A Phase 2 Trial Evaluating Sargramostim in Patients With COVID-19 Associated Acute Hypoxemia
Phase: PHASE2
Conditions: COVID-19, SARS-CoV-2
Sponsor: Partner Therapeutics, Inc.

NCT04411680

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Protocol Approval Signature Page 
 
Protocol Number: PTX-001-002 
 
A Phase 2 trial evaluating sargramostim in patients with COVID-19 
associated acute hypoxemia 
 
 
 
 
 
 
 
I acknowledge the study protocol contains all necessary details for me and my staff to conduct the study 
as described. I will conduct this study in compliance with all applicable regulations and guidelines as 
stated in the protocol and other information supplied to me. 
 
Signature Principal Investigator: __________________________________________________ 
 
Print name:________________________________________________________________________  
Date:______________________________________________________________________________ 
 
 

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Protocol Synopsis 
Sponsor: 
Name of Medical Products: 
Study Phase:                   
Partner Therapeutics 
PTX-001-002 
Phase 2 
Study Title 
A Phase 2 trial evaluating sargramostim in patients with COVID-19 associated acute hypoxemia 
Study Center(s) 
Up to approximately 20 sites (US) 
Study Design 
This Phase 2, randomized, open-label study will enroll approximately 120 patients with COVID-
19 associated acute hypoxemia randomized 2:1 to evaluate sargramostim treatment plus 
institutional standard of care compared to institutional standard of care alone.  A Data Safety 
Monitoring Board (DSMB) will review the safety and benefit/risk of sargramostim after 
approximately 10 and 20 patients are enrolled and complete the sargramostim treatment 
period.  Enrollment of patients will be paused until the DSMB has conducted the safety review 
and permitted the study to proceed.  An additional DSMB review will occur after approximately 
60 patients (total of both treatment arms) are enrolled to the study. Upon completion of this 
safety review, the DSMB may request an additional review after approximately 80 patients have 
been randomized. Enrollment will not be paused during these reviews at approximately 60 and 
80 patients. 
Primary objective 
The aim of the study is to determine if inhaled sargramostim, as an adjunct to institutional SOC, 
improves clinical outcomes in patients with COVID-19-associated acute hypoxemia. 
Primary Outcome Measures: 
• 
Change in oxygenation parameter of P(A-a)O2 gradient by Day 6 and % of patients who have 
been intubated by Day 14 
Secondary Outcome Measures: 
• 
Change in ordinal scale 
• 
All cause 28-day mortality 
• 
Number of patients with treatment-emergent serious adverse events or clinically significant 
adverse drug reactions (ADRs) 
• 
Survival time and causes of death 
• 
Time to improvement in oxygenation (PaO2/FiO2 ratio, SpO2/FiO2 ratio and P(A-a)O2 
gradient) 
• 
Rate of nosocomial infection (as determined by local institution practice) 
• 
Duration of hospitalization  
• 
Number of patients requiring initiation of mechanical ventilation 

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Sponsor: 
Name of Medical Products: 
Study Phase:                   
Partner Therapeutics 
PTX-001-002 
Phase 2 
• 
Duration of invasive and non-invasive ventilation and/or supplemental oxygen 
• 
Time to normalization of WBC and lymphocytes  
Exploratory Outcome Measures: 
• 
National Early Warning Score (NEWS-2) 
• 
Sequential organ failure assessment (SOFA) scores 
• 
ROX index 
• 
Progression to ARDS 
• 
Changes on chest X-ray or CT  
Inclusion Criteria 
1. Patients aged ≥ 18 years 
2. Patients (or legally authorized decision maker) must provide informed consent 
3. Test positive for SARS-CoV-2 virus by PCR (positive confirmation prior to start of 
sargramostim) 
4. Admitted to hospital 
5. Presence of acute hypoxemia defined as (either or both) 
a) saturation below 93% on ≥ 2 L/min oxygen supplementation  
b) PaO2/FiO2 below 350 

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Sponsor: 
Name of Medical Products: 
Study Phase:                   
Partner Therapeutics 
PTX-001-002 
Phase 2 
Exclusion Criteria 
1. Patients requiring invasive (mechanical ventilation) or non-invasive (CPAP, BiPAP for  
hypoxemia) ventilation or ECMO (Note: oxygen supplementation using high flow oxygen 
systems or low flow oxygen systems would not exclude patients from this study) 
2. Intractable metabolic acidosis 
3. Cardiogenic pulmonary edema 
4. Hypotension requiring use of vasopressors 
5. Hyperferritinemia (serum ferritin ≥2,000 mcg/L) 
6. White blood cell count > 50,000/mm3 
7. Participation in another interventional clinical trial for COVID-19 therapy  
8. Highly immunosuppressive therapy or anti-cancer combination chemotherapy within 24 
hours prior to first dose of sargramostim 
9. Known or suspected intolerance or hypersensitivity to sargramostim, or any component 
of the product 
10. Previous experience of severe and unexplained side effects during aerosol delivery of 
any kind of medical product 
11. Presence of any preexisting illness that, in the opinion of the Investigator, would place 
the patient at an unreasonably increased risk through participation in this study 
12. Pregnant or breastfeeding females 
13. Severe or uncontrolled pulmonary comorbid conditions, including systemic steroid 
dependent asthma, systemic steroid dependent COPD, oxygen dependent COPD, lung 
transplant, known interstitial lung disease, or cystic fibrosis 
 

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Sponsor: 
Name of Medical Products: 
Study Phase:                   
Partner Therapeutics 
PTX-001-002 
Phase 2 
Patient population: 
Patients with COVID-19 associated acute hypoxemia 
Rationale: 
GM-CSF is a critical cytokine for healthy pulmonary function. Detailed studies have shown that 
GM-CSF is necessary for the maturation of alveolar macrophages from fetal monocytes and the 
maintenance of these cells in adulthood (Dranoff, 2017; Guilliams, 2013). GM-CSF has a wide 
array of effects on myeloid cells. GM-CSF has been shown to be a myelopoietic growth factor 
that has pleiotropic effects not only in promoting the differentiation of immature precursors 
into polymorphonuclear neutrophils, monocytes/ macrophages and dendritic cells, but also in 
controlling the function of fully mature myeloid cells (Zhan, 2019). GM-CSF is also known to 
reverse immunoparalysis seen in sepsis by immune activation, resulting in beneficial outcomes 
(Mathias, 2015; Meisel, 2009). Additionally, researchers have shown that in response to lung 
infection, GM-CSF signals B1a B cells to secrete polyreactive emergency immunoglobulin M 
(IgM) and ensures effective early frontline defense against bacteria invading the lungs (Weber, 
2014). 
There is evidence that inhaled GM-CSF prevents bacteremia in post influenza bacterial 
pneumonia primarily through locally-mediated improved lung antibacterial resistance to 
systemic bacteremia during influenza A viral infection (Umstead, 2020; Steinwede, 2011) and 
through increased production of reactive oxygen species by the alveolar macrophages 
(Subramanian, 2014). Pulmonary delivery of this cytokine has the potential to reduce morbidity 
and mortality due to viral pneumonia, potentially to include COVID-19. 
The safety and efficacy of sargramostim 125 mcg has been evaluated in several clinical studies. 
In one clinical study of six patients with moderate to severe community-acquired pneumonia or 
ventilator-associated pneumonia acute respiratory distress syndrome (ARDS), 125 mcg of 
sargramostim was administered by an Aeroneb Solo nebulizer device (Covidien, Neustadt, 
Germany) at an interval of 48 hours for 2 doses (Herold, 2014). At this dose, a significant 
improvement of oxygenation in response to sargramostim inhalation (p=0.0035), with no drug-
related toxicity, was observed.  Inhaled sargramostim has been evaluated at doses higher than 
125 mcg in patients with autoimmune pulmonary alveolar proteinosis (aPAP) (Wylam, 2006; 
Tazawa, 2019; Campo, 2016).  Patients with aPAP have extremely high titers of anti-GM-CSF 
antibodies, which sequesters native GM-CSF leading to accumulation of surfactant in alveolar 
sacs with resultant hypoxia.  To overcome the high anti-GM-CSF antibody levels in aPAP 
patients, sargramostim has been administered at doses of up to 500 mcg total daily dose, 
although daily doses of 125 mcg and 250 mcg have been used and associated with an 
improvement in clinical outcome (Wylam, 2006; Tazawa, 2019; Campo, 2016).  Given the 
demonstrated efficacy of 125 and 250 mcg doses, 125 mcg is considered a minimally effective 
dose when treating viral-related diseases. 

