, consisting of all randomized patients who received at 
least one dose of the study drug. This is also known as the modified intent to treat population or 
mITT. Reporting of the SAF population will be done according to the majority treatment received 
(as treated), whereas analysis of the mITT population will be analyzed according to randomization 
assignment. The Per Protocol (PP) Population will consist of all patients who received at least 
80% of planned therapy and did not have any major protocol deviations. Planned therapy will be 
calculated as the duration in days that the subject received study treatment according to 
randomization arm divided by the duration of hospitalization after randomization, in days. Major 
protocol deviations can be assessed from the database and will include those patients that did not 
meet inclusion criteria or met exclusion criteria, permanently discontinued assigned study 
medication after randomization not due to an outcome event, and did not undergo the Day 10+4 
lower extremity (LE) Screening Doppler compression ultrasonography (CUS). 
The primary analysis will be done in the per-protocol population. The primary analysis will be 
conducted in the mITT population as well. There will be a single interim analysis as described 
below. 
Under the design assumptions with 246 patients, therapeutic dose treatment with LMWH treatment 
will be deemed to be superior to prophylactic/intermediate dose UFH or LMWH treatment (i.e., 2- 
sided p < 0.05) if upon trial completion the absolute risk reduction with therapeutic LMWH group is 
-0.117 (11.7%) lower than in the prophylactic/intermediate dose group. A single interim analysis is 
planned after the primary outcome status is observed on half (123) of the randomized patients. The 
interim analysis will allow early termination for evidence of efficacy if the absolute risk reduction 
(ARR) is -0.234 (23.4%) lower in the therapeutic dose group than in the prophylactic/intermediate 
dose group. Table 1 shows the statistical inference that would be reported if the trial stops at the 
critical value (15 fewer events) at both the interim and final analyses. Table 2 shows the statistical 
operating characteristics of the design. 


31 
 
Table 1: Statistical inference upon trial completion. 
 
Efficacy Decision 
Futility Decision 
Observed 
CIlo 
P-value 
Observed 
CIlo 
P-value 
Interim Analysis 
-0.234 
(-0.338, -0.068) 
0.0027 
0.000 
(-0.166, 0.105) 
0.3750 
Final Analysis 
-0.117 
(-0.234, 0.000) 
0.0250 
-0.117 
(-0.234, 0.000) 
0.0250 
 
For example, the trial will stop for efficacy at the interim analysis if the ARR is smaller than -0.234 
(23.4% reduction in risk of the primary efficacy event. The trial will stop for futility if the risk of 
and event is larger with therapeutic dosing than with prophylactic dosing. The study will continue to 
the final analysis if the observed ARR is between -0.234 and 0.000. At the final analysis superiority 
is decided (1-sided p<0.025) if the observed ARR is smaller than -0.0117. The confidence intervals 
and p-values show the result that would be reported (e.g., the hypotheses that would be ruled out) if 
the observed ARR was equal to the decision boundary. For example, if the observed ARR equals - 
0.234 at the interim analysis, then the 95% confidence rules out reductions smaller than 33.8% or 
larger than 6.8% with 1-sided p=0.0027. 


32 
 
Table 2: Statistical properties of the interim monitoring design. 
 
True treatment effect 
Statistical properties of the design 
P1 
ARR 
Power 
Average 
Sample Size 
Probability of 
early stopping 
0.252 
-0.168 
0.804 
216.6 
0.239 
0.210 
-0.210 
0.941 
197.5 
0.394 
0.168 
-0.252 
0.988 
173.8 
0.587 
 
The statistical properties of the interim analysis design include the power the average sample size of 
trials that are monitored using this design and the probability of stopping at the interim analysis. 
These properties are a function of the true treatment effect; specifically, ARR = -0.168, ARR = - 
0.210, and ARR = -0.252 denotes a relative risk of 60%, 50%, and 40% of therapeutic dose relative to 
prophylactic dose (risk = 0.42); e.g. P1= 0.252 = 0.42*0.6 so ARR = 0.252 - 0.420 = -0.168 
 
9.3 Efficacy Analyses 
 
9.3.1 Summaries of Baseline Demographic and Clinical Data 
All baseline demographics and clinical data will be summarized by treatment arm using 
frequencies, rates, means, medians, standard deviations and quartiles appropriate to the dataset. 
There will be no inferential comparison of treatment arms with respect to baseline and 
demographic clinical data; such comparisons will be descriptive only. Unless otherwise 
specified, all results will be considered significant if p<0.05. 
 
9.3.2 Comparability of Randomized Subjects and Historical Controls 
N/A. 
 
9.3.3 Primary Efficacy Analyses 
 
9.3.3.1 Analysis of the Primary Clinical Endpoint 
The analysis of the primary clinical endpoint (Day 30 ± 2) will be carried out as follows: 
 
The composite of arterial thromboembolism, venous thromboembolism, and  all-cause 
mortality defined as follows: 
 
 
1. Any arterial thromboembolic event defined by: 
a. Documented thromboembolic stroke by imaging (Head CT, Brain MRI) defined as a new focal 
neurologic defect lasting at least 24 hours that is not due to a readily identifiable non-vascular cause 
b. Documented peripheral arterial thromboembolism by imaging (CT scan, arteriography, arterial 
Doppler of extremities) 
c. Documented acute myocardial infarction defined by 2 of the 3 following conditions: 1) an 
appropriate clinical condition such as new EKG changes, 2) elevation of CK-MB or Troponin-T or I 
≥ 
2 X ULN (if CK-MB or troponin unavailable then total CK ≥ 2 X ULN), 3) new significant (≥0.04 
seconds) Q waves in ≥ two contiguous leads 


33 
 
2. Any new venous thromboembolic event (symptomatic DVT or asymptomatic proximal DVT 
found by screening ultrasonography or as an incidental finding of PE on CT scan) including DVT of 
upper or lower extremities, PE, splanchnic vein thrombosis, cerebral vein thrombosis defined by: 
a. One or more new filing defects at compression ultrasonography, venography, CT venography, or 
MR venography 
b. A new perfusion defect of at least 75% of a segment with a local normal ventilation result (high 
probability) on ventilation/perfusion scan (V/Q scan) 
c. A non-compressible venous segment on compression ultrasonography, or in patients with a history 
of previous DVT, either a new non-compressible segment or a substantial increase (4mm or more) in 
the diameter of the vein during full compression in a previously abnormal segment on 
ultrasonography 
d. In the absence of an imaging test in a hemodynamically unstable patient, evidence of right 
ventricular dysfunction by transthoracic or trans esophageal echocardiogram (ESC Criteria) 
 
 
3. All-cause mortality 


34 
 
 
9.3.4 Secondary Analyses 
The analysis of the key secondary endpoint, the composite of arterial thromboembolic events 
(including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including 
symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal 
DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at 
Hospital Day 10 + 4 will be carried out in the same manner as the primary efficacy endpoint. 
Descriptive statistics of the other secondary endpoints, including the Sepsis-induced coagulopathy 
(SIC) score, progression to Acute Respiratory Distress Syndrome (ARDS), new-onset atrial 
fibrillation (AF), acute kidney injury (AKI), non-fatal cardiac arrest, need for intubation, need for 
Extracorporeal Membrane Oxygenation (ECMO), re- hospitalization at Day 30 ± 2 days will also 
be conducted. 
 
