A Multicenter, Randomized, Double-blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Efficacy of Liquid Alpha1-Proteinase Inhibitor (Human) Plus Standard Medical Treatment (SMT) Versus Placebo Plus SMT in Hospitalized Subjects With COVID-19
Phase: PHASE2
Conditions: COVID-19
Sponsor: Grifols Therapeutics LLC

Official Title: 
A Multicenter, Randomized, Double-blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Safety and Efficacy of Liquid Alpha1-Proteinase Inhibitor (Human) Plus 
NCT Number: 
NCT04547140
Document Date: 
Protocol Version 6.0: 08 December 2021
Standard Medical Treatment (SMT) Versus Placebo Plus SMT in Hospitalized Subjects 
With COVID-19

Signed by:  
Reason:  
Date / Time (UTC):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Completion of the signature block below signifies the review and approval of this document.  
07-Dec-2021 17:32:10
03-Dec-2021 15:05:48
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Clinical Study Protocol
Protocol Title:
A Multicenter, Randomized, Double-blind, Placebo-
Controlled, Parallel Group Study to Evaluate the Safety 
and Efficacy of Liquid Alpha1-Proteinase Inhibitor 
(Human) plus Standard Medical Treatment (SMT) 
versus Placebo plus SMT in Hospitalized Subjects with 
COVID-19
Investigational 
Product:
Liquid Alpha1-Proteinase Inhibitor (Human) or Liquid 
Alpha1-PI
Sponsor’s Name and 
Address:
Grifols Therapeutics LLC
79 TW Alexander Drive
Research Triangle Park, NC 27709
Study Number:
GC2006
Additional Identifier
Liquid Alpha1-Proteinase Inhibitor (Human) COVID-19
IND Number:
IND22462
Development Phase:
2
Sponsor Signatory:
 M.D.
Grifols Therapeutics, LLC.
email address: 
Phone: 
Grifols Bioscience Industrial Group
Email address:
Telephone number: 
Confidentiality 
Statement:
The following confidential information is the property of Grifols.  As long as the 
information contained in this protocol has not been published, it may only be used after 
permission has been obtained from Grifols.  It is not possible to make reproductions of all 
or sections of this protocol. Commercial use of the information is only possible with the 
permission of the proprietor and is subject to a license fee.
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Protocol Version History
Protocol Version
Date of 
Approval/Effective Date
6.0
Amendment 5 + Integrated Protocol
See left margin
5.0
Amendment 4 + Integrated Protocol
19 Jul 2021
4.0
Amendment 3 + Integrated Protocol
02 Mar 2021
3.0
Amendment 2 + Integrated Protocol
30 Jul 2020
2.0
Amendment 1 + Integrated Protocol
01 Jul 2020
1.0
Original
18 May 2020
Amendment 5
The protocol for GC2006 (Version 5.0, dated 19 Jul 2021) has been amended as Protocol 
Amendment 5, Version 6.0. See the table in Appendix 5 for a summary of changes for 
Protocol Amendment 5.
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PROTOCOL SYNOPSIS
Title of Study: A Multicenter, Randomized, Double-blind, Placebo-Controlled, Parallel 
Group Study to Evaluate the Safety and Efficacy of Liquid Alpha1-Proteinase Inhibitor 
(Human) plus Standard Medical Treatment (SMT) versus Placebo plus SMT in Hospitalized 
Subjects with COVID-19
Short Title: Study to Evaluate the Safety and Efficacy of Liquid Alpha1-Proteinase Inhibitor 
(Human) in Hospitalized Subjects with Coronavirus Disease (COVID-19)
Study Number: GC2006
Phase: 2
Study Objectives:
Primary Efficacy Objective
To determine if Liquid Alpha1 Protease Inhibitor (Human) (Liquid Alpha1-PI) plus SMT can 
reduce the proportion of subjects dying or requiring intensive care unit (ICU) admission on or 
before Day 29 or who are dependent on high flow oxygen devices or invasive mechanical 
ventilation on Day 29 versus placebo plus SMT in hospitalized subjects with COVID-19.
Secondary Efficacy Objective
To compare Liquid Alpha1-PI plus SMT versus placebo plus SMT with regard to clinical 
efficacy as assessed by clinical severity, duration of hospital stay, dependency on oxygen or 
new need for ventilatory support, clinical response criteria including National Early Warning 
Score (NEWS), and clinical status scale through Day 29 in hospitalized subjects with 
COVID-19.
Exploratory Efficacy Objectives
•
To evaluate the effect of Liquid Alpha1-PI (Human) plus SMT versus placebo plus SMT 
with regard to quantitative severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-
2) viral load and anti-SARS-CoV-2 antibodies in hospitalized subjects with COVID-19.
•
To evaluate whether Liquid Alpha1-PI (Human) plus SMT versus placebo plus SMT 
reduces the frequency of hyperinflammation based on a pre-specified biochemical 
definition through Day 29.
•
To evaluate cytokine profile changes from baseline for Liquid Alpha1-PI (Human) plus 
SMT versus placebo plus SMT through Day 29.
•
To evaluate levels of alpha1-proteinase inhibitor (alpha 1-PI, also known as alpha 1-
antitrypsin [AAT]) activity and antigen through Day 29 (samples to be stored for 
measurement of both antigenic content and functional activity [potency] assays)
Safety Objective
To determine the safety and tolerability profile through Day 29 of Liquid Alpha1-PI (Human)
plus SMT versus placebo plus SMT in hospitalized subjects with COVID-19.
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Overall Study Design and Description:
This is a prospective, multi-center, randomized (1:1), double-blind, placebo-controlled study 
of Liquid Alpha1-PI (Human) plus SMT versus placebo plus SMT in subjects with COVID-19 
who are hospitalized. Symptomatic subjects with positive polymerase chain reaction (PCR; 
reverse transcriptase [RT]-PCR) or nucleic acid amplification technology (NAT) for SARS-
CoV-2 (or other commercial or public health assay approved by regulatory authorities) will 
receive placebo plus SMT or SMT plus Liquid Alpha1-PI (Human) given as two intravenous 
(IV) doses of 120 mg/kg (body weight) one week apart (on Day 1 and Day 8); if the subject is 
discharged from hospital then the 2nd infusion is not mandatory, and is at the discretion of the 
Principal Investigator and subject.
Subjects will be assessed daily while hospitalized. Discharged subjects will be evaluated on 
Days 15 and 29. Phone Checks will occur at Day 60 and Day 90 for vital status (living or 
deceased), any hospital re-admissions, or serious/non-serious adverse events after the Day 29 
Final Clinic Visit. Details are provided in Appendix 1 (Schedule of Study Procedures).
The first 6 subjects randomized will be staggered with an interval of no less than 1 week 
between subjects. If there are no definitely related serious adverse events (SAEs) reported by 
the time Day 8 is completed by the 6th subject, competitive enrollment would ensue thereafter. 
If a definitely related SAE were to be reported among these 6 subjects, and the subject was 
found by the Study-Independent Safety Review Committee (SISRC) to be randomized to the 
Liquid Alpha1-PI (Human) plus SMT arm, the SISRC would carefully review and evaluate the 
case and make appropriate recommendations with regard to study status.
Number of Subjects Planned:
Approximately 100 subjects will be randomized (1:1) with an interim analysis after 50 
subjects (approximately 25 per group).  Due to the exploratory nature of this phase 2 study, the 
multiplicity adjustments will not be considered; full details will be described in the statistical 
analysis plan. This interim evaluation is part of Sponsor safety due diligence.
Interim Futility Analysis: An interim futility analysis will be conducted to assess whether the 
trial will be terminated due to lack of efficacy (futility) based on all available data assessable 
for the primary endpoint and key secondary efficacy endpoints.
Diagnosis and Main Criteria for Eligibility
Inclusion Criteria:
A subject must meet all the following inclusion criteria to be eligible for participation in this 
study.
1.
Hospitalized male or female subject ≥ 18 years of age at time of Screening who is being 
treated for COVID-19. Subjects must be screened within 48 hours (≤ 48 hours) of hospital 
admission.
2.
Has laboratory-confirmed novel coronavirus (SARS-CoV-2) infection as determined by 
qualitative PCR (reverse transcriptase [RT]-PCR), or other commercial or public health 
assay approved by regulatory authorities as a diagnostic test for COVID-19 in any 
specimen during the current hospital admission OR 96 hours prior to the hospital 
admission date and prior to randomization ( the SARS-CoV-2 test results must be 
performed by a hospital laboratory and the documentation available). 
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3.
COVID-19 illness (symptoms) of any duration, including both of the following:
a)
Radiographic infiltrates by imaging (chest X-Ray, CT scan, etc.) and/or clinical 
assessment (evidence of rales/crackles on exam) with SpO2 <94% on room air
b)
Any One of the following related to COVID-19: i. Ferritin > 400ng/mL, ii. 
LDH > 300 U/L, iii. D-Dimers > reference range, or iv. C-reactive protein 
(CRP) > 40 mg/L
4.
Subject provides informed consent prior to initiation of any study procedures.
5.
Female subjects of childbearing potential (and males with female partners of childbearing 
potential) must agree to use of acceptable contraception methods during study (e.g., oral, 
injectable, or implanted hormonal methods of contraception, placement of an intrauterine 
device or intrauterine system, condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository, male sterilization, or true abstinence*) throughout the 
study.
*True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods], 
declaration of abstinence for the duration of a trial, and withdrawal are not acceptable 
methods of contraception.)
Diagnosis and Main Criteria for Eligibility:
Exclusion Criteria
A subject meeting any of the following exclusion criteria is NOT eligible for participation in 
the study.
1.
Subjects requiring invasive mechanical ventilation or ICU admission or with PaO2/FIO2 ≤ 
150 mm Hg (i.e., arterial oxygen in mm Hg divided by fraction inspired oxygen 
concentration [e.g., 0.21 for room air])
2.
Clinical evidence of any significant acute or chronic disease that, in the opinion of the 
investigator, may place the subject at undue medical risk.
3.
The subject has had a known serious anaphylactic reaction to blood, any blood-derived or 
plasma product, or known Selective IgA Deficiency with anti-IgA antibodies.
4.
A medical condition in which the infusion of additional fluid is contraindicated (e.g., 
decompensated congestive heart failure or renal failure with fluid overload). This includes 
currently uncontrolled congestive heart failure New York Heart Association Class III or IV 
stage heart failure.
5.
Shock that is unresponsive to fluid challenge and/or multiple vasopressors and 
accompanied by multiorgan failure considered not able to be reversed by the Principal 
Investigator
6.
Known alpha-1 antitrypsin deficiency for which the subject is already receiving alpha1-
proteinase inhibitor augmentation therapy
7.
Women who are pregnant or breastfeeding. Female subjects of child-bearing potential 
must have a negative test for pregnancy blood or urine human chorionic gonadotropin 
(HCG)-based assay at Screening/Baseline Visit.
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8.
Subjects for whom there is limitation of therapeutic effort such as “Do not resuscitate” 
status Note: If the decision is made not to apply treatments or therapeutic procedures that 
will provide little benefit for the suffering or agony the subject is experiencing, such a 
subject would not be appropriate for participation in this study and should be excluded.
9.
Currently participating in another interventional clinical trial with investigational medical 
product or device
10. Subjects previously requiring long-term oxygen therapy (home oxygen therapy)
11. History (within the last 2 years) of myocardial infarction, unstable angina, stroke or 
transient ischemic attacks, pulmonary embolism or deep venous thrombosis
12. Subject has medical condition (other than COVID-19) that is projected to limit lifespan to 
≤ 1 year
13. Systolic blood pressure < 100 mm Hg or > 160 mm Hg (uncontrolled hypertension) at the 
time of Screening
14. Alanine aminotransferase (ALT) ≥ 2 times the upper limit of normal (ULN)
15. Any elevation of total bilirubin at the time of Screening
16. Estimated glomerular filtration rate (eGFR) < 45 mL/min (or subject is dependent on 
dialysis/renal replacement therapy) at the time of Screening
eGFR is calculated by the Cockcroft-Gault equation:
For men:
(140 −age in years)(body weight [kg])
(72)(serum creatinine  mg
dL")
For women:
0.85 x (140 −age in years)(body weight [kg])
(72)(serum creatinine  mg
dL")
17. Hemoglobin < 10 g/dL at the time of Screening
18. Absolute neutrophil count < 1000/mm3 at the time of Screening
19. Platelet count < 75,000/mm3 at the time of Screening
20. Subject has history of drug or alcohol abuse within the past 24 months
21. Subject is unwilling to commit to follow-up visits
22. Known history of prothrombin gene mutation 20210, homozygous Factor V Leiden 
mutations, antithrombin III deficiency, protein C deficiency, protein S deficiency or 
antiphospholipid syndrome
Investigational Product, Dose and Mode of Administration
Subjects randomized to combination Liquid Alpha1-PI (Human) plus SMT will receive the 
first dose of blinded Liquid Alpha1-PI (Human) given as an IV dose of 120 mg/kg (body 
weight) on Day 1. A second dose of blinded Liquid Alpha1-PI (Human) (120 mg/kg) will be 
infused on Day 8. If the subject has been discharged from the hospital at the time of the Day 8 
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blinded Liquid Alpha1-PI (Human) infusion, the 2nd infusion is not mandatory, and is at the 
discretion of the Principal Investigator and subject. Liquid Alpha1-PI (Human) has a 
concentration of alpha1-proteinase inhibitor of 50 mg/mL. For a subject weighing 75 kg each 
dose of 120 mg/kg (on Day 1 and Day 8) will require 180 mL of Liquid Alpha1-PI (Human) to 
achieve the specified 120 mg/kg dose.
Liquid Alpha1-PI (Human) is clear, colorless or pale yellow or pale green. Do not use if 
discolored or cloudy. Before delivery to the subject, Liquid Alpha1-PI (Human) should be 
brought to room temperature and administered at room temperature for comfort to the subject. 
Pooled Liquid Alpha1-PI (Human) solution should be maintained at room temperature for 
administration within 3 hours.
Subjects will be randomized to either Liquid Alpha1-PI (Human) 120 mg/kg or the same 
volume of normal saline as a placebo. Both treatment arms will filter the solution during 
administration using an IV administration set with a suitable 5 to 15-micron infusion filter. 
Infuse Liquid Alpha1-PI (Human) separately, without mixing with other agents or diluting 
solutions. Infuse Liquid Alpha1-PI (Human) IV at 0.08 mL/kg/min as determined by subject
response and comfort. Both treatment arms’ infusion lines can be flushed with 0.9% sodium 
chloride for injection. Do Not flush with heparin.
Duration of Treatment:
Subjects will receive blinded Liquid Alpha1-PI (Human) or placebo on Day 1 and Day 8; for 
all subjects SMT will be continued throughout the subject’s hospitalization. Subject 
participation (from Screening Visit to the Final Visit) will be approximately 30 days. After the 
Day 29 Final Clinic Visit, phone checks will occur at Day 60 and Day 90 for follow-up of vital 
status (living or deceased), any hospital re-admissions, or serious/non-serious adverse events.
Reference Therapy, Dose and Mode of Administration
Reference therapy will be standard medical treatment for COVID-19 plus sterile 0.9% sodium 
chloride injection, United States Pharmacopeia (0.9% NaCl, USP) or equivalent used as placebo. 
The infusion solution will be at a volume commensurate to that required for the appropriate 
weight-based dose of Liquid Alpha1-PI (Human) and visually masked to maintain the blind.
Key Study Variables:
The primary efficacy variable is the proportion of subjects dying or requiring ICU admission 
on or before Day 29 or who are dependent on high flow oxygen devices or invasive 
mechanical ventilation on Day 29.
The secondary efficacy variables include:
•
Assessment of Clinical Severity: Change in NEWS from baseline (Day 1 through Day 29)
•
The NEWS has demonstrated an ability to discriminate patients at risk of poor outcomes. 
This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any 
supplemental oxygen, temperature, systolic blood pressure, heart rate, level of 
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consciousness [Alert, Voice, Pain, Unresponsive]). https://www.mdcalc.com/national-
early-warning-score-news (Appendix 2)
•
Time to clinical response: NEWS ≤ 2 maintained for 24 hours, Day 1 through Day 29 
•
Time to hospital discharge: defined as duration of hospitalization from Day 1 of study
•
If admitted to ICU post randomization: Duration of ICU stay through Day 29
•
Duration of any oxygen use Day 1 through Day 29
•
If requiring mechanical ventilation post randomization: Duration mechanical ventilation 
through Day 29
•
Absolute value and mean change from baseline in the Ordinal scale Day 1 through Day 29
The Ordinal scale is as follows: 
1) Death; 
2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO); 
3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
4) Hospitalized, requiring supplemental oxygen; 
5) Hospitalized, not requiring supplemental oxygen; 
6) Not hospitalized, limitation on activities; 
7) Not hospitalized, no limitations on activities.
•
Proportion (percentage) of subjects in each severity category of the 7-point Ordinal scale at 
Day 15 and Day 29
•
Time to sustained normalization of temperature and proportion of subjects with 
normalization of fever at all time points, defined as temperature < 36.6 °C armpit, 
< 37.2°C oral, or < 37.8 °C rectal sustained for at least 24 hours
•
Number of subjects who develop Acute Respiratory Distress Syndrome (ARDS) through 
Day 29 (Appendix 3) 
•
Length of time to clinical progression through Day 29 (defined as the time to death, 
mechanical ventilation, or ICU admission)
The exploratory efficacy variables include: 
•
Change from baseline in quantitative SARS-CoV-2 viral load by NAT or PCR (real-time 
RT-PCR) to Day 5± 1 day, Day 15± 1 day, and Day 29 ± 1 day
•
Change from baseline in quantitative anti- SARS-CoV-2 IgM and IgG antibodies to Day 
5± 1 day, Day 15± 1 day, and Day 29 ± 1 day
•
Proportion of subjects with evidence of hyperinflammation on Day 1, Day 5, Day 15, and 
Day 29 defined as:
a)
Lymphocyte counts <1000 cells/μL, AND 
b)
Two of the following 4 criteria: 
i)
Ferritin > 500ng/mL, 
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ii)
LDH > 300 U/L, 
iii)
D-Dimers > 1000 ng/mL (fibrinogen equivalent units [FEU]) or 
> 2 times upper normal limit, 
iv)
C-reactive protein (CRP) > 70 mg/L 
•
Change from baseline in cytokine profile (cytokine panel includes IL-1β, IL-10, IL-6, IL-
8, IL-2, interferon γ, and tumor necrosis factor-α [TNF-α]) to Day 5± 1 day, Day 15± 1 
day, and Day 29 ± 1 day
•
Change from baseline in levels of alpha 1-PI (AAT) activity and antigen through Day 29 
(both plasma [sodium citrate] and serum samples to be stored for measurement of both 
antigenic content and functional activity [potency])
The safety variables include:
•
Cumulative incidence of treatment-emergent serious adverse events (SAEs) and potentially 
related SAEs through Day 90 phone check
•
Cumulative incidence of Grade 3-5 treatment-emergent adverse events (TEAEs) and 
potentially related TEAEs through Day 29 as defined in the Common Terminology 
Criteria for Adverse Events (CTCAE), US Department of Health and Human Services, 
National Institutes of Health (NIH), and National Cancer Institute (NCI)
•
Cumulative incidence of all TEAEs and potentially related TEAEs through Day 29
In this clinical study, disease progression is defined as the worsening of a subject’s condition 
attributable to the disease for which the investigational product is being studied. It may be an 
increase in the severity of the targeted disease and/or increases in the symptoms of the targeted 
disease. Anticipated symptoms of COVID-19 include fever, cough, hypoxia, dyspnea, 
hemoptysis, myalgia, fatigue, pharyngitis, which may develop at any time during the course of 
the disease. The development of COVID-19 symptoms during the clinical study should not be 
recorded as individual TEAEs, unless there is evidence suggesting a causal relationship 
between blinded Liquid Alpha1-PI (Human)/Placebo and the TEAE.
Study Assessments and Procedures:
A complete schedule of study procedures and events are located in Appendix 1.
Clinical status will be evaluated for all hospitalized subjects daily with vital signs, Ordinal 
Scale, and NEWS at Screening/Baseline, during and after Liquid Alpha1-PI (Human) plus 
SMT or placebo plus SMT treatment and during Follow-up. The NEWS calculation is 
delineated in Appendix 2 and can be calculated using the on-line web tool at 
https://www.mdcalc.com/national-early-warning-score-news
All subjects will be followed daily through Day 10 (note: for Day 6 through Day 10, this 
stipulation is for as long as subjects are hospitalized). After Day 6, if subjects are discharged 
from the hospital, evaluations at Day 15 and 29 are required.  Subjects remaining hospitalized 
will be followed daily through Day 29. Phone Checks will occur at Day 60 and Day 90 for 
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vital status (living or deceased), any hospital re-admissions or serious/non-serious adverse 
events after the Day 29 Final Clinic Visit.
Respiratory samples for quantitative measurement of SARS-CoV-2 viral load by NAT or PCR 
(real-time RT-PCR) will be obtained on Day 1, and subsequently on Day 5± 1 day, Day 15± 1 
day, and Day 29 ± 1 day (obtained via nasopharyngeal swab). The results of these samples are 
not necessary for continuing on study. Similarly, blood samples for quantitative measurement 
of IgM and IgG antibodies to SARS-CoV-2 via enzyme linked immunosorbent assay (ELISA), 
Indirect Fluorescent Antibody (IFA) or other assay methodology will be drawn at the same 
time points: Day 1, and subsequently on Day 5± 1 day, Day 15± 1 day, and Day 29 ± 1 day. 
The results of these samples are not necessary for continuing on study. These laboratory tests 
will be performed at a central/external lab.
Ferritin, D-dimer, CRP and Basic chemistry analytes (creatinine, albumin, alanine 
aminotransferase [ALT], total bilirubin, lactate dehydrogenase [LDH]) will be assessed on 
Day 1 and on Day 5± 1 day, Day 15± 1 day, and Day 29 ± 1 day. An estimated glomerular 
filtration rate (eGFR) will also be calculated at these time points using the Cockcroft-Gault 
formula.
Hematology (hemoglobin, hematocrit, platelet count, absolute neutrophil & lymphocyte count, 
leukocyte count with differential) will be assessed on Day 1, on Day 5± 1 day, Day 15± 1 day, 
and Day 29 ± 1 day. A cytokine panel will be performed on Day 1, and on Day 5± 1 day, Day 
15 ± 1 day, and Day 29 ± 1 day. Cytokine panel includes IL-1β, IL-10, IL-6, IL-8 IL-2, 
interferon γ, and TNF-α. Note: serum samples must be stored at -70° C for later analysis at a 
reference laboratory. Levels of alpha 1-PI (AAT) activity and antigen will be evaluated on 
Day 1, on Day 8± 1 day, Day 15± 1 day, and Day 29 ± 1 day; both plasma (sodium citrate) and 
serum samples to be stored at - 70° C for measurement of both antigenic content and 
functional activity (potency) (all samples are mandatory at all time points regardless of 
hospital discharge status, except for the Day 8 AAT activity and antigen which is not required 
if subjects are discharged from the hospital and no 2nd blinded study drug infusion is 
administered).
Statistical Methods:
Descriptive statistics will include the number of non-missing observations, mean, standard 
deviation (SD), median, minimum, and maximum values for the continuous/quantitative data 
or absolute and relative frequency counts and percentages for categorical/qualitative data. All 
statistical tests will be 2-sided at a significance level of 0.05.
An interim analysis will be conducted after 50 subjects (25 per group) for safety variables. 
Due to the exploratory nature of this phase 2 study, the multiplicity adjustments will not be 
considered; full details will be described in the statistical analysis plan. This interim evaluation 
is part of Sponsor safety due diligence.
Interim Futility Analysis: An interim futility analysis will be conducted to assess whether the 
trial will be terminated due to lack of efficacy (futility) based on all available data assessable 
for the primary endpoint and key secondary efficacy endpoints.
Determination of Sample Size
Because of the urgency and lack of previous prospective COVID-19 data, sample size 
estimation remains incompletely defined; however, the size of this pilot study is 
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commensurate with other Phase 2 investigations ongoing during the COVID-19 pandemic. 
Approximately 100 subjects are allowed to be randomized as part of a humanitarian effort 
against COVID-19.
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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ..........................................................................................................4
GLOSSARY AND ABBREVIATIONS..................................................................................17
1
GENERAL INFORMATION..........................................................................................19
2
BACKGROUND INFORMATION ................................................................................19
2.1
Name and Description of the Investigational Product(s).......................................22
2.2
Relevant Findings from Nonclinical and Clinical Trials.......................................24
2.2.1
Dose Response for Inflammatory Biomarkers – Preclinical Data...............27
2.3
Known and Potential Risks and Benefits to Human Subjects ...............................28
2.3.1
Benefits ........................................................................................................28
2.3.2