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Sponsor: 
Name of Medical Products: 
Study Phase:                   
Partner Therapeutics 
PTX-001-002 
Phase 2 
Number of Patients: 
Approximately 120: of which 80 patients will receive sargramostim + SOC, and 40 patients who 
will receive SOC alone. 
Duration of Therapy 
All patients randomized to the sargramostim treatment arm will receive sargramostim for the 
duration of treatment and remain on study for the duration of study period, unless the patient 
has unacceptable toxicity to sargramostim or patient/legally authorized decision 
maker/investigator decides to discontinue the patient, or patient has rapid deterioration 
requiring other advanced treatments or medical care not conducive to continued treatment with 
sargramostim.  Patients will receive sargramostim treatment for up to 5 days.  
For the purpose of this study, Day 1 is the day the patient receives the first dose of sargramostim 
and/or SOC. 
Following the sargramostim treatment period (Day 1-5), patients will continue to receive SOC as 
appropriate following institutional guidelines.  The study period (Days 6-28) will continue until 
completion of all safety and efficacy assessments on Day 28 (end of study).   
Patients on the control arm will receive institutional standard of care alone. 
All patients, including those who discontinue treatment early, will be followed for the duration 
of the study period. 
Duration of Follow-Up 
All patients should be followed for safety evaluations for up to Day 90.  Data from a final follow-
up visit at day 90 (+/-30 days) should also be collected. 
Duration of Study 
Study completion will be defined as the date when the last patient completes the follow-up 
period, or has withdrawn from the study.  Alternatively, the study may be stopped earlier for 
reasons such as feasibility, poor enrollment, ethical or safety reasons. 
Test Product/Device, Dose, and Mode of Administration: 
All patients randomized to the sargramostim treatment arm will be treated with 125 mcg 
inhaled sargramostim twice daily (with the interval between doses per institutional practice for 
twice a day dosing) for 5 days delivered via a mesh nebulizer. 
Patients cannot start the study using intravenous (IV) administration of sargramostim.  If a 
patient cannot continue to receive inhaled sargramostim upon progression to an invasive 
mechanical ventilator, administration of sargramostim may be delivered by IV infusion to 
complete a total of 5 days (including days delivered via inhalation). 
Patients on the control arm will receive institutional standard of care alone. 
Study Design:  
Randomized two-arm open-label study 

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Sponsor: 
Name of Medical Products: 
Study Phase:                   
Partner Therapeutics 
PTX-001-002 
Phase 2 
Safety Assessments 
Hematology laboratory parameters should include complete blood count with differential, 
hemoglobin, hematocrit, and absolute counts for white blood cells, platelets, neutrophils, 
lymphocytes, eosinophils and monocytes. 
Chemistry laboratory parameters should include albumin, amylase, lipase, BUN, creatinine, ALT, 
AST, LDH, serum alkaline phosphatase, direct and total bilirubin, glucose, total protein, sodium, 
potassium, chloride, bicarbonate, calcium and uric acid. 
Required laboratory measurements of ferritin, d-dimer and C-reactive protein should also be 
collected at screening, Days 1-6 and any other time it is performed as part of SOC. 
Immune profiling, if performed, including CD4+, CD8+, HLA-DR, IL-6, IL-1, GM-CSF. 
Efficacy Assessments 
Efficacy data will include the following: 
• 
Need for ventilation, or other means of respiratory support 
• 
Arterial blood gases / Oxygenation parameters 
• 
Identification / occurrence of nosocomial infections 
• 
SOFA score, NEWS-2 score, Ordinal score, ROX Index 
• 
Chest radiographic changes 
• 
Mortality 
Statistical Plan 
Approximately 120 patients will be randomized: of which 80 will receive sargramostim + SOC, 
and 40 patients who will receive SOC alone.  The sample size was based on practical and clinical 
considerations to ensure that the efficacy endpoints and safety profile could be appropriately 
evaluated and was not based on any statistical assumptions or hypotheses.  As a result, the 
analyses of this study will be considered as descriptive analyses. 
Derivation of two-sided 95% confidence intervals and p-values will be generated where 
applicable. 
 
 
 
 
 
 
 

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Table of Contents 
Protocol Approval Signature Page ......................................................................................................2 
Protocol Synopsis ...............................................................................................................................4 
1 
SCHEMATIC OF STUDY DESIGN .................................................................................................. 10 
2 
ABBREVIATIONS ....................................................................................................................... 14 
3 
BACKGROUND .......................................................................................................................... 17 
3.1 
Sargramostim .................................................................................................................... 17 
3.2 
Role of GM-CSF in Lung Function ....................................................................................... 17 
3.3 
Use of sargramostim in conditions that are similar to COVID-19 ARDS ................................ 18 
3.4 
Recent translational data in COVID-19 ............................................................................... 19 
3.5 
Clinical experience of inhaled sargramostim ...................................................................... 20 
3.6 
Use of sargramostim inhalation in COVID-19 ...................................................................... 21 
4 
OBJECTIVES .............................................................................................................................. 21 
4.1 
Primary Objective.............................................................................................................. 21 
4.2 
Primary Outcome Measure ................................................................................................ 21 
4.3 
Secondary Outcome Measures .......................................................................................... 22 
4.4 
Exploratory Outcome Measures......................................................................................... 22 
5 
STUDY DESIGN .......................................................................................................................... 22 
5.1 
Study Description .............................................................................................................. 22 
5.2 
Randomization .................................................................................................................. 23 
6 
KEY ELIGIBILITY CRITERIA .......................................................................................................... 23 
6.1 
Inclusion Criteria ............................................................................................................... 23 
6.2 
Exclusion Criteria ............................................................................................................... 23 
6.3 
Replacement of ineligible patients ..................................................................................... 24 
7 
DRUG INFORMATION ................................................................................................................ 24 
7.1 
Sargramostim Treatment Regimen .................................................................................... 24 
7.2 
Sargramostim Dose Modifications ..................................................................................... 24 
7.2.1 
Dose modification for AEs...................................................................................................................... 24 
7.3 
Concomitant Medications and Medical Procedures ............................................................ 24 
8 
SAFETY MONITORING ............................................................................................................... 24 
8.1 
Definitions ........................................................................................................................ 25 
8.1.1 
Adverse Event ........................................................................................................................................ 25 
8.1.2 
Serious Adverse Event ........................................................................................................................... 25 

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8.2 
Safety Reporting ............................................................................................................... 25 
8.2.1 
Adverse Event Reporting ....................................................................................................................... 25 
8.2.2 
Attribution of the AE .............................................................................................................................. 26 
8.2.3 
Grading of AEs........................................................................................................................................ 26 
8.2.4 
Serious Adverse Event Reporting ........................................................................................................... 26 
8.3 
Expected Toxicities ............................................................................................................ 27 
8.4 
Unexpected Toxicities ....................................................................................................... 27 
9 
RISKS AND TOXICITIES ............................................................................................................... 27 
9.1 
Overdose .......................................................................................................................... 27 
9.2 
Pregnancy or Lactation ...................................................................................................... 27 
9.2.1 
Pregnancy Risk Summary ....................................................................................................................... 27 
9.2.2 
Lactation Risk Summary ......................................................................................................................... 28 
10 
SCHEDULE OF EVENTS AND STUDY PARAMETERS ................................................................... 28 
10.1 
Safety Evaluations ............................................................................................................. 31 
10.2 
Efficacy Evaluations ........................................................................................................... 31 
11 
STUDY DURATION AND EARLY TERMINATION ........................................................................ 32 
11.1 
Patient Discontinuation Criteria ......................................................................................... 32 
11.2 
Study Completion .............................................................................................................. 33 
11.3 
Duration of Treatment (Days 1-5) ...................................................................................... 33 
11.4 
Duration of Study Period (Days 6-28) ................................................................................. 33 
11.5 
Duration of Follow-up (up to Day 90) ................................................................................. 33 
12 
STATISTICAL PLAN ................................................................................................................. 33 
12.1 
Sample size consideration ................................................................................................. 33 
12.2 
Data Safety Monitoring Board ........................................................................................... 34 
12.3 
General Statistical Methods ............................................................................................... 34 
12.3.1 
Primary Endpoint(s): Oxygenation at Day 6, and Intubation by Day 14 ............................................ 35 
12.3.2 
Secondary and Exploratory Endpoints .............................................................................................. 35 
13 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................................... 36 
14 
QUALITY CONTROL AND QUALITY ASSURANCE....................................................................... 36 
15 
ETHICS .................................................................................................................................. 36 
15.1 
Informed consent .............................................................................................................. 36 
16 
DATA HANDLING AND RECORD KEEPING ............................................................................... 37 
17 
FINANCING AND INSURANCE ................................................................................................. 37 
18 
PUBLICATION POLICY ............................................................................................................ 37 

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19 
REFERENCES.......................................................................................................................... 38 
APPENDIX A: Glasgow Coma Score ................................................................................................... 42 
APPENDIX B: SOFA score .................................................................................................................. 43 
APPENDIX C: Ordinal Score ............................................................................................................... 44 
APPENDIX D: NEWS-2 score .............................................................................................................. 45 
APPENDIX E: ROX Index .................................................................................................................... 46 
 
 
 

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2 ABBREVIATIONS 
ADR: 
adverse drug reaction 
ADL 
activities of daily living 
AE: 
adverse event 
AEC: 
alveolar epithelial cell 
ALT: 
alanine aminotransferase 
AM: 
alveolar macrophage 
aPAP: 
autoimmune pulmonary alveolar proteinosis 
ARDS:  
acute respiratory distress syndrome 
AST:  
alanine aminotransferase 
BAL: 
bronchoalveolar lavage 
BiPAP: 
bilevel positive airway pressure 
BUN:  
blood urea nitrogen 
CFR:  
Code of Federal Regulations 
CIOMS:  
Council for International Organizations of Medical Sciences 
c-Met: 
tyrosine-protein kinase Met 
CPAP: 
continuous positive airway pressure 
COPD 
chronic obstructive pulmonary disease 
CRF: 
case report form 
CRP: 
C-reactive protein 
Cstat: 
static compliance 
CT:  
Computed tomography 
CTCAE: 
Common Terminology Criteria for Adverse Events 
DC: 
dendritic cell 
DSMB: 
Data Safety Monitoring Board 
EC: 
European commission 
ECG: 
electrocardiogram 
EGFR: 
epidermal growth factor receptor 
ECMO: 
extracorporeal membrane oxygenation 
FcγR: 
Fcγ receptor 
FDA: 
Food & Drug Administration 
FiO2:  
fraction of inspired oxygen 
GCP:  
Good clinical practice  

