Clinical trial NCT04362085
Conditions: COVID-19
Keywords: coagulopathy anticoagulation
Sponsor: Unity Health Toronto
Start date: 2020-05-11; Completion date: 2021-10-14
Enrollment: 465 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Coagulopathy of COVID-19 afflicts approximately 20% of patients with severe COVID-19 and is associated with need for critical care and death. COVID-19 coagulopathy is characterized by elevated D-dimer, an indicator of fibrin formation and clot lysis, and a mildly prolonged prothrombin time, suggestive of coagulation consumption. To date, it seems that COVID-19 coagulopathy manifests with thromboembolism, thus anticoagulation may be of benefit. We propose to conduct a parallel pragmatic multi-centre open-label randomized controlled trial to determine the effect of therapeutic anticoagulation compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer.

Detailed description:
2-arm, parallel, pragmatic, multi-centre, open-label randomized controlled trial to determine the effect of therapeutic anticoagulation, with low molecular weight heparin or unfractionated heparin (high dose nomogram), compared to standard care in hospitalized patients with COVID-19 and an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Eligible participants will be randomized to one of two treatment regimens, receiving either therapeutic anticoagulation or standard care until discharged from hospital, death or day 28.

The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation, or all-cause death up to 28 days.

Key secondary outcomes between study arms up to day 28 include:

1. All-cause death
2. Composite outcome of ICU admission or all-cause death
3. Composite outcome of mechanical ventilation or all-cause death
4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation
5. Number of participants who received red blood cell transfusion (≥1 unit)
6. Number of participants with transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate
7. Renal replacement therapy;
8. Number of hospital-free days alive
9. Number of ICU-free days alive
10. Number of ventilator-free days alive
11. Number of organ support-free days alive
12. Number of participants with venous thromboembolism
13. Number of participants with arterial thromboembolism
14. Number of participants with heparin induced thrombocytopenia
15. Changes in D-dimer up to day 3

The treatment arm is therapeutic anticoagulation with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram). The choice of LMWH versus UFH will be at the clinician's discretion. LMWH options include: Tinzaparin, Enoxaparin, or Dalteparin. UFH will be administered using a weight-based nomogram with titration according to the center-specific protocol. Therapeutic anticoagulation will be administered until discharged from hospital, 28 days or death. If the patient is admitted to the ICU or requiring ventilatory support, we recommend continuation of the allocated treatment as long as the treating physician is in agreement. The standard care arm is the administration of LMWH, UFH or fondaparinux at thromboprophylactic doses in the absence of contraindication.

No study specific bloodwork will be ordered aside from a single D-dimer test (if not collected through standard of care) up to and including day 3 after randomization for all participants in both study arms. In those on the active treatment arm who are receiving UFH, the aPTT or UFH anti-Xa will be drawn according to local institutional UFH nomogram protocol guidance. All laboratory results will be collected from standard of care from admission to hospital discharge, death or 28 days, where available. An optional biobanking component will collect blood at baseline and 2 follow up time points.

This study will immediately impact the clinical care of patients with severe COVID-19 internationally, whether the findings are positive or negative, as COVID-19 coagulopathy is a highly prevalent complication of severe COVID-19 and may precede the respiratory manifestations that characterize it.

Arms: arm 1: Therapeutic anticoagulation with LMWH or UFH (high dose nomogram). The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. Therapeutic anticoagulation will be administered until discharged from hospital, 28 days or death. If the patient is admitted to the ICU or requiring ventilatory support, we recommend continuation of the allocated treatment as long as the treating physician is in agreement. arm 2: Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is considered standard care.
Interventions: intervention 1: Therapeutic Anticoagulation
Intervention descriptions: intervention 1: The choice of low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) will be at the clinician's discretion. LMWH options include: Tinzaparin, Enoxaparin or Dalteparin. UFH will be administered using a weight-based nomogram with titration according to center-specific institutional protocol.

Protocol documents:
Prot_000.pdf: 
 
1 
Version 1.3 – 13 Oct 2020 
Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of 
Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the 
COVID-19 Pandemic (RAPID COVID COAG) 
Co-Principal Investigators:  
Dr. Michelle Sholzberg, St. Michael’s Hospital, Li Ka Shing Knowledge Institute, University of Toronto  
Dr. Peter Jüni, St. Michael’s Hospital, Li Ka Shing Knowledge Institute, University of Toronto  
Dr. Mary Cushman, University of Vermont Medical Center 
 
Steering Commitee: 
Dr. Musaad Alhamzah, King Saud University Medical City, King Saud University 
Dr. Lisa Baumann Kreuziger, Versiti, Medical College of Wisconsin  
Dr. Andrew Beckett, St. Michael’s Hospital, University of Toronto 
Dr. Marc Carrier, The Ottawa Hospital, University of Ottawa 
Dr. Bruno da Costa, St. Michael’s Hospital, Applied Health Research Centre (AHRC), Li Ka Shing 
Knowledge Institute, University of Toronto 
Dr. Mike Fralick, Mount Sinai Hospital, University of Toronto 
Dr. Paula James, Kingston General Hospital, Queen’s University 
Dr. Agnes Lee, Vancouver General Hospital, University of British Columbia  
Dr. David Lillicrap, Kingston General Hospital, Queen’s University 
Dr. Saskia Middeldorp, Amsterdam UMC, University of Amsterdam, The Netherlands. 
Dr. Fionnuala Ní Áinle, Mater Misericordiae University Hospital,University College Dublin, Ireland 
Dr. Elnara Negri, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo 
Ms. Grace Tang, St. Michael’s Hospital, University of Toronto  
Dr. Kevin E. Thorpe, St. Michael’s Hospital, Applied Health Research Centre (AHRC), Li Ka Shing 
Knowledge Institute, University of Toronto 
 
Study Summary 
Coagulopathy of COVID-19 afflicts approximately 20% of patients with severe COVID-19 and is 
associated with need for critical care and death. COVID-19 coagulopathy is characterized by elevated D-
dimer, an indicator of fibrin formation and clot lysis, and a mildly prolonged prothrombin time, 
suggestive of coagulation consumption. To date, it seems that COVID-19 coagulopathy manifests with 
thromboembolism, thus anticoagulation may be of benefit. We propose to conduct a parallel pragmatic 
multi-centre open-label randomized controlled trial to determine the effect of therapeutic 
anticoagulation compared to standard care in hospitalized patients admitted for COVID-19 with an 
elevated D-dimer. 
 
Current Protocol Version:    Version 1.4 – 13 Oct 2020 
 
Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04362085  
 
Sponsor: 
Unity Health Toronto – St. Michael’s Hospital 


 
Version 1.4 – 13 Oct 2020 
2
30 Bond St, Toronto, ON M5B 1W8 
Canada 
GCP Statement 
 
This study document is the protocol for research involving human participants.  This study is to be 
conducted according to Canadian and international standards, and in compliance with the protocol, 
International Conference on Harmonisation Good Clinical Practice E6 (ICH-GCP), World Medical 
Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Participants, 
and all applicable regulatory and institutional requirements and research policies. 
 
Confidentiality Statement 
This clinical study protocol contains information which is of a confidential, trade-secret or proprietary 
nature. The protocol is for the use of Sponsor-Investigators and their designated representatives 
participating in the investigational trial. It is not to be disclosed to any other person or party without the 
prior written approval of Sponsor-Investigator. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version 1.4 – 13 Oct 2020 
3
 
Table of Contents 
Protocol Synopsis ................................................................................................................... 5 
1.0 Background ..................................................................................................................... 8 
2.0 Objectives ........................................................................................................................ 9 
3.0 Study Design .................................................................................................................. 10 
4.0 Study Population ............................................................................................................ 11 
4.1 Informed Consent Process....................................................................................................... 12 
4.2 Treatment Allocation .............................................................................................................. 12 
5.0 Description of Treatment vs. Standard Care .................................................................... 12 
5.1 Therapeutic Anticoagulation ................................................................................................... 12 
Table 1. Therapeutic Dose Anticoagulation .......................................................................... 13 
Table 2. Investigational Products Rationale for Inclusion ...................................................... 14 
5.2 Standard Care ......................................................................................................................... 15 
Table 3. Standard care (low dose, prophylactic) anticoagulation .......................................... 16 
Table 4. Formulations of Investigational Products and Standard Care ................................... 17 
6.0 Study Procedures and Evaluations .................................................................................. 19 
6.1 Bloodwork .............................................................................................................................. 19 
6.2 Optional Biobanking ............................................................................................................... 19 
6.3 Endpoint Assessment .............................................................................................................. 20 
6.4 Duration of the study .............................................................................................................. 21 
7.0 Statistical Plan ............................................................................................................... 21 
7.1 Sample Size Calculation........................................................................................................... 21 
7.2 Statistical Analysis .................................................................................................................. 21 
7.3 Interim Analysis ...................................................................................................................... 22 
8.0 Safety and Adverse Events ............................................................................................. 22 
8.1 Definitions .............................................................................................................................. 24 
8.2 Reporting of Serious Adverse Events ....................................................................................... 26 
8.3 Monitoring of AEs/SAEs .......................................................................................................... 27 
8.4 Treatment Discontinuation ..................................................................................................... 27 


 
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8.5 Premature Study Withdrawal of an Individual Participant ........................................................ 28 
8.6 Protocol Violations/Deviations................................................................................................ 28 
9.0 Data Handling and Record Keeping ................................................................................ 28 
9.1 Data Management Responsibilities ......................................................................................... 28 
9.2 Confidentiality ........................................................................................................................ 29 
9.3 Record Retention .................................................................................................................... 30 
10.0 Quality Control and Quality Assurance ......................................................................... 30 
10.1 Study Monitoring Plan .......................................................................................................... 30 
10.2 Role of the Data Safety Monitoring Board ............................................................................. 30 
10.3 Ethics and Research Governance: .......................................................................................... 31 
10.4 Feasibility ............................................................................................................................. 31 
10.5 Study Product Supply and Accountability............................................................................... 32 
11.0 Study Significance ........................................................................................................ 32 
12.0 Disclosure and Publication Policy .................................................................................. 32 
12.1 Publication of Study Results .................................................................................................. 32 
12.2 Data Sharing for Secondary Research .................................................................................... 33 
12.3 Conflict of interest ................................................................................................................ 33 
Table 5. Study Schedule of Events......................................................................................... 34 
13.0 References ................................................................................................................... 37 
Appendix 1. Racial and Ethnic Categories and Definitions ..................................................... 39 
Appendix 2. Requirement for prohibited concomitant medications in the therapeutic 
anticoagulation (experimental arm)..................................................................................... 40 
Appendix 3. Fraction of Inspired Oxygen (FiO2) for Various Oxygen Delivery Devices ............ 41 
Appendix 4. Outcome Definition for Organ-support Free Days .............................................. 43 
 
 


 
5 
Version 1.3 – 13 Oct 2020 
Protocol Synopsis 
Full Title 
Coagulopathy of COVID-19: A Pragmatic Randomized 
Controlled Trial of Therapeutic Anticoagulation versus 
Standard Care as a Rapid Response to the COVID-19 
Pandemic 
Short Title 
RAPID COVID COAG 
Version Number and Date 
Version 1.4, 13 Oct 2020  
Clinical Phase 
III 
Study Duration 
Enrollment period: April 24, 2020 to March 10, 2022 
Study period: April 24, 2020 to April 24, 2022 
Co-Principal Investigators 
Dr. Michelle Sholzberg, Dr. Peter Jüni and Dr. Mary Cushman 
Study Design 
Open-label, parallel, 2-arm randomized controlled trial  
Primary Objective 
To determine the effect of therapeutic anticoagulation, with 
low molecular weight heparin or unfractionated heparin (high 
dose nomogram), compared to standard care in hospitalized 
patients admitted for COVID-19 with an elevated D-dimer  on 
the composite outcome of intensive care unit (ICU) admission, 
non-invasive positive pressure ventilation, invasive 
mechanical ventilation or death at 28 days.  
Secondary Objectives 
To compare the following secondary outcomes between study 
arms up to day 28: 
1. All-cause death; 
2. Composite of ICU admission or all-cause death; 
3. Composite of mechanical ventilation or all-cause 
death;  
4. Major bleeding as defined by the ISTH Scientific and 
Standardization Committee (ISTH-SSC) 
recommendation;  
5. Red blood cell transfusion (>1 unit);  
6. Transfusion of platelets, frozen plasma, prothrombin 
complex concentrate, cryoprecipitate and/or 
fibrinogen concentrate; 
7. Renal replacement therapy; 
8. Hospital-free days alive; 
9. ICU-free days alive; 
10. Ventilator-free days alive; 