Multiple Thrombotic Events - 
Two secondary analyses will be carried out to address the issue of multiple thrombotic events.  
Specifically, these analyses will address the following question and hypothesis: 
Question: Does intensity of antithrombotic therapy change the risk for multiple thrombotic 
events? Multiple thrombotic events are associated with greater morbidity and mortality and are an 
indication of a worse prognosis after the 30-day outcome period in this trial. 
Hypothesis: When compared to prophylactic therapy, therapeutic antithrombotic therapy will 
reduce the risk of multiple thrombotic events. 
The hypothesis will be evaluated in two analyses: the first (analysis A) will compare the number 
of thrombotic events in all randomized subjects and the second (analysis B) will compare the 
number of additional thrombotic events among patients who experienced at least one event. Both 
analyses will evaluate the ratio of rate of thrombotic events in the two randomized groups using a 
Poisson probability model.  (The Poisson modeling will also include consideration of a zero-
inflated Poisson regression model or a negative binomial over-dispersion model.  Goodness-of-fit 
tests available in SAS will be used to explore the use of these two alternative models.)  
Analysis A: Comparison of the incidence rate for thrombotic events in all randomized subjects.  
 Analysis set:  All randomized subjects with separate analyses for the mITT and per protocol sets 
Analysis approach: Poisson regression with the following parameterization: 
Event definition: All thrombotic events including thrombosis-related death using protocol 
definitions. 
Exposure time: Time from randomization until the earliest of the 30-day outcome assessment, 
withdrawal of consent, or death. Exposure time will be included as an "offset" in the Poisson 
model. 
Explanatory variable: Treatment group assignment. 
Interpretation:  The rate ratio is an expression of the relative risk of one or more thrombotic event 
with therapeutic antithrombotic therapy relative to prophylactic therapy.   The analysis will report 
the estimated rate ratio, the 95% confidence interval, and the p-value for testing whether the ratio 
differs from 1. 
 
Analysis B:  Comparison of the incidence rate for subsequent thrombotic events following the first 
such event.  
Analysis set:  All randomized subjects who experienced a first thrombotic event. Subjects who 
died of their first thrombotic event or who died of other causes without a thrombotic event will be 
excluded. Subjects who did not experience a thrombotic event will also be excluded.  Separate 
analyses will be conducted for the mITT and per protocol sets. 
Analysis approach: Poisson regression with the following parameterization: 
Event definition: All thrombotic events subsequent to the first event including thrombosis-related 
death following a first event. 


Exposure time: Time from the first thrombotic event to the earliest of the 30-day outcome 
assessment, withdrawal of consent, or death. Exposure time will be included as an "offset" in the 
Poisson model. 
Explanatory variable: Treatment group assignment. 
Interpretation:  The rate ratio is an expression of the relative risk of subsequent thrombotic events 
with therapeutic antithrombotic therapy relative to prophylactic therapy.   The analysis will report 
the estimated rate ratio, the 95% confidence interval, and the p-value for testing whether the ratio 
differs from 1. 
 
. 
9.3.5 Interim Analysis 
A single interim analysis is planned after the primary outcome status is observed on half (123) of the 
randomized patients. The interim analysis will allow early termination for evidence of efficacy if the 
absolute risk reduction (ARR) is -0.234 (23.4%) lower in the therapeutic dose group than in the 
prophylactic/intermediate dose group. 
 
 
9.3.6 Missing Data 
Every effort will be made to minimize the amount of missing data. Due to the critical and time 
sensitive nature of this protocol, the focus will be on three outcome variables: Day 10 +4 
screening lower extremity ultrasonography and Day 30 ± 2 primary efficacy and principal safety 
outcomes. There should be no missing data on the most important component of the primary 
efficacy endpoint, all-cause mortality 


35 
 
 
9.3.7 Sample Size and Power Calculation 
Assuming a 40% relative risk reduction in the primary efficacy outcome with LMWH treatment (4) 
and an incidence of the primary efficacy endpoint of 42% in the usual medical care arm (2, 4, 
internal Northwell data), 246 patients will be needed to be enrolled (123 in each arm) to have 80% 
power with a two-sided significance level of 0.05. Assuming a 20% drop out rate, we will need 308 
patients in total. The primary analysis will  be  done  in  the  mITT  and  per-protocol  population. 
The SAF Population consisting of all randomized patients who received at least one dose of the study 
drug is also known as the mITT population. Reporting of the SAF population will be done according 
to the majority treatment received (as treated), whereas analysis of the mITT population will be 
analyzed according to randomization assignment. The Per Protocol (PP) Population will consist of all 
patients who received at least 80% of planned therapy and did not have any major protocol 
deviations. Planned therapy will be calculated as the duration in days that the subject received study 
treatment according to randomization arm divided by the duration of hospitalization after 
randomization, in days. Major protocol deviations can be assessed from the database and will include 
those patients that did not meet inclusion criteria or met exclusion criteria, permanently discontinued 
assigned study medication after randomization not due to an outcome event, and did not undergo the 
Day 10+4 lower extremity (LE) Screening Doppler compression ultrasonography (CUS) 
 
 
9.3.8 Secondary Efficacy Analyses 
The secondary outcomes described above will be analyzed using a combination of methods for 
continuous, ordinal, categorical and binary data. 
 
 
9.4 Biomarker Analyses 
N/A 
 
9.5 Safety Analyses 
 
Safety population: The SAF Population consists of all randomized patients who received at 
least one dose of the study drug. Reporting of the SAF population will be done according to the 
majority treatment received (as treated).. 
 
9.6 Data Safety Monitoring Board 
An independent data safety monitoring board (DSMB) will actively monitor interim data to 
review the ongoing safety of patients and can make recommendations about early study closure 
or changes to the protocol. The DSMB members will include 3 voting members, 2 physicians 
with relevant medical specialty training and experienced in clinical trials research and 1 clinical 
trial statistician. All DSMB members must be free of both substantial intellectual and financial 
conflicts of interests. The DSMB chair reviews subject safety results every 2 weeks by group 
assignment, judges whether the overall safety of the project remains acceptable, has ongoing 
access to un-blinded information, and makes recommendations after discussion with the DSMB 
committee and including review of Interim Analysis results, about early study closure or 
changes to the protocol to the study Principal Investigator (PI) and Executive Committee, who 
has the responsibility to accept, reject or to modify DSMB recommendations. The DSMB 
meeting frequency will be as follows ~25%, ~50%, ~75% and ~100% enrollment. Furthermore, 
the detailed operation of the DSMB is governed by a charter describing further details such as 
frequency of meeting, procedures (including but not limited to periodic safety monitoring) and 
requirements for reporting (Appendix G). 


36 
 
9.7 Executive Committee 
There will be a study Executive Committee consisting of the study Principal Investigator as 
Chair and other study investigators, as well as up to 4 external members with expertise in 
antithrombotic trials. This Executive Committee will assist the study Chair in managing quality 
oversight of trial-related activities during the conduct of the clinical trial. 
 
 
10 DATA INTEGRITY AND QUALITY ASSURANCE 
 
10.1 Monitoring 
 
The PI or designee will visit each site prior to enrollment and throughout the study duration to 
ensure safety and adherence to study protocols. The number of visits for any given site may vary 
based on site risk indicators. Study-related monitoring may also be done by internal and external 
regulatory agencies, including the IRB and OHRP. Study monitors will perform ongoing source 
data review to verify that data recorded in the CRF by authorized site personnel are accurate, 
complete, and verifiable from source documents, that the safety and rights of patients are being 
protected, and that the study is being conducted in accordance with the current approved protocol 
version and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
Quality assurances for monitoring the local adjudication process for events may be used at the 
discretion of the DSMB Chair and Principal Investigator or designee, and if high variability is 
observed, additional review (e.g. central review of some evens) may be conducted. 


