Antithrombin III (AT3) in Infectious Disease Caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2)/ Coronavirus Disease of 2019 (COVID-19)
Phase: PHASE2
Conditions: Antithrombin III Deficiency, Covid19
Sponsor: Enrique Ginzburg

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 1 of 23
1) Protocol Title
Antithrombin III (AT3) in Infectious Disease Caused by Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2)
Sponsor: 
Enrique Ginzburg, MD 
Professor of Surgery
Principal Investigator:
Brandon Parker, DO 
Assistant Professor of Surgery
Sub-Investigators:
Kenneth Proctor, PhD 
Professor of Surgery
Andrew Pastewski, MD 
Intensivist - Critical Care Services
Antonio Marttos, MD Associate 
Professor of Surgery
Waleed Sneij, MD
Pulmonologist – Critical Care 
Services
Division of Trauma and Surgical Critical Care, Department of Surgery 
Miller School of Medicine, University of Miami
Ryder Trauma Center / Jackson Memorial Hospital 
1800 N.W. 10th Avenue, T-215
Miami, Florida 33136
Office: 305-585-1178
FAX: 305-326-7065
Research Facility:
Jackson South Medical Center 
9333 S.W. 152nd Street, 
Miami, FL, 33157
Jackson Memorial Hospital
1611 NW 12th Ave, 
Miami, FL 33136
IRB:
University of Miami Human Subject Research Office 
Dominion Tower, 1400 NW 10th Avenue 12th Floor (M809) 
Miami, FL, 33136
ClinicalTrials.gov Identifier 
NCT04899232
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 2 of 23
1)
Objectives*
This will be a prospective, randomized, open label, interventional pilot trial to test the hypothesis that 
deficient endogenous AT3 is associated with a prothrombotic hyperinflammatory state associated with 
COVID-19.
2)
Background*
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2). As of 6/24/20, as social distancing was easing, the U.S. 
recorded >2.3M COVID-19 infections and >121K deaths, with new cases rising in at least 27 states 
[https://coronavirus.jhu.edu/map.html]. Worldwide, cases are rising at an even more alarming pace; 
there were 1M on 4/1/20, and >9.2 M cases with 478K deaths by 6/24/20. 
[https://coronavirus.jhu.edu/map.html].
A unique feature of the acute respiratory distress syndrome (ARDS) associated with COVID is a 
relatively preserved lung compliance and acute inflammation associated with a high alveolar-arterial 
oxygen gradient [PMID: 32267998]. The pathogenesis involves a rapid increase in airway cytokines 
which promotes pulmonary leukocyte sequestration, further propagating the local inflammatory 
response. Fibrin is deposited in the air spaces and lung parenchyma with elevated D-dimers and 
fibrinogen. Tissue factor (TF) is exposed on damaged alveolar endothelial cells and on the surface of 
leukocytes promoting more fibrin deposition, while increasing plasminogen activator inhibitor 1 (PAI- 
1) from lung epithelium and endothelial cells which creates a hypofibrinolytic state [PMID: 
32329246]. The signature finding on autopsy is diffuse pulmonary microthrombi associated with an 
ARDS caused by vascular occlusion rather than the more classic findings of low-compliance [PMID: 
32267998].
The most severely ill patients often present with mild symptoms that rapidly progress within 12- 
24h to multi-system involvement including ARDS, myocarditis, arrhythmias, cardiac arrest, 
gastrointestinal symptoms, hypoxemic brain injury, acute liver, renal function impairment, and 
cutaneous lesions. The common link seems to be microvascular occlusion with thrombi or viral laden 
antigen-antibody immune complexes [PMID: 32559324].
Thus, COVID might be a dysregulated inflammatory state superimposed on disseminated 
intravascular coagulation (DIC) with consumptive coagulopathy [PMID: 32302438]. These patients 
are at high risk for both thrombosis and bleeding, as well as an overwhelming cytokine storm. The 
pathogenic mechanism is not fully elucidated, but the dysregulated coagulation is probably 
orchestrated by inflammatory cytokines, lymphocyte cell-death, hypoxia, and endothelial damage 
[PMID: 32558075]. This is a project to develop an entirely novel evidence-based treatment that targets 
both the coagulopathy and the inflammation.
In 183 consecutive patients with COVID, the overall mortality was 11.5%. On admission, the 
non-survivors had higher D-dimer and fibrin degradation product (FDP) levels, longer prothrombin 
time and activated partial thromboplastin time compared to survivors; 71.4% of the deaths and only 
0.6% survivors met the criteria of DIC [PMID: 32073213]
In 40 patients with COVID, whole blood thromboelastometry (TEM) was consistent with 
hypercoagulability characterized by an acceleration of blood clot formation and higher clot strength. 
This hypercoagulable state persists for at least 5-10 days and was associated with deep vein thrombosis 
in six patients (15%), thromboembolism in 2 patients (5%), and catheter-related thrombosis in 12 
patients (30%). The ICU and the hospital mortality were 10% and 12.5%, respectively. [PMID: 
32394236]
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 3 of 23
In 16 COVID patients, the pro-coagulant TEM profile was characterized by an increased clot 
strength (CS), platelet contribution to CS, fibrinogen contribution to CS elevated D-dimer levels, and 
hyperfibrinogenemia. Fibrinogen levels were associated with interleukin-6 values. [PMID: 32302448].
In 24 COVID patients, the R, K, Alpha, and MA TEM parameters were all consistent with 
hypercoagulability. Platelet count was normal or increased, prothrombin time and activated partial 
thromboplastin time were near normal. Fibrinogen, D-dimer, C-reactive protein, Factor VIII and von 
Willebrand factor, protein C were all increased whereas AT3 was decreased [PMID: 32302438].
In 94 patients with COVID vs 40 healthy controls, whereas D-dimer, fibrin/fibrinogen degradation 
products (FDP), and fibrinogen (FIB) in all SARS-CoV-2 cases were all higher, but AT3 was lower 
[PMID: 32172226].
The most logical prophylaxis or treatment for this hypercoagulable state is either unfractionated 
heparin (UFH) or low molecular weight heparin (LMWH), but this often fails. One possible 
explanation is that both UFH and LMWH require AT3 to exert their anticoagulant effect. [PMID: 
32516429]. Therefore, endogenous AT3 deficiency can result in failure to achieve adequate 
anticoagulation with standard chemoprophylaxis with either UFH or LMWH.