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GCS:  
Glasgow coma score 
GM-CSF: 
granulocyte macrophage colony stimulating factor 
HGF: 
hepatocyte growth factor 
HLA-DR: 
human leukocyte antigen – DR isotype 
ICF: 
Informed consent form 
ICH: 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU: 
intensive care unit 
IgM: 
immunoglobulin M 
IL-1: 
Interleukin-1 
IL-6: 
Interleukin-6 
IRB:  
Institutional Review Boards 
IV: 
Intravenous 
LDH: 
lactate dehydrogenase 
NEWS-2: 
National Early Warning Score 2 
P(A-a)O2: 
gradient (alveolar-arterial) oxygen gradient 
PaCO2: 
partial pressure of carbon dioxide 
PAGE: 
Pulmonary Alveolar Proteinosis GM-CSF Inhalation Efficacy (PAGE) trial 
PaO2:  
partial pressure of oxygen 
PCR:  
polymerase chain reaction 
PEEP:  
positive end expiratory pressure 
PI: 
Principal Investigator 
Pplat: 
plateau pressure  
PTX:  
Partner Therapeutics 
PU.1: 
transcription factor PU.1 
rhu-GM-CSF: 
recombinant human granulocyte-macrophage colony stimulating factor 
ROS: 
reactive oxygen species 
SAE:  
serious adverse event 
SOC: 
Standard of care 
SOFA: 
sequential organ failure assessment 
SpO2:  
peripheral oxygen saturation 
SUSAR:  
suspected unexpected serious adverse reaction 
TGF-α: 
transforming growth factor alpha  

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US: 
United States 
USP: 
United States Pharmacopoeia 
VFD: 
ventilator free days 
WBC:  
white blood cells 
 
 

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3 BACKGROUND 
3.1 
Sargramostim 
Sargramostim (Leukine) is a recombinant human granulocyte-macrophage colony stimulating factor 
(rhu-GM-CSF), and has been approved since 1991. GM-CSF, a pleiotropic cytokine, is an important 
leukocyte growth factor known to play a key role in hematopoiesis, effecting the growth and maturation 
of multiple cell lineages as well as the functional activities of these cells in antigen presentation and cell 
mediated immunity.  Since the initial FDA approval in 1991, 
 patients have been estimated 
to have received Leukine, providing extensive clinical and post-marketing data in a broad range of 
treated individuals across several disease states.  This includes preterm neonates as well as the elderly, 
including males and females, representing a well-characterized safety profile for Leukine. 
3.2 
Role of GM-CSF in Lung Function 
GM-CSF is a critical cytokine for healthy pulmonary function. Detailed studies have shown that GM-CSF 
is necessary for the maturation of alveolar macrophages from fetal monocytes and the maintenance of 
these cells in adulthood (Dranoff, 2017; Guilliams, 2013). GM-CSF has a wide array of effects on myeloid 
cells. It has been shown to be a myelopoietic growth factor that has pleiotropic effects not only in 
promoting the differentiation of immature precursors into polymorphonuclear neutrophils, monocytes/ 
macrophages and dendritic cells, but also in controlling the function of fully mature myeloid cells (Zhan, 
2019). GM-CSF is also known to reverse immunoparalysis seen in sepsis by immune activation, resulting 
in beneficial outcomes (Mathias, 2015; Meisel, 2009). Additionally, researchers have shown that in 
response to lung infection, GM-CSF signals B1a B cells to secrete polyreactive emergency 
immunoglobulin M (IgM) and ensures effective early frontline defense against bacteria invading the 
lungs (Weber, 2014).  In the lung, the alveolar epithelial cells (AEC)-released GM-CSF is known to 
improve the innate immune responses of myeloid cells, in particular the alveolar macrophage (AM).  It 
has been shown to enhance viral clearance and modulate surfactant lipid metabolism, preventing its 
accumulation in the alveoli and maintaining the optimal physiologic gas exchange.  In addition, the AEC-
expressed GM-CSF also has direct beneficial effects on the injured epithelial barrier by orchestrating 
epithelial proliferation and barrier repair (Subramaniam, 2014; Subramaniam, 2015). 
There is a large body of evidence generated with GM-CSF in animal studies suggesting the potential use 
in ARDS and infections. For the purpose of brevity, we will point to the data that reflects the potential 
value in viral lung infections and preventing secondary bacterial infections.  
Halstead and colleagues demonstrated that in vivo high airway levels of GM-CSF profoundly rescue mice 
from lethal influenza pneumonia. While in vitro GM-CSF is canonically described as an M1-polarizing 
cytokine, their data demonstrated that in vivo, during influenza A virus infection, GM-CSF instead 
temporizes the type II interferon-induced M1 polarization of airway macrophages and reduces 
inflammation induced damage (Halstead, 2018).  Unkel and colleagues demonstrated GM-CSF– 
dependent cross-talk between influenza virus infected alveolar epithelial cells and CD103+ dendritic cells 
is crucial for effective viral clearance and recovery from injury and thus pointing to the potential use of 
GM-CSF treatment in severe influenza virus pneumonia (Unkel, 2012). Investigations have shown that 
GM-CSF conferred resistance to influenza in mice via alveolar phagocytes and through alveolar 
macrophages which became more resistant to influenza- induced apoptosis. Delivery of intranasal GM-
CSF to wild-type mice also conferred resistance to influenza (Huang, 2011).  
There is evidence that inhaled GM-CSF prevents systemic bacteremia in post influenza bacterial 
pneumonia primarily through locally-mediated improved lung resistance during infection (Umstead, 

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2020; Steinwede, 2011) and through increased production of reactive oxygen species by the alveolar 
macrophages (Subramanian, 2014).  
In conclusion, GM-CSF confers resistance to influenza by enhancing innate immune mechanisms that 
depend on alveolar macrophages, for their health and normal functioning. Pulmonary delivery of this 
cytokine has the potential to reduce morbidity and mortality due to viral pneumonia (Figure 1). 
 
Figure 1 GM-CSF-modulated immune response to influenza virus infection (Rosler, 2016). GM-CSF-modulated immune 
response to influenza virus infection. After pulmonary influenza virus infection GM-CSF is released from alveolar epithelial cell II, 
mediated through HGF/c-Met and TGF-α/EGFR signaling. In an autocrine manner, it stimulates epithelial repair, including 
epithelial proliferation and barrier restoration. Innate and adaptive immunity are activated, resulting in accelerated viral 
clearance. Via PU.1, GM-CSF improves alveolar macrophage resistance, maturation, ROS production, and phagocytosis capacity, 
e.g., by the FcγR-mediated opsonophagocytosis. GM-CSF also stimulates activation and proliferation of dendritic cells, especially 
CD103+ dendritic cells, and T cells and enhances antigen priming and influenza virus-specific CD8+ T cell recruitment. Altogether 
alveolar epithelial cells GM-CSF leads to increased survival and reduced lung injury. [AEC alveolar epithelial cells, AM alveolar 
macrophage, c-Met hepatocyte growth factor receptor, DC dendritic cell, EGFR epithelial growth factor receptor, FcγR Fcɣ 
receptor, GM-CSF granulocyte and macrophage colony stimulating factor, HGF hepatocyte growth factor, PU.1 transcription 
factor PU.1, ROS reactive oxygen species, TGF-α transcriptional growth factor α]. 
3.3 
Use of sargramostim in conditions that are similar to COVID-19 ARDS 
A small (18 patient) double blind randomized placebo controlled clinical trial of low-dose (3 mcg/kg daily 
for 5 days) intravenous GM-CSF treatment in adult patients with severe sepsis and respiratory 
dysfunction, led to the conclusion that GM-CSF treatment was associated with improved gas exchange 
and might play a homeostatic role (Rosler, 2016). In a phase II study, 130 patients with severe sepsis 
with respiratory dysfunction were randomized to GM-CSF (250 mcg/m2 intravenously daily for 14 days) 
or placebo. The results showed an improvement in 28 day mortality on GM-CSF; this did not reach 
statistical significance (Paine, 2012). 
Herold and colleagues used sargramostim by inhalation route on a compassionate basis in six patients 
with moderate to severe community-acquired pneumonia or ventilator-associated pneumonia-
associated acute respiratory distress syndrome (ARDS) who were not improving despite all measures 
and at least 6 days of mechanical ventilation (Herold, 2014). Sargramostim 125 mcg was applied by 
Aeroneb Solo device (Covidien, Neustadt, Germany) at an interval of 48 hours for 2 doses. Compared to 
historical controls, the authors observed significant improvement in oxygenation and lung compliance 

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with GM-CSF therapy. This resulted in improved morbidity using standard scoring systems and 4 of the 
six patients recovered and were discharged from the hospital. 
Six clinical studies evaluated sargramostim administered via intravenous, subcutaneous, or inhaled 
routes in critically ill patients and monitored systemic cytokines, markers of inflammation, and safety 
(Meisel, 2009; Hall, 2011; Pinder, 2018; Paine, 2012; Herold, 2014; Rosenbloom, 2005).  In these studies, 
there was no increase in systemic cytokines, including IL-6, IL-8, IL-1β, IL-10, TNFα, GMCSF, and IL-12-
p70, nor an indication of treatment-related organ toxicity or increased rates of treatment-related 
serious adverse events.  Indeed, in the clinical studies where IL-6, a key driver of cytokine storm, was 
monitored, no change in the systemic levels were observed.  Importantly, there was no adverse effects 
of sargramostim observed in any of these studies that increased or exacerbated organ toxicity or 
mortality.  In totality, these data suggest that sargramostim does not increase the risk of cytokine storm 
in critically ill patients.  While these studies were of various sizes, improvements in clinical outcomes 
were observed. 
3.4 
Recent translational data in COVID-19 
A recent study has shown that the replication of SARS-CoV-2 in alveolar cells can result in a limited 
antiviral response, void of IFN-I and IFN-III response in both a human lung alveolar carcinoma cell line 
and in vivo in ferrets (Blanco-Melo, 2020).  In addition, by using ex vivo human lung tissue explants 
respectively challenged by the same inoculum of SARS-CoV-2 and SARS-CoV, it was found that SARS-
CoV-2 was capable of infecting and producing significantly higher amount of virus in human lung tissues 
while triggering suboptimal levels of IFNs and pro-inflammatory cytokines/chemokines during that same 
time period.  These findings could possibly implicate an escape from innate immune detection (Chu, 
2020).  An efficient immune suppression in the early phase may allow the SARS-CoV-2 to replicate 
unchecked in the respiratory tract, achieving high viral load and eventually contributing to its efficient 
person-to-person transmission before onset of severe clinical symptoms (Wei, 2020).  Evidence of 
additional immune dysfunction comes from the autopsy reports of COVID-19 patients demonstrating a 
low number of CD8 positive T lymphocytes infiltrating lung tissue (Yao, 2020).  As described in 
laboratory reports, along with the increased levels of cytokines in systemic circulation, a decrease of 
immune cell populations such as CD4, CD8 and NK cells in peripheral blood were identified as risk factor 
of cytokine storm in COVID-19-infected pneumonia patients (Chen, 2020; Wenjun, 2020; Ruan, 2020).  
Additionally, the NK cells and cytotoxic lymphocytes appeared to be exhausted with a reduced ability to 
produce CD107a, IFN-γ, IL-2, granzyme B, and TNF-α (Zheng, 2020).  The T cells from COVID-19 patients 
also have significantly higher levels of the exhaustion markers PD-1 as compared to the healthy controls 
(Zheng, 2020).  These increases in PD-1 and Tim-3 expression on T cells were reported as the patients 
progressed from mildly symptomatic to severe stage, further indicative of T cell exhaustion.  
Interestingly, the SARS-CoV protease 3CLPro-transfected lung epithelial cells were shown to have a 
decreased GM-CSF mRNA and protein expression suggesting that the SARS-CoV may play a role in the 
mechanism of lung fibrosis of SARS through the suppression of GM-CSF (Liao, 2011). 
If there is viral immune evasion, the host may be predisposed towards a more belligerent wave of 
cytokine and chemokine activity with marked inflammatory responses as the viral load increases.  
Profound lung damage due to unchecked viral replication can cause a complete breakdown of epithelial 
barrier function leading to diffuse alveolar damage with increased microvascular permeability.  There is 
leakage of hallmark inflammatory cytokines such as IL-6 and IL-1 into systemic circulation and a 
concurrent recruitment of neutrophils and pro-inflammatory monocytes into the lung.  This ensuing 
‘cytokine storm’, with incessant proinflammatory cytokine production and accumulation of pro-
inflammatory cells can eventually overwhelm the homeostatic tissue repair functions in the lung leading 
to irreversible tissue damage and depletion of AMs (Herold, 2011; Wong, 2019).  During this process the 