Risks.............................................................................................................29
2.4
Description of and Justification for the Route of Administration, Dosage, Dosage 
Regimen, and Treatment Periods...........................................................................30
2.4.1
Administration of Investigational Product...................................................30
2.4.2
Justification for Selection of Doses/Timing of Investigational Product......30
2.5
Compliance Statement ...........................................................................................31
2.6
Study Population....................................................................................................31
2.7
Relevant Data and Literature Review....................................................................31
2.7.1
COVID-19 Therapeutic Approaches ...........................................................31
3
STUDY OBJECTIVES AND PURPOSE .......................................................................32
3.1
Efficacy Objectives................................................................................................32
3.1.1
Primary Efficacy Objective..........................................................................32
3.1.2
Secondary Efficacy Objective......................................................................33
3.1.3
Exploratory Efficacy Objectives..................................................................33
3.2
Safety Objective.....................................................................................................33
4
STUDY DESIGN.............................................................................................................33
4.1
Primary Endpoint and Secondary Endpoints .........................................................33
4.1.1
Primary Efficacy Endpoint ..........................................................................33
4.1.2
Secondary Efficacy Endpoints.....................................................................33
4.2
Study Design and Plan...........................................................................................35
4.3
Measures Taken to Minimize/Avoid Bias .............................................................39
4.3.1
Subject Numbering ......................................................................................39
4.3.2
Randomization.............................................................................................39
4.3.3
Blinding........................................................................................................39
4.4
Study Treatments ...................................................................................................39
4.4.1
Treatments to Be Administered ...................................................................39
4.4.1.1
Liquid Alpha1-PI (Human) ................................................................40
4.4.1.2
Placebo...............................................................................................40
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4.4.2
Labeling of Investigational Product.............................................................40
4.4.3
Packaging of Investigational Product ..........................................................40
4.4.4
Storage of Investigational product (Liquid Alpha1-PI (Human)) ................41
4.5
Expected Duration of Subject Participation in the Study ......................................41
4.6
Discontinuation Criteria for Individual Subjects and Study..................................41
4.6.1
Discontinuation Criteria for Individual Subjects.........................................41
4.6.2
Premature Termination of Study/Closure of Center....................................41
4.7
Accountability Procedures for Investigational Product .........................................41
4.8
Maintenance of Treatment Randomization Codes.................................................42
4.9
Data to Be Recorded..............................................................................................42
5
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................42
5.1
Inclusion Criteria ...................................................................................................42
5.2
Exclusion Criteria ..................................................................................................43
5.3
Subject Withdrawal Criteria ..................................................................................45
5.3.1
Screen Failures.............................................................................................45
5.3.2
Removal of Subjects ....................................................................................45
5.3.3
Subject Replacement....................................................................................46
5.3.4
Follow-up of Subjects Withdrawn from Study............................................46
5.3.5
Definition of the End of Study.....................................................................46
6
TREATMENT OF SUBJECTS.......................................................................................47
6.1
Administration and Timing of Investigational Product for Each Subject..............47
6.2
Prior and Concomitant Therapy.............................................................................48
6.2.1
Prohibited Medications Prior to Study Participation ...................................48
6.2.2
Prohibited Concomitant Medications during the Study...............................48
6.2.3
Restricted Concomitant Medications during the Study ...............................48
6.3
Treatment Compliance...........................................................................................48
7
ASSESSMENT OF EFFICACY .....................................................................................49
7.1
Efficacy Variables..................................................................................................49
7.1.1
Primary Efficacy Variable ...........................................................................49
7.1.2
Secondary Efficacy Variables......................................................................49
7.1.3
Exploratory Efficacy Variables....................................................................50
7.2
Methods and Timing for Assessing, Recording, and Analyzing Efficacy 
Parameters..............................................................................................................50
7.2.1
Observations and Measurements .................................................................50
7.2.2
Screening/Baseline and Randomized Treatment (Day 1)............................51
7.2.3
SMT and Daily Evaluations (Days 2 through 10 if still hospitalized) and 
Mandatory Day 5 Assessments for All Subjects..........................................52
7.2.4
Day 11-14  for Subjects Still Hospitalized: SMT and Daily Evaluations....54
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7.2.4.1
Day 8 2nd Liquid Alpha1-PI (Human) or Placebo Infusion for 
Hospitalized Subjects (optional if subject discharged from the 
hospital)..............................................................................................54
7.2.5
Day 15±1 day Mandatory for All Subjects..................................................54
7.2.6
Day 16-28 for Subjects Still Hospitalized: SMT and Daily Evaluations.....55
7.2.7
Day 29±1 day – All Subjects .......................................................................55
7.2.8
Day 60±2 days and Day 90±2 days Phone Checks – All Subjects..............56
7.2.9
Description of Laboratory Tests and Procedures.........................................56
8
ASSESSMENT OF SAFETY..........................................................................................57
8.1
Safety Parameters...................................................................................................57
8.2
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters58
8.3
Procedures for Eliciting Reports of and for Recording and Reporting Adverse 
Event and Intercurrent Illnesses.............................................................................58
8.3.1
Warnings/Precautions ..................................................................................58
8.3.2
Adverse Event Monitoring...........................................................................58
8.3.3
Adverse Event Definitions...........................................................................59
8.3.3.1
Adverse Events ..................................................................................59
8.3.3.2 Suspected Adverse Drug Reactions/Adverse Reactions............................59
8.3.4
Assessment of Causality of Adverse Event .................................................59
8.3.5
Severity of Adverse Event or Suspected Adverse Drug Reaction...............60
8.3.6
Expectedness of Adverse Event or Suspected Adverse Drug Reaction 
(Reference Safety Information) ...................................................................61
8.3.7
Seriousness of Adverse Event or Suspected Adverse Drug Reaction .........61
8.3.8
Adverse Event Documentation ....................................................................62
8.3.9
Reporting of Serious Adverse Events..........................................................63
8.3.9.1
Reporting of Serious Adverse Events................................................63
8.4
Type and Duration of the Follow-Up of Subjects after Adverse Events...............63
8.4.1
Reporting Pregnancy....................................................................................64
8.5
Study-Independent Safety Review Committee (SISRC) and Stopping Rules.......64
9
STATISTICS ...................................................................................................................65
9.1
Statistical Methods.................................................................................................65
9.2
Determination of Sample Size ...............................................................................66
9.3
Interim Futility Analysis........................................................................................66
9.4
Criteria for Termination of the Study ....................................................................68
9.5
Procedure for Accounting for Missing, Unused, and Spurious Data.....................68
9.6
Reporting Deviations from the Statistical Analysis Plan.......................................68
10
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS..............................................68
11
QUALITY CONTROL AND QUALITY ASSURANCE...............................................69
12
ETHICS............................................................................................................................69
12.1
Institutional Review Board/Ethics Committee ......................................................69
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12.2
Ethical Conduct of the Study.................................................................................69
12.3
Regulatory Authority Approvals/Authorizations...................................................70
12.4
Subject Information and Consent...........................................................................70
12.5
Confidentiality .......................................................................................................70
13
DATA HANDLING AND RECORD KEEPING ...........................................................71
13.1
Data Handling........................................................................................................71
13.2
Record Retention ...................................................................................................71
14
FINANCING AND INSURANCE..................................................................................72
15
PUBLICATION POLICY ...............................................................................................72
16
REFERENCES ................................................................................................................73
17
APPENDICES .................................................................................................................79
Appendix 1
Schedule of Study Procedures ...........................................................80
Appendix 2
National Early Warning Score (NEWS)............................................84
Appendix 3
Acute Respiratory Distress Syndrome (ARDS) Berlin Definition ....87
Appendix 4
Excerpt from: FDA Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Public Health Emergency (73) ...................89
Appendix 5
Summary of Changes from Version 5.0 to Version 6.0.....................92
LIST OF IN-TEXT TABLES
Table 2-1
Investigational product.................................................................................23
Table 2-2
Tabular Summary of Clinical Trials Utilizing Higher than 60 mg/kg/week 
Dose Levels of Alpha1-PI ............................................................................................25
Table 7-1
Name, Description, and Location of Laboratory Tests and Procedures ......57
LIST OF IN-TEXT FIGURES
Figure 2-1
AAT modulation of different cell types during inflammation ....................20
Figure 2-2
Selected anti-inflammatory and immunoregulatory activities of AAT. .....21
Figure 2-3
Schematic representation of the immunomodulating effects of AAT .........22
Figure 4-1
Overall Study Schema..................................................................................38
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GLOSSARY AND ABBREVIATIONS
AAT
alpha1-antitrypsin
ACE2
Angiotensin-converting enzyme 2 
ADE
antibody dependent enhancement
ADR
adverse drug reaction
AE
adverse event
ALI
acute lung injury 
alpha1-PI
alpha1-proteinase inhibitor 
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AR
adverse reaction
ARDS
acute respiratory disease syndrome 
ARMA
Acute Respiratory Management of ARDS (database)
AMS
aseptic meningitis syndrome
BAFF
B-cell-activating factor 
CathG
cathepsin G 
CI
confidence interval
CoVs
coronaviruses
COVID-19
Coronavirus disease 2019 
CRF
case report form
CTCAE
Common Terminology Criteria for Adverse Events
DVT
deep vein thrombosis
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
ELISA
Enzyme-linked immunosorbent assay
EU
European Union
FcR
Fc receptors
FDA
US Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FiO2
inspired oxygen concentration
GCP
Good Clinical Practice
hAAT
human alpha1-antitrypsin
HCG
human chorionic gonadotropin
HCoVs
highly pathogenic CoVs
HFI
hereditary fructose intolerance
HIV
human immunodeficiency virus
HR
heart rate
IB
investigator’s brochure
ICF
informed consent form
ICH
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICU
intensive care unit
IFA
indirect fluorescent antibody 
IgG
immunoglobulin G
IL-1β 
interleukin-1β
IL-6
interleukin-6
IP
investigational product
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IQR
interquartile range
IRB/EC
Institutional Review Board/Ethics Committee
ITT
intention to treat
IV
intravenous
LD50
lethal dose, 50%
MABP
mean arterial blood pressure
MCP-1
monocyte chemoattractant protein-1 
MedDRA
Medical Dictionary for Regulatory Activities
MERS
Middle East respiratory syndrome 
NaCl
Sodium chloride
NAT
nucleic acid amplification technology
NCI
National Cancer Institute
NE
neutrophil elastase
NEWS
National Early Warning Score 
NF-κB
Nuclear Factor-kappaB
NIH
National Institutes of Health
p38
mitogen-activated protein kinase
PCR
polymerase chain reaction
PE
pulmonary embolism
PEEP
positive end-expiratory pressure
PI
primary immunodeficiency 
PICs
pro-inflammatory cytokines 
PK
pharmacokinetics
PP
Per Protocol
PR3
proteinase 3 
RR
respiratory rate
RT-PCR
reverse transcriptase PCR
SAE
serious adverse event
SaO2
arterial oxygen saturation
SAP
statistical analysis plan
SARS
severe acute respiratory syndrome 
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SBP
systolic blood pressure
SD
standard deviation
SISRC
Study-Independent Safety Review Committee 
SMT
standard medical treatment
SOFA
Sequential Organ Failure Assessment 
SpO2
Peripheral oxygen saturation by pulse oximetry
T
Temperature
T1DM
type 1 diabetes mellitus
TEAE
treatment-emergent adverse event
TGF-β1
transforming growth factor β 1 
Th17
T helper 17 cells 
TNF-α
tumor necrosis factor-α 
TRALI
transfusion-related acute lung injury
US
United States
USP
United States Pharmacopeia 
WBC
white blood cell
WHO
World Health Organization
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1
GENERAL INFORMATION
Protocol title and other key study information are provided on the title page. Information 
regarding additional key personnel and organizations involved in the conduct of the study, 
including names and contact details of participating investigators, monitors, clinical laboratories, 
technical departments and/or institutions, as well as information on members of additional study 
committees, will be found in the study files of the sponsor and at the investigator sites within the 
study reference manual/file.  
Investigators and staff will receive training in appropriate individual site training session(s)
depending on what is feasible, given the emergency epidemic situation.
2
BACKGROUND INFORMATION
Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a newly 
emergent coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that was 
first recognized in Wuhan, China, in December 2019 (WHO Interim guidance 13 March 2020). 
Genetic sequencing of the virus suggests that SARS-CoV-2 is a betacoronavirus closely linked to 
the severe acute respiratory syndrome (SARS) virus (Team NCPERE 2020). While most people 
with COVID-19 develop mild or uncomplicated illness, approximately 14% develop severe 
disease requiring hospitalization and oxygen support and 5% require admission to an intensive 
care unit (Team NCPERE 2020). In severe cases, COVID-19 can be complicated by acute 
respiratory disease syndrome (ARDS), sepsis and septic shock, multiorgan failure, including 
acute kidney injury and cardiac injury (Yang 2020). Older age and co-morbid disease have been 
reported as risk factors for death, and recent multivariable analysis confirmed older age, higher 
Sequential Organ Failure Assessment (SOFA) score and d-dimer > 1 μg/L on admission were 
associated with higher mortality. This study also observed median duration of viral RNA 
detection was 20.0 days (interquartile range [IQR] 17.0–24.0) in survivors, but SARS-CoV-2 
virus was detectable until death in non-survivors. The longest observed duration of viral 
shedding in survivors was 37 days (Huang 2020; Zhou 2020).
Currently there are no approved treatments for COVID-19 and no approved prophylactic, post-
exposure, or therapeutic treatment modalities exist for SARS-CoV-2. This study will enroll 
subjects who have COVID-19 requiring hospital admission in order to evaluate treatment with 
Prolastin®-C Liquid, as it is considered that it may provide therapeutic benefit via its modulating 
and potentially anti-inflammatory properties in this critical situation.
Prolastin-C Liquid is a formulation of alpha1-proteinase inhibitor (alpha1-PI), also known as 
alpha1-antitrypsin (AAT), which has a number of anti-inflammatory properties that have been 
demonstrated in vitro and in vivo animal models. AAT is a member of the Serpin (serine 
protease inhibitors) family of protease inhibitors and is one of many plasma proteins that 
comprise the ‘‘acute phase proteins’’ although AAT also demonstrates unique anti-inflammatory 
properties (Bergin 2012). The primary role of AAT is to function as a serine protease inhibitor,
and it has been shown to inhibit a range of proteases derived from:
•
Degranulating neutrophils including neutrophil elastase (NE), cathepsin G and proteinase 3 
(PR3) (Duranton 2003). 
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•
Mast-cell-derived tryptase and chymase (Chen 2004; He 2004) 
•
Lymphocyte-derived granzyme B (Mahrus 2004)
•
The epithelial-cell membrane- bound protease matriptase (Janciauskiene 2008). 
•
Other serine proteases associated with coagulation (Gallimore 1975; Mast 1991), digestive 
enzymes (Beatty 1980), kalkriens derived from serum and tissue (Luo 2006; Patston 1990) 
and urokinase (Clemmensen 1976). 
•
Other classes of proteases including neutral and aspartic-cysteine proteases (Al-Omari 2011; 
Petrache 2006) 
•
The matrix metalloprotease, ADAM-17 (Bergin 2010).
The various modulatory effects of AAT are illustrated in Figure 2-1 wherein the thickness of the 
arrow reflects the perceived depth of knowledge (thicker indicates more data available).
Source: Bergin 2012
Figure 2-1
AAT modulation of different cell types during inflammation .
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In addition to in vitro results, in vivo models of anti-inflammatory properties and reported 
modulating effects of AAT are shown in Figure 2-2. In murine models, exogenous human AAT 
protected islet cell allografts from rejection and increased survival in an allogeneic marrow 
transplantation model (Janciauskiene 2013). In other models AAT therapy protected against 
tumor necrosis α (TNF-α) / endotoxin induced lethality, cigarette smoke induced emphysema 
and inflammation and appeared to suppress bacterial proliferation during infections (Lewis 
2012). Furthermore, human AAT given to mice during renal ischemia–reperfusion (I/R) injury 
lessened tissue injury and attenuated organ dysfunction (Daemen 2000).
Source: Janciauskiene 2013
Figure 2-2
Selected anti-inflammatory and immunoregulatory activities of AAT. 
In terms of inflammatory cytokines, the influence of AAT is multifaceted. AAT changes the 
cytokine milieu in the tissue microenvironment influencing both innate and adaptive immune 
responses; it downregulates proinflammatory cytokines (interleukin IL-6, IL-8, IL-1β, tumor 
necrosis factor-α [TNF-α], B-cell-activating factor [BAFF] and IL-32) while promoting anti-
inflammatory mediators [IL-10, IL-1RA and transforming growth factor-β. These effects are 
displayed in Figure 2-3 (Baraldo 2016).
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Source: Baraldo 2016
Figure 2-3
Schematic representation of the immunomodulating effects of AAT
The severity of COVID-19 in vulnerable individuals in the setting of the ongoing pandemic 
warrants investigation regarding whether Liquid Alpha1-PI (Human) may therapeutic benefit and
impact illness severity and mortality. While the majority of affected patients will recover, a 
significant number require hospitalization; morbidity and sequelae can be severe (Guan 2020). 
In addition to the information provided below, please also refer to the Investigator’s Brochure 
(IB) and any additional data supplied by the sponsor.
2.1
Name and Description of the Investigational Product(s)
See Section 4.4 Study Treatments for detail.
The investigational product (IP) is Liquid Alpha1-PI (Human). 
The following IP will be used in this clinical trial (Table 2-1):
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Table 2-1 Investigational product
INVESTIGATIONAL PRODUCT
Investigational Product:
Liquid Alpha1-PI (Human)
Liquid Alpha1-PI (Human) is supplied in glass vials as a 
sterile, stable, liquid concentrate of alpha1-PI (Human)
(nominally 50 mg/mL of functionally active alpha1-PI 
(Human)) and has a purity of ≥90% alpha1-PI (Human).
The product is a sterile solution containing 0.013-
0.025M sodium phosphate and is stabilized with 0.20-
0.30M alanine. The total sodium concentration is ≤ 100 
mEq/L.
Liquid Alpha1-PI (Human) must be refrigerated at 2°C 
to 8°C (36°F to 46°F). Do not freeze.
Liquid Alpha1-PI (Human) will be the investigational product being tested in combination with 
standard medical treatment (SMT) versus placebo plus SMT in subjects with COVID-19.
Liquid Alpha1-PI (Human) is indicated for chronic augmentation and maintenance therapy in 
adults with clinical evidence of emphysema due to severe hereditary with alpha1-PI deficiency 
(e.g., phenotypes PiZZ, PiZ(null), Pi (null,null) and PiSZ).
Prior to infusion visually inspect parenteral drug products for particulate matter and 
discoloration. The product may contain a few protein particles. The solution is clear, colorless or 
pale yellow or pale green. Do not use if discolored or cloudy. Before delivery to the subject, 
Liquid Alpha1-PI (Human) should be brought to room temperature and administered at room 
temperature for comfort to the subject. Liquid Alpha1-PI (Human) is for intravenous (IV)
administration only. Pooled Liquid Alpha1-PI (Human) solution should be maintained at room 
temperature for administration within 3 hours.
Filter the solution during administration using an IV administration set with a suitable 5 to 15-
micron infusion filter. Infuse Liquid Alpha1-PI (Human) separately, without mixing with other 
agents or diluting solutions. Infuse Liquid Alpha1-PI (Human) IV at 0.08 mL/kg/min as 
determined by subject response and comfort.
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2.2
Relevant Findings from Nonclinical and Clinical Trials
Single and repeat dose toxicology studies of IV-administered Prolastin have demonstrated a wide 
margin of safety for alpha1-PI in mice, rats, and rabbits. Toxicology studies of IV Prolastin did 
not reveal any toxicologically relevant findings. Single-dose IV toxicology (lethal dose, 50% 
[LD50]) studies in mice, rats and rabbits failed to demonstrate alpha1-PI toxicity from 
administered alpha1-PI at doses ranging from 517.5 to 3900 mg/kg. IV administration of 5 daily 
doses of Liquid Alpha1-PI (Human) to rabbits at a dose up to 600 mg/kg per day (10-fold higher 
dose than a human dose of 60 mg/kg administered weekly), did not result in any signs of 
toxicity. Further, there were no differences in safety and tolerability of Prolastin-C and Liquid 
Alpha1-PI (Human) in nonclinical testing.
The augmentation therapeutic dose of 60 mg/kg body weight for patients with inherited AAT 
deficiency (AATD) and emphysema is well established. Prolastin was licensed for use as 
augmentation therapy for AATD, at a dose of 60 mg/kg weekly, in the United States (US) in 