37 
 
 
10.2 Data Collection 
 
Subjects enrolled in this study will undergo laboratory testing as part of standard-of-care. The 
results of these tests will be collected, as indicated. Certain tests that are not necessarily part of 
standard-of-care will also be collected as part of this study, as indicated. Subjects will be made 
aware of and will be required to consent to additional procedures during the Informed Consent 
process. Detailed instructions for blood/NP swab sample collections will be in the laboratory 
manual provided to study sites. 
 
10.3 Data Management 
 
A data management plan specifying all relevant aspects of data processing for the study will be 
maintained with the regulatory documentation for this protocol. All data coding (SAEs, baseline 
findings, medication, medical history, etc.) will be done using internationally recognized and 
accepted abbreviations. Northwell Health has designed and implemented a HIPAA compliant 
COVID-19 DataMart data collection tool (see Appendix H.) which will be utilized to obtain 
clinical data for COVID-19 patients within the health system in addition to the medical record. 
 
10.4 Electronic Systems 
 
Electronic systems that may be used to process data in this study will include: 
 
• Biostatistics Randomization Management System (BRMS) –randomization 
• REDCap – data collection CRF 
• Statistical Analysis System (SAS) –statistical review and analysis 
 
10.5 Study Documentation 
 
10.5.1 Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded onsite on paper Case 
Report Forms (CRFs), and then transferred to REDCap by trained study staff. All required  
CRFs must be completed for every study subject. The PI will ensure the  accuracy, 
completeness, and timeliness of the data and will provide his electronic signature upon review. 
Copies of paper CRFs will be retained as part of the study record and available for inspection by 
regulatory authorities. The electronic systems used for data management all employ an audit trail 
that will reflect any changes made to study records. 
 
10.5.2 Record Retention and Storage 
All essential study documents, including ICFs, source documents, CRFs, drug accountability 
records, and regulatory documentation will be stored in a locked office at the Center for Health 


38 
 
 
Innovations and Outcomes Research at Northwell Health with access limited to approved study 
personnel only. All documents will be retained for at least 15 years following the completion or 
discontinuation of the study. 
 
10.6 Operational Procedures 
 
An ‘Investigator-Initiated Multicenter Coordinating Site’ will be established to coordinate study 
personnel working remotely and/or external to the Health System and monitor study tasks. 
These tasks will include but are not limited to the following: 1) track all data, 2) coordinate 
meetings (1x monthly or more as needed), 3) maintain regulatory documentation, 4) oversee 
study personnel and address staffing needs (if applicable). A Meta-Site Principal Investigator 
will be identified to oversee these tasks at each site. 
 
The Main Principal Investigator will ensure the conduct of human subject research at each site 
involved in the Multicenter HSR Clinical Trial meets the requirements of 45 CFR 46/21 CFR 50 
(Protection of Human Subjects), and 21 CFR 56 (Institutional Review Board). All Meta-Site 
Principal Investigator(s) and corresponding research staff members will attend an extensive Site 
Initiation Visit (SIV) prior to onboarding where the IRB approved protocol and all study related 
material will be discussed. Furthermore, prior to any study related activities at corresponding 
external research site(s) there will be a fully executed contract between both the Coordinating 
Center (i.e. Sponsor) and External Site(s) which will clearly address the responsibilities of the 
External Site and ensure the study will be conducted in compliance with federal regulations, all 
applicable state and local regulations, and ethical principles governing research involving human 
subjects. The roles and responsibilities of each party will be outlined in the External Agreement 
Contract (Appendix J). 
 
As per [21CFR56.114] the External Sites will rely upon the review of their own qualified 
Institutional Review Board as outlined in the External Agreement Contract (Appendix J). Due 
to the nature of the COVID-19 pandemic, all external sites will utilize their local site-specific 
IRB, which will be responsible for reviewing the proposed research and activities at that site [21 
CFR 56.111, 45 CFR 46.111]. 
 
The Main Principle Investigator will ensure each external site(s) maintain a comprehensive 
study management plan which will outline the following: 
• Compliance plan that details: 
o Actions for ensuring and monitoring protocol and regulatory compliance 
o Actions to be taken in the event unanticipated problem involving risks to 
subjects or others, and 
o A process for receipt and evaluation of protocol deviations and exceptions. 
• Study management plan that addresses: 
o Documentation of initial and continuing IRB review for each site, 
o Confirmation that each external institution has a Federal-Wide Assurance on 
File with Office of Human Research Protection (if applicable); 
o Initial and continued training of sites, 
o Method for assuring that all sites have and implement the most current version 
of study documents (including protocols, investigator’s brochure (if 
applicable), Informed consent forms and case report forms), and 
o The collection and security of data (External REDCap Setup) 


39 
 
o A process for handling the commercial product (responsibility of site-specific 
pharmacy) 
o A Data Monitoring Plan, Data Safety Monitoring Board or Committee 
(Appendix G), 
o A process for evaluating and reporting of serious adverse events (SAEs) from 
sites, and 
o A plan to monitor the conduct and progress of the human subject research 
study (which includes a plan for the management of noncompliance). 
 
Documentation of compliance with the responsibilities mentioned above will be maintained at 
each corresponding external site(s) and readily available to Coordinating Center (as 
requested). The main Study PI will receive and confirm IRB approvals from each site prior to 
each site starting study subject enrollment. Each site will be responsible for IRB/Institutional 
approval of the protocol from the corresponding site-specific local IRB. The main PI will be 
responsible for collecting the approval documents and ensuring it is readily available for 
review as per regulatory compliance. Furthermore, the main Study PI and lead research team 
will coordinate a mandated site initiation visit (SIV) for all study sites both internal and 
external prior to study activation. 
 
There shall be no fees, charges or other payments made or payable by Sponsor to Participating Institution 
for conducting this Trial or otherwise in connection with the Clinical Trial. Participating Institution shall 
be responsible for funding its own activities, including those of Site Investigator, in the conduct of the 
Clinical Trial (Appendix J). 
 
In the event of a degradation of system-wide resources and/or significant staffing reduction due 
to the nature of the COVID-19 pandemic, every effort will be made to collect data as described 
in this protocol. A majority of data will be collected from the COVID-19 Data Mart and/or 
REDCap Database (Secure setup for External Users) established and maintained by the Center 
for Health Outcomes Research at Northwell Health. Protocol deviations will be reported as 
feasible. Subjects will continue to receive care while hospitalized, however will not be 
prioritized over non-study participants for available equipment and/or other resources. 
 
Of note, regardless of study participation, the decision for ventilator support is based on the 
clinical decision making of the care team. 
 
 
11 PUBLICATION POLICY 
 
11.1 Publication and Public Disclosure of Clinical Trial Information 
This study and results will be made publicly available on ClinicalTrials.gov. Processes for 
publications resulting from this study will be outlined separately in the Executive 
Committee Charter. 
 