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activated fibroblasts can deposit excess collagen to impair gas exchange in the lung (Meduri, 1993).  
Epithelial cell death may also expose the basement membrane to secondary microbial pathogens 
offering them access to the systemic circulation (Plotkowski, 1986).  AMs are the sentinels of innate 
immune system against the respiratory pathogens.  They do so via secretion of oxygen metabolites, anti-
microbial proteases and by initiating an inflammatory response that can recruit activated neutrophils 
into alveolar spaces. They can also aid in resolving inflammation after the infectious challenge gets 
resolved, by phagocytosing the apoptotic neutrophils.  This can reduce the pro-inflammatory cytokine 
secretion by macrophages and the production of anti-inflammatory cytokines such as TGF- and IL-10 
(Haslett, 1999; Knapp, 2003).  Therefore, the loss of AMs could be one of the likely contributors of failed 
lung functions in COVID-19 patients.  Importantly, while AMs were found to as the principle lung 
macrophages in both heathy controls and mildly infected COVID-19 patients, they were almost 
completely lost in the severely infected lungs in these patients (Liao, 2020). 
Viral, bacterial, and fungal pulmonary infections can all cause the cytokine storm syndrome that may be 
challenging to differentiate on clinical grounds. A complex cytokine response that builds in infection is 
characterized by series of overlapping networks that may show similarities across indications but may 
also be different in amplitude and features, such that it is important to highlight them. A more 
aggressive form, labeled cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome 
characterized by fever and multiple organ dysfunction that is associated with chimeric antigen receptor 
(CAR)-T cell therapy, therapeutic antibodies, and haploidentical allogeneic transplantation. Levels of 
inflammatory markers and cytokines may differ dramatically between this and other manifestations of 
cytokine storms (Vardhana, 2020). The hyperinflammatory response in COVID-19 has been likened to 
conditions including classical ARDS, macrophage activation syndrome or hemophagocytic 
lymphohistiocytosis, or simply “cytokine storm.” It is likely that none of these syndromes can precisely 
fit all COVID-19 patients due to the complexity and heterogeneity in inflammatory effects and diverse 
pathophysiology of the disease seen across different patients, however, several biomarkers (ferritin, C-
reactive protein (CRP) and d-dimers) have shown a strong correlation of worsening disease or mortality 
(Chen 2020a; Chen, 2020b; Richardson, 2020). 
3.5 
Clinical experience of inhaled sargramostim 
There is a large body of evidence of inhaled sargramostim in autoimmune pulmonary alveolar 
proteinosis (aPAP), which results in accumulation of surfactant in alveolar sacs with resultant hypoxia. 
Tazawa and colleagues conducted a phase II study of inhaled sargramostim at 9 pulmonary centers 
throughout Japan in patients with unremitting or progressive aPAP with hypoxia and symptoms 
(Tazawa, 2010). Patients received 250 mcg daily by inhalation, using an LC-PLUS nebulizer with a manual 
interrupter valve connected to a PARI Turbo BOY compressor, for 7 days and this cycle was repeated 
every other week for six cycles (total 12 weeks). The treatment was well tolerated with no serious 
adverse events. Adverse events were reported in 7 of the 39 patients receiving GM-CSF, and these were 
all transient. The treatment led to an improvement in oxygenation, radiological changes as well as 
symptoms.  Thirty five of these patients were followed for a 30-month observation period and 
sargramostim was shown to sustain remission in over half of the patients (Tazawa, 2014).  A study using 
the I-neb nebulizer, conducted in 6 aPAP patients evaluated inhaled sargramostim 250 mcg once daily in 
a 4 days on, 4 days off schedule as long as needed (Papiris, 2014).  Upon remission, the dose of 
sargramostim was reduced.  All patients achieved remission and 3 patients maintained remission when 
the dose was reduced; no significant adverse events were noted (Papiris, 2014). 
Following these results, a larger randomized phase 3 study (also referred to as the PAGE study) was 
conducted by the Japanese investigators in 12 centers. Sixty-four patients with mild to moderate aPAP 
with hypoxia were randomized to receive placebo or sargramostim (33 patients) at a dose of 125 mcg 

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twice a day for 7 days followed by a week of no treatment and this two week cycle was repeated 12 
times over a period of 24 weeks. The treatment was well tolerated with no significant differences in 
adverse events between the two groups. The GM-CSF treated patients had a significantly improved 
hypoxia parameter as were the radiological changes (Tazawa, 2019). 
This clinical experience of use of sargramostim in viral pneumonia and aPAP suggests salutary effects. In 
addition, these studies establish the safety of inhaled sargramostim and also provide evidence for 
activity of inhaled sargramostim. 
3.6 
Use of sargramostim inhalation in COVID-19  
An investigator-sponsored study in Belgium [NCT04326920], “Prospective, Randomized, Open-label, 
Interventional Study to Investigate the Efficacy of Sargramostim (Leukine®) in Improving Oxygenation 
and Short- and Long-term Outcome of COVID-19 (Corona Virus Disease) Patients With Acute Hypoxic 
Respiratory Failure”, was initiated on March 26, 2020. Patients were randomized to receive either 
inhaled sargramostim 125 mcg twice daily via a Philips© InnoSpire Go portable mesh nebulizer for 5 days 
(active group) together with institutional standard of care (SOC), or SOC alone (control group). SOC 
included: administration of antibiotics, anti-viral therapy, and use of supplemental oxygen and 
noninvasive or invasive ventilation (as necessary). A data safety monitoring board (DSMB) is overseeing 
the study.  
 
 
 
 
 
 
 
 
   
Based on the scientific rationale that GM-CSF is critical to maintain and restore lung function as well as 
the totality of clinical data in critically ill patients as well as patients with COVID-19, this study will 
evaluate whether inhaled sargramostim can improved clinical outcomes in patients with acute 
hypoxemia due to COVID-19.  As discussed above in Section 3.4, the biomarkers ferritin, CRP and d-
dimers are correlated with worsening of disease and high mortality in patients with COVID-19.  To 
enable constant safety monitoring during the study, daily monitoring of these biomarkers during the 
sargramostim treatment period is required and will be evaluated (alongside adverse events and other 
routine laboratory tests) by the Data Safety Monitoring Board (see Section 12.2 for more details).  After 
the first 9 and 22 patients were enrolled and treated with up to 5 days of sargramostim, the DMSB 
reviewed safety data. Following its second review, the DSMB supported a) expanding the study to 120 
patients and b) excluding patients with serious baseline pulmonary comorbid conditions. 
4 OBJECTIVES 
4.1 
Primary Objective 
The aim of the study is to determine if inhaled sargramostim, as an adjunct to institutional SOC, 
improves clinical outcomes in patients with COVID-19-associated acute hypoxemia. 
4.2 
Primary Outcome Measure 
• 
Change in oxygenation parameter of P(A-a)O2 gradient by Day 6 and % of patients who have been 
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4.3 
Secondary Outcome Measures 
• 
Change in ordinal scale  
• 
All cause 28-day mortality 
• 
Number of patients with treatment-emergent serious adverse events or clinically significant adverse 
drug reactions (ADRs) 
• 
Survival time and causes of death 
• 
Time to improvement in oxygenation (PaO2/FiO2 ratio, SpO2/FiO2 ratio and P(A-a)O2 gradient) 
• 
Rate of nosocomial infection (as determined by local institution practice) 
• 
Duration of hospitalization  
• 
Number of patients requiring initiation of mechanical ventilation 
• 
Duration of invasive and non-invasive ventilation and/or supplemental oxygen 
• 
Time to normalization of WBC and lymphocytes 
4.4 
Exploratory Outcome Measures 
• 
National Early Warning Score (NEWS-2) 
• 
Sequential organ failure assessment (SOFA) scores 
• 
ROX Index 
• 
Progression to ARDS 
• 
Changes on chest X-ray or CT 
5 STUDY DESIGN 
This study is a randomized two-arm open-label study. 
5.1 
Study Description 
This Phase 2 study will randomize approximately 120 patients with COVID-19: of which 80 will receive 
sargramostim + SOC, and 40 patients who will receive SOC alone. 
All patients on the sargramostim arm will be treated with 125 mcg inhaled sargramostim twice daily 
(with the interval between doses per institutional practice for a twice daily dosing) for 5 days delivered 
via a mesh nebulizer, in addition to institutional standard of care. 
Patients cannot start the study using intravenous (IV) administration of sargramostim.  If a patient 
cannot continue to receive inhaled sargramostim upon progression to an invasive mechanical ventilator, 
sargramostim may be delivered by IV infusion to complete a total of 5 days (including days delivered via 
inhalation).   
Patients on the control arm will receive institutional standard of care alone. 
This study is designed as a proof of concept study and will enroll 120 patients.  The sample size was 
increased from 60 patients to 120 patients (80 sargramostim treated patients and 40 control patients) to 
collect additional safety and efficacy data of inhaled sargramostim in hospitalized patients. This study is 
not designed nor expected to show substantial evidence of effectiveness sufficient to support a label 