1987 and in Germany in 1988. Prolastin has been administered intravenously for over 30 years 
and has a well-defined safety profile. It is authorized in 14 European Union countries as well as 
in Switzerland.
Grifols Prolastin-C which has a modified process with a higher concentration of AAT (50 
mg/mL when lyophilized product reconstituted) has been approved for marketing since 2009 for 
weekly IV administration, at a dose of 60 mg/kg, for the treatment of patients with severe alpha1-
antitrypsin deficiency (AATD) and clinically evident emphysema. Grifols Liquid alpha1-
proteinase inhibitor (Prolastin-C Liquid) manufacturing process is the same as that for Prolastin-
C until the final formulation step where alanine is added as a stabilizer versus sodium chloride 
for the formulation of the lyophilized Prolastin-C product.
Prolastin-C Liquid has been approved for marketing since September 2017 for weekly IV 
administration, at a dose of 60 mg/kg, for chronic augmentation and maintenance therapy in 
adults with clinical evidence of emphysema due to severe hereditary AATD; it is approved in the 
United States and Canada. Prolastin-C Liquid is a sterile, stable, liquid preparation of purified 
human alpha1-PI prepared from pooled human plasma by modification and refinements of the 
cold ethanol fractionation method of Cohn using purification by polyethylene glycol 
precipitation, anion-exchange chromatography, and cation-exchange chromatography.
A multicenter, randomized, double-blind, crossover study (GTI1402) was conducted in which 
Prolastin-C was used as a comparator to assess the safety and pharmacokinetics (PK)of a Liquid 
formulation of alpha1-PI, Liquid Alpha-1 PI (Prolastin-C Liquid). The safety profile of Prolastin-
C Liquid (n=32 subjects with AATD) administered weekly at 60 mg/kg for 8 weeks either before 
or after 8 weeks of infusions with Prolastin-C was consistent with that found in previous studies. 
The primary bioequivalence analysis indicated that steady-state serum exposure to alpha1-PI was 
bioequivalent between Liquid Prolastin-C 60 mg/kg/week and Prolastin-C 60 mg/kg/week as 
determined by AUC0-7days (antigenic content) values among 31 subjects in the PK population. 
The safety profile of both formulations of Prolastin-C was good and was well tolerated among 
subjects.
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Grifols has conducted a number of clinical studies at higher dose levels of alpha1-PI than 60 
mg/kg body weight per week. While these studies were performed with Grifols Prolastin-C®, the 
results are directly applicable to the Liquid Alpha1-PI (Human) product as well. All studies have 
demonstrated a good tolerability profile at doses up to 180 mg/kg per week in clinical trials. 
These studies are summarized in Table 2-2.
Table 2-2 Tabular Summary of Clinical Trials Utilizing Higher than 60 mg/kg/week
Dose Levels of Alpha1-PI
Study Title (Acronym)
Number of 
Subjectsa
Study Design, 
Duration of 
Treatment
Treatment(s)
Important Findings
Completed Clinical Trials
A Multi-center, 
Randomized, Double-
blind, Crossover Study to 
Assess the Safety and 
Pharmacokinetics of Two 
Different Doses of 
Weekly Intravenous 
Administration of Alpha1-
Proteinase Inhibitor 
(Human) in Subjects with 
AATD (SPARK)
30
Randomized, 
cross-over 
(two 8-week 
double-blind 
treatment 
periods)
60 mg/kg alpha1-
PI;
120 mg/kg alpha1-
PI
The steady-state mean serum trough 
concentration of alpha1-PI following 
weekly doses of 60 mg/kg alpha1-PI was 
above the historical “protective 
threshold” of 11 µM in all subjects. In 
addition, all subjects after the 120 mg/kg 
dose had an average steady-state serum 
trough value that was greater than the 
lower limit (20 µM) of the range of 
alpha1-PI serum levels in non-AATD 
individuals. The weekly dose of 
120 mg/kg alpha1-PI provided an 
average steady state mean trough 
concentration of alpha1-PI (27.7 µM) 
that was within the reported range of 
alpha1-PI serum levels (20 to 53 µM) in 
non-AATD individuals. Alpha1-PI 
administered at doses of 60 mg/kg and 
120 mg/kg for 8 weeks was safe and 
well-tolerated; no SAEs were reported 
and there were no discontinuations due 
to an AE. TEAEs that were assessed as 
being drug-related after starting 
treatment with 60 mg/kg alpha1-PI were 
cognitive disorder, rosacea, and 
subcutaneous nodule; cognitive disorder 
was the only TEAE that was considered 
to be drug-related after starting treatment 
with 120 mg/kg alpha1-PI. There were 
no mean changes from baseline that 
were of clinical concern for any 
laboratory parameter after starting 
alpha1-PI treatment.  
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Study Title (Acronym)
Number of 
Subjectsa
Study Design, 
Duration of 
Treatment
Treatment(s)
Important Findings
Clinical Trial Ended Early (futility/insufficiently powered for efficacy)
A Multicenter, 
Randomized, Partial-
Blinded, Placebo-
Controlled Study to 
Evaluate the Safety and 
Efficacy of a Human 
Plasma-Derived Alpha1-
Proteinase Inhibitor in 
Subjects with New-Onset 
Type 1 Diabetes Mellitus 
(GTI1302)
60
Randomized, 
partial-blind, 
placebo-
controlled
13 or 26 
weeks of 
treatment
180 mg/kg weekly 
infusions of 
alpha1-PI for 26 
weeks
90 mg/kg weekly 
infusions of 
alpha1-PI for 26 
weeks
180 mg/kg weekly 
infusions of 
alpha1-PI for 13 
weeks
90 mg/kg weekly 
infusions of 
alpha1-PI for 13 
weeks
Placebo (Saline, 
0.9% Sodium 
Chloride Solution)
26 weeks of 
weekly infusions 
or
13 weeks of 
weekly infusions
Treatment with Alpha-1 MP (Prolastin-
C) was well tolerated. The most 
frequently reported TEAEs were upper 
respiratory infection, headache, 
nasopharyngitis, and vomiting. No 
clinically meaningful differences in 
TEAE incidences were noted among 
treatment groups. One subject in the 
high dose alpha1-PI treatment group 
received a 2.2-fold overdose without any 
associated AEs reported. Three subjects 
reported SAEs, all in the 13-week high 
dose alpha1-PI treatment group (1 
subject each: completed suicide, 
spontaneous abortion, and 
hyperglycemia). All SAEs started 
several weeks after starting treatment, all 
were considered unrelated to study 
treatment, and all except the suicide 
resolved. One subject in the 26-week 
high dose alpha1-PI treatment group was 
discontinued due to a nonserious, 
moderate TEAE (migraine), which 
started on Day 45, resolved on Day 49, 
and was considered possibly related to 
study treatment.
Ongoing Clinical Trials
A Randomized, Double-
Blind, Placebo-Controlled 
Study to Assess the 
Efficacy and Safety of 
Two Dose Regimens (60 
mg/kg and 120 mg/kg) of 
Weekly Intravenous 
Alpha1-Proteinase 
Inhibitor (Human) in 
Subjects with Pulmonary 
Emphysema due to 
Alpha1-Antitrypsin 
Deficiency
(GTi1201, SPARTA)
339 
planned;
224 
enrolled 
and 
dosed
Randomized, 
double-blind, 
placebo-
controlled
156 weeks of 
treatment
60 mg/kg/week 
alpha1-PI by IV 
administration
120 mg/kg/week 
alpha1-PI by IV 
administration
Placebo, weekly, 
by IV 
administration
Treatments in this ongoing study remain 
blinded. A total of 130 treatment-
emergent SAEs have been reported in 
70/224 (31.1%) randomized subjects. 
All reported SAEs were unrelated to 
study drug with 2 exceptions:  1 SAE of 
supraventricular tachycardia that was 
considered unlikely related to study drug 
and 1 SAE of thrombocytopenia that 
was considered related to study drug and 
led to subject withdrawal from the study.
a
Number of subjects who received any amount of study drug.
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2.2.1
Dose Response for Inflammatory Biomarkers – Preclinical Data
The strongest available data pertaining to a well-defined dose response for effects of specific 
doses of AAT on inflammatory biomarkers stems from preclinical investigations with Prolastin-
C®.
Preclinical data of different internal Grifols studies support the use of high dose human alpha1-
antitrypsin (hAAT) as a therapy for inflammation related diseases. 
Pharmacokinetic studies in mice (C57BL/6 strain) treated twice a week with intraperitoneal 
hAAT were performed, following two dosing regimens:
!
hAAT increasing dose (60 mg/kg from Day 0 to Day 15, and 60 mg/kg to 180 mg/kg, 
with 15 mg/kg twice a week increment from Day 15 to Day 39) 
!
hAAT constant dose (60 mg/kg) from Day 0 to Day 39 
The obtained data demonstrated that animals treated with the increasing dose regimen of hAAT 
reached higher anti-elastase activity plasma levels than the ones treated with a hAAT constant 
dose of 60 mg/kg:
!
hAAT 180 mg/kg: anti-elastase activity at Day 39: 3.0±0.1 mg/mL
!
hAAT 60 mg/kg: anti-elastase 1.7±0.0 mg/mL 
!
Non-treated animals anti-elastase activity: 1.3±0.1 mg/mL
Using this increasing dose regimen of hAAT, a positive effect was observed in an experimental 
model of type 1 diabetes (a transgenic mice expressing IFN-β in pancreatic β-cells that present a 
marked lymphocytic infiltration) (Casellas et al., 2006). hAAT treated animals showed a reduced 
infiltration of lymphocytes in pancreatic islets resulting in an approximately half reduction of 
overall insulitis index score. 
Furthermore, in an experimental mice model of neonatal hypoxic ischemic encephalopathy, a 
disease characterized by cerebral inflammation and profound brain injury, hAAT (25 to 200 
mg/kg, intraperitoneal daily for 7 days) increased in a dose dependent manner the preserved area 
after the hypoxia damage.  
Specifically, a high dose of human AAT (100 mg/kg) reduced the neutrophil infiltration in 
different brain areas, p<0.001 hAAT vs. vehicle in both areas. Results for CD25 positive cells 
were the following:
!
in cortex 35±1% (vehicle) vs. 15±1% (hAAT)
!
in hippocampus 39±3% (vehicle) vs. 17±1% (hAAT) 
In relation to the levels of proinflammatory cytokines, high dose of hAAT (100 mg/kg) 
decreased TNFα, IL-1 and IL-6 in brain cortex, p<0.001 in the 3 cytokines. Specific results (% in 
respect to healthy animals were as follows:
!
TNFα: vehicle 257±17% vs. hAAT 153±10.7%
!
IL1: vehicle 223±16% vs. hAAT 147±9.9%
!
IL6: vehicle 227±13% vs. hAAT 139±11%
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Finally, similar results were obtained in a mice preclinical model of spinal cord injury. Human 
AAT (25 to 200 mg/kg, intraperitoneal, daily for 14 days) decreased in a dose dependent manner 
the lesioned area in mice after weigh drop injury. Specific results were the following:
!
A high dose of hAAT (100 mg/kg) reduced TNFα and IL6 levels in this model at the end 
of treatment (Day 14), p<0.001 for both TNFα and IL-6. Results for % in respect to 
healthy animals were the following: 
o
TNFα: vehicle 257±14.6% vs. hAAT 138.9±10.1% 
o
IL6: vehicle 231±7.9% vs. hAAT 111±9.1 
!
This anti-inflammatory effect lasted 14 days after treatment end (Day 28); results (% in 
respect to healthy animals) were the following: 
o
TNFα: vehicle 276±17.1% vs. hAAT 201±7.1% (p<0.01); 
o
IL6: vehicle 201±11.3% vs. hAAT 159±8.7 % (p<0.05). 
Altogether, these pre-clinical data support a dose depending effect of human AAT with an anti-
inflammatory effect specially at high doses.
2.3
Known and Potential Risks and Benefits to Human Subjects
2.3.1
Benefits
No approved prophylactic, post-exposure, or therapeutic treatment modalities exist for SARS-
CoV-2. The subjects enrolled in this study have COVID-19 requiring hospital admission, and it 
is considered that Liquid Alpha1-PI (Human) may provide therapeutic benefit via its potential 
anti-inflammatory properties in this critical situation.
One of the primary functions of alpha1-PI (AAT) in the human body is to irreversibly bind NE. 
NE is an omnivorous serine protease released by activated or disintegrating neutrophils. NE 
levels and activity are markedly increased in the airways of patients with ARDS, and previous 
studies have shown that IV administration of AAT in humans results in augmented anti-elastase 
capacity of airway epithelial lining fluid, reduced NE activity in bronchoalveloar lavage fluid 
and decreased breakdown of lung tissue (Campos 2019; Chapman 2015; McElvaney 2017; 
Wewers 1987). Although these studies were performed in subjects with congenital AAT 
deficiency. While AAT chiefly inhibits NE, it also other exerts an antiprotease effect on 
chymotrypsin, cathepsin G (CathG) and proteinase 3 (PR3) (Greene 2009). 
In addition to its antiprotease effects (Matheson 1981; Ogushi 1987; Sinden 2015), AAT is a 
potent anti-inflammatory and immunomodulator (Bergin 2010; Bergin 2014; Hurley 2014; 
O'Dwyer 2015; Jonigk 2013). Of particular relevance to COVID-19, it has been shown to 
modulate suppress the production and activity of several key pro-inflammatory cytokines, 
including interleukin IL-1, IL-6, IL-8 and TNF-α (Bergin 2010; Bergin 2014; Pott 2009; 
McCarthy 2018), while preserving the production of the anti-inflammatory cytokine IL-10 
(Janciauskiene 2007). As such, it is feasible that exogenous administration of alpha1-PI (AAT) 
may alleviate the hyperinflammatory component of COVID-19 which can cause accentuating 
respiratory impairment. For this reason, the current randomized, controlled study in hospitalized 
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COVID-19 subjects is being undertaken to evaluate whether therapeutic benefit is feasible to 
attain following IV administration of Liquid Alpha1-PI (Human). 
Decreasing morbidity and mortality remain the theoretical benefit and aim of administration of 
Liquid Alpha1-PI (Human) in patients with COVID-19. In this study, therapeutically high doses 
of Liquid Alpha1-PI (Human) will be administered to those patients hospitalized with COVID-19
in an effort to reduce their symptoms and improve outcomes by leveraging the modulatory and 
anti-inflammatory effects of Prolastin described above. These doses are commensurate with prior 
clinical experience with alpha1-PI. 
2.3.2
Risks
There are no known drug interactions with IV alpha1-PI. No known drug interactions have been 
encountered in clinical studies of Prolastin.
Individuals with known selective or severe IgA deficiency who have known antibodies against 
IgA should not receive Alpha1-PI since these subjects may experience severe reactions, including 
anaphylaxis, to IgA which may be present in the preparation.
When medicines are made from human plasma, certain measures are put in place to prevent 
infections being passed on to patients. These include:
•
Careful selection of blood and plasma donors to make sure those at risk of carrying infections 
is excluded
•
The testing of each donation and pools of plasma for signs of virus/infections
•
The inclusion of steps in the manufacturing of plasma derivatives with virus 
inactivation/removal capacity
Despite these measures, when medicines prepared from human blood or plasma are 
administered, the possibility of passing on infection cannot be totally excluded. This also applies 
to any unknown or emerging viruses or other types of infections.
In clinical trials the most common adverse reactions observed at a rate of >5% in subjects 
receiving Liquid Alpha1-PI were diarrhea and fatigue, each of which occurred at a rate of 6% 
(two subjects each).
The post-marketing adverse reactions for Prolastin®-C Liquid (the formulation of Liquid Alpha1
-Proteinase Inhibitor used in this study) are as follows:
•
General/Body as a whole: fatigue, malaise, influenza-like illness, pain, asthenia
•
Immune system: hypersensitivity including anaphylactoid/anaphylactic reactions
•
Cardiovascular: tachycardia
•
Musculoskeletal: arthralgia, myalgia
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•
Gastrointestinal: vomiting, diarrhea
•
Investigation: blood pressure increased
2.4
Description of and Justification for the Route of Administration, 
Dosage, Dosage Regimen, and Treatment Periods
2.4.1
Administration of Investigational Product
Subjects randomized to the combination arm Liquid Alpha1-PI (Human) plus standard medical 
treatment (SMT), will receive IV Liquid Alpha1-PI (Human) and SMT. 
Subjects in the placebo plus SMT arm will receive all standard of care interventions required and 
Placebo.
2.4.2
Justification for Selection of Doses/Timing of Investigational Product
The route of administration and the dosage regimen of 60 mg/kg body weight once weekly IV of 
Liquid Alpha1-PI (Human) is recommended for chronic augmentation and maintenance therapy 
in in adults with clinical evidence of emphysema due to severe AAT deficiency (e.g., phenotypes 
PiZZ, PiZ [null], Pi [null] [null]; PiSZ) (Prolastin-C Liquid- alpha1-proteinase inhibitor [human] 
injection, solution US prescribing information, 2020).
Augmentation therapy with weekly IV infusions of 60 mg/kg AAT may be sufficient to slow 
progression of lung density decline in patients with AATD patients (Dirksen 2009); however, 
other dosing regimens have been also widely used: 120 mg/kg every 2 weeks, 180 mg/kg every 3 
weeks, 250 mg/kg once a month (Stoller 2003; Miravitlles 1999, Vidal 1995). The safety profile 
of AAT has not been modified according to the dosing regimen, and there has been no indication 
of any dose-dependent toxicity in AAT deficient subjects. AAT is a normal constituent of human 
plasma, which does not contribute significantly to plasma osmolality, and suffers no appreciable 
glomerular filtration.
Higher doses than 60 mg/kg at weekly intervals have been well tolerated with no safety issues. 
Campos and colleagues evaluated weekly doses of 120 mg/kg in patients with AATD which had 
the salutary effect of bringing AAT levels to within the normal range and improvement in 
biomarkers (Campos 2019). In the SPARK clinical study in subjects with AATD, weekly doses 
of 120 mg/kg alpha1-PI resulted in an average steady state mean trough concentration of AAT 
(27.7 µM) that was within the reported normal range of AAT serum levels (20 to 53 µM) in non-
AATD individuals. The SPARK study was conducted by Grifols to assess the safety and PK of 
weekly IV infusions of alpha1-PI at 120 mg/kg compared to the approved (product labeling) dose 
of 60 mg/kg in 30 subjects. In this study, a total of 30 subjects received weekly doses of 120 
mg/kg for 8 weeks, and the results demonstrated that alpha1-PI, was also safe and well-tolerated
at this dose (Campos 2013). Additionally, Grifols is currently investigating the efficacy of 
60 mg/kg and 120 mg/kg alpha1-PI using CT densitometry as the primary efficacy endpoint in a 
randomized, placebo-controlled trial in subjects with pulmonary emphysema due to AATD; 
safety and tolerability of the 120 mg/kg/week dose has been good in this ongoing clinical trial.
Data from an additional proof-of-concept study in 75 subjects with new onset type 1 diabetes 
mellitus (T1DM) with residual β cell function evaluated the safety and potential therapeutic 
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effect of weekly 90 mg/kg and 180 mg/kg alpha1-PI for 13 or 26 weeks. This study (GTI1302) 
showed that both doses were well-tolerated, however it was not powered adequately to 
demonstrate efficacy of alpha1-PI at Week 52, and additional data would not change the 
outcome, so for reasons of futility the study was discontinued. However, safety of all doses 
(including weekly alph1-PI at 180 mg/kg) was shown.
Subjects randomized to combination with SMT will receive 2 doses of 120 mg/kg of Liquid
Alpha1-PI (Human) administered with the first infused on Day 1 and the second on Day 8.
2.5
Compliance Statement
This study will be conducted under the conditions described in this protocol and in compliance 
with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) Good Clinical Practice (GCP) and all applicable regulatory requirements.
2.6
Study Population
The purpose of this study is to determine if Liquid Alpha1-PI (Human) plus SMT can reduce the 
proportion of subjects dying or requiring intensive care unit (ICU) admission on or before Day 
29 or who are dependent on high flow oxygen devices or invasive mechanical ventilation on Day 
29 versus placebo plus SMT in hospitalized subjects with COVID-19.
Approximately 100 subjects will be randomized (1:1) with an interim analysis after 50 subjects 
(approximately 25 per group). There will be no interruption in study conduct during interim 
analysis as this simply represents sponsor safety due diligence during the COVID-19 pandemic.
Interim Futility Analysis: An interim futility analysis will be conducted to assess whether the 
trial will be terminated due to lack of efficacy (futility) based on all available data assessable for 
the primary endpoint and key secondary efficacy endpoints.
2.7
Relevant Data and Literature Review
2.7.1
COVID-19 Therapeutic Approaches
Coronaviruses (CoVs) typically affect the respiratory tract of mammals, including humans, and 
lead to mild to severe respiratory tract infections. In the past two decades, two highly pathogenic 
human CoVs (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) 
and Middle East respiratory syndrome coronavirus (MERS-CoV), emerging from animal 
reservoirs, have led to global epidemics with high morbidity and mortality.
Several studies demonstrate that cells infected by SARS-CoV produce elevated levels of pro-
inflammatory cytokines (PICs) in order to combat the invading viruses. However, the 
overproduced PICs (including monocyte chemoattractant protein-1 [MCP-1], transforming growth 
factor β 1 [TGF-β1], tumor necrosis factor-α [TNF-α], interleukins- 1β and -6 [IL-1β, and IL-6]), 
may cause immuno-mediated damage to the lungs and other organs, resulting in acute lung injury 
(ALI) and ARDS (He 2006; DeDiego 2014). 
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The elevated levels of PICs in blood released from the SARS-CoV-infected cells and the 
uninfected cells stimulated by viral antigens or some PIC-regulatory factors, e.g. Nuclear Factor-
kappaB (NF-κB) and p38 (a mitogen-activated protein kinase) (He 2006; DeDiego 2014), may 
damage the cells in the lungs and other organs. In addition, blood hypo-oxygenation due to ARDS 
and disseminated intravascular coagulation resulting from impairment of microvessel endothelial 
cells may further damage the structure and function of different organs in SARS patients, resulting 
in multi-organ dysfunction.
The ACE2 expressing cells are the primary targets for SARS-CoV infection in vivo humans 
initiating a massive cascade of pro-inflammatory cytokines via macrophages over-activation 
causing ARDS. High levels of PICs are expressed in the SARS-CoV-infected ACE2+ cells, but 
not in the uninfected cells (He et al., 2006). 
Therefore, application of PIC antagonists may reduce the severity and mortality of SARS and may 
potentially reduce other pathogenic human coronaviruses (He 2006; DeDiego 2014; Tse 2004). In 
the current study it is considered that the modulatory and anti-inflammatory properties of Liquid 
Alpha1-PI (Human) may attenuate the deleterious effects of cytokine release syndrome engendered 
in COVID-19.
Currently, there are no approved treatments for COVID-19 in Europe or the United States. The 
lack of disease-directed therapeutic options has led to urgent interventions in anticipation of
some potentially promising effects. Some antivirals are currently under evaluation. These include 
favipirivir (AVIGAN) manufactured by Fujifilm in Japan, Gilead’s remdesivir, and Kaletra®
(lopinavir/ritonavir) commercially available for human immunodeficiency virus (HIV). Although 
Kaletra® did not show demonstrable efficacy in a recently reported study in China (Cao et al., 
2020), additional trials are underway. There are also investigations of chloroquine and 
hydroxychloroquine as treatment modalities and potential applications for post-exposure 
prophylaxis according to Clinicaltrials.gov and other clinical trial registries. These and other 
potential therapeutic agents are described on the World Health Organization (WHO) website file:
WHO Landscape Therapeutics under investigation 17 Feb 2020.pdf (accessed 19 March 2020).
To date there are no confirmed specific disease modifying agents. Therefore, the potential 
therapeutic benefit conveyed by the immunomodulatory effects of Liquid Alpha1-PI (Human)
warrants clinical investigation. This is particularly true given the urgency and extent of the 
COVID-19 pandemic.
3
STUDY OBJECTIVES AND PURPOSE
3.1
Efficacy Objectives
3.1.1
Primary Efficacy Objective
To determine if Liquid Alpha1-PI (Human) plus SMT can reduce the proportion of subjects 
dying or requiring intensive care unit (ICU) admission on or before Day 29 or who are dependent 
on high flow oxygen devices or invasive mechanical ventilation on Day 29 versus placebo plus 
SMT in hospitalized subjects with COVID-19.
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3.1.2
Secondary Efficacy Objective
To compare Liquid Alpha1-PI (Human) plus SMT versus placebo plus SMT with regard to
clinical efficacy as assessed by clinical severity, duration of hospital stay, dependency on oxygen 
or new need for ventilatory support, clinical response criteria including National Early Warning 
Score (NEWS), and clinical status scale through Day 29 in hospitalized subjects with COVID-
19.
3.1.3
Exploratory Efficacy Objectives
•
To evaluate the effect of Liquid Alpha1-PI (Human) plus SMT versus placebo plus SMT with 
regard to quantitative severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2) viral 
load and anti-SARS-CoV-2 antibodies in hospitalized subjects with COVID-19.
•
To evaluate whether Liquid Alpha1-PI (Human) plus SMT versus placebo plus SMT reduces 
the frequency of hyperinflammation based on a pre-specified biochemical definition through 
Day 29.
•
To evaluate cytokine profile changes from baseline Liquid Alpha1-PI (Human) plus SMT 
versus placebo plus SMT through Day 29.
•
To evaluate levels of alpha 1-PI (AAT) activity and antigen through Day 29
3.2
Safety Objective
To determine the safety and tolerability profile through Day 29 of Liquid Alpha1-PI (Human)
plus SMT versus placebo plus SMT in hospitalized subjects with COVID-19.
4
STUDY DESIGN
4.1
Primary Endpoint and Secondary Endpoints
4.1.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects dying or requiring ICU admission on 
or before Day 29 or who are dependent on high flow oxygen devices or invasive mechanical 
ventilation on Day 29. 
4.1.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints include the following:

Assessment of Clinical Severity: Change in NEWS from baseline (Day 1 through Day 29)
The NEWS has demonstrated an ability to discriminate patients at risk of poor outcomes. 
This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any 
supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness 
[Alert, Voice, Pain, Unresponsive]). https://www.mdcalc.com/national-early-warning-score-
news (Appendix 2)
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
Time to clinical response: NEWS ≤ 2 maintained for 24 hours, Day 1 through Day 29 

Time to hospital discharge: defined as duration of hospitalization from Day 1 through Day 29

If admitted to ICU post randomization: Duration of ICU stay through Day 29

Duration of any oxygen use Day 1 through Day 29

If requiring mechanical ventilation post randomization: Duration mechanical ventilation 
through Day 29

Absolute value and mean change from baseline in the Ordinal scale Day 1 through Day 29
The Ordinal scale is as follows: 
1) Death; 
2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation 
(ECMO); 
3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
4) Hospitalized, requiring supplemental oxygen; 
5) Hospitalized, not requiring supplemental oxygen; 
6) Not hospitalized, limitation on activities; 
7) Not hospitalized, no limitations on activities.

Proportion (percentage) of subjects in each severity category of the 7-point Ordinal scale at 
Day 15 and Day 29

Time to sustained normalization of temperature and proportion of subjects with 
normalization of fever at all time points, defined as temperature < 36.6 °C armpit, < 37.2 °C 
oral, or < 37.8 °C rectal sustained for at least 24 hours

Number of subjects who develop Acute Respiratory Distress Syndrome (ARDS) through Day 
29 (Appendix 3) 

Length of time to clinical progression through Day 29 (defined as the time to death, 
mechanical ventilation, or ICU admission)
4.1.3
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints include:

Change from baseline in quantitative SARS-CoV-2 viral load by nucleic acid amplification 
technology (NAT) or polymerase chain reaction (PCR; real-time reverse transcriptase [RT]-
PCR) to Day 5± 1 day, Day 15± 1 day, and Day 29 ± 1 day

Change from baseline in quantitative anti- SARS-CoV-2 IgM and IgG antibodies to Day 5± 1 
day, Day 15± 1 day, and Day 29 ± 1 day
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
Proportion of subjects with evidence of hyperinflammation on Day 1, Day 5, Day 15, and 
Day 29 defined as:
a)
Lymphocyte counts <1000 cells/μL, AND
b)
Two of the following 4 criteria:
i)
Ferritin > 500ng/mL, 
ii)
LDH > 300 U/L,
iii)
D-Dimers > 1000 ng/mL (fibrinogen equivalent units [FEU]) or 
> 2 times upper normal limit, 
iv)
C-reactive protein (CRP) > 70 mg/L

Change from baseline in cytokine profile (cytokine panel includes IL-1β, IL-10, IL-6, IL-8,
IL-2, interferon γ, and tumor necrosis factor-α [TNF-α]) to Day 5± 1 day, Day 15± 1 day, and 
Day 29 ± 1 day

Change from baseline in levels of alpha 1-PI (AAT) activity and antigen through Day 29 
(both plasma [sodium citrate] and serum samples to be stored for measurement of both 
antigenic content and functional activity [potency])
4.1.4
Safety Endpoints
The safety endpoints include:

Cumulative incidence of treatment-emergent serious adverse events (SAEs) and potentially 
related SAEs through Day 90 phone check

Cumulative incidence of Grade 3-5 treatment-emergent adverse events (TEAEs) and 
potentially related severe TEAEs through Day 29 as defined in the Common Terminology 
Criteria for Adverse Events (CTCAE), US Department of Health and Human Services, 
National Institutes of Health (NIH), and National Cancer Institute (NCI)

Cumulative incidence of all TEAEs and potentially related TEAEs through Day 29
In this clinical study, disease progression is defined as the worsening of a subject’s condition 
attributable to the disease for which the investigational product is being studied. It may be an 
increase in the severity of the targeted disease and/or increases in the symptoms of the targeted 
disease. Anticipated symptoms of COVID-19 include fever, cough, hypoxia, dyspnea, 
hemoptysis, myalgia, fatigue, pharyngitis, which may develop at any time during the course of 
the disease. The development of COVID-19 symptoms during the clinical study should not be 
recorded as individual TEAEs, unless there is evidence suggesting a causal relationship between 
blinded Liquid Alpha1-PI (Human)/Placebo and the TEAE. 
4.2
Study Design and Plan
This is a prospective, multi-center, randomized (1:1), double-blind, placebo-controlled study of 
Liquid Alpha1-PI (Human) plus SMT versus placebo plus SMT in subjects with COVID-19 who 
are hospitalized. The first 6 subjects randomized will be staggered, so randomization is no closer 
than 1 week apart. If there are no definitely related serious adverse events (SAEs) reported by the 
time Day 8 is completed by the 6th subject, competitive enrollment would ensue thereafter. If a 
definitely related SAE were to be reported among these 6 subjects, and the subject was found by 
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the Study-Independent Safety Review Committee (SISRC) to be randomized to the Liquid 
Alpha1-PI (Human) plus SMT arm, the SISRC would carefully review and evaluate the case and 
make appropriate recommendations with regard to study status.
In this study, symptomatic subjects with positive polymerase chain reaction (PCR; reverse 
transcriptase [RT]-PCR) or nucleic acid amplification technology (NAT) for SARS-CoV-2 (or 
other commercial or public health assay approved by regulatory authorities) will receive placebo 
plus SMT or SMT plus Liquid Alpha1-PI (Human) given as two intravenous (IV) doses of 120 
mg/kg (body weight) one week apart (on Day 1 and Day 8); if the subject is discharged from the 
hospital then the 2nd infusion is not mandatory, and is at the discretion of the Principal 
Investigator and subject.
Specifically, subjects randomized to combination Liquid Alpha1-PI (Human) will receive the 
first IV infusion of blinded Liquid Alpha1-PI (Human) (120 mg/kg body weight) or Placebo on 
Day 1. A second Placebo/ Liquid Alpha1-PI (Human) dose of 120 mg/kg body weight will be 
administered a week later on Day 8. If the subject has been discharged from the hospital at the 
time of the Day 8 blinded Placebo/Liquid Alpha1-PI (Human) infusion, the 2nd infusion is not 
mandatory, and is at the discretion of the Principal Investigator and subject.
Approximately 100 subjects will be randomized (1:1) with an interim analysis after 50 subjects 
(approximately 25 per group). There will be no interruption in study conduct during interim 
analysis as this simply represents sponsor safety due diligence during the COVID-19 pandemic.
Interim Futility Analysis: An interim futility analysis will be conducted to assess whether the 
trial will be terminated due to lack of efficacy (futility) based on all available data assessable for 
the primary endpoint and key secondary efficacy endpoints.
All subjects will be followed daily through Day 10 (note: for Day 6 through Day 10, this 
stipulation is for as long as subjects are hospitalized). After Day 6, if subjects are discharged 
from the hospital, evaluations at Day 15 and 29 are required. Berlin criteria for ARDS (Appendix 
3) will be assessed on Day 1, 5, 15, and 29. Subjects remaining hospitalized will be followed 
daily through Day 29. Phone Checks will occur at Day 60 and Day 90 for vital status (living or 
deceased), any hospital re-admissions or serious/non-serious adverse events after the Day 29 
Final Clinic Visit. Details are provided in Appendix 1 (Schedule of Study Procedures). Clinical 
status will be evaluated for all hospitalized subjects daily with vital signs, Ordinal Scale (7
categories analogous to Cao et al. 2020), and NEWS at Screening/Baseline and during Liquid 
Alpha1-PI (Human) plus SMT or placebo plus SMT treatment and during Follow-up. The NEWS 
calculation is delineated in Appendix 2 and can be calculated using the on-line web tool at 
https://www.mdcalc.com/national-early-warning-score-news. 
For all subjects, all laboratory samples must be drawn prior to infusion of Placebo/Liquid 
Alpha1-PI (Human), if laboratory assessments are required for a day in which Placebo/Liquid 
Alpha1-PI (Human) is being infused. 
Respiratory samples for quantitative measurement of SARS-CoV-2 viral load by NAT or PCR 
(real-time RT-PCR) will be obtained on Day 1, and subsequently on Day 5± 1 day, Day 15± 1 
day, and Day 29 ± 1 day (obtained via nasopharyngeal swab). The results of these samples are 
not necessary for continuing on study. Similarly, blood samples for quantitative measurement of 
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IgM and IgG antibodies to SARS-CoV-2 via enzyme linked immunosorbent assay (ELISA), 
Indirect Fluorescent Antibody (IFA) or other assay methodology will be drawn at the same time 
points: Day 1, and subsequently on Day 5± 1 day, Day 15± 1 day, and Day 29 ± 1 day. The 
results of these samples are not necessary for continuing on study. 
Ferritin, D-dimer, CRP and Basic chemistry analytes (creatinine, albumin, alanine 
aminotransferase [ALT], total bilirubin, lactate dehydrogenase [LDH]) will be assessed on Day 1 
and on Day 5± 1 day, Day 15± 1 day, and Day 29 ± 1 day. An estimated glomerular filtration 
rate (eGFR) will also be calculated at these time points using the Cockcroft-Gault formula. 
Hematology (hemoglobin, hematocrit, platelet count, absolute neutrophil & lymphocyte count, 
leukocyte count with differential) will be assessed Day 5± 1 day, Day 15± 1 day, and Day 29± 1 
day. All routine laboratory tests will be assessed locally at the hospital/site’s laboratory. A 
cytokine panel will be performed at the same time points. Cytokine panel includes IL-1β, IL-10, 
IL-6, IL-8, IL-2, interferon γ, and TNF-α. Note: serum samples must be stored at -70° C for later 
analysis at a reference laboratory. Levels of alpha 1-PI (AAT) activity and antigen will be 
evaluated on Day 1, on Day 8± 1 day, Day 15± 1 day, and Day 29 ± 1 day; both plasma (sodium 
citrate) and serum samples to be stored at - 70° C for measurement of both antigenic content and 
functional activity (potency) (all samples are mandatory at all time points regardless of hospital 
discharge status, except for the Day 8 AAT activity and antigen which is not required if subjects 
are discharged from the hospital and no 2nd blinded study drug infusion is administered).
This clinical trial will consist of the following phases: 

Screening/Baseline (Day 1) during which eligibility criteria are reviewed. Once all eligibility 
criteria are met and all pre-infusion assessments are completed, blinded Liquid Alpha1-PI 
(Human) or Placebo administration can begin as expeditiously as feasible. On Day 8 a 
second IV dose of blinded Liquid Alpha1-PI (Human) or Placebo will be administered on 
Day 8. If the subject has been discharged from the hospital at the time of the Day 8 blinded 
Liquid Alpha1-PI (Human) or Placebo infusion, the 2nd infusion is not mandatory, and is at 
the discretion of the Principal Investigator and subject.

SMT, Observations, and Follow-up (Days 2 to Day 29): SMT will be provided to all subjects 
with daily assessments while hospitalized and follow-up from Day 2 through Day 29±1 day
(inclusive). 

Phone Checks will occur at Day 60 and Day 90 for vital status (living or deceased), any 
hospital re-admissions or serious/non-serious adverse events after the Day 29 Final Clinic 
Visit.
The overall study schema is shown in Figure 4-1.
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IV = intravenous; SMT = standard medical treatment
*Note: If the subject has been discharged from the hospital at the time of the Day 8 blinded Liquid Alpha-1 PI infusion, the 2nd infusion is not 
mandatory, and is at the discretion of the Principal Investigator and subject
Figure 4-1
Overall Study Schema
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4.3
Measures Taken to Minimize/Avoid Bias
4.3.1
Subject Numbering
Within each study site, subjects in the study will receive a consecutive subject number. 
Subject numbers are generated beginning with the study center number (3 digits, assigned by 
the sponsor) followed consecutively with a unique number for each subject (4 digits, 
including leading zeros). For example, if the investigator’s center number is 301, subject 
number will be 3010001, 3010002, 3010003, etc., in consecutive order. Subject numbers, 
once assigned, will not be reused at any center.
4.3.2
Randomization
Subjects will be randomized 1:1 to receive either combination treatment with Liquid Alpha1-
PI (Human) plus SMT or placebo plus SMT.
4.3.3
Blinding
The unblinded study pharmacist or designee, will be the only unblinded study person at each 
site. Preparation and pooling of study drug (Liquid Alpha1-PI (Human) and placebo) will be 
the responsibility of the local unblinded pharmacist or designee. The placebo is sterile 0.9% 
sodium chloride injection, United States Pharmacopeia (0.9% NaCl, USP) or equivalent. The 
same total volume of placebo will be prepared so that there are no differences in infusion volume.
Since this is a double-blind, placebo-controlled study, measures will be taken to assure that 
the placebo infusion will be indistinguishable in terms of commensurate volume from Liquid 
Alpha1-PI (Human) infusion volume to that required for the appropriate weight-based dose of 
Liquid Alpha1-PI (Human) to maintain blinding. 
Additionally, the unblinded pharmacist or designee will prepare all study drug infusion bags 
to assure no obvious visual differences between Liquid Alpha1-PI (Human) and placebo by 
covering the infusion bag with a non-transparent blinding bag cover.
Furthermore, results of the central laboratory analysis of AAT (activity & antigen) will not 
be shared with the Investigator, blinded study staff, clinical research organization or blinded 
Sponsor personnel involved in study conduct.
4.4
Study Treatments
4.4.1
Treatments to Be Administered