AT3 is currently FDA approved for prophylaxis and treatment of thrombotic and 
thromboembolic disorders in patients with hereditary AT3 deficiency (i.e. AT3 below 70% of normal). 
In this project, we test the intriguing idea that AT3 can be repurposed, to treat the procoagulant state 
and resulting cytokine storm associated with COVID. There are virtually no studies on whether low 
endogenous AT3 explain the COVID-associated coagulopathy and/or cytokine storm.
AT3 is a nonvitamin K-dependent serine protease inhibitor that anticoagulates by neutralizing 
the enzymatic activity of thrombin. It is a glycoprotein produced by the liver and consists of 432 
amino acids. Its activity is potentiated by UFH or by LMWH such as dalteparin or enoxaparin. TEG- 
guided adjusted enoxaparin dosing increased anti-Xa activity, but this did not decrease the rate of 
venous thromboembolism (VTE) in trauma patients. Failure to reduce the VTE rate despite high 
supplemental LMWH and increased anti-Xa activity was consistent with AT3 deficiency (PMID 
24662855). Thus, the effectiveness of thromboprophylaxis may depend in part endogenous AT3.
Furthermore, some evidence suggests that AT3 has anti-inflammatory properties.
AT3 is protective against renal, myocardial and cerebral ischemic injury by suppressing 
macrophage activity and reducing production of pro-inflammatory cytokines In contrast, AT3 
deficiency augments coagulation and inflammation in the brain in a mouse model of acute cerebral 
ischemia-reperfusion [PMID: 32305521]..
The fact is that several factors have major modulatory role in both coagulation and inflammation 
[PMID: 26676884]. AT3, tissue factor pathway inhibitor, and protein C, all suppress proinflammatory 
mediators. Conversely, inflammation blunts anticoagulant activity and, when uncontrolled, promotes 
DIC. AT3 has broad anticoagulant activity and potent anti-inflammatory properties in hereditary or 
acquired AT deficiency [PMID: 26676884]. AT3 modulates inflammation by inhibiting thrombin and 
other clotting factors that induce cytokine activity and leukocyte-endothelial cell interaction, and also 
by coagulation-independent effects, including direct interaction with cellular mediators of 
inflammation [PMID: 26676884]. An increasing body of evidence suggests that AT3 may
be a potential therapeutic agent in certain clinical settings associated with inflammation 
[PMID: 26676884], but there is no data on whether AT3 modulates the 
hypercoagulation/ inflammation associated with COVID.
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 4 of 23
3)
Inclusion and Exclusion Criteria*
INCLUSION CRITERIA:
a.
>18y of age,
b.
Subject or proxy who can provide informed consent
c.
Positive SARS COV2 by PCR or as determined by clinical team
EXCLUSION CRITERIA:
a.
Adults or Proxy unable to consent
b.
Individuals who are not yet adults (infants, children, teenagers)
c.
Pregnant women
d.
Prisoners
e.
Patients expected to die within 24 hours or with a “do not resuscitate” order,
f.
Multi-organ failure,
g.
History of hypersensitivity or allergy to any component of the study drug,
h.
Ongoing massive surgical or unexplained bleeding,
i.
History of bleeding or clotting disorder,
j.
Severe traumatic brain injury (Glasgow Coma Scale <6),
k.
Spinal or multiple-trauma,
l.
Cancer (incurable/terminal phase) and/or patients receiving palliative care,
m.
Enrollment in another concurrent clinical interventional study
-
if considered interfering with this study objectives
n.
Per study team discretion, any condition(s) that may prevent safe treatment, preclude adequate 
evaluation or adding further risk to their underlying illness.
4)
Number of Subjects*
The study population will be comprised of 75 patients assigned to one of three groups of 25 COVID 
(+) patients each.
The proportion of subjects with AT3 levels < 100% will be 50/50 randomization of which 25 subjects 
with AT3 <100% will be standard of care and 25 subjects with AT3<100% will be standard of care 
with exogenous AT3 supplementation. The third group will be subjects with AT3 levels ≥100%.
a.
25 patients with endogenous AT3 >100% who receive standard of care only or
b. 25 patients with endogenous AT3 <100% who receive standard of care only or
c.
25 patients with endogenous AT3 <100% who receive standard of care plus supplemental AT3.
5)
Study-Wide Recruitment Methods*
Potential subjects will be recruited as inpatients under the care of an attending which may include the 
PI or Sub-Is on this study. Eligibility will be determined by any member of the study team under 
direction of the PI and in collaboration with the attending physician through review of inclusion and 
exclusion criteria as compared to the patients’ presentation, diagnoses and medical history. Jackson 
Health System’s medical records within Cerner will be accessed under a waiver of HIPAA 
authorization (see section 21). After collaboration with the clinical team and initial screening for entry 
criteria, a member of the study team will approach potential subjects for consent and enrollment.
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 5 of 23
6)
Study Timelines*
a.
Subject participation will be approximately 11 days from the time of consent to the last blood 
draw. After the last blood draw, only routine clinical data will be followed and captured from the 
medical record to outcomes.
b. Enrollment of 75 subject will be over the course of 12 to 18 months.
c.
The primary analyses should be completed within 24 months from the time of study initiation.
7)
Study Endpoints*
The Primary endpoint is change from baseline in the ISTH DIC Score to Day 9.
The Secondary endpoints include change from baseline D-dimers, Fibrinogen & Prothrombin time, 
length of hospital stay (days), mortality (%), and Pulmonary function (including Time (days) to 
mechanical ventilation and/or ECMO Duration (days) of new ventilator or extracorporeal membrane 
oxygenation (ECMO) use, Change from baseline SOFA and SOFA Respiratory sub-score, Number of 
venous thromboembolisms, Number of major bleeding events
Subjects discharged prior to completion of intervention would be classified as having a successful 
outcome. We anticipate that all cause morbidity will occur in 10-20% of the COVID study population, 
despite standard of care. We anticipate that these patients will be deficient in endogenous AT3.
8)
Procedures Involved*
Any member of the study team will discuss potential subjects with the clinical team for 
appropriate pursuit of informed consent and screening for eligibility.