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indication.  Inclusion of additional patients will enable evaluation of less common adverse events. 
Furthermore, enrolling more patients will also enable greater precision of estimates of safety and 
efficacy measures.  
5.2 
Randomization 
Randomization will be performed, using a 2:1 randomization ratio, with the strata defined as: 
• 
investigational site,  
• 
SOFA score (<6 versus ≥ 6),  
6 KEY ELIGIBILITY CRITERIA 
6.1 
 Inclusion Criteria 
1) Patients aged ≥ 18 years 
2) Patients (or legally authorized decision maker) must provide informed consent form 
3) Test positive for SARS-CoV-2 virus by PCR (positive confirmation prior to start of sargramostim) 
4) Admitted to hospital 
5) Presence of acute hypoxemic respiratory failure defined as (either or both) 
a) Saturation below 93% on ≥ 2 L/min oxygen supplementation 
b) PaO2/FiO2 below 350 
6.2 
Exclusion Criteria 
1) Patients requiring invasive (mechanical ventilation) or non-invasive (CPAP, BiPAP for hypoxemia) 
ventilation or ECMO.  (Note: oxygen supplementation using high flow oxygen systems or low 
flow oxygen systems would not exclude patients from this study) 
2) Intractable metabolic acidosis 
3) Cardiogenic pulmonary edema 
4) Hypotension requiring use of vasopressors 
5) Hyperferritinemia (serum ferritin ≥2,000 mcg/L) 
6) White blood cell count > 50,000/mm3 
7) Participation in another interventional clinical trial for COVID-19 therapy 
8) Highly immunosuppressive therapy or anti-cancer combination chemotherapy within 24 hours 
prior to first dose of sargramostim 
9) Known or suspected intolerance or hypersensitivity to sargramostim, or any component of the 
product 
10) Previous experience of severe and unexplained side effects during aerosol delivery of any kind 
of medical product 
11) Presence of any preexisting illness that, in the opinion of the Investigator, would place the 
patient at an unreasonably increased risk through participation in this study. 
12) Pregnant or breastfeeding females 

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13) Severe or uncontrolled pulmonary comorbid conditions, including systemic steroid dependent 
asthma, systemic steroid dependent COPD, oxygen dependent COPD, lung transplant, known 
interstitial lung disease, or cystic fibrosis 
6.3 
Replacement of ineligible patients 
In the event a patient has been enrolled to the study pending their COVID-19 PCR result, which is 
subsequently confirmed as negative, they may continue on the study per protocol, provided the 
investigator believes continuation in the study is in the best interest of the patient, taking into account 
potential benefits and risks.  
Any ineligible patients are to be replaced to ensure approximately 80 eligible patients are enrolled to 
the sargramostim arm and 40 eligible patients are enrolled to the SOC arm. 
7 DRUG INFORMATION 
Each investigational site is expected to follow its own institutional standards for COVID-19 treatment 
regimens and duration of treatment for standard of care.  All patients in this study will receive standard 
of care per their institutional standards. 
7.1 
Sargramostim Treatment Regimen 
All patients randomized to the sargramostim treatment arm will be treated with 125 mcg inhaled 
sargramostim twice daily (with the interval between doses per institutional practice for a twice daily 
dosing) for 5 days delivered via a mesh nebulizer. 
Patients cannot start the study using IV administration of sargramostim.  If a patient cannot continue to 
receive inhaled sargramostim upon progression to an invasive mechanical ventilator, administration of 
sargramostim may be delivered by IV infusion to complete a total of 5 days (including days delivered via 
inhalation).  Sargramostim IV dose is 125 mcg/m2 administered intravenously over 4 hours once daily. 
Refer to the Pharmacy Manual for full details on sargramostim supply, preparation and accountability.  
Follow local institution practice regarding inhaled medications for the administration of sargramostim to 
patients on ventilator. 
7.2 
Sargramostim Dose Modifications 
7.2.1 
Dose modification for AEs 
Patients with documented white blood cell count > 50,000/mm3 should stop sargramostim treatment. 
7.3 
Concomitant Medications and Medical Procedures 
Patients should receive appropriate standard of care for COVID-19-associated acute hypoxemia, and for 
any other medical condition’s patients may have or develop.  This study does not restrict, or limit 
concomitant medications or medical procedures patients may need. 
8 SAFETY MONITORING 
All Adverse events (AE) will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 

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8.1 
Definitions 
8.1.1 
Adverse Event 
An Adverse Event is any untoward medical occurrence in a patient administered with a pharmaceutical 
product and which does not necessarily have to have a causal relationship with this treatment. 
This includes the following: 
• 
AEs not previously observed in the patient that emerge during the reporting period, that were 
not present prior to the AE reporting period 
• 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
reporting period 
8.1.2 
Serious Adverse Event 
A Serious Adverse Event (SAE) is any untoward medical occurrence regardless of causality that results in 
any of the following: 
• 
Death 
• 
A life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant disability/incapacity 
• 
Congenital anomaly/birth defect; 
• 
An important medical event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above 
8.2 
Safety Reporting 
8.2.1 
Adverse Event Reporting 
All AEs regardless of seriousness, starting from informed consent (i.e., occurring during the baseline 
period even in the absence of any administration of treatment), up to 30 days following the last dose of 
treatment, are to be recorded on the case report form (CRF). Any SAEs experienced after this 30 day 
period should only be reported if the investigator suspects a causal relationship to the study drug. 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms.  The 
Investigator should specify the date of onset, severity, action taken with respect to study drug, 
corrective treatment/therapy given, additional investigations performed, outcome, and his/her opinion 
as to whether there is a reasonable possibility that the AE was caused by the study drug. Adverse events 
should be followed until the event has resolved, stabilized, has decreased in severity to the same or less 
than baseline (pre-treatment), or patient has completed the follow-up period. 
Vital signs or ECG abnormalities are to be recorded as AEs only if they are symptomatic and/or requiring 
corrective treatment and/or leading to treatment discontinuation and/or modification of dosing and/or 
fulfilling a seriousness criterion. 
Laboratory abnormalities are to be recorded as AEs only if they lead to treatment discontinuation, 
modification of dosing, fulfill a seriousness criterion, additional concomitant therapy, and/ or additional 
medical procedures. 

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Treatment-emergent adverse events are adverse events that begin or worsen after the start of 
treatment. 
8.2.2 
Attribution of the AE 
The relationship or attribution of an adverse event to treatment is defined as follows: 
- 
Definite - The AE is clearly related to the study treatment 
- 
Probable - The AE is likely related to the study treatment 
- 
Possible - The AE may be related to the study treatment 
- 
Unlikely - The AE is doubtfully related to the study treatment 
- 
Unrelated - The AE is clearly NOT related to the study treatment 
8.2.3 
Grading of AEs 
All adverse events will be graded using the Common Terminology Criteria for Adverse Events (CTCAE), 
version 5.0 or later.  Grade refers to the severity of the AE.  The CTCAE displays Grades 1 through 5 with 
unique clinical descriptions of severity for each AE based on this general guideline: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL; i.e. preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc) 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL (i.e. bathing, dressing 
and undressing, feeding self, using the toilet, taking medications, and not bedridden) 
Grade 4: Life-threatening consequences; urgent intervention indicated 
Grade 5: Death related to AE 
CTCAE resources:  https://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
Quick reference guide: 
https://ctep.cancer.gov/protocoldevelopment/electronic applications/docs/CTCAE v5 Quick Referenc
e 5x7.pdf 
8.2.4 
Serious Adverse Event Reporting 
In the case of a SAE, a pregnancy report, or an overdose, the Investigator must immediately: 
• 
REPORT (within 24 hours by fax or e-mail) the CIOMS information related to the SAE, pregnancy 
or overdose to PTx 
e-mail: 
  
fax number: 
 
ENTER the information related to the SAE in the appropriate SAE form and AE CRF and 
include a photocopy of all examinations carried out and the dates on which these 
examinations were performed. Care should be taken to ensure that the patient's 
identity is protected and the patient's identifiers in the clinical trial are properly 