 
Version 1.4 – 13 Oct 2020 
6
11. Organ support-free days alive;  
12. Venous thromboembolism (defined as symptomatic 
or incidental, suspected or confirmed via diagnostic 
imaging and/or electrocardiogram where 
appropriate); 
13. Arterial thromboembolism (defined as suspected or 
confirmed via diagnostic imaging and/or 
electrocardiogram where appropriate); 
14. Heparin induced thrombocytopenia;  
15. Trajectories of COVID-19 disease-related biomarkers. 
Sample Size 
462 patients (231 per group). 
Randomization 
1:1 randomization, centralized web-based randomization.  
Study Population  
The study population includes hospitalized adults admitted for 
COVID-19 prior to the development of critical illness. We have 
excluded individuals where the bleeding risk or risk of 
transfusion would generally be considered unacceptable, 
those already therapeutically anticoagulated and those who 
would have already met components of our primary outcome. 
Investigational Product Description 
Therapeutic dose low molecular weight heparin (Dalteparin, 
Enoxaparin, Tinzaparin) or high dose nomogram of 
unfractionated heparin.  
Control 
Standard care (thromboprophylactic doses of low molecular 
weight heparin (Dalteparin, Enoxaparin, Tinzaparin, 
Fondaparinux) or unfractionated heparin.  
Duration of Treatment 
Therapeutic anticoagulation will be administered  until 
discharged from hospital, 28 days or death. If the patient is 
admitted to the ICU or requiring ventilatory support, we 
recommend continuation of the allocated treatment as long 
as the treating physician is in agreement. 
Outcome Measures 
Primary: composite outcome of intensive care unit (ICU) 
admission, non-invasive positive pressure ventilation, invasive 
mechanical ventilation or death at 28 days. 
Secondary (evaluated up to day 28):  
1. All-cause death 
2. Composite of ICU admission or all-cause death 
3. Composite of mechanical ventilation or all-cause 
death  


 
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4. Major bleeding as defined by the ISTH Scientific and 
Standardization Committee (ISTH-SSC) 
recommendation;  
5. Red blood cell transfusion (>1 unit);  
6. Transfusion of platelets, frozen plasma, prothrombin 
complex concentrate, cryoprecipitate and/or 
fibrinogen concentrate; 
7. Renal replacement therapy; 
8. Hospital-free days alive; 
9. ICU-free days alive; 
10. Ventilator-free days alive; 
11. Organ support-free days alive;  
12. Venous thromboembolism (defined as symptomatic 
or incidental, suspected or confirmed via diagnostic 
imaging and/or electrocardiogram where 
appropriate); 
13. Arterial thromboembolism (defined as suspected or 
confirmed via diagnostic imaging and/or 
electrocardiogram where appropriate); 
14. Heparin induced thrombocytopenia;  
15. Trajectories of COVID-19 disease-related biomarkers. 
Statistical Analysis 
Primary analyses will be by in the intention-to-treat 
population of all randomized patients in accordance with the 
originally allocated intervention. We will conduct a chi-square 
test for the main analysis of the primary outcome and use a 
generalized linear regression model with binary distribution 
and identity link to derive risk difference with 95% confidence 
intervals. 
 


 
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Version 1.3 – 13 Oct 2020 
1.0 Background 
Coagulopathy of COVID-19 appears to afflict approximately 20% of patients with severe COVID-19 and is 
associated with need for critical care and death (1–3). COVID-19 coagulopathy is characterized by 
elevated D-dimer, an indicator of fibrin formation and clot lysis, and a mildly prolonged prothrombin 
time (PT), suggestive of coagulation consumption (2–6). In the largest study to date, Guan et al. 
described 560 patients with COVID-19 where D-dimer was measured and was elevated D-dimer (>0.5 
mg/L) in 60% of those with severe illness (1,4). In fact, Zhou et al. noted that a D-dimer concentration 
greater than 1 µg/mL was associated with mortality in 191 patients with COVID-19 (odds ratio [OR] 
18.42, 95%CI: 2.64-128.55, p =0.0033) (5).  In a study by Tang et al., where they specifically examined 
laboratory coagulation parameters in 183 patients, they found that non-survivors of COVID-19 had a D-
dimer of 2.12µg/mL (range: 0.77-5.27µg/mL) compared to survivors with 0.61µg/mL (range: 0.61-1.29 
µg/mL) (3). Low fibrinogen has been more rarely described with severe COVID-19 and seems to occur 
later in the course of hospitalization (3). Interestingly, thrombocytopenia, typically associated with 
sepsis mortality, is not a consistent manifestation of COVID-19 coagulopathy and does not appear to 
correlate with severity of illness. In fact, very few patients have clinically relevant thrombocytopenia (i.e. 
a platelet count below 50 x 109/L) (6,7).   
In the published literature thus far, it seems that COVID-19 coagulopathy may manifest with thrombosis 
of the pulmonary microvasculature with secondary pulmonary hemorrhagic infarction and necrosis(2,8). 
Moreover, there are numerous animal models of acute lung injury describing the benefit of 
anticoagulation (9,10). Tang et al. found that in patients with severe COVID-19 and laboratory evidence 
of early disseminated intravascular coagulation (DIC), using the sepsis-induced coagulopathy (SIC) score, 
had a lower risk of death when treated with low molecular weight heparin (LMWH) or unfractionated 
heparin (UFH) at thromboprophylactic doses for 7 days or longer (2). In fact, the authors found that 28-
day mortality of heparin users were lower than non-users in patients with SIC scores  > 4 (40.0% vs. 
64.2%, p= 0.029), or D-dimer > 6 times the upper limit of normal (ULN) (32.8% vs. 52.4%, p=0.017)(2). 
However, this study was limited by its retrospective nature and did not account for other treatments 
that were provided. Moreover, a recent study by Klok et al. of 184 critically ill patients with COVID-19, 
reported a 31% incidence of arterial and venous thromboembolism despite pharmacological 
thromboprophylaxis (11). To the best of our knowledge, there have been very few published reports of 
clinically significant hemorrhage as a clinical manifestation of COVID-19 coagulopathy (12). Thus, 
anticoagulation with heparin-based therapy, whether unfractionated or low molecular weight 
(Dalteparin, Enoxaparin, Tinzaparin), for severe COVID-19 may theoretically be of benefit (9,10). 
Currently, our group is conducting a systematic review and meta-analysis to describe hemostatic 
parameters and relevant clinical outcomes (e.g. thromboembolism, bleeding, death) among patients 
with COVID-19 (PROSPERO: (13)). To date, there are 62 full-text articles that have met our inclusion 
criteria and data extraction is ongoing.  
COVID-19 coagulopathy is such an increasingly recognized manifestation of severe illness, that the 
International Society on Thrombosis and Haemostasis (ISTH) recently published a guidance document on 
its management despite the current paucity of evidence (4). In addition, anticoagulation for patients 
with severe COVID-19 has been recommended by a Chinese expert consensus statement, however 
without proper evidence to support its efficacy (14). Moreover, there is evidence that D-dimer levels 
and markers of inflammation vary at baseline according to race/ethnicity with more adverse levels in 
Hispanic and especially African-American persons (15,16). This, combined with the observation that 
individuals of minority groups are more likely to experience severe and fatal COVID-19 highlights the 
need to evaluate whether the effect of anticoagulation, and COVID-19 coagulopathy biomarkers differ 
by race/ethnicity.      


 
Version 1.4 – 13 Oct 2020 
9
We believe that the current knowledge of COVID-19 coagulopathy provides rationale for a pragmatic 
randomized controlled trial (RCT) to evaluate the effectiveness of therapeutic anticoagulation with 
LMWH or UFH (high dose nomogram) in patients with severe COVID-19 and an elevated D-dimer 
compared to standard care, which typically includes LMWH or UFH at thromboprophylactic doses.  
 
2.0 Objectives  
Primary objective:  
To determine the effect of therapeutic anticoagulation, with LMWH or UFH (high dose nomogram), 
compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer  on 
the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure 
ventilation, invasive mechanical ventilation or death at 28 days.  
Secondary objectives:  
To determine the effect of therapeutic anticoagulation, with LMWH or UFH (high dose nomogram), 
compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer, up 
to day 28, on: 
1. All-cause death; 
2. Composite of ICU admission or all-cause death; 
3. Composite of mechanical ventilation or all-cause death; 
4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) 
recommendation;  
5. Red blood cell transfusion (>1 unit);  
6. Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate 
and/or fibrinogen concentrate; 
7. Renal replacement therapy defined as continuous renal replacement therapy {CRRT} or 
intermittent hemodialysis {IHD}; 
8. Hospital-free days alive; 
9. ICU-free days alive; 
10. Ventilator-free days alive; 
11. Organ support-free days alive (see Appendix 4 for definition);  
12. Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed 
via diagnostic imaging and/or electrocardiogram where appropriate recognizing that access 
to diagnostic imaging may be limited in the midst of the COVID-19 pandemic. Confirmatory 
testing at a later date once exposure risk/personal protective utilization is not an issue is 
encouraged); 
13. Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or 
electrocardiogram where appropriate recognizing that access to diagnostic imaging may be 
limited in the midst of the COVID-19 pandemic. Confirmatory testing at a later date once 
exposure risk/personal protective utilization is not an issue is encouraged); 
14. Heparin induced thrombocytopenia;  
15. Trajectories of COVID-19 disease-related biomarkers. 
 
Tertiary Objective 
16. To explore whether the above outcomes differ by age, sex, diabetes mellitus, coronary 
artery disease, hypertension, race/ethnicity, D-dimer levels and hypoxia. 


 
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10
The use of BIPAP or CPAP at night or when sleeping for sleep apnea is not considered non-invasive 
mechanical ventilation or organ support for the purpose of this trial.  
3.0 Study Design 
We propose to conduct a 2-arm, parallel, pragmatic, multi-centre, open-label randomized controlled 
trial to determine the effect of therapeutic anticoagulation on the composite outcome of ICU admission, 
invasive mechanical ventilation or death in hospitalized patients admitted for COVID-19. Eligible 
participants will be randomized to one of two treatment regimens, receiving either therapeutic 
anticoagulation or standard care until discharged from hospital, death or day 28. If the patient is 
admitted to the ICU or requiring ventilatory support, we recommend continuation of the allocated 
treatment as long as the treating physician is in agreement. Randomization will be stratified by site and 
age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable 
block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital 
admission. However, it is recommended that randomization occurs as early as possible after hospital 
admission.  Central randomization using an interactive web response system will ensure allocation 
concealment. This is an open label study. Blinding of participants, clinical research staff, and clinicians is 
not possible due to the nature of the intervention. However, the biostatisticians will be blinded at the 
data analysis phase. Given the objective nature of the primary outcome and the need for pragmatic 
approaches for this rapid response trial, an independent, blind clinical events committee is not planned 
(17). See Figure 1 for study schematic.  
   
 
Figure 1. RAPID COVID-COAG Study Schematic  
1Administer until hospital discharge, death or day 28, if the patient is admitted to the ICU or requiring 
ventilatory support, we recommend continuation of the allocated treatment as long as the treating physician 
is in agreement;  
2For participants treated with UFH: aPTT or UFH anti-Xa will be drawn according to local institutional UFH 
nomogram protocol guidance; 
3a single D-dimer test (if not collected through standard of care) on day 2 after randomization (+/- 24 hours) 
will be collected for participants in both study arms (considering the day of randomization as day 1). 
4All laboratory results, when available, will be collected from standard of care from admission to hospital 
discharge, death or 28 days from patient chart  


 
Version 1.4 – 13 Oct 2020 
11
 
4.0 Study Population 
The study population includes hospitalized adults admitted for COVID-19 prior to the development of 
critical illness. We have excluded individuals where the bleeding risk or risk of transfusion would 
generally be considered unacceptable, those already therapeutically anticoagulated and those who 
would have already met components of our primary outcome. Participants are recruited from hospital 
sites in Argentina, Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of 
America. 
 
The inclusion criteria are:  
1) Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase 
chain reaction as per the World Health Organization protocol or by nucleic acid based 
isothermal amplification). Positive test prior to hospital admission OR within first 5 days (i.e. 120 
hours) after hospital admission;  
2) Admitted to hospital for COVID-19;  
3) One D-dimer value above ULN (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER:  
a. D-Dimer ≥2 times ULN OR  
b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; 
4) > 18 years of age;  
5) Informed consent from the patient (or legally authorized substitute decision maker).  
 