75 eligible subjects, after consent, will have laboratory blood tests for further screening. 
25 of those subjects with endogenous AT3 ≥ 100% will continue with SOC.
50 of those subjects with endogenous AT3 < 100% will be will be randomly assigned to begin SOC 
plus treatment with exogenous AT3 supplementation or only SOC treatment. The randomization 
schedule will be established by a member of the study team that is not involved in the informed 
consent process.
They will all be followed up for laboratory blood tests, study endpoints and adverse events. 
If they do not meet entry criteria they will be excluded from the study.
Consented subjects will be scored according to The International Society of Thrombosis and 
Haemostasis Disseminated Intravascular Coagulation scale (ISTH DIC) on study visit days 1, 3, 5, 
7, 9 and 11.
The SOFA score will be performed only when the parameter is obtained clinically and monitored 
for changes in patient status on study visit days 1, 3, 5, 7, 9 and 11. Each organ system is assigned a 
point value from 0 (normal) to 4 (high degree of dysfunction/failure)). It will be calculated on 
admission and Day 11 using the worst parameters measured during the study visit day. If a 
parameter is not obtained clinically it will be voided for research purposes.
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 6 of 23
Thrombate Dose =
_ (120% - baseline AT3%) x body weight (kg)_
1.4
25 subjects will receive standard 
medical care for Cov19 infection 
and anticoagulation according to 
the institutional protocol
25 subjects will receive standard 
medical care for Cov19 infection 
and anticoagulation according to 
the institutional protocol
25 subjects will receive standard of care 
for Cov19 infection and anticoagulation 
according to the institutional protocol and
+ Thrombate targeting 120% activity 
level
25 subjects with AT3 
activity levels ≥100%
50 subjects with AT3 
activity levels <100% will 
be randomized to 1 of 2 
groups
Upon consent, 75 eligible patients will 
be screened for AT3 level and 
assigned to 1 of 2 groups
After enrollment and each 48h period (+/- 12 hours) thereafter, blood samples are collected and 
assayed for routine clinical coagulation and inflammation markers, including AT3 activity, D-Dimer, 
anti-Xa, fibrinogen, and prothrombin time until Day 11.
Dosing Rationale-
In those COVID(+) patients with an endogenous AT3 activity level <100% and at the discretion of the 
attending physician, Day 1 infusion of AT3 will be at a dose to be adjusted based on initial body 
weight up to 100 kg maximum and to a set target plasma activity level of 120% according to the 
following formula:
= (120% - baseline AT3%) x body weight (kg) 
1.4
Based on an example of an 85kg patient with a baseline AT activity level of 90%,
-
The dose would be 1,821 units on a dosing schedule of Day 1, 3, 5, 7 & 9
-
For a total of approximately 9100 units
-
Each Thrombate III vial contains 500 units each reconstituted with 10 mL of Sterile Water for 
Injection, USP, the final concentration is approximately 50 units per mL.
-
Requiring 4 vials per dose or 20 vials per patient
Each 85kg patient will receive ~9100 IUs over 5 doses requiring 20 vials
-
(10% overage to account for any dose adjustments needed)
-
therefore each patient would require 10,000 IUs
-
for a total of 250,000 IUs or 500 vials for the study.
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 7 of 23
AT3 will be drawn every other day, pre-dose, for monitoring, and verification of 120% target plasma 
activity level. Dosing schedule will be as follows: Day 1, 3, 5, 7 & 9 a dose will be given if AT3 
activity level remains less than 100% on those days, otherwise no dose will be given. Days refer to a 
24 hour period.
Data to be collected from the medical record according to the Study Flowsheet (Appendix B) will 
include:
a.
Demographics: age, comorbidities, medical history, concomitant meds, vital signs, height and 
weight,
b. ISTH DIC score and a Sofa Score,
c.
Laboratory values:
a.
Platelets, PT, INR, PTT, D-Dimer, Fibrinogen, AT3 level, Anti-Xa,
d. Outcomes:
a.
Length of Stay, Mortality, change in PF ratio, Vent/ECMO days, # and severity VTE’s, 
# and severity of bleeding events
9)
Statistics*
Statistical analyses will be performed using SPSS version 21 (IBM Corporation, Armonk, NY). 
Parametric data are reported as M±SD and nonparametric data are reported as median (interquartile 
range). Missing values for continuous variables are handled by applying imputation methods before 
calculating their statistics. The study population will be stratified into two halves based on the primary 
outcome of change from baseline SOFA and/or ICTH DC. Those with the fastest rate of recovery are 
compared to those with the slowest rate of recovery. We expect that AT3 will correlate with rate of 
recovery and/or with one or more of the secondary outcomes. The demographics and physiologic 
variables in the fastest and slowest groups are compared using a t test or Mann-Whitney U-test, as 
appropriate. Categorical variables are compared using a χ2 or Fisher’s exact test, as appropriate.
Statistical significance is determined at p<0.05. Then multivariate models will be evaluated for 
predicting the primary or secondary outcomes, using various performance metrics, such as area under 
the receiver operating characteristic curve, sensitivity and specificity, positive predictive value, and 
negative predictive value, as we have described in multiple previous studies. In addition, propensity 
scores will be assigned for each patient based on a 1:1 fixed ratio nearest neighbor matching was 
performed to compare those with fastest or slowest recovery. A 1:1 fixed ratio nearest neighbor 
matching is performed to minimize bias without sacrificing power, as we have described in multiple 
previous studies.
10)
Provisions to Monitor the Data to Ensure the Safety of Subjects*
Study Staff will maintain the data on paper Case Report Forms and in an electronic database stored 
in a secure location and on a password- protected computer system. The consent forms will be kept 
in files which will be stored in a secure location within Jackson Health System. De-identified data 
will be uploaded to the electronic database. The PI and/or a member of the study team will confirm 
the completeness of data being entered in the electronic database
In order to protect all subjects’ confidentiality, we will store data on a password-protected network. 
Subjects will receive a study-specific unique identifier and the medical record number (MRN) will be 
uncoupled from the data. The decoder key for study identifier and MRN will be stored in a separate, 
password-protected file.