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mentioned on any copy of source document provided to PTx. For laboratory results, 
include the laboratory normal ranges. 
o All further data updates should be recorded in the SAE form and AE CRF as appropriate, 
and further documentation as well as additional information (for laboratory data, 
concomitant medication, patient status) should be reported (by fax or e-mail as detailed 
above) to PTx within 24 hours of knowledge.  In addition, effort should be made to 
further document each SAE that is fatal or life threatening within the week (7 days) 
following initial notification. 
o An SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event. 
8.3 
Expected Toxicities 
For inhaled sargramostim use in patients with COVID-19, no serious adverse events are considered to be 
expected except for COVID-19 disease-related adverse events. If the investigator considers a COVID-19 
disease related event to be related to inhaled sargramostim, or if the event is more severe than 
anticipated for the disease, and the event is serious, it must be reported as a suspected unexpected 
serious adverse reaction (SUSAR). 
COVID-19 is a very recent syndrome, on which few data are available.  Clinical features that will be 
considered as events due to the disease, include dyspnea, cough, sputum production, expectoration, 
pneumonia, malaise, myalgia, fatigue, fever, anorexia, vomiting, diarrhea, headache, sore throat, chest 
tightness, chest pain, chest discomfort, abnormal laboratory values (leukopenia, lymphopenia, 
thrombocytopenia, elevated levels of C-reactive protein), drop in oxygen saturation, progression to 
respiratory failure, progression to acute respiratory distress syndrome, hypotension, or progression to 
multi-organ failure (Wang, 2020; Huang, 2020; Chen, 2020a; Yang, 2020).  Severe COVID-19 may lead to 
death. 
8.4 
Unexpected Toxicities 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as 
per national regulatory requirements in participating countries. 
9 RISKS AND TOXICITIES 
9.1 
Overdose 
There is no clinical experience with overdose of sargramostim, and no specific antidote or detoxification 
measures can be recommended to date. If accidental overdose is suspected, the patient should be 
treated symptomatically. 
9.2 
Pregnancy or Lactation 
There are limited data in pregnant and breastfeeding women.  There is potential for increased risk of 
spontaneous abortion based on rabbit studies.  Investigators should counsel patients of the risk to the 
fetus. Do NOT use diluents with preservatives. 
Note - this information is based on systemic administration of sargramostim.  There are no data 
available for inhaled sargramostim. 
9.2.1 
Pregnancy Risk Summary 
 

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The limited available data on sargramostim use in pregnant women are insufficient to inform the drug-
associated risk of adverse developmental outcomes. Based on animal studies sargramostim may cause 
embryofetal harm. In animal reproduction studies, administration of sargramostim to pregnant rabbits 
during organogenesis resulted in adverse developmental outcomes including increased spontaneous 
abortion at systemic exposures ≥1.3 times the human exposure expected at the recommended human 
dose. Advise pregnant women of the potential risk to a fetus.  
The estimated background risk of major birth defects and miscarriage for the indicated population is 
unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the 
U.S. general population, the estimated background risks of major birth defects and miscarriage in 
clinically recognized pregnancies are 2%-4% and 15%-20%, respectively.  
9.2.2 
Lactation Risk Summary  
There is no information regarding the presence of sargramostim in human milk, the effects on the 
breastfed child, or the effects on milk production. Administration of sargramostim to rabbits during 
lactation resulted in reduction in postnatal offspring survival. Because of the potential for serious 
adverse reactions advise a lactating woman not to breastfeed during treatment and for at least 2 weeks 
after the last dose.  
10 SCHEDULE OF EVENTS AND STUDY PARAMETERS 
The following safety and efficacy parameters are anticipated to be collected as standard patient care.  
This protocol aims to minimize protocol-specific procedures and additional data collection that would 
not be routinely performed as standard patient care. 
All procedures should follow institutional practice for managing patients with COVID-19.  There may be 
procedures defined in the schedule below that are not performed or collected as part of an institution’s 
SOC for managing patients with COVID-19.  For procedures that are not SOC, these can be marked not 
done when not performed or not collected.

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Table 1: Schedule of Events 
Procedure 
Screening 
Period 
Within 48 hours 
of 
randomization 
Treatment 
Period 
Post-treatment 
Follow-up Period 
Days 1-5 
Day 6 or day of 
Discharge 
(whichever is 
earlier) (1) 
Day 7-27 or 
Until Discharge 
(2) 
Day 28 
(End of Study)  
Day 58 
Day 90 
(+/- 30 days) 
Visit Location 
Hospital 
Hospital 
Hospital 
Hospital 
Hospital, Virtual 
Visit, or Phone 
Call (3) 
Virtual visit or 
Phone call 
Hospital, Virtual 
Visit, or Phone 
Call (4) 
Informed consent 
X* 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
COVID-19 PCR 
X 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
 
X 
Ordinal Scale, NEWS-2, SOFA, 
ROX scales 
X 
X 
X 
X 
X 
 
X 
ECG 
X 
X 
X 
X 
 
 
X 
Documentation of ventilation 
and Supplemental Oxygen 
X* 
X* 
X* 
X*(7) 
X* 
 
X* 
Oxygen saturation 
X 
X 
X 
X 
X 
 
X 
Serum pregnancy test 
X* 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
 
X 
Ferritin, d-dimer, CRP 
X* 
X* 
X* 
X 
X 
 
X 
Chemistry 
X 
X 
X 
X 
X 
 
X 
Arterial blood gases (8) 
(P(A-a)O2 gradient, etc.) 
X* 
X* 
X* 
X 
X 
 
X 
Immune profiling 
X 
X 
X 
X 
X 
 
X 
Chest X-ray / CT 
X 
X 
X 
X 
X 
 
X 
Ventilator parameters 
X 
X 
X 
X 
X 
 
 
Sargramostim administration 
 
X* 
 
 
 
 
 
Concomitant medications 
 
X 
X 
X 
X 
 
 
Adverse events* 
 
X* 
X* 
X* 
X* 
X*(5) 
X*(5) 
Survival status 
 
 
 
 
X*(6) 
X*(6) 
X*(6) 
 
*Indicates required study-specific procedures considered beyond institutional SOC for patients with COVID-19. 

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(1) Day 6 study assessments will be conducted up to 24 hours after the last dose of sargramostim. Should the patient be discharged before Day 6, the last day of study drug 
administration will be recorded, and post-treatment assessments will be conducted within 24 hours of the last dose, before the patient is discharged from the hospital. 
(2) During Days 7-27, study procedures and data will be collected until Day 27 or discharge, whichever is earlier.  
(3) If a virtual visit or telephone call is conducted, collect adverse events, and documentation of ventilation and supplemental oxygen. 
(4) Collection of final follow-up on Day 90 can occur anytime between Day 60-120. If the patient had a hospital visit during this period, collect all relevant data as indicated. If 
patient had a virtual visit or phone call during this period collect adverse events, survival status , and documentation of ventilation and supplemental oxygen. 
(5) AE data should be collected up to 30 days following the last dose of treatment.  Any SAEs experienced after this 30 day period should only be reported if the investigator 
suspects a causal relationship to the study drug. 
(6) Survival status can also be obtained using public records, such as obituaries or vital records search, where country and local regulations permit. 
(7) Documentation of ventilation (and supplemental oxygen if admitted) is required on Day 14 only. 
(8) Arterial blood gases should be performed via arterial puncture on Day 1 or within 24 hours before first sargramostim and/or standard of care and at Day 6 or day of 
discharge, whichever is earlier.  On all other days, if arterial blood gas assessment is not done, PaO2 will be estimated from percent O2 saturation (SpO2) by pulse oximetry.  For 
sites located at higher altitudes (> 1000m above sea level), an altitude correction to the PaO2/FiO2 ratio should be made by multiplying the PaO2/FiO2 ratio using average 
ambient to sea level barometric pressure correction.  See  Section 10.2 for more details.

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10.1 Safety Evaluations 
Laboratory data, as performed and collected as part of SOC (see Table 1), will be collected and include 
the following: 
• 
Hematology laboratory parameters:  complete blood count with differential, hemoglobin, 
hematocrit, and absolute counts for white blood cells, platelets, neutrophils, lymphocytes, 
eosinophils and monocytes. 
• 
Chemistry laboratory parameters:  albumin, amylase, lipase, BUN, creatinine, ALT, AST, LDH, 
serum alkaline phosphatase, direct and total bilirubin, glucose, total protein, sodium, potassium, 
chloride, bicarbonate, calcium and uric acid.  
• 
Required laboratory measurements of ferritin, d-dimers and C-reactive protein should also be 
collected at screening, Days 1-6 and any other time it is performed as part of SOC. 
• 
Immune profiling, if performed, including CD4+, CD8+, HLA-DR, IL-6, IL-1, GM-CSF 
10.2 Efficacy Evaluations 
Efficacy data, as performed and collected as SOC  (see Table 1), will be collected and include the 
following: 
• 
The need for and duration of mechanical ventilation, or other means of respiratory support. 
• 
Evaluation of arterial blood gases for oxygenation parameters including PaO2 (partial pressure of 
oxygen), FiO2 (fraction of inspired oxygen), PaO2/FiO2ratio, SpO2 (peripheral oxygen saturation), 
PaCO2 (partial pressure of carbon dioxide), bicarbonate, pH and P(A-a)O2 gradient (alveolar-
arterial) oxygen gradient.  
o For sites located at higher altitudes (> 1000m above sea level), an altitude correction to 
the PaO2/FiO2 ratio should be made by multiplying the PaO2/FiO2 ratio using average 
ambient to sea level barometric pressure correction (e.g. correction of 0.86 for sites 
located in Salt Lake City, Utah or correction of 0.84 for sites located in Denver, 
Colorado). 
o Arterial blood gases should be performed via an arterial puncture taken on Day 1 (or 
within 24 hours) prior to the first dose of sargramostim and/or standard of care and at 
Day 6 (or day of discharge, whichever is earlier).  Assessment of oxygenation on all other 
days can be determined using a noninvasive measurement by estimating PaO2 from 
percent saturation of hemoglobin with oxygen as measured by pulse oximetry (SpO2). 
The table below provides the imputed PaO2/FiO2 ratio (cells) for combinations of SpO2 
(rows) and FiO2 (columns). 