12 ETHICS AND ADMINISTRATIVE INFORMATION 
 
12.1 Good Clinical Practice Statement 
It is the responsibility of the PI and all study personnel to ensure that this clinical study will be 
conducted in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 


40 
 
12.2 Confidentiality 
 
All appropriate measures will be taken to ensure that the anonymity of each subject is 
maintained. Subjects will be identified by an alphanumeric code only on CRFs and other related 
documentation. Source documentation that may not be coded will be kept confidential. 
 
12.3 Informed Consent 
It is the responsibility of the PI or other IRB-approved study personnel to obtain 
informed consent from each subject or a legally authorized representative (LAR) prior to his/her 
participation in the study and after the aims, methods, objectives, and potential hazards of the 
study have been explained to the potential subject in language that he/she can understand. The 
following procedures are based on the FDA Guidance on Conduct of Clinical Trials of Medical 
Products during the COVID-19 Pandemic and will be applied to this study. 
 
For patients that are able to sign for themselves: 
• 
Healthcare worker who enters the room (can be the investigator, but does not have to be) 
provides the patient with a copy of the consent form 
• 
If the consenting investigator is in the room with the patient during the consent process, 
the patient and the consenting investigator will sign the consent form. Witness signature 
will be waived. The consent process will be documented in an enrollment note as per 
Northwell Policy GR089. 
• 
If direct communication with the patient is not feasible due to isolation, the investigator 
obtaining consent from outside of the room will arrange a three-way call or video 
conference with (a) the patient, (b) a witness, and (c) if desired by the patient, 
additional participants (e.g., next of kin) 
 
The consent process will include the following steps: 
 Each attendee on the call or video conference identifies him/herself 
(include name and role/relationship to patient) 
 Investigator reviews the consent form with the patient and answers 
any questions that occur during the conversation. 
 Witness verbally confirms that patient’s questions have been 
answered. If the healthcare worker in the room serves as the witness, 
the healthcare worker must sign the consent form as witness to the 
consent process. 
 Investigator asks the patient to confirm that the patient is willing to 
participate in the trial and to sign the consent document while the 
witness is present or listening on the phone or video conference. 
 Patient verbally confirms that s/he would like to participate in the 
trial and patient signs and dates the consent form. 
 The signed consent form is collected from the patient room 
following infection control protocols. More specifically, pen used by 
patient to sign the consent form is thrown away and consent form 
signed by the patient is placed in a biohazard bag and then in a clean 
bag. Investigator will sign the consent form once the paper copy 
becomes available and ensure that the fully signed consent form is 
filed in the patient’s record. 
 
• 
If it is not possible to collect the consent form due to contamination of document by 
infectious material, one of the following will be done: 
• 
The Investigator and witness will sign and date a copy the consent form and 
provide individual attestation using the COVID-19 Witness Attestation form 


41 
 
& COVID-19 Investigator Attestation form that the patient agreed to 
participate in the study and signed the informed consent form. 
 
OR 
 
• 
The healthcare worker in the room (in her/his capacity as witness) can 
photograph the signature page of the consent form as signed by the patient and 
witness and forward to the investigator to print and place in the patient’s 
record. An attestation (using the COVID-19 Investigator Attestation form) by 
the person entering the photograph in the study record must indicate how the 
photograph was obtained and confirm that it is a photograph of the informed 
consent form signed by the patient. 
 
When informed consent is to be obtained from a Legally Authorized Representative (LAR), who is 
not present due to isolation rules, and have access to email: 
• 
The investigator will contact the LAR on the phone and request an email address to email a 
copy of the informed consent form. 
• 
Consent form will be emailed to the LAR for review during consent conversation with the 
investigator. 
• 
The investigator obtaining consent arranges a three way call or video conference with (a) the 
patient’s LAR, (b) an impartial witness, and (c) if desired by LAR, additional participants 
(e.g., patient’s next of kin) 
• 
The consent process will include the following: 
• 
Each attendee who is on the call or video conference identifies 
him/herself (include name and role/relationship to patient) 
• 
Investigator reviews the consent form with the LAR and answers any 
questions that occur during the conversation 
• 
Witness verbally confirms that LAR's questions have been answered 
• 
Investigator asks the LAR to confirm that the LAR is in agreement with 
patient’s participation in the trial while the witness is listening on the 
phone or video conference 
• 
LAR verbally confirms that s/he would like the patient to participate in 
the trial and LAR signs and dates the consent form (if feasible). 
• 
Investigator and impartial witness will sign and date a copy of the consent form. 
• 
Investigator will ask LAR to: 
• Sign and date the LAR’s copy of consent form and email back a scanned copy. 
OR 
• 
Take a photograph of the signature page of the LAR’s signed and dated consent form 
and forward to the investigator. The photo of the LAR’s signed and dated signature 
page of the consent form will be printed and placed in the patient’s record along with 
the paper consent form signed by the investigator and witness. 
OR 
• 
Send an email response to the investigator indicating agreement to allow patient’s 
participation in the clinical trial (if they cannot email or scan the signed consent form). 
The Investigator and witness will provide individual attestation that the LAR is in 
agreement with the patient’s participation in the study (using the COVID-19 Witness 
Attestation form & COVID-19 Investigator Attestation form). In addition, the 
investigator will send, through certified mail, a copy of the consent form to the LAR 
and ask for the LAR to sign and date the consent and send it back by mail for 
confirmation of signature. 


42 
 
• 
The enrollment note must include a description of the consent process followed and if 
applicable, will indicate why the original signed document was not retained (using 
COVID-19 Enrollment Note). 
 
When informed consent is to be obtained from a Legally Authorized Representative (LAR), who is 
not present due to isolation rules AND does not have access to email or one does not exist, verbal 
consent can be obtained as follows: 
• 
The investigator will contact the LAR on the phone and inform him/her that a three way call or 
video conference with (a) an impartial witness, and (b) if desired by the LAR, additional 
participants (e.g., patient’s next of kin) will be conducted to discuss the study. 
• 
During the consent conversation, investigator will review the consent form with the LAR and 
any additional participants. 
• 
The consent process must include the following: 
• 
Each attendee who is on the call or video conference identifies him/herself (include 
name and role/relationship to patient) 
• 
Investigator reviews the consent form with the LAR and answers any questions asked 
during the conversation 
• 
Impartial witness verbally confirms that LAR's questions have been answered 
• 
Investigator asks the LAR to confirm that the LAR is in agreement with patient’s 
participation in the trial while the impartial witness is listening on the phone or video 
conference 
• 
LAR verbally confirms that s/he would like the patient to participate in the trial. 
• 
Following the LAR’s verbal confirmation that he/she agrees to allow patient’s participation in 
the clinical trial, the investigator will mail a copy of the consent form to the LAR and ask for 
the LAR to sign and date the consent and send it back by mail for confirmation of signature. 
• 
Investigator and impartial witness will sign and date a copy of the consent form and each will 
provide attestation (using the COVID-19 Witness Attestation form & COVID-19 Investigator 
Attestation form) that the LAR is in agreement with the patient’s participation in the study. 
• 
The enrollment note will include a description of the consent process and if applicable, should 
indicate why the signed document was not retained (using the COVID-19 Enrollment Note). 
 
 
 
Patients with Limited English Proficiency (LEP) will not be excluded from this study. Informed 
Consent will be obtained in this case following the procedures detailed above, using an impartial 
interpreter and a short form translated into the patient’s preferred language, and in accordance 
with Northwell Health policy GR089 for obtaining informed consent for patients with Limited 
English Proficiency. 


