Conditions: COVID-19 SARS-CoV-2
Keywords: COVID-19 sargramostim Leukine rhu-GM-CSF acute hypoxemia iLeukPulm SARS-CoV-2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 123
Healthy volunteers: no

Brief summary:
The purpose of this research is to find out if a drug (sargramostim) also known as Leukine® could help patient recover faster from COVID-19. Sargramostim may help the lungs recover from the effects of COVID-19, and this research study will help to find this out.

Detailed description:
This Phase 2 study is designed as a proof of concept study and will randomize 2:1 approximately 120 patients with COVID-19 associated acute hypoxemia: of which 80 patients will receive sargramostim plus standard of care, and 40 patients who will receive standard of care alone. The aim of the study is to determine if inhaled sargramostim, as an adjunct to institutional standard of care, improves clinical outcomes in patients with COVID-19-associated acute hypoxemia. All patients on the sargramostim arm will be treated with 125 mcg inhaled sargramostim twice daily for 5 days, in addition to institutional standard of care. If required, upon progression to an invasive mechanical ventilator, administration of sargramostim may be delivered by intravenous infusion to complete a total of 5 days (including days delivered via inhalation).

GM-CSF is a critical cytokine for healthy pulmonary function and is necessary for the maturation and maintenance of alveolar macrophages. Preclinical studies have shown GM-CSF confers resistance to influenza by enhancing innate immune mechanisms that depend on alveolar macrophages for their health and normal functioning. Clinical studies of sargramostim in patients with severe sepsis and respiratory dysfunction or acute respiratory distress syndrome have shown improvements in oxygenation and lung compliance.

Arms:
arm 1: Day 1 - 5: Sargramostim treatment in addition to standard of care for COVID-19 arm 2: Standard of care for COVID-19

Interventions: intervention 1: Sargramostim intervention 2: Standard of care
Intervention descriptions: intervention 1: Sargramostim is a glycosylated, yeast-derived recombinant human granulocyte-macrophage colony stimulating factor (rhu-GM-CSF). Dosage for inhaled sargramostim: 125 mcg twice a day. Dosage for intravenous sargramostim: 125mcg/m2/day given over a 4 hour period. intervention 2: Standard of care for COVID-19

Protocol document:
Prot_000.pdf: 
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 
intubated by Day 14 


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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 
attribution) 


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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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Weber GF, Chousterman BG, Hilgendorf I, Robbins CS, Theurl I, Gerhardt LMS, et al. Pleural innate 
response activator B cells protect against pneumonia via a GM-CSF- IgM axis. J Exp Med. 2014; 
211(6):1243-56. 
Wei WE, Li Z, Chiew CJ, Yong SE, Toh MP, Lee VJ.  Presymptomatic Transmission of SARS-CoV-2 — 
Singapore, January 23–March 16, 2020. MMWR Morb Mortal Wkly Rep 2020. doi: 
http://dx.doi.org/10.15585/mmwr.mm6914e1  
Wenjun W, He J, Lie P, Huang L, Wu S, Lin Y, et al.  The definition and risks of Cytokine Release 
Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and 
Retrospective Analysis. medRxiv preprint 2020; doi: https://doi.org/10.1101/2020.02.26.2002698 
Wong JM, Leong JY, Lee JH, Albani S, Yeo JG. Insights into the immuno-pathogenesis of acute respiratory 
distress syndrome. Ann Transl Med 2019;7(19):504. http://dx.doi.org/10.21037/atm.2019.09.28 
Wylam ME, Ten R, Prakash UB, Nadrous HF, Clawson ML, Anderson PM.  Aerosol granulocyte-
macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur Respir J. 2006; 27(3):585-
593. 
Yang W, Cao Q, Qin L, Wang X, Cheng Z, Ashan Pan, et al. Clinical characteristics and imaging 
manifestations of the 2019 novel coronavirus disease (COVID-19):A multi-center study in Wenzhou city, 
Zhejiang, China. Journal of Infection 2020; 80:388–393. 


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Yao X, Li T, He Z, Ping Y, Liu H, Yu S, et al.   Histopathological study of three cases of new coronavirus 
pneumonia (COVID-19) with multiple sites of puncture. Chinese Journal of Pathology. 2020;49 (2020-03-
15).  
Zhan Y, Lew AM, Chopin M. The pleiotropic effects of the GM-CSF rheostat on myeloid cell 
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. 