The exclusion criteria are:  
1) pregnancy;  
2) hemoglobin <80 g/L in the last 72 hours; 
3) platelet count <50 x 109/L in the last 72 hours;  
4) known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior 
to the initiation of anticoagulation);  
5) known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the 
initiation of anticoagulation);  
6) patient already on intermediate dosing of LMWH that cannot be changed (determination of 
what constitutes an intermediate dose is to be at the discretion of the treating clinician taking 
the local institutional thromboprophylaxis protocol for high risk patients into consideration);  
7) patient already on therapeutic anticoagulation at the time of screening (low or high dose 
nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, 
rivaroxaban, edoxaban); 
8) patient on dual antiplatelet therapy, when one of the agents cannot be stopped safely; 
9) known bleeding within the last 30 days requiring emergency room presentation or 
hospitalization;  
10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder;  
11) known history of heparin-induced thrombocytopenia;  
12) known allergy to UFH or LMWH;  
13) admitted to the intensive care unit at the time of screening; 
14)  treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the 
time of screening (of note: high flow oxygen delivery via nasal cannula is acceptable and is not 
an exclusion criterion); 
15) Imminent death according to the judgement of the most responsible physician;  


 
Version 1.4 – 13 Oct 2020 
12
16) enrollment in another clinical trial of antithrombotic therapy involving pre-intensive care unit 
hospitalized patients. 
4.1 Informed Consent Process 
Potential eligible patients will be confirmed with both the most responsible physician (MRP) and the site 
investigator within the first 5 days (i.e. 120 hours) of hospital admission. Eligible patients will be 
consented by a research coordinator or health care worker (other than the MRP) within the first 5 days 
(i.e. 120 hours) of hospital admission using remote methods (such as telephone consent or eConsent) to 
obtain verbal or written consent to minimize the risk of COVID-19 exposure, conserve the use of 
personal protective equipment and prevent COVID-19 research document contamination. Informed 
consent is to be obtained directly from the patient or from their legally authorized substitute decision 
maker (applies to initial consent and ongoing consent, should the participant lose capacity during the 
trial). Capacity will be assessed  by the circle of care. Also, where possible, to minimize the burden to the 
patient, patients may be consented to more than one COVID-19-related clinical trial at a time.  
 
We will follow Health Canada’s Management of clinical trials during the COVID-19 pandemic: Notice to 
Clinical Trial Sponsors. 
4.2 Treatment Allocation 
PI/Co-I will determine eligibility prior to notifying the research coordinator by phone and email to begin 
randomization process. Central randomization will occur using an interactive web response system. This 
is an open label study thus once a participant is randomized, a research coordinator will document the 
treatment allocation in the case report form and notify the MRP and study team by email and phone of 
the patient’s study treatment allocation (therapeutic or standard care arm). The MRP will then order the 
study drug in the patient’s medical chart and notify the study team. The research coordinator will then 
email or fax research pharmacy the order.  Research pharmacy will follow their SOP to dispense study 
drug and study drug will be dispensed via research pharmacy to the treating medical team.  
5.0 Description of Treatment vs. Standard Care 
5.1 Therapeutic Anticoagulation 
Therapeutic anticoagulation with LMWH or UFH (high dose nomogram). The choice of LMWH versus 
UFH will be at the clinician’s discretion and dependent on local institutional supply. LMWH options are 
described in Table 1 (18–20). UFH will be administered using a weight-based nomogram (bolus plus 
continuous infusion) with activated partial thromboplastin time (aPTT) or UFH anti-Xa titration according 
to the center-specific institutional protocols as per venous thromboembolism treatment (i.e. high dose 
nomogram). UFH anti-Xa titration is preferred over aPTT if available as achieving a therapeutic aPTT may 
be challenging in patients with a pro-inflammatory state such as COVID-19. Therapeutic anticoagulation 
will be administered until hospital discharge, death or day 28. If the patient is admitted to the ICU or 
requiring ventilatory support (i.e. patient reaches a component of the primary outcome), we 
recommend continuation of the allocated treatment as long as the treating physician is in agreement. 


 
13 
Version 1.3 – 13 Oct 2020 
Table 1. Therapeutic Dose Anticoagulation  
Any of the following strategies may be used for high-dose anticoagulation: 
CrCl 
BMI 
Enoxaparin 
Dalteparin 
Tinzaparin 
UFH 
≥30 
<40 
1 mg/kg SC q12h OR  
1.5 SC mg/kg q24h 
200 units/kg SC 
q24h OR 
100 IU/kg SC q12h 
175 U/kg SC 
q24h 
IV bolus, with 
continuous infusion to 
titrate to institution 
specific anti-Xa or aPTT 
values* 
≥40 
1 mg/kg q12h& 
100 units/kg SC 
q12h& 
175 U/kg SC 
daily& 
<30 
<40 
UFH IV bolus, with continuous infusion to titrate to institution specific anti-Xa or 
aPTT values* or LMWH per hospital protocol taking BMI into consideration as above 
≥40 
Abbreviations: CrCl = creatinine clearance; BMI = body mass index; * Initial bolus dose determined by sites, 
encouraging use of dosing algorithm designed for treatment of VTE. UFH anti‐Xa titration is preferred over aPTT if 
available as achieving a therapeutic aPTT may be challenging in patients with a pro‐inflammatory state such as 
COVID‐19.  
&For patients with BMI above 40, measurement of anti-Xa to confirm therapeutic effect can be used. 
 
 
Table 2 outlines the investigational products chosen for this study, mechanism of action and rationale 
for use.  
 
 


 
Version 1.4 – 13 Oct 2020 
14
Table 2. Investigational Products Rationale for Inclusion 
Drug 
Mechanism of 
Action 
Route 
Rationale for 
Inclusion 
Unfractionated 
heparin 
Indirect 
anticoagulant that 
forms a complex 
with antithrombin 
enhancing the 
inhibition of several 
activated blood 
coagulation factors: 
thrombin (factor 
IIa), factor IXa, Xa, 
XIa and XIIa. 
 
Intravenous (IV) 
Subcutaneous 
(SC) 
Considered standard 
care for both 
prophylactic and 
therapeutic dose 
anticoagulation for 
acutely ill 
hospitalized medical 
patients therefore, 
included as an 
option in both the 
standard care 
(control) arm and 
therapeutic 
anticoagulation 
(experimental) arm. 
Dalteparin 
Indirect 
anticoagulant that 
forms a complex 
with antithrombin 
enhancing the 
inhibition of 
coagulation factor 
Xa and thrombin 
(factor IIa).  
 
SC 
Considered standard 
care for both 
prophylactic and 
therapeutic dose 
anticoagulation for 
acutely ill 
hospitalized medical 
patients therefore, 
included as an 
option in both the 
standard care 
(control) arm and 
therapeutic 
anticoagulation 
(experimental) arm. 
Enoxaparin 
Indirect 
anticoagulant that 
forms a complex 
with antithrombin 
enhancing the 
inhibition of 
coagulation factor 
Xa and thrombin 
(factor IIa).  
SC 
Considered standard 
care for both 
prophylactic and 
therapeutic dose 
anticoagulation for 
acutely ill 
hospitalized medical 
patients therefore, 
included as an 


 
Version 1.4 – 13 Oct 2020 
15
 
option in both the 
standard care 
(control) arm and 
therapeutic 
anticoagulation 
(experimental) arm. 
Tinzaparin 
Indirect 
anticoagulant that 
forms a complex 
with antithrombin 
enhancing the 
inhibition of 
coagulation factor 
Xa and thrombin 
(factor IIa).  
 
SC 
Considered standard 
care for both 
prophylactic and 
therapeutic dose 
anticoagulation for 
acutely ill 
hospitalized medical 
patients therefore, 
included as an 
option in both the 
standard care 
(control) arm and 
therapeutic 
anticoagulation 
(experimental) arm. 
Fondaparinux 
Indirect 
anticoagulant that 
forms a complex 
with antithrombin 
enhancing the 
inhibition of 
coagulation factor 
Xa. 
 
SC 
Considered standard 
care for prophylactic 
dose anticoagulation 
for acutely ill 
hospitalized medical 
patients therefore, 
included as an 
option in the 
standard care 
(control) arm but 
not in the 
therapeutic 
anticoagulation 
(experimental) arm. 
 
5.2 Standard Care 
In Canada and the US, administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for 
acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered 
standard care. Importantly, the doses of thromboprophylaxis only include those listed below (Table 3) 
given the current equipoise surrounding the effectiveness of weight-based dose adjusted 
thromboprophylaxis in acutely ill medical inpatients.  


 
Version 1.4 – 13 Oct 2020 
16
 
Descriptions of the Investigational Products and Standard Care are provided in Table 3 below.  
 
Table 3. Standard care (low dose, prophylactic) anticoagulation  
Any of the following strategies may be used for low-dose anticoagulation (doses above those listed 
would not be considered as low dose {prophylactic}. A patient is receiving a lower dose of either LMWH 
or UFH than listed below, due to extremely low weight/BMI, would still be acceptable and considered as 
part of standard care {low dose, prophylactic anticoagulation}): 
Prophylactic Dose Anticoagulation  
CrCl 
BMI 
Enoxaparin 
Dalteparin 
Tinzaparin 
Fondaparinux 
Unfractionated 
Heparin (UFH) 
≥30 
<40 
40 mg SC q24h 
5000 units SC 
q24h 
4500 U SC q24h 
2.5 mg SC q24h 
5000 units SC 
q8-12h 
≥40 
40 mg SC q12h 
5000 units SC 
q12h 
9000 (+/- 1000) 
U SC q24h 
not applicable 
7500 units SC 
q8h 
<30 
<40 
UFH 5000 units SC q8-12h or LMWH per hospital protocol taking BMI into consideration as 
above 
≥40 
UFH 7500 units SC q8h or LMWH per hospital protocol taking BMI into consideration as 
above 
Abbreviations: CrCl = creatinine clearance; BMI = body mass index 
 
Type and doses of thromboprophylactic LMWH or UFH will be recorded in the case report forms. 
Concomitant medications and co-enrollment of other COVID-19 trials will also be recorded.  
 
Full therapeutic dose anticoagulation (therapeutic dose UFH or LMWH) is permitted as rescue therapy in 
the event of suspected or confirmed thromboembolism. Additional rescue therapy, in the form of 
thrombolysis (with tissue plasminogen activator), is also permitted if deemed clinically warranted by the 
treating clinical team. 
 
Insitutional drug stock will be used, and the institutional pharmacy will be responsible for labelling and 
distribution. No repackaging of drugs will occur.   


 
17 
Version 1.3 – 13 Oct 2020 
Table 4. Formulations of Investigational Products and Standard Care 
 
Common Name 
Brand Name 
Formulation 
Manufacturer 
DIN(s) 
Tinzaparin Sodium 
Innohep 
10000 Unit / mL, 
20000 Unit / mL, 
8000 Unit / 0.4 mL, 
12000 Unit / 0.6 mL, 
16000 Unit / 0.8 mL 
Leo Pharma Inc. 
02167840, 02229515, 02229755, 
02231478, 02358158, 02358166, 
02358174, 02358182, 02429462, 
02429470, 02429489 
Enoxaparin Sodium 
Lovenox 
30 mg / 0.3 mL, 
40 mg / 0.4 mL, 
60 mg / 0.6 mL, 
80 mg / 0.8 mL, 
100 mg / mL 
Sanofi-Aventis 
Canada Inc. 
02012472, 02236883, 02378426, 
02378434, 02378442 
Enoxaparin Sodium 
Lovenox HP 
120 mg / 0.8 mL, 
150 mg / mL 
Sanofi-Aventis 
Canada Inc. 
02242692, 02378469 
Enoxaparin Sodium 
Lovenox With 
Preservative 
300mg/3mL 
100 mg / mL 
Sanofi-Aventis 
Canada Inc. 
02236564 
Dalteparin Sodium 
Fragmin 
2500 Unit / 0.2 mL, 
5000 Unit / 0.2 mL, 
10000 Unit / mL, 
25000 Unit / mL, 
7500 Unit / 0.3 mL, 
10000 Unit / 0.4 mL, 
12500 Unit / 0.5 mL, 
15000 Unit / 0.6 mL, 
18000 Unit / 0.72 mL, 
3500 Unit / 0.28 mL 
Pfizer Canada 
Inc. 
02132621, 02132648, 02132664, 
02231171, 02352648, 02352656, 
02352664, 02352672, 
02352680, 02430789 
Heparin Sodium 
Heparin Leo 
100 Unit / mL, 
Leo Pharma Inc. 
0727520, 00453811 


 
Version 1.4 – 13 Oct 2020 
18
1000 Unit / mL 
Heparin Sodium 
Heparin Sodium 
Injection, USP 
1000 Unit / mL, 
10000 Unit / mL, 
Fresenius Kabi 
Canada Ltd. 
02264307, 02264315, 02392453 
Heparin Sodium 
Heparin Sodium 
Injection USP  
1000 Unit / mL, 
10000 Unit / mL 
Sandoz Canada 
Inc. 
02303086, 02303108, 02303094 
Heparin Sodium 
Heparin Sodium 
Injection USP 
5000 Unit / 0.5 mL 
Sterinova Inc. 
02456958 
Heparin Sodium 
Heparin Sodium 
Injection USP 
10000 Unit / ML 
Pfizer Canada 
Inc. 
02382326 
Heparin Sodium 
Heparin Sodium In 
0.9% Sodium 
Chloride Injection 
2 Unit / mL 
Pfizer Canada 
Inc. 
01990748 
Heparin Sodium 
Heparin Sodium And 
0.9% Sodium 
Chloride Injection 
2 Unit / mL 
Baxter 
Corporation 
00828750 
Heparin Sodium 
Heparin Sodium 
25000 Units In 5% 
Dextrose Injection 
10000 Unit / 100 mL 
B. Braun Medical 
Inc. 
 