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 8 of 23
Trial Monitoring, Auditing, and Inspecting
The investigator will permit trial-related monitoring, quality audits, and inspections by, government 
regulatory authorities, of all trial-related documents (e.g., source documents, regulatory documents, 
data collection instruments, case report forms). The investigator will ensure the capability for 
inspections of applicable trial-related facilities. The investigator will ensure that the trial monitor or 
any other compliance or QA reviewer is given access to all trial-related documents and trial-related 
facilities.
Participation as an investigator in this trial implies the acceptance of potential inspection by 
government regulatory authorities.
In addition to the Clinical Monitoring component of this protocol, Quality Assurance (QA) to assess 
compliance with GCP and applicable regulatory requirements. Data or documentation audited shall be 
assessed for compliance to the protocol, accuracy in relation to source documents and compliance to 
applicable regulations.
Adverse Event (AE) Definition
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical/medicinal product. An AE does not necessarily have to have a causal 
relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporarily associated with the use of 
a medicinal product (investigational or marketed), whether or not considered related to treatment with 
the medicinal product.
An AE includes:
•
An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality
•
An illness, sign, symptom, or clinically significant laboratory abnormality that is detected or 
diagnosed after study drug administration
•
Pretreatment or post-treatment events that occur as a result of protocol-mandated procedures
An AE does not include:
•
The disease or disorder being studied or signs and symptoms associated with the disease or 
disorder, unless there is worsening of the condition of the disease or disorder
•
A pre-existing disease or condition, present at the start of the study, that does not worsen.
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported, obtained through non-leading questioning, or noted 
during examination of a subject. Adverse events will be recorded from the signing of informed 
consent through the last dose of study drug. Serious adverse events will be recorded from the signing 
of informed consent through hospital discharge.
At each visit, new AEs are recorded sequentially on the Adverse Event log. The AE term will note 
the diagnosis whenever possible, not the individual signs or symptoms (e.g., myocardial infarction will 
be recorded rather than chest pain, elevated cardiac enzymes, and abnormal ECT). Also recorded are:
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 9 of 23
•
Start and stop date and time
•
Whether or not the event is continuing
•
Severity (mild, moderate, severe)
-
Mild: usually transient, requiring no special treatment and generally not interfering with 
usual daily activities
-
Moderate: usually ameliorated by simple therapeutic maneuvers and impairs usual activities
-
Severe: requires vigorous therapeutic intervention and interrupts usual activities.
Hospitalization may or may not be required.
Relationship to Study Medication
The relationship of an AE to the administration of study medication (unrelated, probable or definite) is 
a clinical decision based on all available information at the time of review. The relationship will be 
evaluated according to the following definitions:
Unrelated: includes the existence of a clear alternative explanation (e.g., mechanical bleeding at 
surgical site) or non-plausibility (e.g., the patient is struck by an automobile, at least where there is no 
indication that the study medication caused disorientation that may have led to the event; cancer 
developing a few days after study medication administration).
Probable: The AE, including clinical laboratory abnormality, follows a reasonable sequence from the 
time of study medication administration, follows a known response pattern of the study medication 
class, is unlikely to be attributed to the patient’s clinical state, and is confirmed by improvement on 
stopping the study medication (de-challenge).
Definite: The AE, including clinical laboratory abnormality, follows a plausible sequence from the 
time of study medication administration; follows a known or expected response pattern to the study 
medication class; cannot be explained by disease or it disappears or decreases on cessation or reduction 
in study medication dose; and/or it reappears or worsens when the study medication is re-administered.
Actions taken (none, study drug dose interrupted, study drug discontinued, change in treatment).
Outcome (resolved, severity or frequency increased, ongoing, fatal). An individual AE receives only 
one outcome.
Adverse events not resolved at the end of treatment will be followed until discharge or until the AE is 
judged by the investigator to have stabilized.
Serious Adverse Events
An event that is serious will be recorded on the Serious Adverse Event log. SAEs will be recorded 
from the signing of informed consent hospital discharge.
The most common adverse events are mild and related to underlying disease such as respiratory 
distress. If these occur, they will be noted in the adverse event tracking log and reported to the IRB 
during Continuing Review.
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 10 of 23
More serious adverse events and any unexpected adverse events will be recorded as per UM HSRO 
policies and procedures.
Disease Related Adverse Events
It is recognized that this patient population who require critical care support will experience a number 
of common aberrations in laboratory values, signs, and symptoms due to the severity of the underlying 
disease and the impact of standard therapies. These will not necessarily constitute an AE unless they 
require significant intervention, lead to discontinuation of study medication, felt to be related to study 
medication or are considered to be of concern, in the Investigator’s clinical judgment. Examples of the 
type of AEs that may be associated with the patient population are listed below.
List of Expected Adverse Events
Acute respiratory failure; respiratory distress; acute lung injury; acute respiratory distress syndrome 
(ARDS); acute renal failure; coagulation dysfunction; decreased platelets count; neutropenia; 
hypothermia; fever, bacteremia; sepsis, septic shock; hypotension; metabolic acidosis, pleural effusion; 
abdominal compartment syndrome; repeated surgeries/debridement; amputation.
For purposes of this study, deaths will be captured as clinical outcomes and do not need to 
be reported as SAEs unless felt related to study drug administration.
11)
Withdrawal of Subjects*
The occurrence of any of the following events may necessitate premature withdrawal of a subject from 
the study:
•
Development of any of the following Inclusion/Exclusion criteria:
o
Subjects with a “do not resuscitate” order,
o
Multi-organ failure,
o
History of hypersensitivity or allergy to any component of the study drug,
o
Ongoing massive surgical or unexplained bleeding,
o
History of bleeding or clotting disorder,
•
Occurrence of a serious adverse event (SAE) thought to be related to study drug and not 
alleviated by symptomatic treatment
•
Unwillingness to continue in the clinical study
•
Death of the subject
•
Principal Investigator decision (i.e. subject non-compliance with study procedures)
•
Significant AE or medical decision that precludes the subject from adhering to study 
requirements
12) Stopping rules.
The following events will require the study to pause and be evaluated prior to resuming the study. 
These events will be reported to the FDA in a timely manner as required per 21 CFR 312.64(b)
a.
Any major bleeding event
b. Any anaphylaxis event
c.