SAP_001.pdf: 
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Table of Contents 
Table of Contents ............................................................................................................................ 2 
1 
Signature Page ........................................................................................................................ 5 
2 
Amendment/Modification History .......................................................................................... 7 
3 
Abbreviations .......................................................................................................................... 8 
4 
Introduction ............................................................................................................................. 9 
5 
Study Objectives and Endpoints ............................................................................................. 9 
5.1 
Study Objectives .............................................................................................................. 9 
5.2 
Study Endpoints ............................................................................................................... 9 
5.2.1 
Primary Endpoints .................................................................................................... 9 
5.2.2 
Secondary Endpoints ................................................................................................ 9 
5.2.3 
Exploratory Endpoints ............................................................................................ 10 
6 
Study Design ......................................................................................................................... 10 
6.1 
Study Design Overview ................................................................................................. 10 
6.2 
Randomization ............................................................................................................... 10 
6.3 
Study Schedule ............................................................................................................... 11 
6.4 
Study Duration and Early Termination .......................................................................... 11 
6.4.1 
Patient Discontinuation Criteria .............................................................................. 11 
6.4.2 
Study Completion ................................................................................................... 11 
6.4.3 
Duration of Treatment (Days 1-5) .......................................................................... 11 
6.4.4 
Duration of Study Period (Days 6-28) .................................................................... 11 
6.4.5 
Duration of Follow-up (up to 30 days following end of study visit) ...................... 11 
6.5 
Study Drug Administration ............................................................................................ 11 
6.6 
Study Assessments ......................................................................................................... 11 


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6.6.1 
Safety Evaluations .................................................................................................. 11 
6.6.2 
Efficacy Evaluations ............................................................................................... 11 
7 
Statistical Analysis Methods ................................................................................................. 12 
7.1 
General Considerations .................................................................................................. 12 
7.1.1 
Study Day................................................................................................................ 13 
7.1.2 
Baseline Definition ................................................................................................. 13 
7.1.3 
Analysis Period  ...................................................................................................... 14 
7.1.4 
Post-Treatment: Up to Day 6 (or Discharge, whichever is earlier)  ....................... 14 
7.1.5 
Missing Data Handling ........................................................................................... 15 
7.2 
Sample Size .................................................................................................................... 16 
7.3 
Data Safety Monitoring Board ....................................................................................... 16 
7.4 
Analysis Population........................................................................................................ 16 
7.5 
Patient Disposition ......................................................................................................... 17 
7.6 
Protocol Deviations ........................................................................................................ 17 
7.7 
Demographics and Baseline Disease Characteristics ..................................................... 18 
7.8 
Medical History .............................................................................................................. 18 
7.9 
Concomitant Medications .............................................................................................. 19 
7.10 
Extend of Exposure and Treatment Compliance ........................................................ 19 
7.11 
Efficacy Evaluations ................................................................................................... 21 
7.11.1 Primary Efficacy Evaluations ................................................................................. 21 
7.11.2 Secondary Efficacy Evaluations ............................................................................. 24 
7.11.3 Exploratory Efficacy Evaluations ........................................................................... 27 
7.12 
Safety Evaluations ...................................................................................................... 28 
7.12.1 Adverse Event ......................................................................................................... 28 


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7.12.2 Laboratory data ....................................................................................................... 30 
7.12.3 Physical Examination.............................................................................................. 31 
7.12.4 Vital Signs ............................................................................................................... 31 
7.12.5 Electrocardiogram (ECG) ....................................................................................... 31 
7.12.6 Patient Profiles ........................................................................................................ 31 
8 
Data Presentation .................................................................................................................. 32 
8.1 
Insufficient Data for Presentation .................................................................................. 32 
9 
Revision History ................................................................................................................... 32 
10 Reference .............................................................................................................................. 32 
 
 
 


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1 Signature Page  
Documents Prepared by: 
 
 
 
 
__________________________________                         __________________  
 
 
 
 
 
 
 
 
 
 
Date 
Statistician 
 
 
 
 


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Reviewer 
 
 
 
 
Consultant – Regulatory, 
Biostatistics & Data Management 
 
 
Printed Name 
 
Title 
 
 
 
 
 
 
 
 
 
Signature 
 
dd-mmm-yyyy 
 
 
Approval 
The undersigned have reviewed and approved the Statistical Analysis Plan and find the 
document to be consistent with the requirements of the Protocol. 
 