02209721 
Heparin Sodium 
Heparin Sodium 
20000 Units In 5% 
Dextrose Injection 
4000 Unit / 100 mL 
B. Braun Medical 
Inc. 
 
02209713 
Heparin Sodium 
Heparin Sodium In 
5% Dextrose 
Injection, 25000 
Unit/500mL 
5000 Unit / 100 mL 
B. Braun Medical 
Inc. 
01935941 
Fondaparinux 
Sodium 
Arixtra 
2.5 mg / 0.5 mL, 
7.5 mg / 0.6 mL, 
Aspen 
Pharmacare 
Canada Inc. 
02245531, 02258056 
Fondaparinux 
Sodium 
Fondaparinux 
Sodium Injection 
2.5 mg / 0.5 mL, 
7.5 mg / 0.6 mL 
Dr. Reddy's 
Laboratories Ltd. 
02406853, 02406896 
 


 
19 
Version 1.3 – 13 Oct 2020 
6.0 Study Procedures and Evaluations 
 
Please refer to Table 5 for Schedule of Events.  
 
6.1 Bloodwork 
No study specific bloodwork will be ordered aside from a single D-dimer test (if not collected through 
standard of care) up to and including day 3 after randomization for all participants in both study arms. In 
those on the active treatment arm who are receiving UFH, the aPTT or UFH anti-Xa will be drawn 
according to local institutional UFH nomogram protocol guidance. Where possible, any study specific 
blood work will be timed along with regularly scheduled clinical blood work to minimize exposure and 
use of personal protective equipment. All laboratory results (see Table 5 for Schedule of Events) will be 
collected from standard of care from admission to hospital discharge, death or 28 days, where available. 
Laboratory parameters of interest include complete blood count (CBC), PT, aPTT or anti-Xa for UFH 
(according to local institutional protocol), anti-Xa for LMWH, fibrinogen, blood group, ferritin, lactate 
dehydrogenase (LDH), troponin, C-reactive protein (CRP), creatinine, alanine aminotransferase [ALT], 
heparin-platelet factor 4 immunoassay.  
 
Details regarding institutional-specific D-dimer coagulation instrumentation and assay, as well as local 
reference intervals, including units of measure, will be collected from each site. 
6.2 Optional Biobanking 
For hospital sites with capable infrastructure, the study team will collect samples for biobanking of 
plasma and serum to evaluate the pathophysiologic mechanism of COVID-19 coagulopathy, an entity 
which is poorly understood, the impact of anticoagulation on biomarkers, and role of biomarkers in 
predicting outcomes. Samples will be used for future measurement of biomarkers of coagulation, 
inflammation, endothelial activation or other relevant measures important in COVID-19.  Informed 
consent for the biobanking component will be conducted, where applicable. Blood will be collected 
three times: 
• 
Day 1 (day of randomization, prior to treatment initiation whenever possible):  One serum (5 
ml), one EDTA plasma (10 ml), and two 4.5 ml citrate (9 ml) tubes.  Total blood volume 24 ml (or 
closest volume according to blood draw tube size availability at sites) 
• 
Day 3 (at 48h +/- 24h) of randomization:  One serum (5 ml), one EDTA plasma (4 ml), and one 
citrate (4.5 ml) tubes. Total blood volume 13.5 ml (or closest volume according to blood draw 
tube size availability at sites) 
• 
One of, (1) Day 14 or if any of the following occur earlier: (2) day of discharge; or (3) day of 
removal from study; or (4) day that the patient reaches a component of the primary outcome 
(i.e. ICU admission, non-invasive/invasive mechanical ventilation). All drawn +/24 hours around 
each time. Repeat Day 3 collection of one serum (5 ml), one EDTA plasma (4 ml), and one citrate 
(4.5 ml) tubes. Total blood volume 13.5 ml (or closest volume according to blood draw tube size 
availability at sites) 
If the time window for blood collection is problematic due to logistical considerations, collection of the 
sample as close as possible (before or after) to the target time window is suggested. Phlebotomy will be 


 
Version 1.4 – 13 Oct 2020 
20
timed along with regularly scheduled clinical blood work to minimize exposure and use of personal 
protective equipment. 
Processing and storage of blood samples will follow a simple protocol to aliquot serum, two types of 
plasma and the cell layer from the EDTA tube will be aliquoted into 6 storage vials. Cryovials and labels 
will be provided to participating sites by the central biorepository site (see below). 
 
The aliquoted samples will be stored in freezers (at -80°C or colder)  in a secure location at the local 
institution until the COVID-19 pandemic allows for shipping to the central biorepository, the Laboratory 
for Clinical Biochemistry Research at the University of Vermont (360 South Park Drive, Colchester, VT, 
05445, USA). Dr. Mary Cushman’s laboratory will be the custodian of the specimens.  
 
The collection, processing and storage of samples will be outlined in Standard Operating Procedures to 
ensure consistency in specimen handling and therefore, optimization of their quality. Samples will be 
used for future measurement of biomarkers of coagulation, inflammation and endothelial activation. 
The Co-PIs and investigator team will establish a committee to review and approve requests for 
samples, following procedures established for multi-center research over the past 30 years in Dr. 
Cushman’s laboratory.  
 
We anticipate use of the samples until they are exhausted, but if all scientific use is completed, samples 
will be destroyed as per institutional practices, at the discretion of the investigator team. All participants 
will provide informed consent in accord with established procedures, but if they desire withdrawal of 
their specimens that can be done. Laboratory staff will have no information on participant identity, 
other personal health information, or randomized treatment assignment. 
 
6.3 Endpoint Assessment  
Primary outcome (primary endpoint): The primary composite outcome of ICU admission, non-invasive 
positive pressure ventilation, invasive mechanical ventilation or death at 28 days.  
 
If a patient is discharged alive before 28 days, vital status will be determined using a telephone follow-
up. If a patient was discharged alive on mechanical ventilation (invasive or non-invasive) prior to day 28, 
a call to the patient or a doctor/nurse from the rehabilitation health facility is needed to confirm 
ventilation status on day 28 and their last day of mechanical ventilation. 
 
Secondary outcomes (secondary endpoints), evaluated up to day 28, include:  
1) All-cause death; 
2) Composite of ICU admission or all-cause death; 
3) Composite of mechanical ventilation or all-cause death; 
4) Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) 
recommendation (21);  
5) Red blood cell transfusion (>1 unit);  
6) Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate 
and/or fibrinogen concentrate; 
7) Renal replacement therapy defined as continuous renal replacement therapy {CRRT} or 
intermittent hemodialysis {IHD}; 
8) Hospital-free days alive; 
9) ICU-free days alive; 
10) Ventilator-free days alive; 


 
Version 1.4 – 13 Oct 2020 
21
11) Organ support-free days alive (see Appendix 4 for definition);  
12) Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via 
diagnostic imaging and/or electrocardiogram where appropriate recognizing that access to 
diagnostic imaging may be limited in the midst of the COVID-19 pandemic, however 
confirmatory testing at a later date once exposure risk/personal protective utilization is not an 
issue is encouraged); 
13) Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or 
electrocardiogram where appropriate recognizing that access to diagnostic imaging may be 
limited in the midst of the COVID-19 pandemic, however confirmatory testing at a later date 
once exposure risk/personal protective utilization is not an issue is encouraged); 
14) Heparin induced thrombocytopenia; 
15) Trajectories of COVID-19 disease-related biomarkers.  
 
Outcome measures will be obtained from participants’ hospital medical records and where applicable 
through a telephone follow-up, as outlined in Table 5: Study Schedule of Events. The use of BIPAP or 
CPAP at night or when sleeping for sleep apnea is not considered non-invasive mechanical ventilation or 
organ support for the purpose of this trial. 
 
6.4 Duration of the study 
We expect to complete the study in approximately 24 months (for site activation, enrollment, follow-up 
and close-out), followed by 0.5 months for completion of analyses. 
7.0 Statistical Plan  
7.1 Sample Size Calculation 
462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group 
to 35% in the experimental group (2), with power of 90% at a two-sided alpha of 0.05. No attrition is 
expected. This calculation takes 2 interim analyses into account. There is no inflation to account for 
losses to follow-up because we expect these to be very infrequent, and given the nature of the trial, 
included patients, and outcomes, we may conclude an absence of the primary outcome in patients 
discharged alive from hospital before 28 days with missing outcome data at day 28. 
7.2 Statistical Analysis 
Primary analyses will be by in the intention-to-treat population of all randomized patients in accordance 
with the originally allocated intervention. We will conduct a chi-square test for the main analysis of the 
primary outcome and use a generalized linear regression model with binary distribution and identity link 
to derive risk difference with 95% confidence intervals. We will conduct subgroup analyses accompanied 
by tests of interaction for the following variables: age, sex, BMI, time from COVID-19 symptom onset, 
diabetes mellitus, coronary artery disease, hypertension and race/ethnicity. Logistic regression and 
linear regression will be used to analyse binary and continuous secondary outcomes after adjustment 
for age (used for stratification of randomization). Secondary outcomes are exploratory and will not be 
adjusted for multiple comparisons. A per-protocol analysis of the primary outcome will be restricted to 
the per-protocol population of participants, defined as those who received experimental or control 
intervention as allocated during the first 48 hours after randomization. The analysis of safety outcomes 
will be done in both, the intention-to-treat and per-protocol populations.  


 
Version 1.4 – 13 Oct 2020 
22
 
If an outcome is missing in more than 5% of the patients, in addition to the pre-planned strategy of 
assuming non-outcome if patients were discharged alive from hospital before 28 days, a complete case 
analysis, an inverse probability weighted analysis and multiple imputation on outcome will also be 
conducted. The statistical analysis plan will be finalized prior to study closure without prior inspection of 
the data. All analyses will be conducted in Stata version 15.1. 
7.3 Interim Analysis 
Interim analyses will be done when approximately 25% and 75% of the originally planned number of 
participants have reached determination of the primary endpoint. A group sequential design has been 
employed that applies a one-sided boundary. The boundary is based on a Hwang-Shih-DeCani spending 
function for efficacy. When approximately 75% of the originally planned number of participants have 
reached determination of the primary endpoint, we will perform a conditional power analysis.  
If the conditional power given the accumulated data is <30% and there is robust evidence of harm – 
either a relevant increase in the risk of major bleeding in the experimental group and the lower limit of 
the 95% confidence interval for major bleeding excluding 5% on an absolute risk difference scale; or a 
relevant increase in the risk of all-cause death in the experimental group and the lower limit of the 95% 
confidence interval for death excluding 1% on an absolute risk difference scale  - there will be a non-
binding recommendation to stop the trial. If the conditional power is <30%, but there is no robust 
evidence of harm, we will complete recruitment as planned. The rationale for this approach is that 
prevention of death (a component of the primary outcome) overrides short-term safety. If major bleeds 
lead to bleeding related deaths to such an extent that no mortality benefit is likely to be realized the 
trial should be stopped.  
If the conditional power is ≥30 and <60%, we will complete recruitment as planned. If the conditional 
power is ≥65% and <80%, there will be a non-binding recommendation to increase the sample size to 
achieve 80% power, if deemed feasible from a recruitment perspective. If the conditional power is 
≥80%, we will complete recruitment as planned, provided that the interim analysis against the one-sided 
boundary for efficacy was negative.  
Safety reviews will be done by the Data Safety and Monitoring Board at the formal interim analyses 
mentioned above, and also when approximately 10% and 50% of the originally planned number of 
participants have reached determination of the primary endpoint. The Data Safety and Monitoring 
Board can recommend termination or changes to the trial at any time if deemed necessary due to safety 
concerns. When 10%, 25% and 50% of the originally planned number of participants have reached 
determination of the primary endpoint, this recommendation will be at the discretion of the Data Safety 
and Monitoring Board. When approximately 75% of the originally planned number of participants have 
reached determination of the primary endpoint, the Data Safety and Monitoring Board will be required 
to also take into account the conditional power when doing the safety review (see above).   
 