During this clinical trial, subjects randomized to combination Liquid Alpha1-PI (Human)
plus SMT will receive the first dose of blinded Liquid Alpha1-PI (Human) given as an IV 
dose of 120 mg/kg (body weight) on Day 1. A second dose of blinded Liquid Alpha1-PI 
(Human) (120 mg/kg) will be infused on Day 8 (see Section 6.1). If the subject has been 
discharged from the hospital at the time of the Day 8 blinded Liquid Alpha1-PI (Human)
infusion, the 2nd infusion is not mandatory, and is at the discretion of the Principal 
Investigator and subject.
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4.4.1.1
Liquid Alpha1-PI (Human)
Liquid Alpha1-PI (Human) has a nominal concentration of Alpha1-Proteinase Inhibitor of 50 
mg/mL. For a subject weighing 75 kg each dose of 120 mg/kg (on Day 1 and Day 8) would 
require 180 mL of Liquid Alpha1-PI (Human) to achieve the specified 120 mg/kg dose.
Prior to administration, visually inspect parenteral drug products for particulate matter and 
discoloration. The product may contain a few protein particles. The solution is clear, 
colorless or pale yellow or pale green. Do not use if discolored or cloudy. Before delivery to 
the subject, Liquid Alpha1-PI (Human) should be brought to room temperature and 
administered at room temperature for comfort to the subject. Liquid Alpha1-PI (Human) is 
for IV administration only. Pooled Liquid Alpha1-PI (Human) solution should be maintained 
at room temperature for administration within 3 hours.
Filter the solution during administration using an IV administration set with a suitable 5 to 
15-micron infusion filter (not supplied). Infuse Liquid Alpha1-PI (Human) separately, 
without mixing with other agents or diluting solutions. Infuse Liquid Alpha1-PI (Human) IV 
at 0.08 mL/kg/min as determined by subject response and comfort. The Liquid Alpha1-PI 
(Human) infusion line can be flushed with 0.9% sodium chloride for injection. Do Not flush 
with heparin.
4.4.1.2
Placebo
Sterile 0.9% sodium chloride injection, United States Pharmacopeia (0.9% NaCl, USP) or 
equivalent will be used as placebo to maintain the blind. The infusion solution will be at a 
volume commensurate to that required for the appropriate weight-based dose of Liquid 
Alpha1-PI (Human) and visually masked to maintain the blind. It will be prepared by the 
unblinded pharmacist or designee and the infusion bag will be covered with a non-
transparent sleeve.
In order to maintain the blind, the placebo infusion will be filtered during administration 
using an IV administration set with a suitable 5 to 15-micron infusion filter (not supplied).
Sterile 0.9% sodium chloride injection, United States Pharmacopeia (0.9% NaCl, USP) or 
equivalent will be supplied by the unblinded pharmacist using commercially available saline. 
4.4.2
Labeling of Investigational Product
Investigational product will be labeled according to the requirements of local law and 
legislation.
4.4.3
Packaging of Investigational Product
Packaging and labeling will comply with local regulatory requirements and will be translated 
into local languages when required per local regulations.
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4.4.4
Storage of Investigational product (Liquid Alpha1-PI (Human))
Store refrigerated at 2-8°C (36-46°F) for the period indicated by the expiration date on its 
label.
Product may be stored at room temperatures not exceeding 25°C (77°F) for up to one month, 
after which the product must be used or immediately discarded.
Discard after expiration date. Do not freeze. Discard any unused solution according to local 
requirements
4.5
Expected Duration of Subject Participation in the Study
The total estimated maximum duration of a subject’s participation in terms of actual Clinic 
Visits will be up to 30 days. Additionally, Phone Checks will occur at Day 60 and Day 90 for 
vital status (living or deceased), any hospital re-admissions or serious/non-serious adverse 
events after the Day 29 Final Clinic Visit.
4.6
Discontinuation Criteria for Individual Subjects and Study
4.6.1
Discontinuation Criteria for Individual Subjects
See Section 5.3 Subject Withdrawal Criteria
4.6.2
Premature Termination of Study/Closure of Center
The sponsor, Institutional Review Board/Ethics Committee (IRB/EC), and/or regulatory 
authorities have the right to close this study or a study center, and the investigator/sponsor 
has the right to close a center, at any time, although this should occur only after consultation 
between involved parties. The IRB/EC must be informed. Should the study/center be closed 
prematurely, all study materials (except documentation that has to remain stored at the site) 
must be returned to the sponsor. The investigator will retain all other documents until 
notification given by the sponsor for destruction.
The reasons a study center may be closed include, but are not limited to, the following:
•
Lack of enrollment 
•
Non-compliance with the requirements of the study protocol
•
Non-compliance with ICH GCP
4.7
Accountability Procedures for Investigational Product
Investigational product is to be used only for the study in accordance with the directions 
given in this protocol. The investigator, or designee such as the study pharmacist, is 
responsible for handling of the IP in accordance with directions given in the protocol.
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The investigator is responsible for maintaining accurate records of the IP for his/her site. 
Investigational product inventory/dispensing documentation verifying the receipt, dispensing, 
destruction, or return must be maintained and kept current by the investigator, or designee. 
The inventory must be made available for inspection by the monitor. Investigational product 
supplies must be accounted for by the monitor and inventory/dispensing logs must be 
verified by the monitor prior to IP return or destruction. Written documentation of any used 
and unused inventory is required. At the end of the study, a copy of the inventory/dispensing 
log(s) will be retrieved by the monitor and returned to Grifols.
4.8
Maintenance of Treatment Randomization Codes 
Randomization codes will be generated through an Interactive Response Technology 
electronic system and access to the actual randomization schedules or codes will be strictly 
controlled during the course of the study. This study is double-blind so there is blinding of 
treatment assignment.
4.9
Data to Be Recorded
All information contained in the medical history and complementary exploration reports 
including laboratory test will be considered as clinical trial source data.
Any data recorded in the Case Report Form should have written or electronic record in the 
subject’s medical records. These written or electronic records will be considered source data 
and should be dated and signed by the investigator or by the qualified delegated person 
(eg, results of vital signs testing, or the IP administration procedure).
For every subject enrolled, the investigator will write into his/her medical history that he/she 
has been enrolled in a clinical trial, specifying its title, study number, and sponsor, as well as 
the date of ICF provision.
The investigator is responsible for maintaining complete and adequate case histories in 
source records of each subject. All study-specific data necessary to be recorded in that cannot 
be found in subjects’ past medical records (such as medical history, past medications, etc.) 
should be recorded by the investigator or their designee in subjects’ medical files, dating and 
signing all new entries.
Source data must be preserved for the maximum period of time as required per local and 
international regulations and made available by the investigator in the cases described above.
5
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1
Inclusion Criteria
A subject must meet all the following inclusion criteria to be eligible for participation in this 
study:
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1. Hospitalized male or female subject ≥ 18 years of age at time of Screening who is being 
treated for COVID-19. Subjects must be screened within 48 hours (≤ 48 hours) of 
hospital admission.
2. Has laboratory-confirmed novel coronavirus (SARS-CoV-2) infection as determined by 
qualitative PCR (reverse transcriptase [RT]-PCR), or other commercial or public health 
assay approved by regulatory authorities as a diagnostic test for COVID-19 in any 
specimen during the current hospital admission OR 96 hours prior to the hospital 
admission date and prior to randomization ( the SARS-CoV-2 test results must be 
performed by a hospital laboratory and the documentation available) .
3. COVID-19 illness (symptoms) of any duration, including both of the following:
a)
Radiographic infiltrates by imaging (chest X-Ray, CT scan, etc.) and/or 
clinical assessment (evidence of rales/crackles on exam) with SpO2 <94% on 
room air
b)
Any One of the following related to COVID-19: i. Ferritin > 400ng/mL, ii. 
LDH > 300 U/L, iii. D-Dimers > reference range, or iv. C-reactive protein 
(CRP) > 40 mg/L
4. Subject provides informed consent prior to initiation of any study procedures.
5. Female subjects of childbearing potential (and males with female partners of childbearing 
potential) must agree to use of acceptable contraception methods during study (e.g., oral, 
injectable, or implanted hormonal methods of contraception, placement of an intrauterine 
device or intrauterine system, condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository, male sterilization, or true abstinence*) throughout the 
study.
*True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods], 
declaration of abstinence for the duration of a trial, and withdrawal are not acceptable 
methods of contraception.)
5.2
Exclusion Criteria
A subject meeting any of the following exclusion criteria is NOT eligible for participation in 
the study.
1. Subjects requiring invasive mechanical ventilation or ICU admission or with PaO2/FIO2 
≤ 150 mm Hg (i.e., arterial oxygen in mm Hg divided by fraction inspired oxygen 
concentration [e.g., 0.21 for room air])
2. Clinical evidence of any significant acute or chronic disease that, in the opinion of the 
investigator, may place the subject at undue medical risk.
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3. The subject has had a known serious anaphylactic reaction to blood, any blood-derived or 
plasma product, or known Selective IgA Deficiency with anti-IgA antibodies.
4. A medical condition in which the infusion of additional fluid is contraindicated (e.g., 
decompensated congestive heart failure or renal failure with fluid overload). This 
includes currently uncontrolled congestive heart failure New York Heart Association 
Class III or IV stage heart failure.
5. Shock that is unresponsive to fluid challenge and/or multiple vasopressors and 
accompanied by multiorgan failure considered not able to be reversed by the Principal 
Investigator
6. Known alpha-1 antitrypsin deficiency for which the subject is already receiving alpha1-
proteinase inhibitor augmentation therapy
7. Women who are pregnant or breastfeeding. Female subjects of child-bearing potential 
must have a negative test for pregnancy blood or urine human chorionic gonadotropin 
(HCG)-based assay at Screening/Baseline Visit.
8. Subjects for whom there is limitation of therapeutic effort such as “Do not resuscitate” 
status Note: If the decision is made not to apply treatments or therapeutic procedures that 
will provide little benefit for the suffering or agony the subject is experiencing, such a 
subject would not be appropriate for participation in this study and should be excluded.
9. Currently participating in another interventional clinical trial with investigational medical 
product or device
10. Subjects previously requiring long-term oxygen therapy (home oxygen therapy)
11. History (within the last 2 years) of myocardial infarction, unstable angina, stroke or 
transient ischemic attacks, pulmonary embolism or deep venous thrombosis
12. Subject has medical condition (other than COVID-19) that is projected to limit lifespan to 
≤ 1 year
13. Systolic blood pressure < 100 mm Hg or > 160 mm Hg (uncontrolled hypertension) at the 
time of Screening
14. Alanine aminotransferase (ALT) ≥ 2 times the upper limit of normal (ULN) 
15. Any elevation of total bilirubin at the time of Screening
16. Estimated glomerular filtration rate (eGFR) < 45 mL/min (or subject is dependent on 
dialysis/renal replacement therapy) at the time of Screening
eGFR is calculated by the Cockcroft-Gault equation:
For men:
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(140 −age in years)(body weight [kg])
(72)(serum creatinine  mg
dL")
For women:
0.85 x (140 −age in years)(body weight [kg])
(72)(serum creatinine  mg
dL")
17. Hemoglobin < 10 g/dL at the time of Screening
18. Absolute neutrophil count < 1000/mm3 at the time of Screening
19. Platelet count < 75,000/mm3 at the time of Screening
20. Subject has history of drug or alcohol abuse within the past 24 months
21. Subject is unwilling to commit to follow-up visits
22. Known history of prothrombin gene mutation 20210, homozygous Factor V Leiden 
mutations, antithrombin III deficiency, protein C deficiency, protein S deficiency or 
antiphospholipid syndrome
5.3
Subject Withdrawal Criteria
Subjects have the right to withdraw from the study at any time for any reason, either before 
or after the infusion of the IP. The investigator can withdraw a subject from the clinical trial 
at any time.
The investigator will document the reason(s) for withdrawal of each subject in source 
documents and study record. All data gathered on the subject prior to termination will be 
made available to the sponsor.
5.3.1
Screen Failures 
Screening evaluations will be used to determine the eligibility of each subject for enrollment. 
Subjects who fail to meet eligibility criteria during screening evaluations will be considered 
screen failures and will not participate in the study. Outcomes of screening evaluations will 
be documented in subject’s source documents (e.g. medical history) - including compliance 
with each individual inclusion/exclusion criterion- and in study records as well.
5.3.2
Removal of Subjects
Subjects may withdraw or be withdrawn from the study for the following reasons:
1.
At their own request or at the request of their legally acceptable representative.
2.
If, in the investigator’s opinion, continuation in the study would be detrimental to the 
subject’s well-being.
3.
At the specific request of the sponsor.
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Also, subjects may be withdrawn for the following reasons:
1.
The subject is not able to adhere to the main protocol requirements (major protocol 
violations). 
2.
The occurrence of an AE which in the investigator’s opinion requires the withdrawal of 
the subject from the clinical trial.
3.
The occurrence of pulmonary embolism whether or not related to COVID-19
4.
The subject is lost to follow-up.
5.
Subject’s death.
6.
Any event which in the opinion of the investigator impedes the subject’s participation in 
the study. 
In all cases, the reason for withdrawal must be recorded in the study record and in the 
subject’s records. 
5.3.3
Subject Replacement 
Subjects who are withdrawn from the study after being randomized will not be replaced.
5.3.4
Follow-up of Subjects Withdrawn from Study
For subjects administered any amount of blinded Liquid Alpha1-PI (Human) or blinded 
placebo who withdraw from the clinical trial prior to Day 29, study procedures and 
assessments scheduled for the Day 15 Visit will be performed at the time of withdrawal, 
during an unscheduled visit. In addition, to assure major clinical outcomes are adequately 
captured as a measure of overall safety, these subjects will be asked to return for their 
chronological Day 29 Clinic Visit (ie, 28 days after Day 1 baseline), provided that they or 
their legally acceptable representative have not withdrawn consent. At the chronological Day 
29 Clinic Visit, all assessments will be performed except for central laboratory testing:
cytokine panel, levels of alpha 1-PI (AAT) activity and antigen, respiratory sample for 
quantitative measurement of SARS-CoV-2 viral load (obtained via nasopharyngeal swab), 
and quantitative measurement of IgM and IgG antibodies, which are not required for these 
subjects at chronological Day 29 for premature withdrawals. Note: A Day 29 Clinic Visit 
would not be necessary if the unscheduled visit is within 4 days of the subject’s 
chronological Day 29 visit because the assessments/outcome measures would be the same 
and would not need to be repeated in such a short a time interval.
5.3.5
Definition of the End of Study
Clinical trial finalization will coincide with the last study visit of the last subject enrolled in 
the clinical trial. For an individual subject, end of study for the purposes of determining 
disposition and successful study completion is the Day 29/Final Clinic Visit performed at the 
scheduled on-study timeframe.
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6
TREATMENT OF SUBJECTS
See Section 4.4 for the treatment to be administered, including the name of the IP, the dose,
and the route/mode of administration.
6.1
Administration and Timing of Investigational Product for Each 
Subject
Subjects randomized to combination blinded Liquid Alpha1-PI (Human) plus SMT will 
receive the first dose of Liquid Alpha1-PI (Human) given as an IV dose of 120 mg/kg (body 
weight) on Day 1. A second dose of blinded Liquid Alpha1-PI (Human) (120 mg/kg) will be 
infused on Day 8. If the subject has been discharged from the hospital at the time of the Day 
8 blinded Liquid Alpha1-PI (Human) infusion, the 2nd infusion is not mandatory, and is at 
the discretion of the Principal Investigator and subject.
Liquid Alpha1-PI (Human) has a nominal concentration of Alpha1-Proteinase Inhibitor of 
50 mg/mL. For a subject weighing 75 kg each dose of 120 mg/kg (on Day 1 and Day 8) 
would require 180 mL of Liquid Alpha1-PI (Human) to achieve the specified 120 mg/kg 
dose.
Visually inspect parenteral drug products for particulate matter and discoloration prior to 
administration. The product may contain a few protein particles. The solution is clear, 
colorless or pale yellow or pale green. Do not use if discolored or cloudy. Before delivery to 
the subject, Liquid Alpha1-PI (Human) should be brought to room temperature and 
administered at room temperature for comfort to the subject. Liquid Alpha1-PI (Human) is 
for IV administration only. Pooled Liquid Alpha1-PI (Human) solution should be maintained 
at room temperature for administration within 3 hours.
Filter the solution during administration using an IV administration set with a suitable 5 to 
15-micron infusion filter. Infuse Liquid Alpha1-PI (Human) separately, without mixing with 
other agents or diluting solutions. Infuse Liquid Alpha1-PI (Human) IV at 0.08 mL/kg/min as 
determined by subject response and comfort. The Liquid Alpha1-PI (Human) infusion line 
can be flushed with 0.9% sodium chloride for injection. Do Not flush with heparin.
Subjects randomized to placebo plus SMT will receive sterile 0.9% sodium chloride injection 
(0.9% NaCl, USP) or equivalent to maintain the blind. The infusion solution will be at a 
volume commensurate to that required for the appropriate weight-based dose of Liquid 
Alpha1-PI (Human) and visually masked to maintain the blind. It will be prepared by the 
unblinded pharmacist or designee and the infusion bag will be covered with a non-
transparent sleeve. In order to maintain the blind, the placebo infusion will be filtered during 
administration using an IV administration set with a suitable 5 to 15-micron infusion filter 
(not supplied).
An infusion may be stopped at the discretion of the medical personnel according to normal 
practice, for instance if there is extravasation at the IV site, and then restarted using a new IV 
site. However, if a hypersensitivity reaction occurs, such as anaphylaxis, the IV infusion 
must be stopped permanently, and no further study infusions will be given. During infusion 
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vital signs will be measured and the subject will be carefully observed. Specifically, vital 
signs will be measured immediately before infusion, then after the first 5 minutes of infusion 
and subsequently at 5 to 10-minute intervals during infusion until the end of infusion, and at 
a time point 2 hours after the end of infusion. Early signs and symptoms of hypersensitivity 
reactions may include pruritus; generalized urticaria; flushing; swollen lips, tongue, or uvula; 
wheezing; tightness of the chest; dyspnea; hypotension; and syncope. If hypersensitivity 
symptoms occur, the infusion must be promptly stopped, and appropriate therapy
administered. Such subjects who discontinue infusion will be monitored according to 
standard of care until hypersensitivity/anaphylaxis resolves and will not receive any further 
IP.
6.2
Prior and Concomitant Therapy
Concomitant medications must be recorded in the medical notes and in CRF, including the 
trade and generic names of the medication, the dose, the route of administration, and the 
duration of the medication (frequency). Concomitant prophylaxis for potential venous 
thrombosis or thromboembolism in hospitalized subjects with COVID-19 is supported within 
this study according to institutional standard practices.
Subjects should be managed according to standard of care for intercurrent illnesses, inclusive 
of influenza vaccine if appropriate depending on the clinical circumstance.
6.2.1
Prohibited Medications Prior to Study Participation
Administration of commercial AAT at study entry is not allowed.
6.2.2
Prohibited Concomitant Medications during the Study
Administration of a non-study commercial AAT product is not allowed during study.
6.2.3
Restricted Concomitant Medications during the Study
There are no restricted concomitant medications.
6.3
Treatment Compliance
Reasons for any deviation from the administration of less than 100% of the IP dose must be 
recorded in the subject’s medical records.
The investigator or designee is responsible for maintaining accurate records of study 
medication administered at his/her study center.
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7
ASSESSMENT OF EFFICACY
7.1
Efficacy Variables
7.1.1
Primary Efficacy Variable
The primary efficacy variable is the proportion of subjects dying or requiring ICU admission 
on or before Day 29 or who are dependent on high flow oxygen devices or invasive 
mechanical ventilation on Day 29. 
7.1.2
Secondary Efficacy Variables
The secondary efficacy variables include:

Assessment of Clinical Severity: Change in NEWS from baseline (Day 1 through Day 
29)
The NEWS has demonstrated an ability to discriminate patients at risk of poor outcomes. 
This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any 
supplemental oxygen, temperature, systolic blood pressure, heart rate, level of 
consciousness [Alert, Voice, Pain, Unresponsive]) https://www.mdcalc.com/national-
early-warning-score-news (Appendix 2)

Time to clinical response: NEWS ≤ 2 maintained for 24 hours, Day 1 through Day 29 

Time to hospital discharge: defined as duration of hospitalization from Day 1 through 
Day 29

If admitted to ICU post randomization: Duration of ICU stay through Day 29

Duration of any oxygen use Day 1 through Day 29

If requiring mechanical ventilation post randomization: Duration mechanical ventilation 
through Day 29

Absolute value and mean change from baseline in the Ordinal scale Day 1 through Day 
29
The Ordinal scale is as follows: 
1) Death; 
2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO); 
3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
4) Hospitalized, requiring supplemental oxygen; 
5) Hospitalized, not requiring supplemental oxygen; 
6) Not hospitalized, limitation on activities; 
7) Not hospitalized, no limitations on activities.

Proportion (percentage) of subjects in each severity category of the 7-point Ordinal scale 
at Day 15 and Day 29
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
Time to sustained normalization of temperature and proportion of subjects with 
normalization of fever at all time points, defined as temperature < 36.6°C armpit, 
< 37.2°C oral, or < 37.8°C rectal sustained for at least 24 hours

Number of subjects who develop ARDS through Day 29 (Appendix 3) 

Length of time to clinical progression through Day 29 (defined as the time to death, 
mechanical ventilation, or ICU admission)
7.1.3
Exploratory Efficacy Variables
The exploratory efficacy variables include: 

Change from baseline in quantitative SARS-CoV-2 viral load by NAT or PCR (real-time 
RT-PCR) to Day 5± 1 day, Day 15± 1 day, and Day 29 ± 1 day

Change from baseline in quantitative anti- SARS-CoV-2 IgM and IgG antibodies to Day 
5± 1 day, Day 15± 1 day, and Day 29 ± 1 day

Proportion of subjects with evidence of hyperinflammation on Day 1, Day 5, Day 15, and 
Day 29 defined as:
a)
Lymphocyte counts <1000 cells/μL, AND
b)
Two of the following 4 criteria:
i)
Ferritin > 500ng/mL, 
ii)
LDH > 300 U/L, 
iii)
D-Dimers > 1000 ng/mL (fibrinogen equivalent units [FEU]) or 
> 2 times upper normal limit, 
iv)
C-reactive protein (CRP) > 70 mg/L 

Change from baseline in cytokine profile (cytokine panel includes IL-1β, IL-10, IL-6, IL-
8, IL-2, interferon γ, and TNF-α) to Day 5± 1 day, Day 15± 1 day, and Day 29 ± 1 day

Change from baseline in levels of alpha 1-PI (AAT) activity and antigen through Day 29 
(both plasma [sodium citrate] and serum samples to be stored for measurement of both 
antigenic content and functional activity [potency])
7.2
Methods and Timing for Assessing, Recording, and Analyzing 
Efficacy Parameters
7.2.1
Observations and Measurements
Before any study-specific screening/baseline procedures are performed, and after completely 
understanding the nature of the clinical trial, informed consent must be obtained. This means 
that the potential subject provides informed consent prior to initiation of any study 
procedures. The preferred process for obtaining informed consent is through the signing of a 
written ICF by the subject. If there are concerns regarding coronavirus (SARS-Cov-2) 
transmission through the process of obtaining written consent, methods recently proposed by 
the FDA should be followed to reduce this risk (see Appendix 4).
Sites subject to local conditions/institutional guidelines that do not allow for a written 
informed consent process due to the risk of coronavirus (SARS-Cov-2) transmission may 
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obtain oral consent only if the site is able to provide written documentation of the specific 
institutional/local guidelines that mandate oral consent as the only permitted consenting 
method and ensure these guidelines are available in the investigator site files. Where proven 
that oral informed consent is the only permittable process, the site must record in the 
subject’s medical history, “I have explained to the subject the characteristics and objectives 
of the study, its risks, and potential benefits. I have been able to answer the subject’s 
questions and I confirm that this subject has given oral informed consent.” Subsequently, and 
when possible, the subject's written informed consent will be obtained in those situations 
where oral consent was initially required. All informed consent procedures must be aligned 
with local laws and regulations.
The following is a description of the procedures/assessments to take place at each study visit. 
See the Schedules of Study Procedures in Appendix 1.
7.2.2
Screening/Baseline and Randomized Treatment (Day 1)
All required screening and baseline (pre-infusion Day 1) procedures/assessments will be 
performed prior to administration of the blinded study drug infusion.
Assessments include the following:

Informed consent

Inclusion/exclusion criteria 

Pregnancy test for females of child-bearing potential

Record demography, (including age [year of birth], gender, race, and ethnicity) disease 
characteristics (date of exposure, date of onset)

Ordinal Scale assessment

National Early Warning Score (NEWS) (Appendix 2)

Record clinical features key symptoms: fever, cough, shortness of breath, fatigue, myalgia 
etc.

Vital signs (temperature, systolic and diastolic blood pressure, pulse, respiratory rate)

Weight

Record result of historical SARS-CoV-2 PCR (qualitative RT-PCR) or NAT or other 
commercial or public health assay approved by regulatory authorities as a diagnostic test 
for COVID-19 in any specimen during the current hospital admission OR 96 hours prior 
to the hospital admission date and prior to randomization (the SARS-CoV-2 test results 
must be performed by a hospital laboratory and the documentation available) (eligibility 
criterion)

If subject is receiving oxygen, record any supplemental oxygen administration (type, %, 
flow start/end date/time)

Record hospital admission date

Record oxygen saturation (specify on or off oxygen supplementation)

Respiratory sample for quantitative measurement of SARS-CoV-2 viral load by NAT or 
PCR (real-time RT-PCR) (obtained via nasopharyngeal swab)
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
Sample for quantitative measurement of IgM and IgG antibodies to SARS-CoV-2 by 
enzyme linked immunosorbent assay (ELISA), Indirect Fluorescent Antibody (IFA), or 
another assay methodology (if antibodies cannot be determined at the site store serum
samples frozen at -70°C for later analysis at an external lab)

Serum Chemistry (creatinine, albumin, alanine aminotransferase [ALT], total bilirubin, 
lactate dehydrogenase [LDH])

Calculate eGFR using the Cockcroft-Gault formula.

Hematology: absolute neutrophil & lymphocyte count and standard hematology
(hemoglobin, hematocrit, platelet count, leukocyte count with differential)

Assessment of ARDS (Berlin Criteria) (Appendix 3)

Ferritin (serum), D-dimer (plasma, sodium citrate tube), CRP (serum)

Cytokine panel (IL-1β, IL-10, IL-6, IL-8, IL-2, interferon γ, and TNF-α). Note: serum 
samples must be stored at -70° C for later analysis at a reference laboratory.

Levels of alpha 1-PI (AAT) activity and antigen; both plasma (sodium citrate) and serum 
samples to be stored at - 70° C for measurement of both antigenic content and functional 
activity (potency).

Record SAEs and TEAEs

Record standard care concomitant medications 
After all Screen/Baseline assessments are complete subjects may be randomized.
Subjects may receive the first infusion of blinded Liquid Alpha1-PI (Human) or Placebo on 
Screen/Baseline and Randomized Treatment visit (Day 1) if eligibility criteria are met, and 
all pre-infusion assessments are performed. The intent is for infusion of blinded Liquid 
Alpha1-PI (Human) or Placebo to commence as rapidly as feasible on Day 1. If there is 
unanticipated delay due to pandemic conditions, while not ideal, proceed with the first 
blinded Liquid Alpha1-PI (Human) or Placebo infusion as rapidly as possible.
During study infusion vital signs will be measured immediately before the start of infusion, 
after the first 5 minutes of infusion, and subsequently at 5-10-minute intervals during 
infusion until the end of infusion. Vital signs will also be measured 2 hours after the end of 
study infusion.
Record all infusion details and date/time in the CRF on the specific “1st IP infusion day” 
page and continue with all protocol-specified assessments. 
All Study Days are relative to Day 1 (Screen/Baseline and Randomized Treatment visit).
7.2.3
SMT and Daily Evaluations (Days 2 through 10 if still hospitalized) and 
Mandatory Day 5 Assessments for All Subjects
All subjects receive continued SMT. On Day 8 all subjects will receive a second double-
blind infusion of blinded Liquid Alpha1-PI (Human) or Placebo. Subjects randomized to 
Liquid Alpha1-PI (Human) will receive a second blinded dose of 120 mg/kg body weight. 
Subjects randomized to Placebo will receive a second blinded infusion of sterile 0.9% 
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NaCl USP, or equivalent of commensurate volume to preserve the blind. If the subject has 
been discharged from the hospital at the time of the Day 8 blinded Liquid Alpha1-PI (Human) 
or Placebo infusion, the 2nd infusion is not mandatory, and is at the discretion of the Principal 
Investigator and subject.
Coinciding with this time point, subjects who opt to receive the 2nd blinded infusion of Liquid
Alpha1-PI (Human) or Placebo will have levels of alpha 1-PI (AAT) activity and antigen 
measured on Day 8. Both plasma (sodium citrate) and serum samples are to be stored at - 70°
C for measurement of both antigenic content and functional activity (potency); for all such 
subjects, samples must be obtained prior to blinded Liquid Alpha1-PI (Human) or Placebo 
infusion. 
During study infusion on Day 8, vital signs will be measured immediately before the start of 
infusion, after the first 5 minutes of infusion, and subsequently at 5-10-minute intervals 
during infusion until the end of infusion. Vital signs will also be measured 2 hours after the 
end of study infusion.
Daily assessments include the following:

Ordinal Scale assessment

NEWS (Appendix 2)

Clinical features key symptoms: fever, cough, shortness of breath, fatigue, myalgia etc.