 
 
 
 
 
Consultant – Regulatory, 
Biostatistics & Data Management 
 
 
Printed Name 
 
Title 
 
 
 
 
 
 
 
 
 
Signature 
 
dd-mmm-yyyy 
 
 
 
 
 
 
 
 
 
 
Executive Director Medical 
Immunology Oncology 
 
 
Printed Name 
 
Title 
 
 
 
 
 
 
 
 
 
Signature 
 
dd-mmm-yyyy 
 
 
 


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2 Amendment/Modification History 
The following table documents any changes made to the previously approved versions of the 
document. 
Version # 
Page # / Section 
Summary of Changes 
Date 
1.0 
Original 
NA 
17-Mar-2021 
 
 
 


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3 Abbreviations 
ADR: 
adverse drug reaction 
ADL:                   activities of daily living 
AE: 
adverse event 
ALT: 
alanine aminotransferase 
ARDS:  
acute respiratory distress syndrome 
AST:  
alanine aminotransferase 
BAL: 
bronchoalveolar lavage 
BUN: 
blood urea nitrogen 
CRF: 
case report form 
CRP: 
C-reactive protein 
Cstat: 
static compliance 
CT:  
Computed tomography 
CTCAE:              Common Terminology Criteria for Adverse Events 
DSMB: 
Data Safety Monitoring Board 
ECG: 
electrocardiogram 
FiO2:  
fraction of inspired oxygen 
GCS:  
Glasgow coma score 
GM-CSF: 
granulocyte macrophage colonystimulating factor 
HLA-DR: 
human leukocyte antigen – DR isotype 
ICF: 
Informed consent form 
IL-1: 
Interleukin-1 
IL-6: 
Interleukin-6 
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 
PaO2:  
partial pressure of oxygen 
PCR:  
polymerase chain reaction 
PEEP:  
positive end expiratory pressure 
PI: 
Principal Investigator 
Pplat: 
plateau pressure  
PTX:  
Partner Therapeutics 
SAE:  
serious adverse event 
SAP:                    statistical analysis plan 
SOC: 
Standard of care 
SOFA: 
sequential organ failure assessment 
SpO2:  
peripheral oxygen saturation 
SUSAR:  
suspected unexpected serious adverse reaction 
US: 
United States 
USP: 
United States Pharmacopoeia 
WBC:  
white blood cells 
 
 


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4 Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and statistical 
methodologies that will be used in the analysis and reporting of results for Partner Therapeutics 
Protocol PTX-001-002. 
This document is prepared based on the following documents: 
• the study protocol version 2.0 dated 02 December 2020;  
• the Case Report Form version 1.7 dated 08 January 2021. 
Readers are referred to the final study protocol (and any amendments or addenda), the case 
report form (CRF), and CRF completion guidelines for details of the study design, conduct and 
data collection. Any significant changes to these documents in terms of the principal features of 
the study analyses may result in an SAP amendment; any other changes will be denoted in the 
Clinical Study Report as changes to the planned analyses. 
This SAP must be finalized prior to the locking of the clinical database for this study. The mock 
summary tables, figures and by subject data listings (TFLs) are provided in a separate document. 
5 Study Objectives and Endpoints 
5.1 
Study Objectives 
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. 
5.2 
Study Endpoints 
5.2.1 Primary Endpoints  
• Change in oxygenation parameter of P(A-a)O2 gradient by Day 6 and % of patients who have 
been intubated by Day 14 
 
5.2.2 Secondary Endpoints  
• Change in ordinal scale.  


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• 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. 
5.2.3 Exploratory Endpoints  
• National Early Warning Score (NEWS-2). 
• Sequential organ failure assessment (SOFA) scores. 
• ROX Index. 
• Progression to ARDS. 
• Changes on chest X-ray or CT. 
6 Study Design 
6.1 
Study Design Overview 
This study is a randomized two-arm open-label study. 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.  Refer to Section 5.1 of the Study Protocol for a more 
detailed description of the study. Section 1 of the Study Protocol is a schematic of the study 
design. 
6.2 
Randomization 
Per Section 5.2 of the Study Protocol, randomization will be performed, using a 2:1 
randomization ratio, with the strata defined as: 