8.0 Safety and Adverse Events  
Safety Assessments 


 
Version 1.4 – 13 Oct 2020 
23
Study drug may be temporarily held by the treating physician if any of the following are present, 
although, ultimately this is at the discretion of the treating physician: 
1) hemoglobin <80g/L; 
2) platelet count <50 x 109/L; 
3) known fibrinogen <1.5 g/L;  
4) known INR >1.8; 
5) aPTT >1.5 ULN (if participant not on intravenous UFH) 
 
Possible anticipated adverse events are those associated with LMWH (given subcutaneously) use and 
include the following: 
Common (>5%) 
Uncommon (1-5%) 
Rare (less than 1%) 
- 
Hemorrhage 
- 
Local irritation 
- 
Erythema 
- 
Mild pain 
 
- 
Urinary Tract Infection 
- 
Chest Pain 
- 
Headache 
- 
Nausea  
- 
Back pain 
- 
Fever 
- 
Pain 
- 
Constipation 
- 
Rash 
- 
Dyspnea 
- 
Vomiting 
- 
Anemia 
- 
Heparin induced 
thrombocytopenia  
- 
Heparin induced thrombosis 
- 
Hepatobiliary disorders  
- 
Abdominal Pain 
- 
Diarrhea  
 
 
Possible anticipated adverse events are those associated with Unfractionated Heparin (intravenous) use 
and include the following: 
Common (>5%) 
Uncommon (1-5%) 
- 
Hemorrhage  
- 
Local irritation 
- 
Erythema 
- 
Mild pain 
- 
Ulceration 
- 
Heparin induced thrombocytopenia  
- 
Heparin induced thrombosis 
 
 
Specification of Safety Parameters 
Meeting any of the following components will be considered a SAE related to the study drug: 
1) Bleeding defined as by the ISTH-SSC recommendation:  
a. Fatal bleeding, and/or 
b. Symptomatic bleeding in critical area or organ (such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with 
compartment syndrome, and/or 
c. Bleeding causing a fall of hemoglobin level of 20g/L or more, or leading to transfusion of 
two or more units of whole blood or red cells; 
2) Death due to hemorrhage; 


 
Version 1.4 – 13 Oct 2020 
24
3) ICU admission due to hemorrhage (e.g. meets ISTH-SSC criteria and requires ICU admission);  
4) Prolongation of an existing hospitalization due to hemorrhage; 
5) Death due to heparin induced thrombocytopenia and thrombosis (HITT); 
6) ICU admission due to HITT; 
7) Prolongation of an existing hospitalization due to HITT. 
 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
The AE reporting period begins on the day of randomization and ends with the final study (follow-up) 
visit. Investigators and study staff will assess the occurrence of AEs and SAEs at all subject evaluation 
time points during the study. Adverse events will be recorded in the subject’s medical records and on 
applicable  AE source documents. Regulatory authorities, REBs and investigators will be notified of SAEs 
in accordance with applicable requirements. 
8.1 Definitions 
Adverse Event (AE): An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries should be regarded 
as adverse events.  In addition, abnormal results of diagnostic procedures are considered to be adverse 
events if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a serious adverse event 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
 
Adverse Drug Reaction (ADR):  Any response to a drug, biologic, or natural health product which is 
noxious and unintended, which occurs at doses normally used or tested for the diagnosis, treatment or 
prevention of a disease or the modification of an organic function. A reaction, as opposed to an adverse 
event, is characterized by the fact that a causal relationship between the product and the occurrence is 
suspected (i.e. judged to be at least a reasonably possibility). 
 
Serious Adverse Event (SAE): 
Adverse events are classified as serious or non-serious. A Serious Adverse Event (SAE) is an event that: 
1. results in death,  
2. are life-threatening,  
3. In-patient hospitalization or requires prolongation of an existing hospitalization,  
4. results in persistent for significant disability,  
5. is a congenital anomaly or birth defect,  
6. an important medical event, which may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. 
 
Meeting any of the following components will be considered a SAE related to the study drug:  
1) Bleeding defined as by the ISTH-SSC recommendation:  
a. Fatal bleeding, and/or 


 
Version 1.4 – 13 Oct 2020 
25
b. Symptomatic bleeding in critical area or organ (such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with 
compartment syndrome, and/or 
c. Bleeding causing a fall of hemoglobin level of 20g/L or more, or leading to transfusion of 
two or more units of whole blood or red cells;  
2) Death due to hemorrhage; 
3) ICU admission due to hemorrhage (e.g. meets ISTH-SSC criteria and requires ICU admission); 
4) Prolongation of an existing hospitalization due to hemorrhage; 
5) Death due to heparin induced thrombocytopenia and thrombosis (HITT); 
6) ICU admission due to HITT; 
7) Prolongation of an existing hospitalization due to HITT. 
 
Serious Unexpected Adverse Drug Reaction (SUSAR): An adverse reaction, the nature or severity of 
which is not consistent with the applicable product information (e.g. the Investigator’s Brochure for an 
unapproved investigational product or package insert/summary of product characteristics for an 
approved product) and also meets the criteria of an SAE (as above).  
 
Unexpected Adverse Drug Reaction (UADR): An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g. the Investigator’s Brochure for an unapproved 
investigational product or package insert/summary of product characteristics for an approved product). 
 
Unanticipated Problem: Any incident, experience, or 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 REB-approved research 
protocol and informed consent document, or the Investigator Brochure; and (b) the 
characteristics of the research participant population being studied; and 
• 
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 study drug or procedures involved in the research); and 
• 
Suggests that the research places research participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
Assessment of Severity  
We will grade events according to the following grading system: 
- 
1 [mild, transient, not interfering with daily activities},  
- 
2 [moderate, inconvenient, some interference with daily activities],  
- 
3 [severe, intolerable, significant interruption with daily activities, requires therapy]) will be 
utilized to assess severity of AEs.  
 
An unexpected event is when the specificity or severity of the event is not consistent with the package 
inserts or investigational brochure for the drugs under study. 
 
Causality: 
The investigator is to assess the causal relation using the following terms:  
1) Related (reasonable possibility that the incident, experience, or outcome may have been caused 
by the study drug) 
2) Probable (reaction that follows a reasonable temporal sequence and response pattern),  


 
Version 1.4 – 13 Oct 2020 
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3) Possible (reaction that follows a reasonable temporal sequence and response pattern but could 
have been produced by a number of other factors), and  
4) Unlikely (reaction that does not follow a reasonable temporal sequence or there is another 
compelling alternative explanation but causation by study drug cannot be entirely ruled out).  
5) Not related (unrelated to the study drug) 
 
Identification of Adverse Events 
In general, grade 1 events will not be considered as adverse events.Some participants in this study will 
have pre-existing medical conditions and those pre-existing conditions will not be considered as adverse 
events. New events that occur or the worsening in frequency or intensity of pre-existing conditions will 
be reported as adverse events (Schedule of Events). All reportable events as defined above, determined 
to be an AE based on physical examination, laboratory findings, or other means will be recorded in the 
source documents and entered in the eCRF. Each event will be recorded on an AE eCRF starting after 
first dose of study drug has been delivered. The investigator will provide date of onset and resolution, 
severity, action(s) taken, changes in study drug dosing, causality to study drug, and outcome. 
 
Follow-up of AEs 
Any safety event that is identified at the last assessment (or an early termination) must be recorded on 
the appropriate eCRF with the status of the safety event noted. All serious suspected adverse reactions 
and serious adverse reactions will be followed until resolution or until the patient is medically stable.  
8.2 Reporting of Serious Adverse Events 
In the event of a serious adverse event that is related to the study drug (i.e. therapeutic 
anticoagulation), a SAE reporting form must be sent to the coordinating centre within 24 hours.  
 
In the event of a serious adverse event that is not related to the study drug (i.e. therapeutic 
anticoagulation), a SAE reporting form must be sent to the study sponsor (St. Michael’s Hospital) within 
72 hours. 
 
Please email all SAE reporting with the subject line: !![SAE ALERT] <SITE> and <PATIENT ID> to 
#########.   
 
The research team will be responsible for reporting SAEs to  Health Canada on behalf of the Sponsor-
Investigator. 
 
Any, serious, related, unexpected (SUSARs), which occur within or outside of Canada will be reported to 
Health Canada according to the following criteria:  
• 
Where it is neither fatal or life threatening, within 15 days after becoming aware of the 
information.  
• 
Where it is fatal or life threatening, immediately where possible, and, in any event within 7 days 
after becoming aware of the information. Within 8 days after having initially informed Health 
Canada of the ADR, submit as complete a report as possible which includes an assessment of the 
importance and implication of any findings. 


 
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27
Promptly report all serious adverse events that occur at each site along with any adverse events that are 
both serious and unexpected, and have been reported to Health Canada to your local REB or Clinical 
Trials Ontario (as applicable).  
8.3 Monitoring of AEs/SAEs  
Any AE that occurs between the times a study participant signs the informed consent form and the time 
s/he departs the study at the end of the final follow-up visit (or at the time of early discontinuation of 
the participant from the study for any reason) will be captured and recorded.  At each contact with the 
participant, the investigator (or designate) must seek information on adverse events by specific 
questioning and, as appropriate, by examination. 
 
All grade 3 AE’s and all non-fatal SAE’s will be followed until resolution or until the site investigator and 
the clinical/medical monitor, or one of the co-PIs are in agreement that the AE/SAE has stabilized and no 
more follow-up is required.  
8.4 Treatment Discontinuation 
The criteria for permanent discontinuation of therapeutic or thromboprophylactic anticoagulation in 
patients allocated to the experimental or standard care arm are as follows: 
• 
Treatment related toxicity (see section 8.0) 
• 
Requirement for prohibited concomitant medications in the therapeutic anticoagulation 
(experimental arm) (i.e. dual antiplatelet therapy where bleeding risk is deemed unacceptably 
high by the treating physician, use of any direct oral anticoagulant or any intravenous direct 
thrombin inhibitor; see Appendix 2) 
• 
Reaching a defined clinical endpoint (i.e. a component of the primary outcome, however, 
continuation of study treatment is ultimately at the discretion of the treating physician)      
• 
Completion of treatment/intervention as defined by the protocol 
• 
Clinical reasons believed to be life-threatening by the physician, even if not addressed in the 
toxicity section of the protocol 
• 
Any clinical adverse event, laboratory abnormality, intercurrent illness, other medical 
condition or situation occurs such that continued anticoagulation would not be in the best 
interest of the participant. 
 
In order to capture accurate prognostic and safety data, the participant will continue to be followed with 
the participant’s permission if the study treatment/intervention is discontinued, and this would not be 
considered premature study withdrawal (see section 8.5).  There will be no changes to the follow-up 
visit schedule, except no study treatment/intervention will be administered. 
 
In the event that the participant’s anticoagulation is discontinued due to an AE or SAE, this must be 
recorded on the CRF.  The participant should be followed and treated by the treating physician until the 
abnormal parameter or symptom has resolved or stabilized.  It is up to the clinician to determine that 
the AE is either resolved or that it has reached a stable state, after which no further follow-up is 
necessary.  There should also be source documentation to support this determination. 
 