Vital signs (temperature, systolic and diastolic blood pressure, pulse, respiratory rate)

Record any supplemental oxygen administration (type, %, flow start/end date/time)

If subject requires mechanical ventilation post randomization: Record mechanical 
ventilation (start/end date/time)

Record oxygen saturation (specify on or off oxygen supplementation)

If subject requires ICU admission post randomization: Record ICU admission date

Record SAEs and TEAEs 

Record standard care concomitant medications 
On Day 5 ± 1 day the following specimens will be obtained (mandatory assessments for 
all subjects with daily assessments for Day 5 detailed immediately above):

Respiratory sample for quantitative measurement of SARS-CoV-2 viral load by NAT or 
PCR (real-time RT-PCR) (obtained via nasopharyngeal swab)

Sample for quantitative measurement of IgM and IgG antibodies to SARS-CoV-2 (if 
antibodies cannot be determined at the site store serum samples frozen at -70°C for later 
analysis at an external lab)

Cytokine panel (IL-1β, IL-10, IL-6, IL-8, IL-2, interferon γ, and TNF-α). Note: serum 
samples must be stored at -70° C for later analysis at a reference laboratory.
Additionally, on Day 5 ± 1 day the following samples will be obtained (all on the same 
day) (mandatory assessments for all subjects):

Ferritin, D-dimer, CRP

Serum Chemistry (creatinine, albumin, ALT, total bilirubin, LDH)
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
Calculate eGFR using the Cockcroft-Gault formula.

Hematology: absolute neutrophil & lymphocyte count and standard hematology 
(hemoglobin, hematocrit, platelet count, leukocyte count with differential)

Assessment of ARDS (Berlin Criteria) (Appendix 3)
7.2.4
Day 11-14 for Subjects Still Hospitalized: SMT and Daily Evaluations
All subjects receive continued SMT.
Daily assessments include the following:

Ordinal Scale assessment

NEWS (Appendix 2)

Clinical features key symptoms: fever, cough, shortness of breath, fatigue, myalgia etc.

Vital signs (temperature, systolic and diastolic blood pressure, pulse, respiratory rate)

Record any supplemental oxygen administration (type, %, flow start/end date/time)

If subject requires mechanical ventilation post randomization: Record mechanical 
ventilation (start/end date/time)

Record oxygen saturation (specify on or off oxygen supplementation)

Record SAEs and TEAEs 

Record standard care concomitant medications 
7.2.4.1
Day 8 2nd Liquid Alpha1-PI (Human) or Placebo Infusion for Hospitalized 
Subjects (optional if subject discharged from the hospital)
Subjects randomized to Liquid Alpha1-PI (Human) or Placebo + SMT will receive a second 
dose on Day 8. If the subject has been discharged from the hospital at the time of the Day 8 
blinded Liquid Alpha1-PI (Human) or Placebo infusion, the 2nd infusion is not mandatory, 
and is at the discretion of the Principal Investigator and subject.
Subjects in the hospital on Day 8 will have levels of alpha 1-PI (AAT) activity and antigen 
measured. Both plasma (sodium citrate) and serum samples are to be stored at -70° C for 
measurement of both antigenic content and functional activity (potency);, samples must be 
obtained prior to IV infusion of blinded study drug.
7.2.5
Day 15±1 day Mandatory for All Subjects
Assessments include the following:

Ordinal Scale assessment

NEWS (Appendix 2)

Clinical features key symptoms: fever, cough, shortness of breath, fatigue, myalgia etc.

Vital signs (temperature, systolic and diastolic blood pressure, pulse, respiratory rate)

Record any supplemental oxygen administration (type, %, flow start/end date/time)
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
If subject requires mechanical ventilation post randomization: Record mechanical 
ventilation (start/end date/time)

Record oxygen saturation (specify on or off oxygen supplementation)

Record SAEs and TEAEs 

Record standard care concomitant medications 

Respiratory sample for quantitative measurement of SARS-CoV-2 viral load by NAT or 
PCR (real-time RT-PCR) (obtained via nasopharyngeal swab)

Sample for quantitative measurement of IgM and IgG antibodies to SARS-CoV-2 (if 
antibodies cannot be determined at the site store serum samples frozen at -70°C for later 
analysis at an external lab)

Serum Chemistry (creatinine, albumin, ALT, total bilirubin, LDH)

Calculate eGFR using the Cockcroft-Gault formula.

Hematology absolute neutrophil & lymphocyte count and standard hematology 
(hemoglobin, hematocrit, platelet count, leukocyte count with differential)

Assessment of ARDS (Berlin Criteria) (Appendix 3)

Ferritin, D-dimer, CRP

Cytokine panel (IL-1β, IL-10, IL-6, IL-8, IL-2, interferon γ, and TNF-α). Note: serum 
samples must be stored at -70° C for later analysis at a reference laboratory.

Levels of alpha 1-PI (AAT) activity and antigen; both plasma (sodium citrate) and serum 
samples to be stored at - 70° C for measurement of both antigenic content and functional 
activity (potency).
7.2.6
Day 16-28 for Subjects Still Hospitalized: SMT and Daily Evaluations
All subjects receive continued SMT.
Daily assessments include the following:

Ordinal Scale assessment

NEWS (Appendix 2)

Clinical features key symptoms: fever, cough, shortness of breath, fatigue, myalgia etc.

Vital signs (temperature, systolic and diastolic blood pressure, pulse, respiratory rate)

Record any supplemental oxygen administration (type, %, flow start/end date/time)

If subject requires mechanical ventilation post randomization: Record mechanical 
ventilation (start/end date/time)

Record oxygen saturation (specify on or off oxygen supplementation)

Record SAEs and TEAEs 

Record standard care concomitant medications 
7.2.7
Day 29±1 day – All Subjects
Assessments include the following:
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
Ordinal Scale assessment

NEWS (Appendix 2)

Clinical features key symptoms: fever, cough, shortness of breath, fatigue, myalgia etc.

Vital signs (temperature, systolic and diastolic blood pressure, pulse, respiratory rate)

Record any supplemental oxygen administration (type, %, flow start/end date/time)

If subject requires mechanical ventilation post randomization: Record mechanical 
ventilation (start/end date/time)

Record oxygen saturation (specify on or off oxygen supplementation)

Record hospital discharge date

If subject requires ICU admission post randomization: Record ICU discharge date

Record SAEs and TEAEs 

Record standard care concomitant medications 

Respiratory sample for quantitative measurement of SARS-CoV-2 viral load by NAT or 
PCR (real-time RT-PCR) (obtained via nasopharyngeal swab)

Sample for quantitative measurement of IgM and IgG antibodies to SARS-CoV-2 (if 
antibodies cannot be determined at the site store serum samples frozen at -70°C for later 
analysis at an external lab)

Serum Chemistry (creatinine, albumin, ALT, total bilirubin, LDH)

Calculate eGFR using the Cockcroft-Gault formula.

Hematology: absolute neutrophil & lymphocyte count and standard hematology 
(hemoglobin, hematocrit, platelet count, leukocyte count with differential)

Assessment of ARDS (Berlin Criteria) (Appendix 3)

Ferritin, D-dimer, CRP

Cytokine panel (IL-1β, IL-10, IL-6, IL-8, IL-2, interferon γ, and TNF-α). Note: serum 
samples must be stored at -70° C for later analysis at a reference laboratory.

Levels of alpha 1-PI (AAT) activity and antigen; both plasma (sodium citrate) and serum 
samples to be stored at - 70° C for measurement of both antigenic content and functional 
activity (potency).
7.2.8
Day 60±2 days and Day 90±2 days Phone Checks – All Subjects

Phone Checks will be performed on Day 60 and Day 90:

to confirm the subject’s vital status (living or deceased)

to record any hospital re-admissions

to record any SAEs/non-serious AEs after the Day 29 Final Clinic Visit
7.2.9
Description of Laboratory Tests and Procedures
Table 7-1 Name, Description, and Location of Laboratory Tests and Procedures
provides a summary of the laboratory tests conducted for this study.
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Table 7-1 Name, Description, and Location of Laboratory Tests and Procedures
Test Panela
Description
Location
Hematology
Absolute neutrophil & lymphocyte count; Basic hematology: 
Hemoglobin, hematocrit, platelets, white blood cell (WBC) count 
with differential
Local
Chemistry
Creatinine, albumin, alanine aminotransferase (ALT), total 
bilirubin, lactate dehydrogenase (LDH)
Local
Markers of inflammation
C-reactive protein (CRP), D-dimer, ferritin
Local
Cytokine panel
Cytokine panel includes IL-1β, IL-10, IL-6, IL-8, IL-2, interferon 
γ, and tumor necrosis factor-α (TNF-α). Note: serum samples 
must be stored at -70° C for later analysis at a reference 
laboratory.
Central
Quantitative measurement of 
SARS-CoV-2 viral load by 
NAT or PCR (RT-PCR)
Quantitative NAT or PCR (real-time RT-PCR) in respiratory 
samples (obtained via nasopharyngeal swab)
Central
Quantitative measurement of 
IgM and IgG antibodies to 
SARS-CoV-2
Quantitative IgM and IgG antibody levels by ELISA, IFA, or 
other assay methodology (if antibodies cannot be determined at 
the site store serum samples frozen at -70°C for later analysis at 
an external lab)
Central
AAT (activity & antigen)
Levels of alpha 1-PI (AAT) activity and antigen; both plasma 
(sodium citrate) and serum samples to be stored at – 70° C for 
measurement of both antigenic content and functional activity 
(potency).
Store 
local/
Central 
analysis
8
ASSESSMENT OF SAFETY
8.1
Safety Parameters
The safety and tolerability of Liquid Alpha1-PI (Human) in subjects with COVID-19 will be 
evaluated in this study. Safety endpoints will include:

Cumulative incidence of treatment-emergent SAEs and potentially related SAEs through 
Day 90 phone check

Cumulative incidence of Grade 3-5 TEAEs and potentially related severe TEAEs through 
Day 29 as defined in the CTCAE, US Department of Health and Human Services, 
NIH, and NCI

Cumulative incidence of all TEAEs and potentially related TEAEs through Day 29
In this clinical study, disease progression is defined as the worsening of a subject’s condition 
attributable to the disease for which the investigational product is being studied. It may be an 
increase in the severity of the targeted disease and/or increases in the symptoms of the 
targeted disease. Anticipated symptoms of COVID-19 include fever, cough, hypoxia, 
dyspnea, hemoptysis, myalgia, fatigue, pharyngitis which may develop at any time during the 
course of the disease. The development of COVID-19 symptoms during the clinical study 
should not be recorded as individual TEAEs, unless there is evidence suggesting a causal 
relationship between blinded Liquid Alpha1-PI (Human)/Placebo and the TEAE. 
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8.2
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters
The Schedule of study procedures is located in Appendix 1.
TEAEs will be recorded in source documents and on Grifols form for recording of TEAEs.
8.3
Procedures for Eliciting Reports of and for Recording and 
Reporting Adverse Event and Intercurrent Illnesses
8.3.1
Warnings/Precautions
Hypersensitivity reactions, including anaphylaxis, may occur. Monitor vital signs and 
observe the subject carefully throughout the infusion.
Individuals with known selective or severe IgA deficiency who have known antibodies 
against IgA should not receive Liquid Alpha1-PI (Human) since these subjects may 
experience severe reactions, including anaphylaxis, to IgA which may be present in the 
preparation.
Since Liquid Alpha1-PI (Human) can cause a transient increase in blood volume, particular 
caution is necessary in subjects with severe heart failure and subjects at risk of circulatory 
overload.
When medicines are made from human plasma, certain measures are put in place to prevent 
infections being passed on to subjects. These include:
•
Careful selection of blood and plasma donors to make sure those at risk of carrying 
infections is excluded
•
The testing of each donation and pools of plasma for signs of virus/infections
•
The inclusion of steps in the manufacturing of plasma derivatives with virus 
inactivation/removal capacity
However, despite these measures, when medicines prepared from human blood or plasma are 
administered, the possibility of passing on infection cannot be totally excluded. This also 
applies to any unknown or emerging viruses or other types of infections.
8.3.2
Adverse Event Monitoring
Subjects must be carefully monitored for AEs particularly in terms of their seriousness, 
severity, and causal relationship to the study drug.
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8.3.3
Adverse Event Definitions
8.3.3.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a medicinal product or study treatment and which does not necessarily 
have a causal relationship with this administration. An AE can therefore be any unfavorable 
and unintended sign (including any abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
In this clinical study, disease progression is defined as the worsening of a subject’s condition 
attributable to the disease for which the investigational product is being studied. It may be an 
increase in the severity of the targeted disease and/or increases in the symptoms of the 
targeted disease. Anticipated symptoms of COVID-19 include fever, cough, hypoxia,
dyspnea, hemoptysis, myalgia, fatigue, pharyngitis, which may develop at any time during 
the course of the disease. The development of COVID-19 symptoms during the clinical study 
should not be recorded as individual TEAEs, unless there is evidence suggesting a causal 
relationship between blinded Liquid Alpha1-PI (Human)/Placebo and the TEAE.
8.3.3.2 Suspected Adverse Drug Reactions/Adverse Reactions
All noxious and unintended responses to a medicinal product or study treatment related to 
any dose should be considered suspected ADRs (i.e., potentially drug related AEs). The 
phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product or study treatment and an AE is at least a reasonable possibility.
8.3.4
Assessment of Causality of Adverse Event
The investigator is required to provide a causality assessment for each AE reported to the 
sponsor. The assessment of the causal relationship of an AE to the administration of IP must 
be a clinical decision based on all available information at the time of the completion of the 
CRF and/or SAE Report Form. The sponsor will consider the investigator’s causality 
assessment and also provide its own assessment. 
Causal relationship to the IP will be established according to medical judgment on whether 
there is a reasonable possibility of a causal relationship between the AE and the IP
administration.
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The investigator must determine and classify the AE causality according to the following 
categories:
Unrelated/Not related: there is not a reasonable possibility of causal relationship between 
the AE and the IP.
Possibly related: there is evidence to suggest a causal relationship between the IP and the 
AE.
Definitely related: there is a reason to conclude that the IP caused the AE.
Criteria to assess the causal relationship should take into account of the following conditions: 
1) a plausible temporal sequence from the IP administration to the AE onset; 2) whether the 
event follows a known response pattern to the suspected treatment; 3) whether the AE could 
be reasonably explained by the subject’s clinical state, comorbidities, or concomitant 
medications, as well as 4) the occurrence of improvement on stopping/reducing the treatment 
(positive dechallenge) and/or reappearance of the event on repeated exposure (positive 
rechallenge).
For expedited safety reporting purposes, AEs assessed as either “definitely related” or 
“possibly related” will be considered POTENTIALLY RELATED or just RELATED.
Any AE reported prior to the first administration of the IP will be considered a non-
treatment-emergent AEs and causal relationship will always be “Unrelated/Not related.”
8.3.5
Severity of Adverse Event or Suspected Adverse Drug Reaction
Adverse events and suspected ADRs (i.e., potentially drug related AEs) will be classified 
depending on their severity according to the following definitions:
Mild: an AE which is well tolerated by the subject, causing minimum degree of malaise and 
without affecting normal activities.
Moderate: an AE that interferes with the subject’s normal activities.
Severe: an AE that prevents the subject from performing their normal activities.
This category is further subdivided into Grade 3-5 AEs defined according to CTCAE criteria, 
US Department of Health and Human Services, NIH, and NCI.
Adverse events and suspected ADR severity gradation must be distinguished from AE and 
suspected ADR seriousness gradation, which is defined according to event consequence. For 
example, headache can be mild, moderate or severe but not necessarily serious in all these 
cases.
The investigator will be responsible for assessing the AE and suspected ADR intensity 
during the clinical trial, taking into account current criteria included in this section.
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8.3.6
Expectedness of Adverse Event or Suspected Adverse Drug Reaction
(Reference Safety Information)
An AE or suspected ADR (i.e., potentially drug related AE) is considered “unexpected” if the 
nature, seriousness, severity or outcome of the reaction(s) is not consistent with the reference 
information, which is the Liquid Alpha1-Proteinase Inhibitor (Human) (Prolastin-C Liquid)
Investigator’s Brochure. The expectedness shall be determined by the sponsor for any serious 
ADRs (potentially related SAEs) according to the reference document for expedited safety 
reporting purposes. 
8.3.7
Seriousness of Adverse Event or Suspected Adverse Drug Reaction 
An AE or suspected ADR (i.e., potentially drug related AE) is considered “serious” if, in the 
view of either the investigator or sponsor, it results in any of the following outcomes: 
•
Death
•
Life-threatening AE (life-threatening in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe)
•
In-patient hospitalization or prolongation of existing hospitalization*
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
•
A congenital anomaly/birth defect
•
An important medical event (important medical event in the definition of “serious” refers 
to those events which may not be immediately life-threatening, or result in death, or 
hospitalization, but from medical and scientific judgment may jeopardize the subject 
or/and may require medical or surgical intervention to prevent one of the other outcomes 
listed above).
*Hospitalization is to be considered only hospital admission (including emergency room 
stay) for equal or more than 24 hours. The following hospitalizations should not be 
reported as SAEs:
- Hospitalization or prolongation of hospitalization needed for procedures required by 
the clinical trial protocol or as part of a routine procedure followed by the center.
- Admissions not associated with an AE (e.g., social hospitalization for the purpose of 
respite care, survey visits, or annual physicals).
- Elective or pre-planned hospitalizations for a pre-existing condition that had not 
worsened from baseline (e.g., elective or scheduled surgery arranged prior to start of 
the study).
This definition permits either the sponsor or the investigator to decide whether an event is 
“serious”. If either the sponsor or the investigator believes that the event is serious, the event 
must be considered “serious” and evaluated by the sponsor for expedited reporting. 
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8.3.8
Adverse Event Documentation
All AEs and SAEs occurring on Day 1 through the Day 29 (±1 day)/Final Visit must be fully 
recorded in the subject’s medical record and CRF, and paper SAE report form (if serious).
At the time of the Day 60 (±2 days) and Day 90 (±2 days) Phone Checks any additional 
SAEs/non-serious AEs will also be collected and recorded.
It is the responsibility of the investigator to ensure that AEs are appropriately recorded.
AEs will be collected through directly observed events or spontaneously volunteered by the 
subject. Clearly related signs, symptoms and abnormal diagnostic procedures should 
preferably be grouped together and recorded as a single diagnosis or syndrome wherever 
possible.
The following variables must be recorded:
•
The verbatim term (a diagnosis is preferred)
•
Date/time of onset
•
Date/time of resolution
•
Severity (mild, moderate, severe [Grade 3 to Grade 5])
•
Causality (unrelated, possibly related, definitely related)*
•
Seriousness (yes, no)
•
Action taken (with regard to IP)
•
Other action (to treat the event)
•
Outcome and sequel (follow-up on AE)
*Causality assessment will be made only when the AE occurs after the subject has initiated at 
least one infusion of the IP. An AE occurring before subject’s exposure to IP will be always 
labeled as “unrelated”.
For AEs that occur during infusions, the infusion rate in effect at the time of onset of the AE, 
the time of onset of the AE and the time of AE change materially in intensity and/or resolve 
will be captured.
In addition to the investigator’s own description of the AE, each AE will be encoded 
according to the Medical Dictionary for Regulatory Activities (MedDRA).
For example, a laboratory test abnormality considered clinically significant, eg, causing the 
subject to withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, or judged clinically significant in the context of the subject’s medical history 
by the investigator, should be reported as an AE. Each event must be described in detail 
along with start and stop dates, severity, relationship to IP, action taken and outcome. Each 
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event must be adequately supported by documentation as it appears in the subject’s medical 
or case file.
8.3.9
Reporting of Serious Adverse Events 
8.3.9.1
Reporting of Serious Adverse Events
Any SAE (see Section 8.3.7) that occurs (after informed consent) on Day 1 through the Day 
29 (±1 day)/Final Visit and any SAE recorded at the time of the Day 60 (±2 days) or Day 90 
(±2 days) Phone Checks must be fully recorded in the subject’s medical record, CRF and 
paper SAE Report form. SAEs must be expeditiously reported whether or not considered 
attributable to the IP. 
Serious adverse events will be reported using the designated paper SAE Report Form. When 
the investigator becomes aware of an SAE, she/he must submit a completed, signed and 
dated SAE Report Form (in English) within 24 hours to the sponsor by email/fax. The date 
of this SAE discovery by the site staff should be documented in the source documents (ie, 
medical records). 
Each SAE must be followed up until resolution or stabilization. After the initial report, all 
relevant information for SAE follow-up, and for the outcome, must also be supplied to the 
sponsor in a timely manner (within 3 days from its identification or within 24 hours for 
relevant new information) by means of the SAE Report Form. In addition, the sponsor may 
request additional information and/or reports.
All SAE Report Forms must be reported to Grifols via email or fax as follows:
Grifols Global Pharmacovigilance
Email
FAX:
(International)
When required, and according to local law and regulations, SAEs must be reported to the 
IRB/EC and regulatory authorities. Copies of the investigator’s reports must be sent to the 
sponsor.
8.4
Type and Duration of the Follow-Up of Subjects after Adverse 
Events 
In so far as is possible, all individuals will be followed up until the AE or suspected ADR has 
been resolved. If an AE/suspected ADR/SAE is present when the subject has completed the 
study, the course of the event must be followed until the final outcome is known, or the event 
has been stabilized and no further change is expected, and the investigator decides that no 
further follow-up is necessary.
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8.4.1
Reporting Pregnancy
While pregnancy itself is not a true “AE,” pregnancy occurring in a clinical study must be 
followed, to collect information regarding the experiences of gestation and pregnancy with 
blinded study drug exposure. The Investigator must report any pregnancy that occurs in a 
female study subject subsequent to informed consent through Day 29.
8.5
Study-Independent Safety Review Committee (SISRC) and 
Stopping Rules
Grifols will utilize a SISRC whose members (from Grifols) will be impartial and independent 
of the clinical trial team, and will consist of a global pharmacovigilance representative, a 
medical director, and a third individual knowledgeable in the epidemiological field or 
knowledgeable in the therapeutic area or a statistician. The SISRC will review relevant safety 
information from the study as outlined in the SISRC Charter. At a minimum, after the first 20 
subjects are enrolled and have completed treatment, the SISRC will conduct an initial safety 
review. The SISRC will perform a causality review of all TEAEs and SAEs. The SISRC will 
be notified of relevant SAEs inasmuch as feasible within 24 hours, but no later than 3 days.
Stopping rules are delineated below. Any change to the study stopping rules must be 
reviewed by the FDA. If the study is suspended it will not be re-opened without prior FDA 
approval.
Stopping criteria for temporary suspension of further study enrollment/recruitment pending 
full safety investigation by the SISRC are detailed below.
The SISRC will conduct a safety evaluation and study enrollment/recruitment will be 
temporarily suspended while the safety investigation is undertaken if any one of the 
following occur: 

1 death, i.e. at the time of each death, regardless of causality attribution by the 
Principal Investigator or whether it may be considered COVID-19 related. 
Pausing enrollment/recruitment after any death will allow the SISRC to perform a 
full investigation of every fatal event. (Note: Further infusions for subjects 
already randomized will only be stopped if there is elevated concern by the 
Principal Investigator or the SISRC that the death is drug related.) 