2 infusion reactions
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 11 of 23
13) Risks to Subjects*
Hypersensitivity reactions, including anaphylaxis, are possible. Should symptoms occur, 
THROMBATE III infusion will be discontinued and appropriate treatment begun as per clinical 
judgement.
• Because THROMBATE III is made from human blood, it may carry a risk of transmitting infectious 
agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the 
Creutzfeldt-Jakob disease (CJD) agent.
• We will perform coagulation tests to avoid excessive or insufficient anticoagulation and monitor for 
bleeding or thrombosis. Assessment will be based on clinical findings at the discretion of the treating 
physician along with laboratory values of PT, PTT, Hemoglobin and Hematocrit analysis. Treatment 
may include heparin for excessive coagulation or blood transfusion for insufficient coagulation 
ultimately left to the discretion of the treating physician.
Two clinical trials were conducted in 33 subjects with congenital AT deficiency. Nine subjects (27%) 
experienced 29 adverse reactions which occurred during 17 of 389 infusions. There were no serious 
adverse reactions reported. The severity of adverse reactions was reported as mild or moderate, except 
for wound secretion and hematoma, which was severe.
Dizziness (12%), Chest discomfort (9%), Nausea (9%), Dysgeusia (6%), Pain (cramps) (6%), and each 
of the following were reported in 3% of the subjects: Chills, Wound secretion and hematoma, Vision 
blurred, Chest pain, Dyspnea, Intestinal dilatation, Pyrexia and Urticaria,
DRUG INTERACTIONS
The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in 
patients with hereditary AT deficiency. Thus, in order to avoid bleeding, the dosage of heparin (or low 
molecular weight heparin) may need to be reduced during treatment with THROMBATE III.
The effect of drugs that use antithrombin to exert their anticoagulation may be altered when 
THROMBATE III is added or withdrawn. We will regularly perform coagulation tests suitable for the 
anticoagulant used (e.g., aPTT and anti-Factor Xa activity) and at close intervals to avoid excessive or 
insufficient anticoagulation. Adjust dosage of anticoagulant as necessary. Additionally, we will 
monitor the patients for the occurrence of bleeding or thrombosis.
14)
Potential Benefits to Subjects*
We expect subjects with deficient endogenous AT3 can lessen the risk associated with a prothrombotic 
hyperinflammatory state with infusion of AT3.
15)
Setting:
Jackson South Medical Center , Jackson Memorial Hospital
16)
Resources Available
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 12 of 23
The PI has experience conducting and being trained for clinical research. All study personnel will be 
trained on the protocol by the investigator or designee and complete CITI training. Those obtaining 
consent will also have prior experience communicating with patients.
17)
Prior Approvals:
We have preliminary approval of funding from Grifols.
18)
Confidentiality
The protected health information collected for the purpose of this research study will be assigned a 
research code number and any obvious patient identifiers (name, social security number, hospital 
record number) will be removed from this information. Both the confidential health information and 
the information linking the research code numbers to the patients’ identities will be stored in a secure 
manner (e.g., locked file cabinet, password protected database) accessible only to the study team. The 
information linking the research code numbers to the patients’ identities will be stored separate from 
the confidential health information.
Data will be de-identified and stored on a password-protected network accessible only to research 
staff. Data will be retained for at least six years following conclusion of the study on this network.
Please note: Any data, including Personally Identifiable Information (PII) and/or Protected Health 
Information (PHI), acquired from JHS with a waiver of HIPAA Authorization (without a signed 
HIPAA authorization) may only be stored in the secure JHS SharePoint environment provided by JHS. 
The Study Team is not permitted to copy or store JHS data in any other system. We will contact the 
JHS Office of Research for additional information or clarification.
Protected Health Information (PHI) is defined under HIPAA in 45 CFR § 160.103. The following list 
of identifiers of an individual, or of relatives, employers, or household members of the individual, are 
defined under HIPAA in 45 CFR § 164.541:
(A) Names;
(B) All geographic subdivisions smaller than a State, including street address, city, county, precinct, 
zip code, and their equivalent geocodes, except for the initial three digits of a zip code if, according to 
the current publicly available data from the Bureau of the Census:
(1) The geographic unit formed by combining all zip codes with the same three initial digits contains 
more than 20,000 people; and
(2) The initial three digits of a zip code for all such geographic units containing 20,000 or fewer 
people is changed to 000.
(C) All elements of dates (except year) for dates directly related to an individual, including birth date, 
admission date, discharge date, date of death; and all ages over 89 and all elements of dates 
(including year) indicative of such age, except that such ages and elements may be aggregated into a 
single category of age 90 or older;
(D) Telephone numbers;
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 13 of 23
(E) Fax numbers;
(F) Electronic mail addresses;
(G) Social security numbers;
(H) Medical record numbers;
(I) Health plan beneficiary numbers;
(J) Account numbers;
(K) Certificate/license numbers;
(L) Vehicle identifiers and serial numbers, including license plate numbers;
(M) Device identifiers and serial numbers;
(N) Web Universal Resource Locators (URLs);
(O) Internet Protocol (IP) address numbers;
(P) Biometric identifiers, including finger and voice prints;
(Q) Full face photographic images and any comparable images; and
(R) Any other unique identifying number, characteristic, or code
The name, date of birth and mrn are required to conduct this study.
19) Choose the statements below that are applicable to this research:
20(a). Will the research collect protected health information or personally identifiable 
information from the EMR or from subjects at UHealth and/or JHS?
☒ Yes (If checked go to 21(b))
☐No (If checked, go to Section 22)
20(b). Check the box next to the correct statement below
☒ Research Subjects will sign a HIPAA Authorization before the research will collect this data.
□Research Subjects will not sign a HIPAA Authorization for this data collection and the
□Research is requesting a waiver of HIPAA authorization from the IRB. (If checked, complete 
Section 17 below
20(c). How will the research store the data? (See Section 21(e) below)
□On a University of Miami electronic device (e.g. encrypted, password-protected computer)
☒ On a cloud-based storage system that is approved by the University of Miami
☒ On a secured JHS SharePoint environment (required for protected health information or identifiable 
information collected from JHS records without a waiver of authorization from IRB.)
☐Other, specify: Click here to enter text.
20(d) Select one of the following:
☐The Principal Investigator (and/or Study Team members) will record (e.g. write down, abstract) 
data acquired in a manner that does not include any indirect or direct identifiers (listed in the 
instructions for Section 19 of this protocol), and the recorded data will not be linked to the 
individual’s’ identity.