If a patient’s medication is discontinued, they will still be followed for primary and secondary outcomes.  
Participants may be withdrawn from the study if the Sponsor-Investigator terminates the trial  (i.e. if 


 
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28
new evidence emerges proving either futility or efficacy of the study drug or potential safety concerns or 
if drug supply becomes an issue). 
8.5 Premature Study Withdrawal of an Individual Participant  
Premature study withdrawal would occur if data collection is to stop before Day 28. The criteria for 
premature withdrawal from the study for an individual participant are as follows: 
• 
Request of the participant or their substitute decision maker to discontinue data collection for 
study purposes 
8.6 Protocol Violations/Deviations 
In the event that an investigator becomes aware of a protocol deviation, it is his/her responsibility to 
document the deviation and report it to the Study Coordinating Centre and the local REB as per local 
guidelines.  
 
 
 
Protocol Deviation: Any alteration/modification to the REB approved protocol.  This can involve 
deviations involving the recruitment or consent process, the sequence and nature of study procedures, 
the information recorded on subjects, and the documentation used with study subjects.   
 
Major Deviation:  A violation that may impact the patient’s rights, safety or welfare, or that can affect 
the integrity of the study data.  Examples are as follows: 
• 
Failure to obtain informed consent 
• 
Enrolment of a patient not meeting inclusion criteria  
• 
Failure to report a serious adverse event 
• 
Study medication dispensing or dosing error 
• 
Study procedure omitted 
• 
Failure to file REB Annual Renewal and/or Modifications 
 
Minor Deviation:  A violation that does not have meaningful impact on the study and does not fall into 
the foregoing categories.  These typically involve only logistical or administrative aspects of the study.  
Examples are as follows: 
• 
Study procedures conducted out of sequence, but with no impact on patient safety or welfare 
• 
Change in contact information of staff 
• 
The use of the same recruitment materials in a new venue (community vs. local newspaper).  
 
9.0 Data Handling and Record Keeping   
9.1 Data Management Responsibilities  
Original subject records (source documents) will be reviewed during the course of the monitoring to 
verify the accuracy of the CRF’s.  This review will be conducted according to sponsor monitoring 
guidelines.  The Investigator(s) institutions(s) will permit trial-related monitoring, audits, REB(s) review 
and regulatory inspections(s) by providing direct access to source data and documentation.  
 


 
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29
The medical (hospital/practice) records for each patient should contain information to provide a means 
by which study data can be verified.  Patient information collected electronically will be available for 
review when the study site is monitored or audited. 
 
 All source documents and lab reports must be reviewed by the clinical team and data entry staff, who 
will ensure that they are accurate and complete.  Adverse events must be graded, assessed by severity 
and causality and reviewed by the site investigator or designee. 
 
Data collection is the responsibility of the research staff at the site under the supervision of the Principle 
Investigator. All data will be entered directly into REDCap (Research Electronic Data Capture). Data will 
be entered by research staff into REDCap at the following times: screening, randomization (day 1), day 3, 
day 7, day 14 and day 28. Data entered will cover the entire 28 day period. During the study the 
investigator must maintain complete and accurate documentation for the study.  
 
If a participant chooses to withdraw from the study prematurely or is withdrawn by the investigator, 
efforts should be made to collect all related study data until the last completed visit.  
 
REDCap is a secure, web-based application designed exclusively to support data capture for research 
studies. REDCap provides: 1) an intuitive interface for data entry (with data validation); 2) 128 bit 
encryption between the data entry client and the server (https); 3) audit trails for tracking data 
manipulation and export procedures; 4) automated export procedures for seamless data downloads to 
common statistical packages (SPSS, SAS, Stata, R); 5) procedures for importing data from external 
sources; and 6) advanced features, such as branching logic and calculated fields. 
 
REDCap is developed and maintained by a team at Vanderbilt University and licensed free of charge by 
the Applied Health Research Centre (AHRC). The application and data are housed inside a secure data 
center located at Unity Health Toronto (St. Michael’s Hospital). The data center is physically secured 
through limited badge access and security cameras. The REDCap servers and application are maintained 
by the AHRC. Local support for REDCap is provided by AHRC.  
 
9.2 Confidentiality  
All participant related information including Case Report Forms, laboratory specimens and etc. will be 
kept strictly confidential and to the extent permitted by the applicable laws.  All records will be kept in a 
secure, locked location and only research staff will have access to the records.  Participants will be 
identified only by means of a coded number specific to each participant. All computerized databases will 
identify participants by alpha-numeric codes only, and will be password protected or encrypted. 
Upon request, participant records will be made available to the study sponsor, monitoring groups 
representative of the study sponsor, representatives of a participating pharmaceutical sponsor and 
applicable regulatory agencies such as Health Canada. 


 
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30
9.3 Record Retention 
To protect the patient’s confidentiality, all study documentation will be kept in a secure location at the 
study site in compliance with local SOP’s. All sites are expected to store all study documentation for the 
legally required time period.  
The Investigator will maintain all study records according to the ICH-GCP and applicable Health Canada 
regulatory requirements. Records will be retained for 25 years, in accordance with applicable Health 
Canada regulatory requirements. If the Investigator withdraws from the responsibility of keeping the 
study records, custody must be transferred to a person willing to accept the responsibility and the 
Sponsor-Investigator notified. The Investigator should ensure that no destruction of medical records 
occurs without the written approval of the Sponsor-Investigator.  
10.0 Quality Control and Quality Assurance  
10.1 Study Monitoring Plan 
Remote risk-based monitoring will be conducted by qualified central research personnel in order to 
ensure (1) that the study is carried out according to ICH-GCP E6(R2) guidelines and applicable 
regulations, and that study related tasks are  performed by staff who are trained and familiar with the 
clinical study protocol; (2) that study procedures are carried out according to the protocol, and (3) that 
the data collected is complete, accurate and collected according to the methods defined in the protocol 
and in associated operational documents. 
The proposed remote monitoring scheme will be composed of: 
1) Centralized review of essential study document at all participating sites related to participant 
protection, such as ICF signature pages, GCP and protocol training records, Delegation log, CV 
and medical license of investigators and Protocol signature page 
2) Targeted source data verification (SDV) of eCRF data on randomly selected participants. Only 
critical data variables identified through risk assessment which are programmed into the EDC 
system will be source verified.  
The monitoring procedures, frequency and country-specific adaptations will be further outlined in the 
Monitoring Plan. 
 
10.2 Role of the Data Safety Monitoring Board 
A Data Safety Monitoring Board is a group of experts who meet periodically to review accumulating data 
gathered from participants in clinical trials with the purpose of protecting 
• 
the safety of the study participants 
• 
the scientific integrity of the study 
• 
the validity of study results 
 
This study will be monitored by an independent data safety monitoring board (DSMB) including a 
biostatistician, a hematologist, a general internist and intensive care specialist. The four members will 
not be listed study investigators. The DSMB will be immediately informed of any serious adverse events 


 
Version 1.4 – 13 Oct 2020 
31
(SAEs) which may potentially be study drug related.  Other SAEs will be reviewed during regular DSMB 
meetings. 
Interim reports, prepared by the data management team for the study, for review by the DSMB will 
include data on recruitment, compliance, adverse effects, baseline comparability and treatment 
comparisons. An agreed upon review package which contains the appropriate data summary by 
treatment will be provided by the study statistician for the purposes of these reviews. Interim analyses 
will be confidentially provided to the board during the period of study recruitment (see Section 7.3) to 
evaluate for unquestionable difference in effect between the two study arms and adverse events 
requiring additional action or discontinuation of the study. DSMB members will review data only by 
masked study group (such as A vs B rather than experimental vs control).  The DSMB may request 
unblinded safety data tables, in case of adverse events associated with study drug or procedures. 
Serious adverse events, which are of concern to members of the Steering Committee (potentially study 
drug related) will also be reviewed by the DSMB.   
Members of the DSMB will also be responsible for developing terms of reference including clinical 
stopping rules. If at any point the DSMB considers continuance of the study unacceptable, the steering 
committee will be immediately notified. Thereafter, the study co-PIs can decide whether or not to 
modify intake to the trial.  
10.3 Ethics and Research Governance: 
This study will be conducted according to Canadian and international standards of Good Clinical Practice 
and the Health Canada, Food and Drug Act, Part C, Division 5, Drugs for clinical Trials Involving Human 
Subjects. The Research Ethics Board (REB) policies and standard operating procedures will also be 
followed. 
This protocol and any amendments will be submitted to the REB for formal approval to conduct the 
study.  The decision of the REB concerning the conduct of the study will be made in writing to the 
investigator.   
All participants for this study will be provided a consent form, describing this study and providing 
sufficient information for participants to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the REB.  The 
formal consent of a participant, using the REB-approved consent form, will be obtained before that 
participant is submitted to any study procedure. REB approval will also be obtained for any protocol 
amendments and ICF revisions prior to implementing the changes. Any protocol deviations will be 
reported to the REB within 15 calendar days. 
10.4 Feasibility 
The Applied Health Research Centre (AHRC) at SMH in Toronto will manage and oversee this trial. AHRC 
is the largest academic research organization in Toronto, and a designated Research Centre of the 
Ontario SPOR Support Unit (OSSU) deemed suitable to provide the enabling infrastructure, scientific 
knowledge and technical support required to conduct patient-oriented research. 
 


 
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10.5 Study Product Supply and Accountability 
All study medications will be stored at room temperature (as per the labelling) in a secure location. This 
is an open label study thus once a participant is randomized, a research coordinator will document the 
treatment allocation in the case report form and notify the MRP and study team by email and phone of 
the patient’s study treatment allocation (therapeutic or standard care arm). The MRP will then order the 
study drug in the patient’s medical chart and notify the study team. The research coordinator will then 
email or fax research pharmacy the order.  Research pharmacy will follow their SOP to dispense study 
drug and study drug will be dispensed via research pharmacy to the treating medical team.  Returned 
and unused study drug will be returned to the pharmacy department where it will be destroyed. 
Research Pharmacy will maintain drug accountability logs, as per their SOPs. 
The study medication should be stored in a secure area according to local regulations. The investigator is 
responsible for ensuring that it is dispensed only to study participants and only from official study sites 
by authorized personnel, as dictated by local regulations.  
The site investigator is responsible for ensuring that the study medication is stored under the 
appropriate environmental conditions (temperature, light and humidity).  
11.0 Study Significance 
We believe that this RCT has the potential to immediately impact the clinical care of patients with 
severe COVID-19, internationally, whether our findings are positive or negative as COVID-19 
coagulopathy appears to be a highly prevalent complication of severe COVID-19 and may even precede 
the respiratory manifestations that characterize it (9,10).  
In the midst of the COVID-19 pandemic and secondary healthcare crisis, it is time, now more than ever, 
for randomized care of agents with sound biological plausibility rather than random, best-guess care 
(22). Thus, our study of a well understood therapy with a predictable adverse effect profile will, 
irrespective of our findings, lead to subsequent patients receiving evidence-based therapies and spared 
from unnecessary harm. Moreover, we are also well positioned to evaluate for ethnic/racial disparities 
in coagulation/inflammatory responses and effect of anticoagulation. 
 
LMWH and UFH are both licensed anticoagulants in North America therefore, we anticipate swift 
approval which means that we could feasibly launch this RCT at multiple centers promptly which is 
crucially required given the worrisome mortality associated with severe COVID-19 that is rapidly 
overwhelming hospitals. 
 
12.0 Disclosure and Publication Policy  
12.1 Publication of Study Results 
Following completion of the study, the lead Principal Investigators are expected to publish the results of 
the primary and secondary analyses from this trial, in peer-reviewed scientific journals.  A detailed 
authorship policy will be developed and agreed upon by all investigators to determine how best to fairly 
acknowledge the contributions of relevant parties. 


 
Version 1.4 – 13 Oct 2020 
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12.2 Data Sharing for Secondary Research  
Data from this study may be used for secondary research. All of the individual participant data collected 
during the trial will be made available after de-identification through expert determination. These data 
will be made available as soon as possible following publication, with no end date, as part of data 
sharing requirements from journals and funding agencies, and in the spirit of open data access. 
12.3 Conflict of interest 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial. 
 