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Table from: Brown et al. Nonlinear Imputation of Pao2/Fio2 From Spo2/Fio2 Among Patients With Acute 
Respiratory Distress Syndrome. Chest 2016; 150(2): 307-313. 
• 
Identification / occurrence of nosocomial infections through the evaluation of BAL 
(bronchoalveolar lavage), sputum, skin, urine and blood culture results or other microbiology 
results. 
• 
Glasgow Coma Score (GCS), as a component of the Sequential Organ Failure Assessment (SOFA) 
score, see Appendix A for assessments. 
• 
Sequential Organ Failure Assessment (SOFA) based on six different scores, one each for the 
respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems, see Appendix 
B for assessments. 
• 
Ordinal score based on an 8-point scoring system, see Appendix C for assessments. 
• 
National Early Warning Score (NEWS-2), see Appendix D for assessments. 
• 
ROX Index, see Appendix E for assessments. 
• 
Radiographic changes on a chest X-ray or CT of thorax region to assess ARDS progression. 
• 
Mortality. 
11 STUDY DURATION AND EARLY TERMINATION 
11.1 Patient Discontinuation Criteria 
Patients will receive sargramostim and/or SOC for the duration of treatment and remain on study for 
the duration of study period, unless:  
- 
Patient withdraws consent or decision by the patient (or his/her legally authorized decision 
maker) or investigator/attending physician to stop treatment 
- 
Unacceptable toxicity to sargramostim and/or SOC 
- 
Occurrence of a treatment-related serious adverse event (see Section 8.2.2 for treatment 
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- 
Occurrence of a treatment-related Grade ≥ 3 adverse event (see Section 8.2.2 for treatment 
attribution) 
- 
Rapid deterioration requiring other advanced treatments or medical care not conducive to 
continued treatment with sargramostim 
- 
Death 
Patients who discontinue treatment early, should remain on study and continue follow-up per the 
schedule of events (unless consent is withdrawn from study participation). 
11.2 Study Completion 
Study completion will be defined as the date when the last patient completes study treatment (including 
SOC), completes the follow-up period, or has withdrawn from the study.  Alternatively, the study may be 
stopped earlier for reasons such as feasibility, poor enrollment, ethical or safety reasons. 
Refer to Table 1, for a complete list of assessments required through the clinical trial. 
11.3 Duration of Treatment (Days 1-5) 
All patients randomized to the sargramostim treatment arm will receive sargramostim treatment for up 
to 5 days. For the purpose of this study, Day 1 is the day the patient receives the first dose of 
sargramostim and/or SOC.  All patients will receive SOC per their institutional standards; SOC may vary 
in duration. 
If at any time the constraints of this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. This includes any clinical adverse event, laboratory abnormality or intercurrent 
illness which, in the opinion of the investigator, indicates that continued treatment with study therapy is 
not in the best interest of the patient. 
11.4 Duration of Study Period (Days 6-28) 
Following the sargramostim treatment period (Days 1-5), patients should continue to receive SOC as 
appropriate following institutional guidelines. The study period (Days 6-28) will continue until 
completion of all safety and efficacy assessments on Day 28 (end of study). 
All patients, including those who discontinue treatment early, should be followed for the duration of the 
study period. 
11.5 Duration of Follow-up (up to Day 90) 
All patients, including those that have withdrawn from the study or discontinued sargramostim, should 
be followed for safety evaluations for up to Day 90. Data from a final follow-up visit at day 90 (+/-30 
days) should also be collected. 
Only patients that have withdrawn their consent to participate in the trial are excluded from further 
follow-up after their consent has been withdrawn. Any available data up to the date of withdrawal of 
consent will be used for the purpose of this study. 
12 STATISTICAL PLAN 
12.1 Sample size consideration 
Approximately 120 patients will be randomized: of which 80 will receive sargramostim + SOC, and 40 
patients who will receive SOC alone to evaluate the clinical efficacy and safety of sargramostim in 
patients with COVID-19 associated acute hypoxemia.   

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The sample size was based on practical and clinical considerations to ensure that the efficacy endpoints 
and safety profile could be appropriately evaluated and was not based on any statistical assumptions or 
hypotheses.  As a result, the analyses of this study will be considered as descriptive analyses. 
12.2 Data Safety Monitoring Board 
The DSMB will comprise of independent external experts to review the safety and benefit/risk data 
using the following guidelines: 
• 
after the first approximately 10 patients are treated for 5 days with sargramostim; enrollment 
will be paused after the 10th patient is enrolled until the safety review is completed  
• 
after the first approximately 20 patients are treated for 5 days with sargramostim; enrollment 
will be paused after the 20th patient is enrolled until the safety review is completed 
• 
after approximately 60 patients (total of both treatment arms) are enrolled to the study. Upon 
completion of this safety review, the DSMB may request an additional review after 
approximately 80 patients have been randomized. Enrollment will not be paused during these 
reviews.  
• 
any reported significant SAE can also trigger a safety review, including, but not limited to ≥2 
patients experiencing a similar SAE or grade ≥3 AE, ≥2 patients discontinue for similar safety 
reasons; an unplanned safety review may require an enrollment pause 
The safety review will occur as a real-time review of patient data, using the data available as well as a 
cumulative safety review as the data accrues. That is, the available data will be accepted as is, and may 
not have gone through any data cleaning processes.  The DSMB will review adverse events and serious 
adverse events, key laboratory parameters such as ferritin, d-dimers, and CRP, and other routine 
laboratory values (hematology, chemistry, coagulation) as well as oxygenation parameter P(A-a)O2 
gradient.  
The DSMB will make recommendations on pausing enrollment, modifying and/or stopping the study, 
including assessing whether randomization should continue, or whether additional changes to the 
treatment arms is warranted.   
The DSMB can also modify the planned schedule of safety reviews based on the observed data, taking 
into account the study enrollment patterns, observed safety profile of the ongoing study, and/or any 
other external data that may emerge.  
Refer to the Data Safety Monitoring Board Charter for additional details. 
12.3 General Statistical Methods 
All patients who receive at least one dose of sargramostim and/or SOC will be included in the efficacy 
and safety analyses.  An additional analyses will be performed on the intent-to-treat population defined 
as all randomized patients. 
A per protocol population will be defined as all patients who receive sargramostim and/or standard of 
care and meet the eligibility criteria of this study.  Violations of the eligibility criteria have the potential 
to influence the efficacy or safety results of the study (see Section 6 for eligibility criteria). 
All analyses will be considered as descriptive analyses.  Derivation of two-sided 95% confidence intervals 
and p-values will be generated where applicable. 
Time to event endpoints will be defined as the start date/time to the end date/time; censoring dates will 
be the last date/time the patient was determined to be event-free.  Kaplan Meier methods will be used 
for time to event endpoint analyses; a logrank test will be performed to compare the two survival 

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curves.  Timepoints estimates and median survival will be derived from the Kaplan Meier analysis.  A Cox 
proportional hazards model may also be used to compare the two treatment arms using a hazard ratio. 
Categorical endpoints will be calculated as the percentage of patients with the event, relative to the 
number of patients treated.  Logistic regression approaches and/or repeated measures statistical 
approaches may be used to compare patients on the sargramostim and control arms, in addition to 
Fisher’s Exact or Chi2 tests (as appropriate). 
Continuous endpoints will be summarized by n, means, medians, minimum, maximum, and 25th and 75th 
percentiles.  Analysis of variance, analysis of covariance, and/or repeated measures statistical 
approaches may be used to compare patients on the sargramostim and control arms. 
In the event that the underlying assumptions and/or distributions for a given statistical method are not 
satisfied, alternative statistical methods will be employed.   
Missing data may be imputed using last-observation-carried forward, or other advanced statistical 
imputation methods. 
Additional exploratory analyses may be performed to evaluate the robustness and sensitivity of the 
study results, including but not limited to the analysis populations, subgroup analyses, treatment 
interactions, adjusted or stratified analyses, and/or alternative statistical methods. 
A statistical analysis plan will contain further details of the planned statistical analyses. Any important 
changes to the planned statistical analyses will be documented as amendments to the statistical analysis 
plan and/or documented in the study report.  
12.3.1 Primary Endpoint(s): Oxygenation at Day 6, and Intubation by Day 14  
The primary endpoint of change in oxygenation parameter of P(A-a)O2 gradient will be evaluated, using 
a repeated measure analyses of variance methods.  Key timepoints of interest include Day 6 (primary 
measure) and Day 14 (secondary measure).   
Another key primary endpoint will be the rate of intubation by Day 14.  That is, any occurrence of 
intubation at any point time in time between Days 1 and 14, will be considered to be an event.  The 
treatment arms will be compared using a Fisher’s Exact or Chi2 tests (as appropriate), and/or by logistic 
regression approaches.  
Handling of missing data is specified above in Section 12.3. 
12.3.2 Secondary and Exploratory Endpoints 
The secondary and exploratory endpoints described in Sections 4.3 and 4.4 above will be analyzed using 
the general statistical methods as described above in Section 12.3.  Key timepoints of interest for 
endpoints include Day 6, Day 14, and Day 28, where data are available.  Assessments of ventilator usage 
will consider alternative devices, in light of possible ventilator shortages.  Refer to FDA Guidance for 
further advice: 
Enforcement Policy for Ventilators and Accessories and Other Respiratory Devices During the 
Coronavirus Disease 2019 (COVID-19) Public Health Emergency: 
https://www.fda.gov/media/136318/download 
Ventilator Supply Mitigation Strategies: Letter to Health Care Providers: 
https://www.fda.gov/medical-devices/letters-health-care-providers/ventilator-supply-
mitigation-strategies-letter-health-care-providers 