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• investigational site,  
• SOFA score (<6 versus ≥ 6) 
6.3 
Study Schedule 
The scheduled assessments will be carried out during the study as described in Section 10 of the 
Study Protocol. 
6.4 
Study Duration and Early Termination  
6.4.1 Patient Discontinuation Criteria 
Refer to Section 11.1 of the Study Protocol 
6.4.2 Study Completion 
Refer to Section 11.2 of the Study Protocol 
6.4.3 Duration of Treatment (Days 1-5) 
Refer to Section 11.3 of the Study Protocol. 
6.4.4 Duration of Study Period (Days 6-28) 
Refer to Section 11.4 of the Study Protocol. 
6.4.5 Duration of Follow-up (up to 30 days following end of study visit) 
Refer to Section 11.5 of the Study Protocol.   
6.5 
Study Drug Administration 
Refer to Section 7.1 of the Study Protocol. 
6.6 
Study Assessments 
6.6.1 Safety Evaluations 
Safety evaluations and definitions are described in Sections 8, 10, and 10.1 of the Study 
Protocol. 
6.6.2 Efficacy Evaluations 
Efficacy evaluations are described in Section 10.2 of the Study Protocol. 


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7 Statistical Analysis Methods 
7.1 
General Considerations 
All safety analyses will be based on Safety Population; all efficacy analyses will be based on 
Modified Intent-to-Treat population, unless otherwise specified. Some specific sensitivity 
analyses of efficacy may be based on ITT and Per Protocol populations (for primary endpoints 
only). See Section 7.4 below for definitions of each analysis population. 
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 log-rank test will be performed to 
compare the two survival 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 in a given analysis population (see Section 7.4). Stratified 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).  The randomization stratification factor for the baseline SOFA score (<6 versus ≥ 
6) will be considered for any stratified analysis. 
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. 
Additional exploratory analyses may be performed to evaluate the robustness and sensitivity of 
the study results, including but not limited to, additional evaluation of endpoints on other 


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analysis populations, subgroup analyses, treatment interactions, adjusted or stratified analyses, 
and/or alternative statistical methods. 
7.1.1 Study Day 
Study day will be calculated as follows: 
• For the sargramostim arm: Assessments/events prior to the first sargramostim dose date, 
study day will be the assessment date minus the first dose date.  The end of treatment is the 
date/time of the last administered dose of sargramostim. 
• For the control arm, the randomization date will be used as the first dose date.  The treatment 
completion or discontinuation date/time from the treatment disposition CRF page will be 
considered the end of treatment for the SOC arm. 
• Assessments/events on or after the first dose date, study day will be the assessment date 
minus the first dose date plus one. 
• The duration of SOC (for both treatment arms) will be based on the start date of 
randomization, and the end date as latest of 1) any concomitant medication end date with 
indication “COVID-19”, or 2) any end date of procedure with indication “COVID-19”, or 3) 
any end date of transfusion, ventilation or supplemental oxygen. 
For assessments captured as an unscheduled visit, if the date of assessment is the same as a date 
of another visit (e.g., Day 6, Day 14, Day 28, Day 58, Day 90), then the visit label for the 
unscheduled assessment can be re-assigned to the appropriate visit label (e.g., Day 6, Day 14, 
Day 28, Day 58, Day 90).  Other appropriate data handling approaches may be used to ensure 
data is analyzed in the appropriate timepoint analysis. 
7.1.2 Baseline Definition  
For both treatment arms, baseline is considered any observation that occurs prior to, or on the 
date of randomization, unless otherwise specified.  That is, baseline date ≤ randomization date. 
Additionally, for the sargramostim arm, baseline assessments must also be prior to the first 
sargramostim dose date/time.  
If there are multiple baseline assessments, the latest one will be used for analysis purposes. 