 
 


 
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Table 5. Study Schedule of Events 
 
Screening1,2, $ 
Randomization1,2,$ 
(Day 1) 
Day 3$ 
Day 7$ 
Day 14$ 
Day 28$ 
Informed Consent  
X 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
Lowest oxygen saturation (%) 
on room air   
X 
 
 
 
 
 
Maximum supplemental oxygen 
(FiO2)ß 
X* 
X* 
X* 
X* 
X* 
X* 
Concomitant Medications 
(including other COVID-19 trial 
treatments)  
X* 
X* 
X* 
X* 
X* 
X* 
Demographics (age, sex, 
race/ethnicity) 
X 
 
 
 
 
 
Medical History (including 
smoking, date of COVID-19 
symptom onset) 
X* 
 
 
 
 
 
Height 
X** 
 
 
 
 
 
Weight 
X** 
 
 
 
 
 
Dose and frequency of 
therapeutic anticoagulation 
administered (treatment arm) 
 
X* 
X* 
X* 
X* 
X* 
Dose and frequency of LMWH 
or UFH at thromboprophylactic 
doses (standard care arm)  
 
X* 
X* 
X* 
X* 
X* 
Complete Blood Count  
 
X* 
X* 
X* 
X* 
X* 
Ferritin  
 
X* 
X* 
X* 
X* 
X* 
D-Dimer 
X* 
X* 
     X*** 
X* 
X* 
X* 
PT 
 
X* 
X* 
X* 
X* 
X* 
aPTT3 
 
X* 
X* 
X* 
X* 
X* 
Anti-Xa for UFH3  
 
X* 
X* 
X* 
X* 
X* 
Anti-Xa for LMWH 
 
X* 
X* 
X* 
X* 
X* 
INR 
 
X* 
X* 
X* 
X* 
X* 


 
Version 1.4 – 13 Oct 2020 
35
Fibrinogen 
 
X* 
X* 
X* 
X* 
X* 
Lactate dehydrogenase  
 
X* 
X* 
X* 
X* 
X* 
Troponin  
 
X* 
X* 
X* 
X* 
X* 
C-Reactive Protein 
 
X* 
X* 
X* 
X* 
X* 
Creatinine  
 
X* 
X* 
X* 
X* 
X* 
ALT 
 
X* 
X* 
X* 
X* 
X* 
Heparin-Platelet Factor 4 
Immunoassay  
 
X* 
X* 
X* 
X* 
X* 
Blood group 
 
X∞ 
X∞ 
X∞ 
X∞ 
X∞ 
Primary outcome assessment4 
 
X* 
X* 
X* 
X* 
X* 
Length of Hospital Stay 
 
X* 
X* 
X* 
X* 
X* 
Bleeding Event5 
 
X* 
X* 
X* 
X* 
X* 
Red Blood Cell transfusion6a 
and/or transfusion of any 
hemostatic blood 
product/component6b  
 
X* 
X* 
X* 
X* 
X* 
Renal replacement therapy7  
 
X* 
X* 
X* 
X* 
X* 
Organ support (see Appendix 4) 
 
X* 
X* 
X* 
X* 
X* 
Venous or arterial 
thromboembolism8   
 
X* 
X* 
X* 
X* 
X* 
AE/ SAE Assessment9  
 
X* 
X* 
X* 
X* 
X* 
Optional Biobanking 
 
X† 
X† 
 
X† 
 
* collected through standard of care when available in the chart;  
** height and weight to be collected from the patient’s chart or obtained verbally from the patient;  
*** D-dimer will be drawn once on day 2 after randomization (+/- 24 hours); if collected through standard of care, study specific D-Dimer is not 
needed);  
ßSee Appendix 3 for FiO2 for nasal cannula and Venturi mask;  
Race/ethnicity of participant collected given known ethnic variation of D-dimers (categories defined in Appendix 1 (23); to obtain verbally from 
the patient); 
∞to be obtained from hospital medical record or verbally from patient if not available from medical record and patient is aware of their blood 
group;  
†Phlebotomy and sample processing on day 1, 3, and 14 OR the time of discharge OR reaching a component of primary outcome OR study 
withdrawal for any reason; 


 
Version 1.4 – 13 Oct 2020 
36
$Research staff will enter data into REDCap on screening, randomization (day 1), Days 3, 7, 14, and 28 including data from the days in between. 
Data entered will cover the entire 28 day period. Day 3 will cover Day 2 to Day 3, Day 7 will cover Day 4 to Day 7, Day 14 will cover Day 8 to Day 
14, and Day 28 will cover Day 15 to Day 28. If multiple laboratory results are available, the most pathological value since last assessment will be 
recorded; 
1within 5 days (i.e. 120 hours) of hospital admission;  
2screening and randomization can be done on the same day;  
3 For participants treated with UFH: aPTT or UFH anti-Xa will be drawn according to local institutional UFH nomogram protocol guidance;  
4If patient is discharged alive before 28 days, vital status will be determined using telephone follow-up by a research coordinator; the use of 
BIPAP or CPAP at night or when sleeping for sleep apnea is not considered non-invasive mechanical ventilation or organ support for the purpose 
of this trial; If a patient was discharged alive on mechanical ventilation (invasive or non-invasive) prior to day 28, a call to the patient or a 
doctor/nurse from the rehabilitation health facility is needed to confirm ventilation status on day 28 and their last day of mechanical ventilation. 
5Bleeding defined as by ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation: 1) Fatal bleeding, and/or 2) symptomatic 
bleeding in critical area or organ (such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with 
compartment syndrome, and/or 3) bleeding causing a fall of hemoglobin level of 20g/L or more, or leading to transfusion of two or more units of 
whole blood or red cells; 
6aDefined as >1 unit;  
6bDefined as platelet, frozen plasma, prothrombin complex concentrate, cryoprecipitate, fibrinogen concentrate; 
7defined as continuous renal replacement therapy or intermittent hemodialysis; 
8defined via diagnostic imaging and/or electrocardiogram where appropriate and possible; 9AE/SAE will be recorded on any day. 
 
 
 


 
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http://products.sanofi.ca/en/lovenox.pdf.  
20.  LEO Pharma. PRODUCT MONOGRAPH - Pr innohep® [Internet]. Available from: https://www.leo-
pharma.ca/Files/Filer/LEO_local_downloads/LEO-Pharma.ca/innohep_PM_(8.0)_-_26-MAY-
2017[1].pdf 
21.  Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic 
medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692–4.  
22.  Cheng MP, Lee TCL, Tan DHS, Murthy S. Generating randomized trial evidence to optimize 
treatment in the COVID-19 pandemic. CMAJ [Internet]. 2020 Jan 1 [cited 2020 Apr 1]; Available 
from: https://www.cmaj.ca/content/early/2020/03/26/cmaj.200438 
23.  NOT-OD-15-089: Racial and Ethnic Categories and Definitions for NIH Diversity Programs and for 
Other Reporting Purposes [Internet]. [cited 2020 Apr 17]. Available from: 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-089.html 
 
 
 
 
 
 
 


 
Version 1.4 – 13 Oct 2020 
39
Appendix 1. Racial and Ethnic Categories and Definitions 
 
Definitions for Racial and Ethnic Categories  
(based on NIH categories that were modified to be inclusive of additional categories defined at 
http://torontohealthequity.ca/wp-content/uploads/2017/05/TC-LHIN-Hospitals-Demographic-
Questions-English-visible-v2-1.pdf) 
 
• 
American Indian, Alaska Native, First Nations, Indigenous/Aboriginal, Metis. A person having 
origins in any of the original peoples of North and South America (including Central America), 
and who maintains tribal affiliation or community attachment. 
• 
Asian. A person having origins in any of the original peoples of the Far East, Southeast Asia, or 
the Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, 
Pakistan, the Philippine Islands, Thailand, and Vietnam. 
• 
Black or African American. A person having origins in any of the black racial groups of Africa. 
Terms such as "Haitian" or "Negro" can be used in addition to "Black or African American." 
• 
Hispanic or Latino. A person of Cuban, Mexican, Puerto Rican, South or Central American, or 
other Spanish culture or origin, regardless of race. The term, "Spanish origin," can be used in 
addition to "Hispanic or Latino." 
• 
Native Hawaiian or Other Pacific Islander. A person having origins in any of the original peoples 
of Hawaii, Guam, Samoa, or other Pacific Islands. 
• 
White. A person having origins in any of the original peoples of Europe, the Middle East, or 
North Africa. 
The categories and definitions provide a common language to promote uniformity and comparability of 
data on race and ethnicity.  Moreover, federal agencies have a continuing commitment to monitor the 
operation of its review and award processes to detect, and deal appropriately with, any instances of real 
or apparent inequities.  All analyses conducted on race and ethnicity report aggregate statistical findings 
and do not identify individuals.


 
Version 1.4 – 13 Oct 2020 
40
Appendix 2. Requirement for prohibited concomitant medications in 
the therapeutic anticoagulation (experimental arm) 
 
Dual therapy with any of the following: 
Aspirin 
Clopidogrel 
Ticagrelor 
Prasugrel 
 
Single agent therapy with any of the following:  
Dabigatran 
Rivaroxaban 
Apixaban 
Edoxaban 
Melagatran 
Inogatran 
Argatroban 
Bivalirudin 
Lepirudin 
Desirudin 
Hirudin 
Alteplase 
Streptokinase 
Urokinase 
Reteplase 
Tenecteplase 


 
Version 1.4 – 13 Oct 2020 
41
Appendix 3. Fraction of Inspired Oxygen (FiO2) for Various Oxygen 
Delivery Devices 
 
For all supplemental oxygen delivery devices, the patient is not just breathing the direct oxygen, but 
rather is breathing a combination of room air plus the oxygen from the supplemental device. 
Different devices deliver to the patient more or less of a % of what is coming in from the tank. 
0 (no oxygen, just room air) 
21% 
 
 
For a Nasal Cannula: 
Oxygen tank FLOW RATE in liters / min 
FiO2 -- Fraction of Inspired Oxygen value 
1 L / min 
24% 
2 L / min 
28% 
3 L / min 
32% 
4 L / min 
36% 
5 L / min 
40% 
6 L / min 
44% 
 
For a Simple Face Mask – Low Flow (approximate values): 
Oxygen tank FLOW RATE in liters / min 
FiO2 -- Fraction of Inspired Oxygen value 
5 L / min 
35% 
6 L / min 
39% 
7 L / min 
43% 
8 L/min 
47% 
9 L/min 
51% 
10 L/min 
55% 
 
 
 
 
 


 
Version 1.4 – 13 Oct 2020 
42
For a Venturi Mask (approximate values):  
The FiO2 is controlled by both the L/min as well as by the valve as indicated by its colour (see below). 
Note colours may vary based on institution (please double check locally). See example below, the colour 
of the valve is the best indicator of the FiO2 provided.  
 
 
 
 
   blue         white        orange      yellow       red          green 
 
Nonrebreather (approximate value): 
Oxygen tank FLOW RATE in liters / min 
FiO2 -- Fraction of Inspired Oxygen value 
15 L/min 
90% 
 
 
High Flow Nasal Cannula: 
For the purposes of this trial, a patient is considered to be receiving high flow nasal 
cannula (HFNC) therapy when the flow rates provided by this device are >30 L/min.   
For HFNC therapy, the FiO2 and flow rate are independent settings.  
Thus, you cannot infer the FiO2 based on the flow rate.  
The user controls both and thus should simply enter the FiO2 that was set for the patient. 
 


 
Version 1.4 – 13 Oct 2020 
43
 
 
Appendix 4. Outcome Definition for Organ-support Free Days 
 
Outcome Definition for Organ-support Free Days  
Defined as the number of days that a patient is alive and free of organ support through 28 days after 
trial entry. Organ support is defined as receipt of non-invasive mechanical ventilation, high flow nasal 
cannula oxygen, invasive mechanical ventilation, or vasopressor therapy.  
• 
Non-invasive mechanical ventilation is defined as BIPAP or CPAP when used for acute 
respiratory support (the use of BIPAP or CPAP at night or when sleeping for sleep apnea is not 
considered organ support). 
• 
High Flow Nasal Cannula Oxygen is defined as receiving ≥ 30 l/min flow at FiO2 ≥ 40%. 
• 
Invasive mechanical ventilation is defined as positive pressure ventilation through endotracheal 
tube or tracheostomy. 
• 
Vasopressor support includes infusion of any vasoactive or inotropic medication. 
• 
A patient must be extubated and not receiving mechanical ventilation for at least 2 days before 
being considered free of mechanical ventilation. If a patient was extubated and re-intubated 
and placed back on mechanical ventilation within 1 or 2 days, the patient is considered to be on 
mechanical ventilation during those 1 or 2 days before re-intubation. 
• 
Any patient dying in the acute hospital stay are assigned 28 Day Organ-Support Free Days of –1. 
• 
If there is intervening time in which a patient is free of organ support but goes back on organ 
support the intervening time does not count toward the organ support free days endpoint.  Only 
time before organ support and after the last use of organ support are counted as “free days.” 
• 
If a patient was discharged alive without mechanical ventilation prior to Day 28, the patient is 
assumed to be free of organ support after hospital discharge for the remainder of the 28 days. 
• 
If a patient was discharged alive on mechanical ventilation (invasive or non-invasive) prior to day 
28, a call to the patient or a doctor/nurse from the rehabilitation health facility is needed to 
confirm ventilation status on day 28 and their last day of mechanical ventilation. 
 