1 Grade 4 treatment-emergent AE occurs in any of the first 3 randomized subjects 
considered potentially related to blinded study drug

1 subject develops a Grade 3 hypersensitivity reaction or serious anaphylactic 
reaction at any time attributable to Liquid Alpha1-PI (Human)

10 subjects develop treatment-emergent AEs in the same system organ class that 
are ≥Grade 2 severity (CTCAE grading criteria)

2 subjects develop treatment-emergent Grade 4 serious AEs of the same kind in 
the first 20 subjects

5 subjects develop Grade 3 or 4 treatment-emergent AEs that are at least possibly 
related to blinded study drug at any time during the study
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
3 or more subjects per 10 subjects enrolled and dosed with Liquid Alpha1-PI 
(Human) develop definitely related treatment-emergent serious AEs of the same 
kind (same or related verbatim terms). This stopping criterion will be applied after 
at least 10 subjects are randomized and treated with Liquid Alpha1-PI (Human).

An unanticipated safety signal is detected by the SISRC that was unexpected and 
of sufficient magnitude to warrant concern
Note that all of these thresholds for SISRC review and hiatus in enrollment/recruitment 
pertain to blinded treatment assignment for study participants (except for Grade 3 
hypersensitivity or anaphylactic reaction for which unblinding would be likely for patient 
management and the threshold pertaining to 10 subjects randomized to Liquid Alpha1-PI 
(Human) which coincides with the first routine SISRC review after 20 subjects are 
randomized). During their full safety investigation, the SISRC will have access to actual 
treatment administered (Liquid Alpha1-PI (Human) or placebo), so that decisions regarding 
the study can be fully informed. Further details will be outlined in the SISRC charter.
The SISRC will receive SAEs within 24 hours. They will be required to meet within 72 hours 
if the above stopping criterion and/or stipulation with regard to serious anaphylactic reaction 
are fulfilled in order to conduct a thorough safety evaluation.
9
STATISTICS
9.1
Statistical Methods 
Descriptive statistics will include the number of non-missing observations, mean, standard 
deviation (SD), median, minimum, and maximum values for the continuous/quantitative data 
or absolute and relative frequency counts and percentages for categorical/qualitative data. All 
statistical tests will be 2-sided at a significance level of 0.05.
An interim analysis will be conducted after 50 subjects (approximately 25 per group) for 
safety variables through Day 29.  Due to the exploratory nature of this phase 2 study, the 
multiplicity adjustments will not be considered; full details will be described in the statistical 
analysis plan.
Interim Futility Analysis: An interim futility analysis will be conducted to assess whether the 
trial will be terminated due to lack of efficacy (futility) based on all available data assessable 
for the primary endpoint and key secondary efficacy endpoints.
There will be 3 analysis populations in this study; 2 populations for efficacy assessments and 
1 population for safety evaluation.
The intention to treat (ITT) population is defined as all subjects who are randomized. The 
ITT population will be used for all efficacy analyses.
The Per-Protocol (PP) population is defined as the subset of subjects included in the ITT 
population who do not present major protocol violations which might have an impact on the 
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primary efficacy endpoint, and complete at least 80% of the IP. The primary efficacy 
analyses will be carried out using the PP population if different from the ITT population.
The Safety population is defined as the subset of subjects who receive at least any amount of 
Liquid Alpha1-PI (Human) plus SMT or placebo plus SMT. Safety analyses will be based on 
the Safety population.
The primary efficacy analysis will be carried out on the ITT population and repeated on the 
PP population (if different from the ITT population) by Fisher’s exact test. Secondary and 
exploratory efficacy analyses will be analyzed by means of Kaplan-Meier survival estimates 
and curves and compared between treatment groups by means of the Log-rank test for time to 
event variables, analysis of covariance (ANCOVA) when adjusting for covariates, or analysis 
of variance (ANOVA) when without covariates for normally-distributed variables or 
Wilcoxon rank-sum test for non-normally-distributed variables. Detailed data handling and 
evaluation procedures and details of the interim review will be described in the Statistical 
Analysis Plan (SAP).
For the primary endpoint, if the value of the subject is missing, then a conservative 
imputation rule will be used such that the subject will be treated as having met the condition 
for the primary efficacy analysis. The choice of analysis method for primary, secondary and 
exploratory efficacy endpoints will be described in detail in the SAP which will be finalized 
and signed off before data analysis is performed.
The SAP may include exploratory analyses of various aspects of SMT inclusive of different 
interventional strategies and evolving treatment modalities. Grifols will analyze the use of 
COVID-19 specific, potentially disease modifying treatments for any potential differences
between study arms. This analysis will be fully detailed in the SAP since medical 
understanding of COVID-19 interventions is rapidly evolving. For ethical reasons, there are 
no restrictions placed on what are perceived to be potentially life-saving therapies (apart 
from participation in another interventional clinical trial).
9.2
Determination of Sample Size
Because of the urgency and lack of previous prospective COVID-19 data, sample size 
estimation remains incompletely defined; however, the size of this pilot study is 
commensurate with other Phase 2 investigations ongoing during the COVID-19 pandemic. 
Approximately 100 subjects are allowed to be randomized as part of a humanitarian effort 
against COVID-19.
9.3
Interim Futility Analysis
An interim futility analysis will be conducted based on all available data assessable for the 
primary endpoint and key secondary efficacy endpoints to assess whether the trial will be 
terminated due to lack of efficacy (futility). The unblinded output will be reviewed by an 
independent unblinded team, and the study team will remain blinded.  
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Determination of futility from the interim futility analysis will be based on the conditional 
power (the power conditional on the observed data accumulated at the interim analysis) for 
the primary outcome, as well as assessment of the secondary efficacy outcomes.
The futility analysis will include for the primary efficacy endpoint variable, all patients with 
data through Day 29, and for the following secondary efficacy endpoint variables, all patients 
with data through Day 29, as specified for each endpoint:
•
Assessment of Clinical Severity: Change in NEWS from baseline (Day 1 through Day 
29)
•
Time to clinical response: NEWS ≤ 2 maintained for 24 hours, Day 1 through Day 29 
•
Time to hospital discharge: defined as duration of hospitalization from Day 1 through 
Day 29 (and duration of hospitalization)
•
If admitted to ICU post randomization: Duration of ICU stay through Day 29
•
Duration of any oxygen use Day 1 through Day 29
•
If requiring mechanical ventilation post randomization: Duration mechanical ventilation 
through Day 29
•
Absolute value and mean change from baseline in the Ordinal scale Day 1 through Day 
29 
o
The Ordinal scale is as follows: 
1) Death; 
2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO); 
3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
4) Hospitalized, requiring supplemental oxygen; 
5) Hospitalized, not requiring supplemental oxygen; 
6) Not hospitalized, limitation on activities; 
7) Not hospitalized, no limitations on activities.
•
Proportion (percentage) of subjects in each severity category of the 7-point Ordinal scale 
at Day 15 and Day 29
•
Time to sustained normalization of temperature and proportion of subjects with 
normalization of fever at all time points, defined as temperature < 36.6°C armpit, < 
37.2°C oral, or < 37.8 °C rectal sustained for at least 24 hours
•
Number of subjects who develop Acute Respiratory Distress Syndrome (ARDS) through 
Day 29  
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•
Length of time to clinical progression through Day 29 (defined as the time to death, 
mechanical ventilation, or ICU admission)
If the results of the interim futility analysis are not promising, the trial may be terminated.  
Otherwise the study will continue as originally planned unless discontinued for business or 
feasibility reasons.
The futility analysis will not inflate the type I error since the trial will not be stopped to claim 
efficacy. The primary outcome will be analyzed according to Section 9.1.  
9.4
Criteria for Termination of the Study 
The sponsor or its representative may terminate the study at any time for scientific or
corporate reasons.
If the trial is prematurely terminated or suspended for any reason, the PI should promptly 
inform the trial subjects, should assure appropriate therapy and follow-up for the subjects and 
should inform the regulatory authority(ies) and/or ethics committee(ies) when required.
9.5
Procedure for Accounting for Missing, Unused, and Spurious Data
Handling of missing, unused and spurious data will be described in the SAP. All available 
efficacy and safety data will be included in data listings.
9.6
Reporting Deviations from the Statistical Analysis Plan
The detailed statistical analysis methodologies will be documented in the SAP. If there are 
any deviations from the originally planned analyses in the SAP, they will be fully described 
and justified in the protocol amendment(s) and/or final Clinical Study Report.
10 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The data will be recorded and kept current in the medical notes, and in the CRF by the study 
site personnel directly responsible for the information. Grifols personnel or designee can 
review the records.
In accordance with ICH GCP guidelines, the monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded for consistency and 
to verify adherence to the protocol, and the completeness, consistency, and accuracy of data 
entered. “Source documentation” includes individual subject files, separate from the study 
forms, which should be maintained and include visit dates, laboratory results, concomitant 
treatment, vital signs, medical history, examinations, AEs, IP logs, and other notes as 
appropriate. The investigator agrees to cooperate with the monitor to ensure that any 
problems noted during the course of these monitoring visits are resolved.
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11 QUALITY CONTROL AND QUALITY ASSURANCE
Monitoring and auditing procedures defined/agreed by the sponsor will be followed, in order 
to comply with ICH GCP guidelines. Each center will be visited by a monitor (or evaluated 
by remote monitoring) to ensure compliance with the study protocol, ICH GCP and legal 
aspects according to the clinical monitoring plan. 
Representatives of regulatory authorities or of Grifols may conduct audits or inspections of 
the investigator study site. If the investigator is notified of an audit or inspection by a 
regulatory authority, the investigator agrees to notify the Grifols Representative 
(e.g., Clinical Assessment Monitor/Medical Monitor, Program Manager, Program Leader) 
immediately. The investigator agrees to provide to representatives of a Regulatory Agency or 
Grifols access to records, facilities, and personnel for the effective conduct of an audit or 
inspection.
12 ETHICS
12.1
Institutional Review Board/Ethics Committee 
Documented approval from appropriate IRBs/ECs will be obtained for all participating 
centers/countries prior to study start, according to ICH GCP guidelines, local laws, 
regulations and organizations. When necessary, an extension, amendment or renewal of the 
IRBs/ECs approval must be obtained and also forwarded to the sponsor. The IRBs/ECs must 
supply to the sponsor, upon request, a list of the IRBs/ECs members involved in the vote and 
a statement to confirm that the IRBs/ECs is organized and operates according to ICH GCP 
guidelines and applicable laws and regulations.
12.2
Ethical Conduct of the Study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
ICH GCP guidelines. The study will also be carried out in keeping with applicable local 
law(s) and regulation(s). This may include an audit by the sponsor representatives and/or an 
inspection by regulatory authority representatives at any time. The investigator must agree to 
the audit or inspection of study-related records by the sponsor representatives and/or 
regulatory authority representatives and must allow direct access to source documents to the 
sponsor and/or regulatory authority representatives.
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard(s) to the study 
subjects without prior IRB/EC/sponsor approval/favorable opinion. As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the IRB/EC/sponsor. Any deviations from the protocol 
must be fully explained and documented by the investigator.
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No medical waivers for protocol inclusion/exclusion criteria will be allowed by the sponsor.
If there is a need for changes to the protocol inclusion/exclusion criteria is identified, the 
protocol will be amended to include such changes. The protocol amendment will be 
submitted to the competent regulatory authority and/or IRB/EC as applicable per regulations, 
which allows implementation of the revised inclusion/exclusion criteria in the study.
12.3
Regulatory Authority Approvals/Authorizations
Regulatory Authority approvals/authorizations/ notifications, where required, must be in 
place and fully documented prior to study start. Study information including contact 
information for investigator sites responsible for conducting the study will be posted on a 
publicly accessible clinical registry(ies) as required by local law.
12.4
Subject Information and Consent
Subject information and ICFs will be provided to investigator sites. Prior to the beginning of 
the study, the investigator must have the IRB/EC written approval/favorable opinion of the 
ICF and any other information to be provided to subjects. The written approval of the 
IRB/EC together with the approved subject information/ICF must be filed in the study files 
and a copy of the documents must also be provided to sponsor by the investigator site.
Informed consent must be obtained prior to the performance of any study specific 
procedure(s). The preferred process for obtaining informed consent is through the signing of 
a written ICF by the subject. If there are concerns regarding coronavirus (SARS-Cov-2) 
transmission through the process of obtaining written consent, methods recently proposed by 
the FDA should be followed to reduce this risk (see Appendix 4).
Sites subject to local conditions/institutional guidelines that do not allow for a written 
informed consent process due to the risk of coronavirus (SARS-Cov-2) transmission may 
obtain oral consent only if the site is able to provide written documentation of the specific 
institutional/local guidelines that mandate oral consent as the only permitted consenting 
method and ensure these guidelines are available in the investigator site files. Where proven 
that oral informed consent is the only permittable process, the site must record in the 
subject’s medical history, “I have explained to the subject the characteristics and objectives 
of the study, its risks, and potential benefits. I have been able to answer the subject’s 
questions and I confirm that this subject has given oral informed consent.” Subsequently, and 
when possible, the subject's written informed consent will be obtained in those situations 
where oral consent was initially required. All informed consent procedures must be aligned 
with local laws and regulations.
12.5
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.
Subject names or other personal data or identifiers will not be supplied to the sponsor. Only 
the subject code number will be recorded in the study records, and if the subject’s name or 
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other personal data identifiers appear on any other document (e.g., pathologist report), it must 
be redacted before a copy of the document is supplied to the sponsor.  Study findings stored 
on a computer will be stored in accordance with local data protection laws.  Subjects will be 
informed in writing that representatives of the sponsor, IRB/EC, or regulatory authorities 
may inspect their medical records and personal health information to verify the information 
collected, and that all personal information made available for an audit or inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential. 
The investigator will maintain a list to enable subjects’ records to be identified.
13 DATA HANDLING AND RECORD KEEPING
13.1
Data Handling
The study data will be recorded and kept current in the study records by the site study 
personnel directly responsible for the information. Entries made in the study records must be 
verifiable against source documents. The data in the study records will be monitored (on site 
or remotely) by Grifols representatives at regular intervals. Data will be reviewed for 
completeness and compared with the source documents at site level or data will be evaluated
by remote monitoring. Remote source data verification will be allowed when appropriate and 
feasible to ensure data integrity, quality, safety of the participants and the patients’ 
confidentiality data is not compromised. Examples of acceptable source documents include 
individual subject medical records, prospective information gathered on source 
documentation worksheets, lab reports and other diagnostics pertinent to this study which are 
separate from the study records. The listing of types of source documents which will be 
defined in the source data agreement will be filed in the trial master file.
All AEs and SAEs must be recorded. All SAEs must be recorded on the SAE Report Form. 
The SAE Report Form must be kept in site records with a copy provided to the designated 
person as detailed in the study file. 
13.2
Record Retention
At study completion, all study data will be transferred to Grifols according to ICH GCP 
guidelines, local laws, regulations, and Grifols requirements. The study file and all source 
data should be retained until notification is given by the sponsor for destruction.
An investigator is required by ICH GCP guidelines to retain the study files for a minimum of 
25 years. If an investigator moves, withdraws from an investigation or retires, the 
responsibility for maintaining the records may be transferred to another person (e.g., other 
investigator). Grifols must be notified in writing of the person responsible for record 
retention and the notification will be retained in the sponsor study file and the investigator 
site file.
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14 FINANCING AND INSURANCE
In the event of subject injury as a direct result of either administration of investigational 
product or any non-standard of care study procedure, sponsor will pay for the costs of 
treatment, provided the subject has followed the instructions given by the study doctor and 
the illness or injury is not due to the natural progression of any conditions existing before the 
subject participated in the study. Financial compensation for such things as lost wages, 
disability, or discomfort due to any research-related injury is not available.
Sponsor shall maintain comprehensive general liability insurance or self-insurance in 
amounts adequate to cover any damage, demand, claim, loss or liability caused or incurred 
by sponsor, or as otherwise required by applicable laws and/or regulations.
15 PUBLICATION POLICY
Institution and the investigator agree that the first publication shall be made in conjunction 
with the presentation of a joint, multi-center publication of the study results from all 
appropriates sites. If such a multi-center publication is not submitted within 18 months after 
conclusion of the study at all sites or after Grifols confirms there will be no joint, multi-
center publication, then institution and/or investigator shall have the right, at their discretion, 
to publish, either in writing or orally, the results of the study performed under the protocol, 
subject to the conditions outlined below:
•
The results of the study will be reported in the publicly accessible registry(ies).
•
Institution and/or investigator shall furnish Grifols with a copy of any proposed 
publication at least thirty (30) days in advance of the date of submission for publication.
•
Within said thirty (30) day period, Grifols shall:
-
Review such proposed publication for Confidential Information (other than Study 
results) and for subject information subject to the Health Insurance Portability and 
Accountability Act of 1996 (“HIPAA”) and other applicable privacy laws;
-
Review such proposed publication for the unauthorized use of the name, symbols 
and/or trademarks of Grifols;
-
By written notice to the investigator, identify with specificity the text or graphics in 
such proposed publication that Grifols contends contains Confidential Information, 
protected subject information, or the unauthorized use of Grifols’ name, symbols 
and/or trademarks so that the proposed publication may be edited appropriately to 
remove such text or graphics before publication; and 
-
By written request, Grifols may delay proposed publications up to sixty (60) days to 
allow Grifols to protect its interests in Grifols Inventions described in such 
publications.
•
Institution and/or investigator shall give Grifols the option of receiving an 
acknowledgment for its sponsorship of the study in all such publications or presentation.
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of alpha 1-antitrypsin mutants against proteolytic enzymes of the kallikrein-kinin, 
complement, and fibrinolytic systems. J Biol Chem 1990; 265(18):10786–10791.
53. Petrache I, Fijalkowska I, Medler TR, Skirball J, Cruz P, Zhen L, Petrache HI, Flotte 
TR, Tuder RM. Alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung 
endothelial cell apoptosis. Am J Pathol 2006; 169(4):1155–1166.
54. Pott GB, Chan ED, Dinarello CA and Shapiro L. Alpha-1-antitrypsin is an 
endogenous inhibitor of proinflammatory cytokine production in whole blood. J 
Leukoc Biol. 2009; 85: 886-895.
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55. Prytherch D, Smith GB, Schmidt PE, Featherstone PI. ViEWS – towards a national 
Early Warning Score for detecting adult inpatient deterioration. Resuscitation 
2010;81:932–937.
56. Research Paper Royal College of Physicians. National Early Warning Score (NEWS) 
Standardising the assessment of acute-illness severity in the NHS. Report of a 
working party. London: RCP, 2012.
57. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to 
COVID-19 based on an analysis of data of 150 patients from Wuhan, China. 
Intensive Care Med. 2020 Mar 3:1-3. Doi: 10.1007/s00134-020-05991-x
58. Sinden NJ, Baker MJ, Smith DJ, Kreft JU, Dafforn TR and Stockley RA. Alpha-1-
antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive 
pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2015; 308: L179-190.
59. Smith GB, Prytherch DR, Meredith P, Schmidt PE, Featherstone PI. The ability of the 
National Early Warning Score (NEWS) to discriminate patients at risk of early 
cardiac arrest, unanticipated intensive care unit admission, and death. Resuscitation. 
2013 Apr;84(4):465-470. Doi: 10.1016/j.resuscitation.2012.12.016. Epub 2013 Jan 4.
60. Stoller JK, Fallat MD, Schluchter MD, et al. Augmentation therapy with α1-
Antitrypsin. Patterns of Use and Adverse Events. Chest 2003; 123: 1425-1434.
61. Tawara I, Sun Y, Lewis EC, Toubai T, Evers R, Nieves E, Azam T, Dinarello CA, 
Reddy P. Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after 
experimental allogeneic bone marrow transplantation. Proc Natl Acad Sci U S A 
2012; 109, 564-569.
62. Team NCPERE. Vital surveillances: the epidemiological characteristics of an 
outbreak of 2019 novel coronavirus diseases (COVID-19) – China. China CDC 
Weekly. 2020;2(8):113-22.
63. Tse GM, To KF, Chan PK, et al. Pulmonary pathological features in coronavirus 
associated severe acute respiratory syndrome (SARS). J Clin Pathol. 2004;57(3):260-
265. doi:10.1136/jcp.2003.013276US Food and Drug Administration. FDA Guidance 
on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency: Guidance for Industry, Investigators, and Institutional Review Boards. 
March 2020. https://www.fda.gov/media/136238/download
64. Vidal R, Miravitlles M. Informe del Registro Español de Pacientes con Déficit de 
Alfa-1-antitripsina. Arch Bronconeumol 1995; 31: 299-302.
65. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, 
Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients 
With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020. 
323(11):1061-1069. E201585. Doi: 10.1001/jama.2020.1585.
66. Wewers MD, Casolaro MA, Sellers SE, et al. Replacement therapy for alpha 1-
antitrypsin deficiency associated with emphysema. N Engl J Med. 1987; 316: 1055-
1062.
67. WHO. Clinical management of severe acute respiratory infection when novel 
coronavirus (nCoV) infection is suspected. Interim guidance. 13 March 2020 
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respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected (accessed 
19 March 2020)
68. WHO. Landscape analysis of therapeutics: 
file:///D:/WHO%20Landscape%20Therapeutics%20under%20investigation%2017%2
0Feb%202020.pdf (accessed 19 March 2020).
69. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk Factors Associated With 
Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus 
Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020. E200994. Doi: 
10.1001/jamainternmed.2020.0994.
70. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of 
critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-
centered, retrospective, observational study. Lancet Respir Med. 2020. Epub 
2020/02/28. Doi: 10.1016/S2213-2600(20)30079-5. PubMed PMID: 32105632.
71. Zhang B, Lu Y, Campbell-Thompson M, Spencer T, Wasserfall C, Atkinson M, Song 
S. Alpha1-antitrypsin protects beta-cells from apoptosis. Diabetes 2007; 56, 1316-
1323.
72. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for 
mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective study. 
Lancet, 2020. Doi: 1016/S0140-6736(20)30566-3.
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17 APPENDICES
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Appendix 1
Schedule of Study Procedures 
Study Period
Screen/
Baseline
IP
SMT and Daily Evaluationsl
Follow-
Up 
Follow-Up Clinic Visit Day
Study Day
Procedures/assessments
1
1st IP 
infusion 
day
2
3
4
5±1
m
day
6
7
8
9
10
11-14 
Daily if 
in 
hospital
15±
1 
day
m
16-28 
Daily if 
in 
hospital
29e ± 1 
daym
Day 
60 ± 
2 
days
Day 
90 ± 
2 
days
Informed consent
X
Inclusion/exclusion criteria
X
Demography, (including age [year of 
birth], gender, race, and ethnicity), 
disease characteristics (date of 
exposure, date of onseta)
X
Pregnancy testb
X
Ordinal Scale (at the 1st assessment of a 
given day)c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
National Early Warning Score (NEWS)
(Appendix 2)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical features key symptoms: fever, 
cough, shortness of breath, fatigue, 
myalgia etc.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (temperature, systolic and 
diastolic blood pressure, pulse, 
respiratory rate)
X
Xi
X
X
X
X
X
X
Xi
X
X
X
X
X
X
Weight
X
Record result of historical SARS-CoV-
2 PCR (qualitative RT-PCR) or NAT or 
other commercial or public health assay 
approved by regulatory authorities as a 
diagnostic test for COVID-19 in any 
specimen during the current hospital 
admission OR 96 hours prior to the 
hospital admission date and prior to 
randomization (the SARS-CoV-2 test 
results must be performed by a hospital 
laboratory and the documentation 
available) (eligibility criterion)
X
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Study Period
Screen/
Baseline
IP
SMT and Daily Evaluationsl
Follow-
Up 
Follow-Up Clinic Visit Day
Study Day
Procedures/assessments
1
1st IP 
infusion 
day
2
3
4
5±1
m
day
6
7
8
9
10
11-14 
Daily if 
in 
hospital
15±
1 
day
m
16-28 
Daily if 
in 
hospital
29e ± 1 
daym
Day 
60 ± 
2 
days
Day 
90 ± 
2 
days
Record any supplemental oxygen 
administration (type, %, flow start/end 
date/time)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
If subject requires mechanical 
ventilation post randomization: Record 
any mechanical ventilation (start/end 
date/time)
X
X
X
X
X
X
X
X
X
X
X
X
X
Record oxygen saturation (specify on or 
off oxygen supplementation)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization (after all 
Screen/Baseline assessments complete)
X
IV dose of blinded Liquid Alpha1-PI 
(Human) 120 mg/kg body weight (or 
Placebo) given on Day 1 and Day 8
X
Xk
Record hospital admission and 
discharge dates
X
Xf
If subject requires ICU admission post 
randomization: Record ICU admission 
& discharge dates
Xf
Assessment of ARDS (Berlin Criteria)
(Appendix 3)
X
X
X
X
Respiratory sample for quantitative 
measurement of SARS-CoV-2 viral 
load by NAT or PCR (real-time RT-
PCR) (obtained via nasopharyngeal 
swab)
Pre 
randomized 
treatment g
X
X
X
Sample for quantitative measurement of 
IgM and IgG antibodies to SARS-CoV-
2 (if antibodies cannot be determined 
quantitatively store serum samples 
frozen at -70°C for later analysis at an 
external lab)
Pre 
randomized 
treatment g
X
X
X
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Study Period
Screen/
Baseline
IP
SMT and Daily Evaluationsl
Follow-
Up 
Follow-Up Clinic Visit Day
Study Day
Procedures/assessments
1
1st IP 
infusion 
day
2
3
4
5±1
m
day
6
7
8
9
10
11-14 
Daily if 
in 
hospital
15±
1 
day
m
16-28 
Daily if 
in 
hospital
29e ± 1 
daym
Day 
60 ± 
2 
days
Day 
90 ± 
2 
days
Serum Chemistry (creatinine, albumin, 
alanine aminotransferase [ALT], total 
bilirubin, lactate dehydrogenase [LDH])
Pre 
randomized 
treatment g
X
X
X
Calculate an estimated glomerular 
filtration rate (eGFR) using the 
Cockcroft-Gault formula
Pre 
randomized 
treatment g
X
X
X
Ferritin, CRP, D-dimer
Pre 
randomized 
treatment g
X
X
X
Hematology & absolute neutrophil & 
lymphocyte count (hemoglobin, 
hematocrit, platelet count, leukocyte 
count with differential)
Pre 
randomized 
treatment g
X
X
X
Cytokine panelh
Pre 
randomized 
treatment g
X
X
X
Levels of alpha 1-PI (AAT) activity and 
antigen (both plasma [sodium citrate] 
and serum samples to be stored for 
measurement of both antigenic content 
and functional activity [potency])
Pre 
randomized 
treatment g
Xgj
X
X
Record SAEs and TEAEsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record standard care concomitant 
medications 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Phone Checks for Vital Status (living or 
deceased), any hospital re-admissions 
or SAEs/non-serious AEs after Day 29 
Final Clinic Visit
X
X
a
Date of first contact with the virus, date of first symptoms, date of PCR (RT-PCR)/NAT positive 
b
Human chorionic gonadotropin-based assay for women of childbearing potential (urine matrix is also valid).
c
Ordinal scale measure of clinical status: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or ECMO; 3) Hospitalized, on non-invasive 
ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not 
hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.
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d
Grade 3-5 TEAEs will be defined according to CTCAE criteria, US Department of Health and Human Services, NIH, and NCI. In this clinical study, 
disease progression is defined as the worsening of a subject’s condition attributable to the disease for which the investigational product is being studied. 
It may be an increase in the severity of the targeted disease and/or increases in the symptoms of the targeted disease. Anticipated symptoms of COVID-
19 include fever, cough, hypoxia, dyspnea, hemoptysis, myalgia, fatigue, pharyngitis, which may develop at any time during the course of the disease. 
The development of COVID-19 symptoms during the clinical study should not be recorded as individual TEAEs, unless there is evidence suggesting a 
causal relationship between blinded Liquid Alpha1-PI (Human)/Placebo and the TEAE.
e
Final Clinic Visit, followed by Phone Checks.
f
Record hospital and ICU discharge date on or before Day 29/Final Visit.
g
All laboratory tests and serum and plasma samples must be obtained from all subjects; samples must be obtained prior to the blinded Liquid Alpha1-PI 
(Human) infusion on Day 1 and Day 8. (Day 8 AAT levels only apply if second infusion given)
h
Cytokine panel includes IL-1β, IL-10, IL-6, IL-8 IL-2, interferon γ, and TNF-α. Note: serum samples must be stored at -70° C for later analysis at a 
reference laboratory.
i.
During study infusions on Day 1 and Day 8 vital signs will be measured immediately before the start of infusion, after the first 5 minutes of infusion, 
and subsequently at 5-10-minute intervals during infusion until the end of infusion. Vital signs will also be measured 2 hours after the end of study 
infusion.
j. Day 8 AAT measurement for activity and antigen is only required if subject is in hospital.
k. If the patient has been discharged from the hospital at the time of the Day 8 blinded Liquid Alpha1-PI (Human) or Placebo infusion, the 2nd infusion is 
not mandatory, and is at the discretion of the Principal Investigator and subject
l. Only applicable if subject remains hospitalized, except for Day 5 when all assessments are mandatory for all subjects.
m. Mandatory even if subject has been discharged from hospital  
Note: For assessment for early withdrawal see Section 5.3.4.
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Appendix 2
National Early Warning Score (NEWS)
The NEWS has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is 
based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, 
temperature, systolic blood pressure, heart rate, level of consciousness [Alert, Voice, Pain, 
Unresponsive]). To calculate you may access https://www.mdcalc.com/national-early-warning-score-
news
Details are also provided below.
Formula: Addition of the selected points; points assigned below: 
Criteria
Point Value
Respiratory Rate (breaths per minute)
≤8
+3
9-11
+1
12-20
  0
21-24
+2
≥25
+3
Oxygen Saturation (%)
≤91
+3
92-93
+2
94-95
+1
≥96
  0
Any Supplemental Oxygen
Yes
+2
No
  0
Temperature in °C (°F)
≤35.0 (95)
+3
35.1-36.0 (95.1-96.8)
+1
36.1-38.0 (96.9-100.4)
  0
38.1-39.0 (100.5-102.2)
+1
≥39.1 (≥102.3)
+2
Systolic BP
≤90
+3
91-100
+2
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Criteria
Point Value
101-110
+1
111-219
  0
≥220
+3
Heart Rate (beats per minute)
≤40
+3
41-50
+1
51-90
  0
91-110
+1
111-130
+2
≥131
+3
AVPU
A
  0
V, P, or U
+3
AVPU, Alert, Voice, Pain, Unresponsive.
Interpretation;
1. A low score (NEWS 1–4) should prompt assessment by a competent registered nurse who should 
decide if a change to frequency of clinical monitoring or an escalation of clinical care is required.
2. A medium score (i.e. NEWS of 5–6 or a RED score) should prompt an urgent review by a clinician 
skilled with competencies in the assessment of acute illness – usually a ward-based doctor or acute 
team nurse, who should consider whether escalation of care to a team with critical-care skills is 
required (i.e. critical care outreach team). ◦A RED score refers to an extreme variation in a single 
physiological parameter (i.e., a score of 3 on the NEWS chart in any one physiological parameter, 
colored RED to aid identification; e.g., heart rate
3. A high score (NEWS ≥7) should prompt emergency assessment by a clinical team/critical care 
outreach team with critical-care competencies and usually transfer of the patient to a higher 
dependency care area.
Evidence Appraisal
The six physiological parameters that were proposed to form the basis standardized National Early 
Warning Score were derived from this study. It retrospectively analyzed data from 35,585 medical 
admissions.
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Original/Primary Reference
Research Paper Royal College of Physicians. National Early Warning Score (NEWS) Standardising the 
assessment of acute-illness severity in the NHS. Report of a working party. London: RCP, 2012.
Validation
Smith GB, Prytherch DR, Meredith P, Schmidt PE, Featherstone PI. The ability of the National Early 
Warning Score (NEWS) to discriminate patients at risk of early cardiac arrest, unanticipated intensive 
care unit admission, and death. Resuscitation. 2013 Apr;84(4):465-470. Doi: 
10.1016/j.resuscitation.2012.12.016. Epub 2013 Jan 4. 
Other References
Prytherch D, Smith GB, Schmidt PE, Featherstone PI. ViEWS – towards a national Early Warning 
Score for detecting adult inpatient deterioration. Resuscitation 2010;81:932–937. 
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Appendix 3
Acute Respiratory Distress Syndrome (ARDS) Berlin Definition  
The Berlin Definition of Acute Respiratory Distress Syndrome is summarized in the table below. 
Timing is usually within 1 week of a known clinical insult or new or worsening respiratory symptoms.
Chest imaginga
Bilateral opacities—not fully explained by 
effusions, lobar/lung collapse, or nodules
Origin of edema 
Respiratory failure not fully explained by cardiac 
failure or fluid overload
Need objective assessment (eg, 
echocardiography) to exclude hydrostatic edema 
if no risk factor present
Oxygenationb,
Mild 200 mm Hg < PaO2/FIO2  ≤ 300 mm Hg 
with PEEP or CPAP ≥ 5 cm H2Oc
Moderate 100 mm Hg < PaO2/FIO2 ≤  200 mm 
Hg with PEEP ≥ 5 cm H2O
Severe PaO2/FIO2  ≤100 mm Hg with PEEP ≥ 5 
cm H2O
Abbreviations: CPAP, continuous positive airway pressure; FIO2, fraction of inspired oxygen; PaO2, partial pressure of 
arterial oxygen; PEEP, positive end-expiratory pressure.
a. Chest radiograph or computed tomography scan.
b. If altitude is higher than 1000 m, the correction factor should be calculated as follows: [PaO2/FIO2 X (barometric 
pressure/760)].
c. This may be delivered noninvasively in the mild acute respiratory distress syndrome group.
The following may be used for the Berlin criteria, for patients who are Not on a ventilator and do 
not have a blood gas performed. Since the effect of positive end-expiratory pressure (PEEP) may 
modify the derivation of SaO2 to SpO2, please do Not use SpO2 to apply Berlin criteria to patients while 
on a mechanical ventilator.
Respiratory Thresholds Determined by Pulse Oximetry Measurement of O2 Saturation (for 
patients Not on mechanical ventilation)
PaO2/FiO2
Corresponding SpO2/FiO2 
Threshold 
≥ 400
≥ 512
<400
<512
<300
<357
<200
<214
<100
<89
Derivation of SpO2/FiO2 values corresponding to PaO2/FiO2 ratios in the combined anesthesia and 
ARMA database* [*Data derived from 4728 matched SpO2/FiO2 and PaO2/FiO2 measurements from 
the combined anesthesia and ARMA database]
References
ARDS Definition Task Force. Acute Respiratory Distress Syndrome – The Berlin Definition. JAMA. 
2012;307(23):2526-2533. Doi:10.1001/jama.2012.5669
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Pandharipande PP, Shintani AK, Hagerman HE, St Jacques PJ, Rice TW, Sanders NW, Ware LB, 
Bernard GR, Ely EW. Derivation and validation of Spo2/Fio2 ratio to impute for Pao2/Fio2 ratio in the 
respiratory component of the Sequential Organ Failure Assessment score. Crit Care Med. 2009 
Apr;37(4):1317-1321.
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Appendix 4
Excerpt from: FDA Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Public Health Emergency
(FDA 2020)
Q10
How do I obtain signed informed consent from a hospitalized patient who is in 
isolation when a COVID-19 infection control policy prevents us from entering the 
patient’s room to collect a signed informed consent form?
FDA regulations generally require that the informed consent of a trial participant (in this case a 
hospitalized patient) be documented by the use of a written consent document that typically includes 
the elements of informed consent, as described in 21 CFR 50.25, and that has been approved by the 
IRB and signed and dated by the trial participant or their legally authorized representative at the time 
of consent (21 CFR 50.27(a)). When feasible, we recommend a traditional method of obtaining and
documenting informed consent using a signed paper copy of the consent form, or use of electronic 
informed consent.9,10,11 If neither of these approaches are possible, the following procedures would 
be considered to satisfy FDA’s informed consent documentation requirement.12
Method 1: 
A photograph of the signed informed consent document can be transmitted to 
the trial staff
1.
An unsigned consent form is provided to the patient by a person who has entered the room.
2.
The investigator/designee arranges a telephone call or video conference call with the patient 
(and, if desired and feasible, additional individuals requested by the patient (e.g., next of 
kin)).
3.
To ensure that patients are approached in a consistent fashion, a standard process should be 
used that will accomplish the following:
o
Identification of who is on the call.
o
Review of the informed consent document with the patient by the 
investigator/designee and response to any questions the patient may have.
o
Verbal confirmation by the patient that their questions have been answered, that they 
would like to participate in the trial, and that they have signed and dated the informed 
consent document that is in their possession.
9 See guidance for institutional review boards, investigators, and sponsors Use of Electronic Informed Consent In Clinical 
Investigations (December 2016), available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/use-electronic-informed-consent-clinical-investigations-questions-and-answers.
10 For example, for FDA-regulated trials conducted during the COVID-19 public health emergency, FDA has made the 
COVID MyStudies App available in the Apple App and Google Play stores as a platform enabling investigators to obtain 
informed consent securely from patients when face-to-face contact is not possible or practical due to COVID-19 public 
health measures to control the virus. To facilitate free use of the app during the public health emergency, FDA intends to 
fund the technical assistance required to operate the COVID MyStudies App, which will be provided by the Harvard 
Pilgrim Healthcare Institute, as resources permit. For more information, investigators interested in using the app should 
see https://www.fda.gov/drugs/science-and-research-drugs/covid-mystudies-application-app.
11 See Q24.
12 The procedures suggested do not apply to the exception from general informed consent requirements under 21 CFR
50.23 or the exception from informed consent requirements for emergency research under 21 CFR50.24.
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4.
The patient (or an individual in the room) takes a photograph of the signed 
informed consent document and sends it to the investigator/designee.
5.
A trial team member enters the photograph into the trial records along with an 
attestation that states how that photograph was obtained and that it is a photograph 
of the informed consent document signed by the patient.
Method 2: 
A witness can attest to the signature, but a photograph of the signed 
informed consent document cannot be transmitted
1. An unsigned consent form is provided to the patient by a person who has entered the
room.
2. The investigator/designee arranges a three-way telephone call or video 
conference call with the patient, a witness who is not otherwise connected with 
the clinical investigation, and, if desired and feasible, additional individuals
requested by the patient (e.g., next of kin). Alternatively, in lieu of using a 
witness, a recording of the conversation can be made.13
3. To ensure that patients are approached in a consistent fashion, a standard 
process should be used that will accomplish the following:
o
Identification of who is on the call.
o
Review of the informed consent document with the patient by 
the investigator/designee and response to any questions the 
patient may have.
o
Verbal confirmation by the patient that their questions have been 
answered, that they would like to participate in the trial, and that they have 
signed and dated the informed consent document that is in their possession.
4. When using a witness, documentation in the trial records includes: (1) a signed 
and dated attestation by the witness who participated on the call that the patient 
confirmed their agreement to participate in the trial and signed the informed 
consent document, and (2) a signed and dated attestation by the 
investigator/designee stating why the informed consent document signed by the 
patient was not retained (e.g., due to potential contamination of the document by 
infectious material).
When using a recording in lieu of a witness, documentation in the trial records 
includes: (1) the recording of the conference call, and (2) a signed and dated 
attestation by the investigator/designee who participated on the call stating why the 
informed consent document signed by the patient was not retained (e.g., due to 
potential contamination of the document by infectious material).
13 If an investigator wants to record the telephone or video conference call, the investigator/designee should 
ensure that the recording is done in a manner consistent with applicable state and local laws and that all 
parties agree to being recorded.
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When either Method 1 or 2 is used to document informed consent, the resulting 
documentation should be (1) collected and archived, as either original paper copies 
or appropriately certified electronic copies (e.g., using a validated process for 
scanning paper copies),14 and (2) retained according to applicable FDA record 
retention requirements as part of the trial record.15
If the patient is unable to provide informed consent and there is a legally authorized 
representative, investigators must obtain written consent from the patient’s legally 
authorized representative in accordance with 21 CFR 50.27(a).
14 FDA guidance on good clinical practice developed with the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) defines a certified copy as “[a] copy 
(irrespective of the type of media used) of the original record that has been verified (i.e., by a dated 
signature or by generation through a validated process) to have the same information, including data that 
describe the context, content, and structure, as the original.” See guidance for industry E6(R2) Good 
Clinical Practice: Integrated Addendum to ICH E6(R1) (March 2018), available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e6r2-good-clinical-practice-
integrated- addendum-ich-e6r1.
15 See 21 CFR 312.57, 312.62, and 812.140.
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Appendix 5
Summary of Changes from Version 5.0 to Version 6.0
(Note: Administrative changes including minor administrative corrections are not included in Protocol 
Summary of Changes)
Sections
Change From:
(Version 5.0, 
dated 21 Jul 
2021)
Change To:
(Version 6.0)
Rationale:
Synopsis, 
2.6, 4.2, 
9.1
New text for 
Interim Futility 
Analysis
Interim Futility Analysis: An interim futility 
analysis will be conducted to assess whether the 
trial will be terminated due to lack of efficacy 
(futility) based on all available data assessable 
for the primary endpoint and key secondary 
efficacy endpoints.
Addition of an interim 
futility analysis which 
will be conducted to 
provide guidance in the 
setting of dynamic 
changes within the 
context of an evolving 
epidemic.
9.3
New section for 
Interim Futility 
Analysis
An interim futility analysis will be conducted 
based on all available data assessable for the 
primary endpoint and key secondary efficacy 
endpoints to assess whether the trial will be 
terminated due to lack of efficacy (futility). The 
unblinded output will be reviewed by an 
independent unblinded team, and the study team 
will remain blinded.  
Determination of futility from the interim futility 
analysis will be based on the conditional power 
(the power conditional on the observed data 
accumulated at the interim analysis) for the 
primary outcome, as well as assessment of the 
secondary efficacy outcomes.
The futility analysis will include for the primary 
efficacy endpoint variable, all patients with data 
through Day 29, and for the following secondary 
efficacy endpoint variables, all patients with data 
through Day 29, as specified for each endpoint:
Assessment of Clinical Severity: Change in 
NEWS from baseline (Day 1 through Day 29)
Time to clinical response: NEWS ≤ 2 maintained 
for 24 hours, Day 1 through Day 29 
Time to hospital discharge: defined as duration 
of hospitalization from Day 1 through Day 29 
(and duration of hospitalization)
If admitted to ICU post randomization: Duration 
of ICU stay through Day 29
Duration of any oxygen use Day 1 through Day 
29
If requiring mechanical ventilation post 
randomization: Duration mechanical ventilation 
through Day 29
Absolute value and mean change from baseline 
Addition of an interim 
futility analysis which 
will be conducted to 
provide guidance in the 
setting of dynamic 
changes within the 
context of an evolving 
epidemic.
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Sections
Change From:
(Version 5.0, 
dated 21 Jul 
2021)
Change To:
(Version 6.0)
Rationale:
in the Ordinal scale Day 1 through Day 29 
The Ordinal scale is as follows: 
1) Death; 
2) Hospitalized, on invasive mechanical 
ventilation or extracorporeal membrane 
oxygenation (ECMO); 
3) Hospitalized, on non-invasive ventilation or 
high flow oxygen devices; 
4) Hospitalized, requiring supplemental 
oxygen; 
5) Hospitalized, not requiring supplemental 
oxygen; 
6) Not hospitalized, limitation on activities; 
7) Not hospitalized, no limitations on 
activities.
Proportion (percentage) of subjects in each 
severity category of the 7-point Ordinal scale at 
Day 15 and Day 29
Time to sustained normalization of temperature 
and proportion of subjects with normalization of 
fever at all time points, defined as temperature < 
36.6°C armpit, < 37.2°C oral, or < 37.8 °C rectal 
sustained for at least 24 hours
Number of subjects who develop Acute 
Respiratory Distress Syndrome (ARDS) through 
Day 29  
Length of time to clinical progression through 
Day 29 (defined as the time to death, mechanical 
ventilation, or ICU admission)
If the results of the interim futility analysis are 
not promising, the trial may be terminated.  
Otherwise the study will continue as originally 
planned unless discontinued for business or 
feasibility reasons.
The futility analysis will not inflate the type I 
error since the trial will not be stopped to claim 
efficacy. The primary outcome will be analyzed 
according to Section 9.1.  
8.5
Grifols will utilize 
a Study-
Independent 
Safety Review 
Committee 
(SISRC) whose 
members (from 
Grifols) will be 
impartial and 
Grifols will utilize a SISRC whose members 
(from Grifols) will be impartial and independent 
of the clinical trial team, and will consist of a 
global pharmacovigilance representative, a
medical director, and a third individual 
knowledgeable in the epidemiological field or 
knowledgeable in the therapeutic area or a 
statistician.
Allowance for 
flexibility in areas of 
expertise for SISRC 
membership.
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Sections
Change From:
(Version 5.0, 
dated 21 Jul 
2021)
Change To:
(Version 6.0)
Rationale:
independent of the 
clinical trial team, 
and will consist of 
a statistician,
global 
pharmacovigilance 
representative, and
a medical director.
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