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13 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Principal Investigator and/or designee, will prepare and maintain adequate and accurate participant 
case histories with observations and data pertinent to the study.  Study specific Case Report Forms 
(CRFs) will document safety and treatment outcomes for safety monitoring and data analysis.  All study 
data will be entered into standardized CRFs in accordance with the overall study schedule. 
The information collected on CRFs shall be identical to that appearing in original source documents.  
Source documents will be found in the patient’s medical records maintained by study site personnel.  All 
original source documentation must be maintained at the study site.  
In accordance with federal regulations, the Investigator is responsible for the accuracy and authenticity 
of all clinical and laboratory data entered onto CRFs.  The PI will approve all completed CRFs to attest 
that the information contained on the CRFs is true and accurate.  
In signing this protocol, the investigator understands and agrees to give access to the necessary source 
documentation and files to enable study monitoring by employees or representatives of Partner 
Therapeutics. 
Monitoring of the study will be performed in compliance with 21 CFR 312.  Alternative methods of 
monitoring may need to be employed in light of the COVID-19 pandemic, and in accordance with FDA 
guidance on “FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency”, available here: https://www.fda.gov/media/136238/download. 
14 QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, a quality assurance audit 
may be conducted. Regulatory agencies may also conduct a regulatory inspection of this study. Such 
audits/inspections can occur at any time during or after completion of the study. If an audit or 
inspection occurs, the investigator and institution agree to allow the auditor/inspector direct access to 
all relevant documents and to allocate his/her time and the time of his/her staff to the auditor/inspector 
to discuss findings and any relevant issues. In the case of an audit or inspection, the Investigator or a 
designee will alert Partner Therapeutics as soon as he/she becomes aware of the audit or inspection. 
The investigator and study staff are responsible for maintaining a comprehensive and accurate filing 
system of all study-related documentation that will be suitable for inspection at any time by Partner 
Therapeutics and its designees, and/or regulatory agencies. 
15 ETHICS 
This study will be conducted in compliance with Institutional Review Board (IRB) and ICH GCP 
Guidelines; United States (US) Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR § 
50, 56, 312); the Declaration of Helsinki, and with applicable ICH guidelines regarding scientific integrity . 
This study will also adhere to all Food and Drug Administration (FDA), state and local regulatory 
requirements, and requirements for data protection. 
15.1 Informed consent 
Investigators must follow local IRB approved institutional practice for obtaining either written or verbal 
informed consent which should be obtained after adequate, thorough and clear explanation of the study 
objectives, procedures, as well as the potential hazards of the study. The investigator must use the most 
current IRB-approved consent form. In cases where the patient is incapable of providing consent and the 

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patients legally authorized decision maker is providing consent, the patient should be informed about 
the study to the extent possible given his/her understanding. 
16 DATA HANDLING AND RECORD KEEPING 
The collection and processing of personal data from patients enrolled in this study will be limited to 
those data that are necessary to fulfill the objectives of the study. These data must be collected and 
processed with adequate precautions to ensure confidentiality and compliance with applicable data 
privacy protection laws and regulations. Records related to the study will be retained for a period of 
fifteen (15) years after the completion or discontinuation of the study, unless otherwise notified by the 
Sponsor.   
Appropriate technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be put in 
place. Sponsor and site personnel whose responsibilities require access to personal data agree to keep 
the identity of patients confidential.  
The informed consent obtained from the patient includes explicit consent for the processing of personal 
data and for the investigator/institution to allow direct access to his or her original medical records 
(source data/documents) for study-related monitoring, audit, Ethics Committee review and regulatory 
inspection, as well as for research purposes unrelated to this study. This consent also addresses the 
transfer of the data to other entities, if applicable.  
17 FINANCING AND INSURANCE 
Before study initiation, each investigator must provide a protocol signature page and a fully executed 
and signed Form FDA 1572 to Partner Therapeutics.  Financial Disclosure Forms must be completed by 
all investigators and sub investigators who will be directly involved in the treatment or evaluation of 
research patients in this study. The investigator(s) are required to disclose any financial arrangement 
whereby the value of the compensation for conducting the study could be influenced by the outcome of 
the study following information; any significant payments of other sorts from Partner Therapeutics, such 
as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing 
consultation, or honoraria; any proprietary interest in sargramostim; any significant equity interest in 
Partner Therapeutics as defined in the US Code of Federal Regulations (21 CFR 54 2(b)). 
18 PUBLICATION POLICY 
The investigator may publish the data pertaining to patients enrolled at their institute on an accelerated 
timeline given the urgency of the COVID-19 pandemic.  The investigator should provide advance 
notification of intent for accelerated disclosure and provide Partner Therapeutics any proposed 
publication or presentation along with information about the scientific journal or presentation forum, at 
least 2 business days prior to submission of the publication or presentation for the initial disclosure. 
 
 

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differentiation and function: More than a numbers game. Front Immunol. 2019; 10:2679. 
Zheng, M., Gao, Y., Wang, G. Song G, Liu S, Sun D, et al. Functional exhaustion of antiviral lymphocytes in 
COVID-19 patients. Cell Mol Immunol 2020; https://doi.org/10.1038/s41423-020-0402-2 
 
 

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APPENDIX A: Glasgow Coma Score 
Feature 
Response 
Score 
Best eye response 
Open spontaneously 
4 
Open to verbal command 
3 
Open to pain 
2 
No eye opening 
1 
Best verbal response 
Orientated 
5 
Confused 
4 
Inappropriate words 
3 
Incomprehensible sounds 
2 
No verbal response 
1 
Best motor response 
Obeys commands 
6 
Localized pain 
5 
Withdrawing from pain 
4 
Flexion to pain 
3 
Extension to pain 
2 
No motor response 
1 
 
 

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APPENDIX B: SOFA score 
System 
Measure 
SOFA Score 
Respiratory 
PaO2/FiO2 [mmHg (kPa)] 
≥ 400 (53.3) 
0 
< 400 (53.3) 
+1 
< 300 (40) 
+2 
< 200 (26.7) and mechanically ventilated 
+3 
< 100 (13.3) and mechanically ventilated 
+4 
Neurological 
Glasgow Coma Score 
15 
0 
13–14 
+1 
10–12 
+2 
6–9 
+3 
< 6 
+4 
Cardiovascular 
Mean arterial pressure OR 
administration of 
vasopressors required 
 
MAP ≥ 70 mmHg 
0 
MAP < 70 mmHg 
+1 
dopamine ≤ 5 μg/kg/min or dobutamine (any dose) 
+2 
dopamine > 5 μg/kg/min OR epinephrine ≤ 0.1 μg/kg/min OR 
norepinephrine ≤ 0.1 μg/kg/min 
+3 
dopamine > 15 μg/kg/min OR epinephrine > 0.1 μg/kg/min OR 
norepinephrine > 0.1 μg/kg/min 
+4 
Hepatic 
Bilirubin (mg/dl) [μmol/L] 
< 1.2 [< 20] 
0 
1.2–1.9 [20-32] 
+1 
2.0–5.9 [33-101] 
+2 
6.0–11.9 [102-204] 
+3 
> 12.0 [> 204] 
+4 
Coagulation 
Platelets×103/μl 
≥ 150 
0 
< 150 
+1 
< 100 
+2 
< 50 
+3 
< 20 
+4 
Renal 
Creatinine (mg/dl) 
[μmol/L 
< 1.2 [< 110] 
0 
1.2–1.9 [110-170] 
+1 
2.0–3.4 [171-299] 
+2 
3.5–4.9 [300-440] (or < 500 ml/d) 
+3 
> 5.0 [> 440] (or < 200 ml/d) 
+4 
 
 
 

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APPENDIX C: Ordinal Score 
Measure 
Ordinal Score 
Death 
8 
Hospitalized, mechanical ventilation + additional organ support 
(i.e. requiring ECMO, pressors, renal replacement therapy) 
7 
Hospitalized, requiring intubation and mechanical ventilation 
6 
Hospitalized, requiring high-flow oxygen therapy, non-invasive 
mechanical ventilation, or both 
5 
Hospitalized, requiring supplemental oxygen by mask or nasal 
prongs 
4 
Hospitalized, not requiring supplemental oxygen 
3 
Not hospitalized, limitation of activities 
2 
Not hospitalized, no limitation of activities 
1 
Not hospitalized, no clinical or virological evidence of infection 
0 
 
 
 

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APPENDIX D: NEWS-2 score 
Measure 
Parameters 
NEWS-2 Score 
Respiratory rate, breaths per 
minute 
≤8 
+3 
9-11 
+1 
12-20 
0 
21-24 
+2 
≤25 
+3 
SpO2 if patient has 
hypercapnic respiratory failure 
≤83% 
+3 
84-85% 
+2 
86-87% 
+1 
88-92%, ≥93% on room air 
0 
93-94% on supplemental O2 
+1 
95-96% on supplemental O2 
+2 
≥97% on supplemental O2 
+3 
SpO2 on room air or 
supplemental O2 
 
≤91% 
+3 
92-93% 
+2 
94-95% 
+1 
≥96% 
0 
Room air or supplemental O2 
Supplemental O2 
+2 
Room air 
0 
Temperature 
≤35.0oC (95oF) 
+3 
35.1-36.0oC (95.1-96.8oF) 
+1 
36.1-38.0oC (96.9-100.4oF) 
0 
38.1-39.0 oC (100.5-102.2oF) 
+1 
≥39.1oC (102.3oF) 
+2 
Systolic BP, mmHg 
≤90 
+3 
91-100 
+2 
101-110 
+1 
111-219 
0 
≥220 
+3 
Pulse, beats per minute 
≤40 
+3 
41-50 
+1 
51-90 
0 
91-110 
+1 
111-130 
+2 
≥131 
+3 
Consciousness 
Alert 
0 
New-onset confusion (or disorientation/agitation), 
responds to voice, responds to pain, or unresponsive 
+3 
 
 
 

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APPENDIX E: ROX Index 
ROX Index calculation = SpO₂/FiO₂*, % / Respiratory rate, breaths/min 
*Estimating FiO₂ from oxygen flow/delivery rates: 
Type of O₂ delivery 
Flow rates, L/min 
FiO₂ 
Nasal cannula 
1-6 
~4% FiO₂ added above room air** per 1 L/min 
Room air = 21%  
1 L/min = 25% 
2 L/min = 29% 
3 L/min = 33% 
4 L/min = 37% 
5 L/min = 41% 
6 L/min = 45% 
Simple face mask 
~6-12 
35-60%* 
Non-rebreather mask 
10-15 
~70-90% 
High-flow nasal cannula 
Up to 60 
30-100% 
**Varies based on respiratory rate and minute ventilation.