43 
 
 
12.4 Regulatory Compliance 
 
The Northwell Health Institutional Review Board (IRB), as described in ICH guidelines for 
GCP, will provide regulatory oversight of this clinical study within the Northwell Health 
System. The IRB will review and approve: 
 
• The protocol, Informed Consent Form, and advertising materials, 
• Amendments or modifications to the protocol or ICF before implementation, 
 
In addition, the IRB will be informed of any event likely to affect the safety of patients or the 
conduct of the study. Records of the IRB review and approval of all study documents will be 
kept on file by the PI. 
 
All External Site(s) will refer to their local site-specific (IRB) as described in ICH guidelines 
for GCP, who will provide regulatory oversight of this clinical study at their local institution. 
 
12.5 Protocol Deviations 
 
Major and minor protocol deviations will be reported according to institutional policy. 
 
12.6 New Information Affecting the Conduct of the Study 


44 
 
 
 
If new information affecting either the conduct of the study or the initial risk/benefit assessment 
becomes available, this protocol will be amended as needed and submitted for IRB review. 
Subjects will be informed and required to provide informed consent. 
 
12.7 Protocol Amendments 
 
All amendments or modifications to this protocol will be reviewed and approved by the IRB 
prior to implementation. In the event that a modification is required in an emergency situation, 
the IRB will be notified immediately. 
 
12.8 Study Termination 
 
The sponsor, investigator, and/or regulatory agencies have the right to terminate the study 
prematurely on the basis of safety, efficacy or futility. 


46 
 
 
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[5] Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular Implications of Fatal Outcomes 
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[6] Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe 
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[7] Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 
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[8] Wang J, Hajizadeh N, Moore EE, McIntyre RC, Moore PK, Veress LA, et al. Tissue Plasminogen 
Activator (tPA) Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome 
(ARDS): A Case Series. J Thromb Haemost JTH 2020. https://doi.org/10.1111/jth.14828. 
[9] Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of Cardiac Injury With Mortality in 
Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol 2020. 
https://doi.org/10.1001/jamacardio.2020.0950. 
[10] Mulloy B, Hogwood J, Gray E, Lever R, Page CP. Pharmacology of Heparin and Related Drugs. 
Pharmacol Rev 2016;68:76–141. https://doi.org/10.1124/pr.115.011247. 
[11] Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. 
Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 
2020:S0049384820301201. https://doi.org/10.1016/j.thromres.2020.04.013. 
[12] Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review 
of immune changes in patients with viral pneumonia. Emerg Microbes Infect 2020;9:727–32. 
https://doi.org/10.1080/22221751.2020.1746199. 
[13] Hunt OBE B, Retter A, McClintock C. Practical guidance for the prevention of thrombosis and 
management of coagulopathy and disseminated intravascular coagulation of patients infected with 
COVID-19 n.d. https://thrombosisuk.org/covid-19-thrombosis.php (accessed April 10, 2020). 
[14] Merli G, Spiro TE, Olsson CG, Abildgaard U, Davidson BL, Eldor A, et al. Subcutaneous 
enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of 
venous thromboembolic disease. Ann Intern Med 2001;134:191–202. https://doi.org/10.7326/0003- 
4819-134-3-200102060-00009. 
[15] Gargiulo G, Carrara G, Frigoli E, Vranckx P, Leonardi S, Ciociano N, et al. Bivalirudin or Heparin 
in Patients Undergoing Invasive Management of Acute Coronary Syndromes. J Am Coll Cardiol 
2018;71:1231–42. https://doi.org/10.1016/j.jacc.2018.01.033. 
[16] Cohoon KP, Mahé G, Tafur AJ, Spyropoulos AC. Emergence of Institutional Antithrombotic 
Protocols for Coronavirus 2019. Res Pract Thromb Haemost n.d.;n/a. 
https://doi.org/10.1002/rth2.12358. 
[17] Carrier M, Khorana AA, Zwicker JI, Noble S, Lee AYY. Management of challenging cases of 


47 
 
patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance 
from the SSC of the ISTH. J Thromb Haemost 2013;11:1760–5. https://doi.org/10.1111/jth.12338. 
[18] Carrier M, Gal GL, Cho R, Tierney S, Rodger M, Lee AY. Dose escalation of low molecular weight 
heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in 
cancer patients. J Thromb Haemost 2009;7:760–5. https://doi.org/10.1111/j.1538- 
7836.2009.03326.x. 
[19] Needleman Laurence, Cronan John J., Lilly Michael P., Merli Geno J., Adhikari Srikar, Hertzberg 
Barbara S., et al. Ultrasound for Lower Extremity Deep Venous Thrombosis. Circulation 
2018;137:1505–15. https://doi.org/10.1161/CIRCULATIONAHA.117.030687. 
[20] Adhikari S, Zeger W, Thom C, Fields JM. Isolated Deep Venous Thrombosis: Implications for 2- 
Point Compression Ultrasonography of the Lower Extremity. Ann Emerg Med 2015;66:262–6. 
https://doi.org/10.1016/j.annemergmed.2014.10.032. 
[21] Lee JH, Lee SH, Yun SJ. Comparison of 2-point and 3-point point-of-care ultrasound techniques for 
deep vein thrombosis at the emergency department: A meta-analysis. Medicine (Baltimore) 
2019;98:e15791. https://doi.org/10.1097/MD.0000000000015791. 


48 
 
14.1 Appendix A 
 
Northwell Health System Guidance on Cardiovascular/Thromboembolic Disease and Hospitalized Patients with 
COVID-19 
 
Patients with cardiovascular disease do worse with COVID-19 and there is an increased frequency of 
CVD-associated SAEs associated with the coronavirus itself or with antivirals and other treatment 
modalities (myocarditis, acute coronary syndromes, cardiac arrhythmias, cardiogenic shock, and venous 
thromboembolism). There is also a worse prognosis for patients with very elevated D-dimer (>6X ULN) 
although mechanisms are incompletely understood: Proposed mechanisms include coagulopathy/DIC, 
cytokine storm, and presence of microthrombi. There may be issues of hepatic enzyme dysfunction 
(CYP3A4 inhibition), with the use of certain antivirals (Lopinavir/Ritonavir), which results in impaired 
metabolism of antithrombotics. Lastly, recent clinical data supports aggressive prophylactic-to- 
intermediate dose pharmacologic thromboprophylaxis with low molecular weight heparin in hospitalized 
COVID-19 patients with severe illness as well as extended thromboprophylaxis in high VTE risk patients 
(IMPROVE VTE score 4 or more, advanced age, elevated D-dimer). Key points: 
 
• Do NOT stop antithrombotics in COVID-19 patients 
• Consider changing clopidogrel/ticagrelor to prasugrel in patients on Lopinavir/Ritonavir or 
consider P2Y12 monitoring 
• Careful consideration of apixaban/rivaroxaban in patients on Lopinavir/Ritonavir or consider 
dabigatran or dose adjusted warfarin 
• Also consider substituting argatroban IV for UFH IV for device associated anticoagulation issues. 
Empiric use of treatment dose heparin (IV UFH/LMWH) or use of systemic tPA should be studied 
in a randomized trial setting 
• For hospitalized non-ICU patients, thromboprohylaxis in patients with CrCl > 15ml/min and BMI 
< 30 using enoxaparin 40mg SQ QD; with BMI > 30 using enoxaparin 40mg SQ BID; in patients 
with CrCl < 15ml/min or RRT and BMI < 30 use UFH 5000U SQ BID or TID; in patients with 
CrCl, 15ml/min or RRT and BMI ≥ 30 use UFH 7500U SQ BID or TID 
• In ICU patients, as above but also use multimodal prophylaxis with mechanical methods (IPCs). 
• Extended thromboprophylaxis with enoxaparin 40mg SQ QD or rivaroxaban 10mg PO QD for 31 
– 39 days’ post-discharge in patients with an IMPROVE VTE score of ≥ 4 or age > 60yrs and/or 
elevated D-dimer (> 2X ULN). 