OR
☒ The Principal investigator (and/or Study Team members) will record (e.g. write down, abstract) the 
data collected in a manner that does not include any direct identifiers (see list in the instructions for
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 14 of 23
Section 19 (Confidentiality) of this protocol) of any subject. Instead, the Principal Investigator and/or 
Study Team members shall will assign a code (that is not derived in whole or in part from any direct 
or indirect identifiers of the individual) to each study subject and link the code to the study subject’s 
identity. The link to each subject’s identity and/ or other identifiable information will be maintained 
on a document separate from the research data.
20(e) Additional requirement for Jackson Health System Data:
This section applies to data that will be collected from JHS under a waiver of HIPAA authorization 
(without a signed HIPAA Authorization from the participant).
☐Not-applicable, no data will be acquired from JHS under a waiver of authorization.
☒ JHS data, including Protected Health Information (PHI) and/or Personally Identifiable Information 
(PII), acquired from JHS for this research under a waiver of authorization shall only be stored on the 
secured JHS SharePoint environment made available by JHS. I and the Study Team members shall not 
copy or store the JHS sourced personally identifiable information (PII), including protected health 
information (PHI) data to any other system, including any systems maintained or provided by the 
University of Miami. I and the Study Team shall only copy or transfer JHS-sourced data that has been 
properly de-identified in accordance with all requirements contained in the HIPAA Rules by removing 
all of the identifiers listed in the instructions for Section 19 of this protocol.
20)
Provisions to Protect the Privacy Interests of Subjects
Access to patients and their protected health information along with the collection and analysis is 
necessary in order to conduct this research study. Consistent with the “minimum necessary standard” 
of the HIPAA privacy rule, we will only access and collect the specific health information necessary to 
complete this research study.
Some of the research investigators who will access and use the protected health information may also 
be involved directly in the care of the respective patients, thus obviating the privacy and confidentiality 
concerns.
Authorization to obtain protected health information will be obtained from the patient as soon as 
possible.
The protected health information collected for the purpose of this research study will be assigned a 
research code number and any obvious patient identifiers (name, social security number, etc) will be 
removed from this information. Both the confidential health information and the information linking 
the research code numbers to the patients’ identities will be stored in a secure manner (e.g., locked file 
cabinet, password protected database) accessible only to the study team.
21)
Consent Process
22a. Remote Consenting for subject proxies unavailable for inperson consenting will include the 
following:
•
Send a copy of the consent document via secure email or U.S. Mail.
•
Arrange for an impartial witness not part of the study team to attend and witness the consent 
discussion.
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 15 of 23
•
Let the participant know that a witness will join the consent meeting.
•
Set up a video meeting or 3-way call and send an invitation to the attendees.
We will ask the participant to scan or take a picture of each page of the documents and email the 
signed/dated documents to the study team. As an alternative, we may establish a secure network 
location for uploading the consent document.
During meeting:
•
Identify everyone on the call.
•
Review the informed consent with the participant, answer the participant’s questions and ask 
questions of the participant to confirm comprehension.
•
Ask the participant if s/he consents to participate/continue participation.
•
If the participant agrees, ask him/her to sign and date the consent document.
•
If using 3-way call, ask the participant to confirm s/he signed & dated the document.
We will ask the participant to scan or take a picture of each page of the documents and email the 
signed/dated documents to the study team. As an alternative, the research could establish a "UM Box" 
location for uploading the consent document.
If the person is unable to take a picture, we will document the circumstances.
The person conducting the consent process will sign and date a copy of the consent document. 
The impartial witness will sign & date on the witness line of a copy of the consent document.
The person conducting the consent process will document the purpose for the remote consent (COVID- 
19), and each step of the process. The note will explain why the research team doesn’t have the signed 
and dated document.
Documenting the Remote Consent process
The originals of the informed consent document signed by the investigator (and possibly the witness) 
will be placed in the participant’s research record.
The person obtaining consent will document how s/he confirmed that the patient consented and signed 
the consent form. The participant may retain the signed original due to contamination. The note will 
include a statement indicating why the informed consent document signed by the participant was not 
retained, (e.g., due to contamination of the document by infectious material.)
If the participant cannot send a picture of the signed document, the person obtaining consent will 
document why a copy of the signed document is not available. See example below.
Example:
Informed consent was obtained on Date at Time. The participant could not come to the site for the 
consent process due to COVID-19 social distancing requirements. A copy of the consent document 
was emailed to the prospective participant before the consent discussion
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 16 of 23
The consent process was performed by phone/ZOOM. The individuals attending the discussion were: 
(list the names of the individuals). The person obtaining consent explained the research to the 
participant and answered the participant’s questions. The person obtaining consent asked the 
participant questions to ascertain whether the s/he understood the study, and the participant was able to 
answer the questions. The participant voluntarily agreed to participate. The subject/LAR signed and 
dated the consent document. The research was not able to obtain a copy of the signed original consent 
document because consent was obtained remotely, and the document may transmit the COVID-19 
infection.
After signing the consent document, the participant took a picture and sent it to the research team/ OR 
The participant was unable to send a picture of the document. An impartial witness observed the 
entire process.
The consenter will then add similar documentation about the HIPAA authorization.
22b. In person consenting:
The subject will be approached in the clinic area by a member of the research staff. Any of the staff 
members listed on the protocol will discuss the risks and benefits of participation. If the staff member 
is not fluent in the patient's preferred language, they will use a translator to obtain informed consent in 
a document written in the patient's preferred language. Initiating this process may also occur over the 
phone and during scheduling and may include mailing of the consent form to allow for more time to 
read and understand prior to coming into clinic.
Subject will be given an ICF in their preferred language (English/Spanish only). They will be given 
ample time to review the ICF with family, clergy, friends or primary physicians. Once they have 
agreed they will be required to sign ICF before any study procedures can be done on the subject. A 
copy of the ICF will be given to the subject and one will be placed in the medical records. The original 
will stay in the subject’s source documentation folder located in the Trauma Research Office.