SAP_001.pdf: 
 
 
Statistical Analysis Plan V1.0 
    Protocol Number: RAPID COVID COAG V1.4 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol Title: Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of Therapeutic 
Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic 
 
 
Short Title: RAPID COVID COAG 
 
 
ClinicalTrials.gov Identifier: NCT04362085 
 
 
Principal Investigators: Dr. Michelle Sholzberga, Dr. Peter Jϋnib, and Dr. Mary Cushmanc 
 
aSt. Michael’s Hospital, Li Ka Shing Knowledge Institute, University of Toronto 
bApplied Health Research Centre (AHRC), St. Michael’s Hospital, Unity Health Toronto 
cUniversity of Vermont Medical Center 
 
 
Last Revision Date: May 6, 2021 
Version: 1.0 
Final Sign-off Date:  
Archive Date: 
 
 
 
 
 
 
The information in this document is confidential. It is understood that information in this document shall not be disclosed to 
any third party, in any form, without prior written consent of an authorized officer of St. Michael’s Hospital. 
 
 
 
 


 
 
Statistical Analysis Plan V1.0 
    Protocol Number: RAPID COVID COAG V1.4 
 
Page 3 of 8 
 
1. INTRODUCTION 
 
This statistical analysis plan (SAP) outlines the planned statistical methods for the summary and 
analysis of data collected within the scope of the Coagulopathy of COVID-19 (RAPID COVID COAG) trial 
protocol version 1.4 dated October 13, 2020.  
 
The SAP should be read in conjunction with the study protocol and the electronic Case Report Form 
(eCRF). This version of the SAP has been developed using the final version of the protocol mentioned 
above and eCRF version 1.3 dated September 17, 2020.  
 
All statistical analyses will be performed using R version 3.6.2 and/or Stata version 15.1, or higher. 
 
2. STUDY OBJECTIVES 
 
2.1 Primary Objective 
 
To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or 
high dose nomogram of unfractionated heparin (UFH) compared to standard care in hospitalized 
patients admitted for coronavirus disease 2019 (COVID-19) with an elevated D-dimer on the composite 
outcome of intensive care unit (ICU) admission, non-invasive mechanical ventilation (positive pressure 
ventilation), invasive mechanical ventilation or death at 28 days.  
 
Primary Outcome 
 
The primary outcome of this trial is the difference in proportions of subjects with the composite of ICU 
admission, non-invasive or invasive mechanical ventilation or death between groups within the first 28 
days post-randomization.  
 
2.2 Secondary Objectives 
 
To compare the following secondary outcomes between the experimental group receiving therapeutic 
doses of LMWH or high dose nomogram of UFH and the control group receiving standard care: 
 
2.2.1 Secondary Outcomes 
 
1) Proportion of all-cause death within the first 28 days post-randomization. 
 
2) Proportion of subjects with the composite outcome of ICU admission or all-cause death within 
the first 28 days post-randomization. 
 
3) Proportion of subjects with the composite outcome of invasive or non-invasive mechanical 
ventilation or all-cause death within the first 28 days post-randomization. 
 


 
 
Statistical Analysis Plan V1.0 
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Page 4 of 8 
 
4) Proportion of subjects with major bleeding, as defined by the ISTH Scientific and 
Standardization Committee (ISTH-SSC), within the first 28 days post-randomization. 
 
5) Proportion of subjects with red blood cell transfusion ≥ 1 unit within the first 28 days post-
randomization. 
 
6) Proportion of subjects who experienced the following: transfusion of platelets, frozen plasma, 
prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate within the 
first 28 days post-randomization. 
 
7) Proportion of subjects who had renal replacement therapy defined as continuous renal 
replacement therapy (CRRT) or intermittent hemodialysis (IHD) within the first 28 days post-
randomization. 
 
8) Hospital-free days alive up to day 28 post-randomization. 
 
9) ICU-free days alive up to day 28 post-randomization. 
 
10) Ventilator-free days alive up to day 28 post-randomization. 
 
11) Organ support-free days alive up to day 28 post-randomization.  
 
12) Proportion of subjects who had venous thromboembolism defined as symptomatic or 
incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where 
appropriate, recognizing that access to diagnostic imaging may be limited in the midst of the 
COVID-19 pandemic. Confirmatory testing at a later date once exposure risk/personal protective 
utilization is not an issue is encouraged within the first 28 days post-randomization. 
 
13) Proportion of subjects who had arterial thromboembolism defined as suspected or confirmed 
via diagnostic imaging and/or electrocardiogram where appropriate, recognizing that access to 
diagnostic imaging may be limited in the midst of the COVID-19 pandemic. Confirmatory testing 
at a later date once exposure risk/personal protective utilization is not an issue is encouraged 
within the first 28 days post-randomization. 
 
14) Proportion of subjects with heparin induced thrombocytopenia within the first 28 days post-
randomization. 
 
15)  D-dimer, a COVID-19 disease-related biomarker at day 2 +/- 24 hours post-randomization. 
 
In addition, the following pre-specified components of the primary composite outcome will be analyzed 
(not pre-specified in the protocol):  


 
 
Statistical Analysis Plan V1.0 
    Protocol Number: RAPID COVID COAG V1.4 
 
Page 5 of 8 
 
16) Proportion of subjects with ICU admission. 
 
17) Proportion of subjects with the composite of invasive or non-invasive mechanical ventilation. 
 
18) Proportion of subjects with invasive mechanical ventilation. 
 
3. STUDY DESIGN 
 
3.1 Study Design 
 
This is an open-label, parallel, two-arm randomized controlled trial (RCT) comparing therapeutic 
anticoagulation with LMWH or high dose nomogram of UFH (experimental group) to standard care 
(control group) to determine the effect of therapeutic anticoagulation on the composite outcome of 
ICU admission, mechanical ventilation (non-invasive or invasive) or death in hospitalized patients 
admitted for COVID-19. 
 
3.2 Study Cohort 
 
The study cohort consists of hospitalized adults admitted for COVID-19 prior to the development of 
critical illness. Individuals with the following characteristics are excluded: bleeding risk or risk of 
transfusion generally considered unacceptable, absolute indication for therapeutic anticoagulation, and 
already met components of the primary outcome.    
 
3.2.1 Intent-to-Treat (ITT) Cohort 
 
The Intent-to-Treat (ITT) cohort will consist of all randomized subjects. The primary analysis will be 
conducted on the ITT cohort according to the treatment group to which the subjects were randomized. 
In the rare event that a subject does not have a 28-day assessment and they were event-free and 
discharged alive prior to day 28, they will be assumed to still be event-free up to day 28. 
 
3.2.2 Per-Protocol (PP) Cohort 
 
The Per-Protocol (PP) cohort will consist of all eligible randomized subjects who received their 
intervention as allocated during the first 48 hours after randomization. The PP analysis will exclude 
subjects who did not receive their allocated treatment during the first 48 hours after randomization.  
 


 
 
Statistical Analysis Plan V1.0 
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Page 6 of 8 
 
3.3 Treatment Definition 
 
There are two treatment groups in the study. Subjects are randomized (1:1) within the age strata (≤65 
and >65 ) to receive (i) therapeutic doses of LMWH or high dose nomogram of UFH (experimental 
group) or (ii) standard care with thromboprophylactic doses of LMWH or UFH (control group). 
 
4. STATISTICAL ANALYSIS 
 
Categorical data will be summarized by counts and percentages, and continuous variables by means 
and standard deviations, or medians and interquartile ranges. All outcome comparisons will include a 
treatment effect estimate along with a 95% confidence interval. All outcome comparisons will include a 
p-value calculated using an appropriate test.  
 
 
4.2 Primary Outcome Analysis  
 
The primary analysis will compare the proportions of subjects experiencing the composite outcome 
within 28 days after randomization between the 2 treatment arms (therapeutic doses of LMWH or high 
dose nomogram of UFH versus standard care). Difference in proportions and the 95% confidence 
interval will be reported. A Chi-squared test of independence will be conducted to obtain the p-value. 
Since randomization was stratified by age a logistic regression model will also be fit to obtain and test 
the treatment effect adjusting for age. These two complementary analyses are being performed since 
an adjusted analysis result in a different interpretation of the treatment effect (conditional) versus the 
unadjusted (marginal or population averaged). Although the protocol specifies binomial models with an 
identity link, these were found to not converge by the unblinded statistician while preparing DSMB 
reports. Therefore, the more stable logistic regression model will be used. Since two interim analyses 
were conducted, the level of significance at which the Chi-squared test of independence is conducted is 
0.048 (two-sided). 
 
4.3 Secondary Outcomes Analysis 
 
For the secondary outcomes outlined in section 2.2.1, a chi-squared test of independence will be used 
to compare the proportions between groups where appropriate. Odds ratios with 95% confidence 
intervals, and p values will be reported. 
 
Hospital-free days alive, ICU-free days alive, ventilator-free days and organ support-free days will be 
respectively analyzed as: the number of days out of hospital alive; the number of days out of ICU alive; 
the number of ventilator-free days alive (alive and free of invasive mechanical ventilation); and the 
number of organ support-free days alive (alive and free of invasive mechanical ventilation, non-invasive 
mechanical ventilation, high flow nasal cannula oxygen and vasopressor therapy)  through day 28; 


 
 
Statistical Analysis Plan V1.0 
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Page 7 of 8 
 
death up to 28 days will be assigned a value of –1. These outcomes will be analyzed using ordinal 
logistic regression. 
 
The post-treatment D-dimer will be compared by means of linear regression (ANCOVA), adjusted for 
baseline. Since the D-dimer assay differed across sites, the raw values are not comparable. Therefore, 
the D-dimer will be analyzed as the logarithm of D-dimer x upper limit of normal (ULN) by taking the 
natural logarithm of the ratio of the actual d-dimer value divided by the ULN for the assay used. 
 
4.4 Subgroup Analysis 
 
Subgroup analyses for the following characteristics at baseline will be conducted, accompanied by tests 
of treatment by subgroup interaction, using a logistic regression model.  
 
The subgroups pre-specified in the protocol are as follows: 
 
x Age (≤65 years versus >65 years) 
x Sex 
x BMI (≤30 kg/m2 versus >30 kg/m2) 
x Time from COVID-19 symptom onset (≤7 days versus >7 days since symptom onset) 
x Diabetes mellitus 
x Coronary artery disease 
x Hypertension 
x Race/ethnicity (Asian, Black or African American, Hispanic or Latino, White) 
 
The following three pre-specified subgroups will also be analyzed (not pre-specified in the protocol): 
 
x D-dimer levels at baseline (<2x upper limit of normal versus ≥2x upper limit of normal) 
x Use of systemic corticosteroids at baseline 
x Regions (North America, Brazil, Middle East, Ireland) 
 


 
 
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Page 8 of 8 
 
4.5 Sensitivity analysis 
 
Sensitivity analyses will be performed (1) excluding those who did not have a follow-up until day 28, 
death, or other primary composite outcome component; (2) excluding those who did not satisfy all 
eligibility criteria; and (3) excluding both types of participants. Sensitivity analyses will be repeated in 
the PP subset, if different from the ITT population. If possible, the binomial model with identity link will 
be performed on the primary outcome as an additional sensitivity analysis.  
 
To address changes in co-interventions over time due to emerging evidence from COVID-19 clinical 
trials, we will conduct a sensitivity analysis of the primary outcome using a logistic regression model 
with restricted cubic splines to model time by treatment interaction. 
 
4.6 Missing data 
 
The primary outcome will not have any missing data as per the definition of the ITT cohort above.  
 
A multiple imputation approach may be applied to age as baseline characteristic for the adjusted 
analysis of the primary outcome in case of data missingness.  
 
The secondary outcomes are also expected to be complete, or nearly complete since they are either 
components of the primary outcome or are measured in-hospital. Since secondary analyses are 
explorative, secondary outcomes will be analyzed as-is. 
 
However, if a primary or secondary outcome is missing in more than 5% of randomized patients, a 
complete case analysis, an inverse probability weighted analysis and multiple imputation on outcome 
will also be conducted in addition to the primary strategies (see Sections 4.2 and 4.3).