49 
 
14.2 Appendix B 
 
ISTH Sepsis Induced Coagulopathy (SIC) Score 
 
 
 
 
Value 
Points 
Platelets, K/µL 
>100 
0 
50-100 
1 
<50 
2 
INR 
<1.3 
0 
1.3-1.7 
1 
>1.7 
2 
D-Dimer, ng/mL 
<400 
0 
400-4000 
2 
>4000 
3 
Fibrinogen, mg/dL 
>100 
0 
<100 
1 


50 
 
14.3 Appendix C 
 
Duplex Doppler Screen 
 
Imaging for screening or suspected DVT [19–21]: 
 
Lower extremity Duplex screening compression ultrasonography will be done at Hospital Day 10+4 or 
sooner at the time of hospital discharge using standardized screening methods. Confirmatory lower 
extremity ultrasound of symptomatic DVT or asymptomatic screening of lower extremity DVT is 
recommended using full duplex Doppler compression ultrasonography of the entire extremity venous 
system. Where resource constraints or local institutional policies preclude use of full ultrasound, point-of- 
care ultrasound using two-region compression can be substituted and has shown reasonable accuracy. 
 
Full duplex ultrasound is the preferred venous ultrasound  test  for  the  diagnosis  of  DVT.  This  
includes compression of the deep veins from the inguinal ligament to the ankle (including posterior tibial 
and peroneal veins in the calf), right and left common femoral vein spectral Doppler waveforms (to 
evaluate symmetry), popliteal spectral Doppler, and color Doppler images. Compression is performed at 
2-cm intervals. 
 
A point-of-care ultrasound consisting of a limited evaluation with compression from thigh to knee 
(extended compression ultrasound) is appropriate when full duplex US is not available in a timely 
manner. Extended compression point of care ultrasound is performed with compression from the inguinal 
ligament extending through the popliteal vein to the calf vein confluence at 2 cm intervals. Extended 
compression, if possible, is favored over 2-region compression because isolated femoral vein DVTs may 
be missed. 
However, in the COVID pandemic, two-region (two-point) compression can be substituted. Two-point 
compression point of care US is performed with the first region of compression extending from 1 to 2 cm 
above to 1-2 cm below the saphenofemoral junction. The second point of compression begins at the origin 
of the popliteal vein extending to the calf vein confluence. Acute venous thrombosis should be defined as 
lack of compressibility, but the thrombus is soft and deformable with increasing probe pressure. Chronic 
post-thrombotic change is seen as rigid, non-compressible intraluminal material which is nondeformable 
with increasing probe pressure. 


51 
 
14.4 Appendix D 
 
 
 
Quick SOFA Score 
 
Assessment 
qSOFA score 
Low blood pressure (SBP ≤ 100 mmHg) 
1 
High respiratory rate (≥ 22 breaths/min) 
1 
Altered mentation (GCS ≤ 14) 
1 


52 
 
14.5 Appendix E 
 
The 7 Factor IMPROVE VTE RAM *(18) 
 
 
 
 
 
 
VTE Risk Factor 
Points for the Risk Score 
Previous VTE 
3 
Thrombophilia** 
2 
Current lower limb paralysis or paresis*** 
2 
Cancer**** 
2 
Immobilization***** 
1 
ICU/CCU stay 
1 
Age > 60 years 
1 
 
 
Abbreviations: 
 
IMPROVE, International Medical Prevention Registry on Venous Thromboembolism; VTE, venous 
thromboembolism; RAM, risk assessment model; [M1] ICU, intensive care unit; CCU, coronary care unit. 
 
*A score of 0-1 constitutes low VTE risk; a score of 2-3 constitutes moderate VTE risk; a score of 4 or more 
constitutes high VTE risk. 
 
**A congenital or acquired condition leading to an excess risk of thrombosis (i.e. FV Leiden, prothrombin gene 
mutation, Protein S, C or antithrombin deficiency, antiphospholipid syndrome, hyperhomocysteinemia). 
 
***Leg falls to bed by 5s, but has some effort against gravity (from NIH stroke scale). 
 
****May include active cancer (excluding non-melanoma skin cancer) or a history of cancer within 5 years. 
 
*****Strict definition is complete immobilization confined to bed or chair ≡ 7 days; modified definition is 
complete immobilization with or without bathroom privileges ≡ 1 day. 


53 
 
 
14.6 Appendix F 
 
Study Flow Chart and Events Schedule 
 
 
Procedure 
Screening (Up to 
72 hours before 
randomization) 
Day 0 (Day of 
randomization) 
Hospital Day 
10 + 4 or 
discharge 
Day 30 ± 2 
Informed consent 
X 
Inclusion/Exclusion 
Criteria 
X 
Medical History 
X 
X 
Study Medication 
X 
X 
Study Labs 
X 
X 
X 
Concomitant 
Medications* 
X 
X 
X 
Use of mechanical 
Thromboprophylaxis 
X 
X 
Clinical scores** 
X 
X 
Primary Outcome 
Assessment 
X 
X 
Secondary Outcome 
Assessment/SAEs 
X 
X 
Screening 
LE Doppler CUS 
X 
 
*including unblinded investigational agents for COVID-19 
 
** SIC score, Quick SOFA score, IMPROVE VTE Risk score, 


54 
 
14.7 Appendix G 
 
DSMB Charter 


55 
 
14.8 Appendix H 
DataMart Data Elements 
 
 
 