22)
Process to Document Consent in Writing
We will document consent with a translated written informed consent document in a language 
understandable to the participant. If subjects who do not speak English are eligible, we ensure that the 
oral and written information provided to those subjects will be in that language either by research 
personnel fluent in that language or by an institutional translator. We will pursue approval of the 
consent documents in Spanish as a significant portion of the subject population may speak Spanish.
We also request permission to utilize the short forms for documentation of consent and translation into 
other than the English or Spanish for the rare circumstance that the subject cannot communicate in 
either of those languages.
23)
Authorization for Use and Disclosure of Protected Health Information (HIPAA)
Type of Request:
☒ Waiver of Authorization for access to medical record for subject identification/recruitment.
☐Waiver of Authorization for access to medical record to obtain data for the research.
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 17 of 23
Confirm that you will destroy the Protected Health Information (PHI) you and/or your Study Team 
acquire receive from JHS and/or UHealth at the earliest opportunity.
☒
I confirm
Confirm that the Protected Health Inform (PHI) you acquire from JHS and/or UHealth will not be re- 
used or disclosed to any other person or entity, except as required by law or for authorized oversight of 
the research study or for other research for which the use or disclosure of PHI is permissible.
☒
I confirm
If you are collecting health information from JHS under a waiver of authorization, you must read the 
paragraph below and sign the signature block to indicate your agreement:
☐Not applicable. This research will not collect data from JHS record under a waiver of authorization
Notwithstanding the preceding “I confirm” statements above, I agree that neither I nor any member of 
the study team listed on the IRB submission for this Protocol shall ever re-use or re-disclose any of the 
information acquired from Jackson Health System in any format, whether identifiable or de-identified, 
to any individual or entity without first obtaining written permission from Jackson Health System, 
even if such re-use or re-disclosure is permissible by law (e.g., HIPAA).
Signature
Date
24)
Drugs or Devices
Drug Administration, Dispensation and Disposition
Once consent is obtained and necessary baseline data collected, and if the subject is enrolled and 
falls into the Thrombate III infusion arm, they will begin receiving THROMBATE III 
(Antithrombin III [Human]) at 120% target dose every other day for 9 days.
Study drug will be packaged, labeled, and delivered to the clinical center by the drug manufacturer. 
All medication supplied to be used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice (GMP).
The pharmacy will conduct an inventory upon receipt of the clinical supplies and will acknowledge 
receipt of the supplies to the sponsor. A copy of the shipping documents will be maintained for 
records. Study drug will be stored in accordance with the package insert in a secure location until 
dispensed to the subject.
Study drug kits will be dispensed according to the dosing schedule. The pharmacy will keep a current 
record of the inventory and dispensing of all clinical supplies. This record will be made available to 
the sponsor’s monitor for the purpose of accounting for all clinical supplies. Any discrepancy or 
deficiency will be recorded, with an explanation. All supplies sent to the investigator will be 
accounted for and in no case will clinical supplies be used in an unauthorized situation.
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 18 of 23
25)
REFERENCES
PMID: 32267998
Wang J, Hajizadeh N, Moore EE, et al. Tissue plasminogen activator (tPA) treatment for COVID-19 
associated acute respiratory distress syndrome (ARDS): A case series. J Thromb Haemost.
2020;18(7):1752-1755. doi:10.1111/jth.14828
PMID: 32329246
Whyte CS, Morrow GB, Mitchell JL, Chowdary P, Mutch NJ. Fibrinolytic abnormalities in acute 
respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. J 
Thromb Haemost. 2020;18(7):1548-1555. doi:10.1111/jth.14872
PMID: 32559324
Garg S, Garg M, Prabhakar N, Malhotra P, Agarwal R. Unraveling the mystery of Covid-19 cytokine 
storm: From skin to organ systems [published online ahead of print, 2020 Jun 19]. Dermatol Ther.
2020;e13859. doi:10.1111/dth.13859
PMID: 32302438
Panigada M, Bottino N, Tagliabue P, et al. Hypercoagulability of COVID-19 patients in intensive care 
unit: A report of thromboelastography findings and other parameters of hemostasis. J Thromb 
Haemost. 2020;18(7):1738-1742. doi:10.1111/jth.14850
PMID: 32558075
Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19 [published online ahead of print, 2020 
Jun 18]. J Thromb Haemost. 2020;10.1111/jth.14975. doi:10.1111/jth.14975
PMID: 32073213
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in 
patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844-847. 
doi:10.1111/jth.14768
PMID: 32394236
Pavoni V, Gianesello L, Pazzi M, Stera C, Meconi T, Frigieri FC. Evaluation of coagulation function 
by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia. J Thromb 
Thrombolysis. 2020;50(2):281-286. doi:10.1007/s11239-020-02130-7
PMID: 32302448
Ranucci M, Ballotta A, Di Dedda U, et al. The procoagulant pattern of patients with COVID-19 acute 
respiratory distress syndrome. J Thromb Haemost. 2020;18(7):1747-1751. doi:10.1111/jth.14854
PMID: 32172226
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 19 of 23
Han H, Yang L, Liu R, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 
infection. Clin Chem Lab Med. 2020;58(7):1116-1120. doi:10.1515/cclm-2020-0188
PMID: 32516429
Arachchillage DJ, Remmington C, Rosenberg A, et al. Anticoagulation with argatroban in patients 
with acute antithrombin deficiency in severe COVID-19 [published online ahead of print, 2020 Jun 9]. 
Br J Haematol. 2020;10.1111/bjh.16927. doi:10.1111/bjh.16927
PMID: 24662855
Louis SG, Van PY, Riha GM, et al. Thromboelastogram-guided enoxaparin dosing does not confer 
protection from deep venous thrombosis: a randomized controlled pilot trial. J Trauma Acute Care 
Surg. 2014;76(4):937-943. doi:10.1097/TA.0000000000000165
PMID: 32305521
Nakano T, Nakamura Y, Irie K, et al. Antithrombin gamma attenuates macrophage/microglial 
activation and brain damage after transient focal cerebral ischemia in mice. Life Sci. 2020;252:117665. 
doi:10.1016/j.lfs.2020.117665
PMID: 26676884
Levy JH, Sniecinski RM, Welsby IJ, Levi M. Antithrombin: anti-inflammatory properties and clinical 
applications. Thromb Haemost. 2016;115(4):712-728. doi:10.1160/TH15-08-0687
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 20 of 23
Appendix A
ISTH DIC, the score is increased by 2 points for abnormal baseline D-dimers (fibrin-related marker) 
and/or abnormal fibrinogen <1.0 gram/L level (1 point). This scoring algorithm was developed by the 
ISTH Scientific and Standardization Committee (SSC) committee on DIC and published in 2001. The 
ISTH DIC is a set of objective criteria for the diagnosis and severity of DIC with a score of ≥5 
correlating with overt DIC, whereas < 5 does not rule out DIC but may indicate DIC that is not overt. 