56 
 
14.9 Appendix I 
BRMS User Manual 


57 
 
15.0 Appendix J 
External Agreement Contract 


58 
 
15.1 Appendix K 
Investigational Drug Service – Standard Operating Procedure 


59 
 
15.2 Appendix L 
Patient Drug Accountability Log 

ICF_004.pdf: 
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Northwell Health
Consent for Participation in a Research Study
Study Title: Systemic Anticoagulation with Full Dose Low Molecular Weight Heparin 
(LMWH) Vs. Prophylactic or Intermediate Dose LMWH In High Risk COVID-19 Patients 
(HEP-COVID Trial)
Principal Investigator: Alex C Spyropoulos, MD, FACP, FCCP, FRCPC
About this research 
You are being asked to participate in a research study.  
This consent form will give you information about the study to help you decide whether you 
want to participate. Please read this form, and ask any questions you have, before agreeing to be 
in the study.
Important Information 
This information gives you an overview of the research. More information about these topics 
may be found in the pages that follow.  
Why am I being asked 
to provide my consent?
This is a research study, which is different than personal medical care.  
Scientists do research to answer important questions which might help 
change or improve the way we do things in the future. 
Do I have to join this 
research study?
No. Taking part in this research study is voluntary.  You may choose not 
to take part in the study or may choose to leave the study at any time.  
Deciding not to participate, or deciding to leave the study later, will not 
result in any penalty or loss of benefits to which you are entitled.
Why is this research 
study being done?
The purpose of this research study is to find out whether Full Dose 
Heparin (LMWH) or Prophylactic (preventative)/Intermediate Dose 
Heparin (LMWH) is a safe and effective treatment in COVID-19 
Hospitalized Adults.
What will happen to 
me during the study?
You will be given Full Dose Heparin (LMWH) or 
Prophylactic(preventive)/Intermediate Dose Heparin (LMWH) to treat 
your illness while you are hospitalized. When you leave the hospital, we 
will follow-up with you within 30 days. Heparin (LMWH) is commonly 
used to treat or prevent blood clots but we do not know if it works against 
COVID-19.
How long will I 
participate?
You will be in this study for a total of 30 days. You will receive 
medication during your hospitalization for COVID-19. Whether you are 
in the hospital or at home, we will follow-up with you in 30 days. 
Will taking part 
expose me to risks?
Taking any medication exposes you to a risk of side effects. It is possible 
that Heparin (LMWH) may cause bleeding including bleeding gums, 
nosebleeds, prolonged bleeding from cuts, anemia,  diarrhea, nausea, 
 
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fever, edema, leg swelling, difficulty breathing, confusion and injection 
site pain. In some cases there have been reports of spinal/epidural 
hematomas (accumulation of blood around the spinal cord) in patients 
receiving local anesthesia around the spine or spinal cord or undergoing 
spinal puncture. There is also an unlikely risk of serious allergic reaction 
while taking Heparin (LMWH). With any research study that collects 
personal information, there is a small risk of loss of confidentiality. 
Are there any benefits 
to participation?
If the medication being studied is effective against COVID-19, 
participation in this research study may benefit you directly. Information 
learned in this study will help us to better treat future patients.
What are my 
alternatives to 
participation?  
If you do not participate in this study, you will not receive the 
medications being studied. You will receive the current standard of care 
for COVID-19. 
Please review the rest of this document for details about these topics and additional things 
you should know before making a decision about whether to participate in this research.  
As the participant's legally authorized representative or next of kin, you are being asked to give 
consent for the participant to be in a research study. You are being asked to do this because the 
participant is not able to give consent. When making this decision you should take into account 
the wishes of the participant. If you agree to allow the participant to take part in this research, the 
participant will also be asked to give consent if the ability to make healthcare decisions is 
regained. 
Introduction
You are being asked to join a research study. The purpose of a research study is to answer 
specific questions, sometimes about the safety of a drug or device and how well it works. Being 
in a research study is different from being a patient. When you are a patient, you and your doctor 
have freedom in making decisions about your healthcare. When you are in a research study, the 
researcher will follow the rules of the research study as closely as possible, while monitoring 
your health.
You do not have to be in this study to receive medical care. You should ask questions before you 
decide if you want to participate. You can also ask questions at any time during the study.
Why is this research study being done?
The purpose of this research is to compare two different dosing mechanisms of Heparin 
(LMWH), a medication commonly used to treat and prevent blood clots, to find out if they are 
effective against COVID-19.
Heparin (LMWH, brand name: Enoxaparin) is drug that has already been approved by the Food 
and Drug Administration (FDA) for preventing blood clots in patients. However, the higher-than 
usual treatment dose (full dose) has not been studied in preventing blood clots, in terms of safety 
and effectiveness, specifically in COVID patients.  In this study, the researchers are testing 
 
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whether the treatment dose (full dose) of Heparin (LMWH) or the usual low (preventative) dose 
is more effective in preventing blood clots in hospitalized COVID patients. 
You are being asked to participate in this study because you have been diagnosed with COVID-
19 and are being admitted to the hospital for treatment.
How many people will take part in this study?  
This research study hopes to enroll a total of 308 study participants and approximately 200 study 
participants will be recruited across multiple sites within the Northwell Health System and the 
remaining 108 subjects will be recruited at external sites. 
How long will you be in this study? 
If you choose to take part in this study, the study procedures will last for the entire time you are 
admitted to the hospital, which will be a minimum of 72 hours, and you will be followed for 30 
days after study entry. If you leave the hospital prior to the 30 day time point, you will have a 
follow-up via telephone or in-person.
What will happen in this research study?
In this study you will be randomized to one of two different treatment groups after giving 
informed consent and within 72 hours of initial (index) hospitalization. This means that you will 
be assigned to a group by chance (like flipping a coin). You will have an equal chance of being 
in either group. Both study groups will receive treatment. The study is done this way because 
knowing which treatment group you are assigned to can change the results of the study. We will 
not tell you which group you are in to prevent study bias. However at any point we can quickly 
find out which group you are in if we ever need to know for your safety. The different treatment 
groups are as following:
1) Patients will receive the standard of care plus open label therapeutic dose Heparin (LMWH) 
2) Patients will receive the standard of care plus Prophylactic (preventive) or Intermediate dose 
Heparin (LMWH)
No other anticoagulation medicines except Heparin (LMWH) will be permitted for the duration 
of your hospital stay. You will receive study medication throughout your hospitalization until the 
time of hospital discharge.
In addition to the standard current treatment for COVID-19, you will undergo a imaging scan of 
your lower body (legs, thighs, etc.) at Hospital Day 10+4 or sooner at the time of hospital discharge 
using standardized screening methods. After hospital discharge you will continue a low dose blood 
thinner (either propylactic dose  LMWH or an oral agent rivaroxaban) for up to 39 days as per 
standard of care.
You will stay in the hospital for as long as is needed to treat you. All other procedures will be
done as part of the current standard of care for COVID-19 and may include having your blood
drawn.. We will collect the results of those and any other tests done and record them for this 
study.
 
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Birth Control
The drugs in this study may affect a baby, before or after the baby is born. As a result, women 
should not be in this study if they are:

pregnant, 

breast-feeding, or

trying to become pregnant.
If you are a woman of childbearing age, you should use birth control for the entire time you are 
in the study. Your doctor will discuss these with you.
What are the risks of the research study? What could go wrong?
Heparin (LMWH) is a drug commonly used to treat and prevent blood clots. It is possible that 
Heparin (LMWH) may cause bleeding including bleeding gums, nosebleeds, prolonged bleeding 
from cuts, anemia,  diarrhea, nausea, fever, edema, leg swelling, difficulty breathing, confusion 
and injection site pain. In some cases there have been reports of spinal/epidural hematomas 
(accumulation of blood around the spinal cord) in patients receiving anesthesia around the spine 
or spinal cord, or undergoing spinal puncture. Heparin (LMWH) has been reported to cause 
warmth or bluish-colored skin in some patients. Lastly, there is an unlikely risk of serious 
allergic reaction while taking Heparin (LMWH).
Thus, as with any drug there might be side effects that are unknown at this time. You will be 
closely watched for side effects. You should report any unusual events to the study staff.
Because you are being randomized to a study group, your group may receive less effective 
treatment or have more side effects than the other group. We do not know if one group is more 
effective than the other.
With any research study that collects personal information, there is a small risk of loss of 
confidentiality.
Blood-Draw 
There are no major risks of having blood drawn.  It can be uncomfortable and can sometimes 
cause a bruise.  In rare cases, it can cause fainting.  Only trained staff will draw your blood.  
What are the benefits of this research study?
If the medication being studied is effective against COVID-19, participation in this research 
study may benefit you directly. It is possible that your study group might receive more effective 
treatment and/or have fewer side effects than the other treatment groups. Information learned in 
this study may help us to treat future patients.
If you do not want to take part in this research study, what are your other choices?
If you do not join this study, you have other choices for treatment. Talk to your doctor about 
your choices.  Your other choices may include:

Another research treatment

Standard treatment
 
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
No treatment

Comfort care

Heparin (LMWH) without participating in this study. 
Your doctor can also tell you the important risks and benefits associated with the alternative 
treatment.
Are there any costs for being in this research study? 
You will not have any added costs from being in this study. The study medication will be
provided to you at no cost. All other costs are part of the standard of care and will be billed to 
you and your insurance company in the usual way, as part of your standard care.
Will you receive any payments for participating in this research study?
You will not be compensated for participation in this research study.
What happens if you are injured while participating in this study?
If you are hurt from being in the study, you will receive medical care and treatment as needed 
from Northwell Health. However, you will be responsible for the costs of such medical 
treatment, directly or through your medical insurance or other forms of medical coverage. No 
money will be given to you.
What are your rights as a research participant?
Your participation in this project is voluntary. The quality of your medical care will be the same, 
whether you join, refuse to join, or decide to leave the study.
If you do not join the study you will not be penalized or lose benefits to which you are entitled. If 
you join the study you may withdraw at any time without prejudice to your future care at 
Northwell Health. Follow-up examinations may be needed to assure your well-being.  
Could you be taken off the study before it is over?
It is also possible that your participation in this study may end without your consent.  This 
decision may be made by a researcher, study sponsor or the Institutional Review Board (IRB- the 
committee that oversees research at this institution).   
Reasons for withdrawal may include:  

failure to follow instructions, 

failure to show up for study visits, 

it is not in your best interest to continue on this study, or 

the study is stopped.  
If you withdraw from this study or if you are withdrawn from the study, any data (or samples) 
already collected will continue to be used.  However, no new data will be collected.  
What happens if new information is learned?
 
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You will be told of any new findings that may change your decision to continue to participate. 
Your consent to continue to take part in this study may be obtained again.  
What information will be collected and used for this study?
If you agree to be in this study, we will collect health information that identifies you. We may 
collect the results of lab tests and medical examinations done while you are in the hospital. We 
will also collect one extra tube of blood (e.g. approx. 1-2 tablespoons) during routine blood 
draws while you are hospitalized. These samples will be stored for this research study, but will 
not identify you. We may also collect information from your medical record. We will only 
collect information that is needed for the research. This information has been described in this 
consent form. If you sign this consent form, you are giving us permission to collect, use and 
share your health information. This permission is called authorization. If you do not want to 
provide authorization, then you cannot participate in this research study.
Who else will see your information? 
Study records that identify you will be kept private. You will not be identified in study records or 
publications disclosed outside Northwell Health, except as detailed below. 
Investigators will share information collected from this research study with:

other researchers,

accrediting agencies,

data safety monitoring board,

clinical staff not involved in the study who may be involved in participant's treatment,

health insurers or payers
The following reviewers may access your study and medical records to make sure that this study 
is being done properly: 

Representatives from Federal and state government oversight agencies, such as the Food 
and Drug Administration (FDA)

Representatives from Northwell Health’s Human Research Protection Program (a group 
of people that oversee research at this institution)
We will do our best to protect the privacy of your records but it is possible that once information 
is shared with people listed on this form, it may be released to others. If this happens, your 
information may no longer be protected by the federal law.
In the future, we may publish results of this study in scientific journals and may present it at 
scientific meetings. If we do we will not identify you. 
If the researchers learn about potential serious harm to you or someone else or other public 
health concerns, it will be shared with the appropriate authorities.
Will you be able to access your records?
If your research records are used for decisions related to your clinical care, then you have the 
right to review this information and request changes. This is limited to information about your 
 
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treatment, and does not include information related to procedures or tests that are for research 
purposes only. You may access this information only after the study analysis is complete. You 
have the right to know who has and who will see your records. To request this information, 
please call the Human Research Protection Program at 516-465-1910.
How long will your health information be kept? 
There is no limit on the length of time we will keep your information for this research because it 
may be analyzed for many years. We will keep it as long as it is useful, unless you decide you no 
longer want to take part or we close the study.  You are allowing access to this information 
indefinitely.  
Can you change your mind?
If you change your mind about being in the study, you may withdraw at any time. If you want us 
to stop collecting your health information, you need to send a letter to the researcher at the 
following address:
Dr. Alex C. Spyropoulos, MD, FACP, FCCP, FRCPC
600 Community Drive, Suite 403
Manhasset, NY 11030
Your letter needs to say that you have changed your mind and do not want the researcher to 
collect and share your health information. You may also need to leave the research study if we 
cannot collect any more health information. We may still use the information we have already 
collected. We need to know what happens to everyone who starts a research study, not just those 
people who stay in it.
Will information about this study be available to the public?
A description of this clinical trial will be available on http://www.ClinicalTrials.gov , as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this website at any time.
Will my information be used for research in the future? 
Information or specimens collected from you for this research may be used for future research 
studies or shared with other researchers for future research.  If this happens, information which 
could identify you will be removed before any information or specimens are shared.  Since 
identifying information will be removed, there will not be an additional consent for future 
research.  By consenting to participate in this study you are agreeing to allow your de-identified 
specimens and/or data to be used by future researchers without additional consent.
Does the investigator of this study receive money if you take part?  
The investigators on this study do not receive money for your participation in this study.
Who can answer your questions about this study?
If you have any questions about the study, you may call Dr. Alex C. Spyropoulos at (212) 434-
6776. If you have questions about side effects or injury caused by research you should call Dr. 
Alex C. Spyropoulos at (212) 434-6776. If you need emergency care, dial 911 or go to the 
 
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IRB #: 20-0340
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nearest Emergency Room. If you have questions about your rights as a research participant, 
concerns about being in the study, or would like to offer input, you may contact the Office of the 
Institutional Review Board (the committee that oversees research at this institution) at (516) 465-
1910. 
A signed copy of this consent form will be given to you.
[Signature Page Follows]
 
 IRB APPROVED
December 03, 2020


Version Date: 12/3/2020
IRB #: 20-0340
Page 9 of 9
Summation/Signature
You have read the above description of the research study. You have been told of the risks and 
benefits involved and all your questions have been answered to your satisfaction. A member of 
the research team will answer any future questions you may have. You voluntarily agree to join 
this study and know that you can withdraw from the study at any time without penalty. By 
signing this form, you have not given up any of your legal rights.
___________________________________________________             __________________
Signature of Participant/Healthcare Agent/Guardian/Next of Kin
         Date
 
____________________________________________________________
Printed Name of Participant /Healthcare Agent/Guardian/Next of Kin 
Impartial Witness Signature Section (if applicable)
_______________________________________________                     __________________
Signature of Impartial Witness  
                                                                    Date
____________________________________________________________
Printed Name of Impartial Witness
 
Investigator’s Statement 
In addition to advising the above participant of other forms of treatment and therapy which are 
appropriate, I have offered an opportunity for further explanation of the risks and discomforts 
which are, or may be associated with this study and to answer any further questions relating to it.
_________________________________________                                     __________________
Investigator’s signature                                                                                            Date 
 
__________________________________________________
Investigator’s printed name                                             
 
 IRB APPROVED
December 03, 2020