The score is only appropriate for use in patients with an underlying disorder that is known to be 
associated with DIC; e.g., sepsis, severe immunological reactions, etc.
The ISTH DIC score is calculated using
•
platelet count (≥100,000 = 0; 50,000-99,999 = 1; <50,000 = 2),
•
fibrinogen level (≥100 mg/dL = 0; <100 mg/dL = 1),
•
prothrombin time prolongation above upper limit of normal (ULN)
o (<3 seconds = 0, 3-6 seconds = 1, >6 seconds = 2),
•
and D-dimer (<2 times ULN = 0, 2-4 times ULN = 2, >4 times ULN = 3).
SOFA SCORE
SOFA SCORE
(Sequential Organ Failure Assessment)
ORGAN 
SYSTEM
0
1
2
3
4
Respiratory*
PaO2 / FIO2
Ratio
> 400
≤ 400
≤ 300
≤ 200 w/support
≤ 100 w/support
Hematologic
Platelets
> 150
≤150
≤ 100
≤ 50
≤ 20
Hepatic
Serum Bilirubin
< 1.2
1.2 – 1.9
2.0 – 5.9
6.0 – 11.9
> 12.0
CV
MAP
No 
hypotension
< 70
Dopamine ≥ 5
or
Any dobutamine
Dobutamine > 5 or 
Epi ≤ 0.1 or 
Norepi ≤ 0.1
Dopamine > 15 or 
Epi > 0.1 or 
Norepi > 0.1
Neurologic* 
Glasgow Coma 
Score
15
13-14
10-12
6-9
< 6
Renal 
Serum 
Creatinine
< 1.2
1.2 – 1.9
2.0 – 3.4
3.5 – 4.9 or
<500 u/o
>5 or
< 200 u/o
*See Appendix D. A Modified GCS is provided for intubated patients. Also provided for cases when it is not 
possible to obtain arterial blood gases to determine the SOFA respiratory parameter, SpO2/FiO2 ratio can be 
imputed for PaO2/FiO2 ratio. For patients on supplemental oxygen via nasal cannula, nasopharyngeal catheter or 
mask and for converting SpO2 values to PaO2 see Appendix D for oxygen conversion tables.
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 21 of 23
Appendix B
Days 3, 5,
7 & 9
Day 11
On 
Discharge
Study Subject Flowsheet
Informed Consent
Enrollment -
Day 1*
x
Entry Criteria
x
Demographics
x
Medical and Surgical History
x
Prior & Concomitant Medications
x
x
x
x
Vital Sign Measurements
x
x
x
ISTH DIC Score
x
x
x
SOFA Score
x
x
Blood Draw
x
x
x
Urine or Serum Pregnancy Test if applicable
x
Platelet
x
x
x
PT,INR
x
x
x
PTT
x
x
x
Hemoglobin and Hematocrit
x
x
x
Fibrinogen
x
x
x
D-Dimer
x
x
x
AT3 Level
x
x
x
Anti-Xa
x
x
x
Dosing if randomized to group with AT3 Infusion1
x1
x1
Adverse Events2
x
x
x
x2
Hospital LOS
x
Mortality
x
PF ratio change
x
Days on Ventilator
x
Days on ECMO
x
VTE’s
x
Bleeding Events
x
*: Day refers to a 24 hour period. 
x: To be completed
1: Only if randomized to AT3 Infusion and AT3 level is at specified level
2: Only Serious Adverse Events will be captured from last dose to hospital discharge.
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 22 of 23
Appendix C
The Secondary endpoint measurements:
a.
D-dimer level change from baseline to Day 9 in mcg/mL FEU or DDU,
b. Fibrinogen level change from baseline to Day 9 in mg/dL
c.
Prothrombin time change from baseline to Day 9 in seconds
d. Length of hospital stay in days,
e.
Mortality (%) of overall and between groups,
f.
Pulmonary function
a.
Time (days) to mechanical ventilation and/or
b. ECMO Duration (days) or extracorporeal membrane oxygenation (ECMO) use,
g. SOFA score change from baseline to Day 9 and
h. SOFA Respiratory sub-score change from baseline to Day 9,
i.
Number of venous thromboembolisms from admission to hospital discharge,
j.
Number of major bleeding events from admission to hospital discharge
-       Study #: 20201048        Effective Date: 2/8/2022

UM IRB# 20201048
AT3 in COVID-19
January 24, 2022, Version 6.2
Page 23 of 23
Estimating Fi02
Method
O2 flow 
(l/min)
~FiO2 
(%)
Nasal cannula
1
24
2
27
3
30
4
33
5
36
6
40
Nasopharyngeal 
catheter
4
40
5
50
6
60
Face mask
5
40
6-7
50
7-8
60
Face mask 
with reservoir
6
60
7
70
8
80
9
90
10
95
Estimated Pa02 
from a given Sp02
SpO2 (%)
PaO2 (mmHg)
80
44
81
45
82
46
83
47
84
49
85
50
86
52
87
53
88
55
89
57
90
60
91
62
92
65
93
69
94
73
95
79
96
86
97
96
98
112
99
145
Modified GCS
Eyes
4 = spontaneously
3 = to verbal
2 = to painful stimuli 
1 = no response
Motor
6 = to verbal command 
5 = localized to pain
4 = withdraws to pain
3 = decorticate, arms flex 
2 = decerebrate, arms ext 
1 = no response
5 = oriented, converses
Verbal
4 = disoriented & talks
No ETT
3 = inappropriate words
2 = incomprehensible
words
1 = no response
5 = seems able to talk
Verbal
3 = questionable ability to
w/ETT
talk
1 = generally unresponsive
Appendix D
-       Study #: 20201048        Effective Date: 2/8/2022