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For assessments on the day of first dose where time is not captured, a nominal pre-dose indicator, 
if available, will serve as sufficient evidence that the assessment occurred prior to first dose. 
Assessments on the day of the first dose where neither time nor a nominal pre-dose indicator are 
captured, will be considered prior to the first dose if such procedures are required by the protocol 
to be conducted before the first dose. 
In all summaries, change from baseline variables will be calculated as the post-treatment value 
minus the value at baseline. The % change from baseline will be calculated as (post-baseline 
value - baseline value) / baseline value x 100. 
7.1.3 Analysis Period  
The main analysis period would be the Treatment Emergent period.  
For all treatment emergent adverse events, it is defined as the period from the date of the first dose 
until the earliest of the following 1) date of Study Day 58; or 2) date of early discontinuation from 
study, or 3) data cutoff date. However, SAEs will include all the serious adverse events collected 
after the first dose.  
The analysis period used for abnormalities in laboratory evaluations is defined as the period from the 
date of the first dose until the earliest of the following 1) date of Study Day 90; or 2) date of Early 
discontinuation from study, or 3) data cutoff date.   
Analysis period for efficacy parameters would be the period from the date of the first dose until the 
earliest of the following 1) Date of Study Day 90; or 2) Date of Early discontinuation from study, or 
3) data cutoff date. 
7.1.4 Post-Treatment: Up to Day 6 (or Discharge, whichever is earlier)  
The post-treatment evaluation is one of the main timepoints for evaluation of efficacy endpoints, 
particularly measures of oxygenation.  In the protocol, this is referred to as the Day 6 evaluation. 
In the context of this document, this will be presented as “Up to Day 6”. 
For the sargramostim arm: any assessment that is performed within 24 hours after the last 
treatment administration date/time may be considered as the “Up to Day 6” evaluation.  That is, 
within last dose date/time + 24 hours. If there are no assessments in that timeframe, then the last 


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post-baseline observation prior to last dose date/time will be used.  To address any missing dose 
times for the known dose dates: 
• if the start time of inhalation dosing is known, then the end time can be assumed to be 15 
minutes later (i.e., end time = start time + 15 minutes) 
• otherwise, the end time will be assumed to be 23:59   
For patients who received standard of care alone, any assessment that is within 1 calendar day 
after the later of, the treatment completion (or treatment discontinuation date) [from the 
treatment disposition CRF page] or Day 6/Post-Treatment visit date, may be considered as the 
“Up to Day 6” evaluation.  If there are no assessments in that timeframe, then the last post-
baseline observation prior to latter of, the treatment completion (or treatment discontinuation 
date) or Day 6/Post-Treatment visit date, will be used.   
7.1.5 Missing Data Handling  
In general, no imputation of missing data is planned for the primary analyses.  However, for 
purposes of any sensitivity analyses, missing data may be imputed using last-observation-carried 
forward, or other advanced statistical imputation methods.  
For the efficacy analyses based on oxygenation parameters, up to Day 6, if the assessment on 
Day 6 is not available, then the last prior non-missing value, after baseline will be used. See 
Sections 7.1.2, 7.1.3, and 7.1.4 for algorithm on determining assessments to be used for analysis. 
Imputation for P(A-a)O2 gradient, intubation rate and ordinal scale will not be performed. 
If using last observation carried forward, a missing follow-up visit value will be imputed as that 
patient's previously observed value. 
In the absence of any other specifications, the following rule will be used for missing time-to-
event data: 
• Patients who are alive (not lost to follow up) and did not experience the event of interest 
will be censored at the date last known to be alive and to be event-free.  
 


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7.2 
Sample Size 
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.  
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. 
7.3 
Data Safety Monitoring Board  
The DSMB will comprise of independent external experts to review the safety and benefit/risk 
data. See Section 12.2 of the Study Protocol and/or DSMB Charter for further information. 
7.4 
Analysis Population 
The following analysis populations will be used to summarize the results from this study. 
• Safety Population includes all patients who received at least one dose of sargramostim 
and/or SOC based on actual treatment received. Patients who did not receive any study 
treatment (either sargramostim and/or SOC) will be excluded from Safety Population. All 
safety analyses will be based on the Safety Population. 
• Intent-to-treat Population (ITT) includes all patients who were randomized, and 
analyzed per the treatment arm as randomized. Selected efficacy analysis (P(A-a)O2 and 
intubation rate) may also be performed based on ITT population for the purpose of 
sensitivity, unless otherwise specified. 
• Modified Intent-to-treat Population (MITT): a subset of the ITT population that 
received at least one dose of any study treatment (either sargramostim and/or SOC).  
Efficacy analyses will be based on the MITT Population. 
• Per Protocol Population (PP) includes all patients who were randomized and received 
at least one dose of sargramostim and/or standard of care based on the treatment assigned 


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at randomization and meet the eligibility criteria of this study. Selected efficacy analyses 
may also be performed based on the Per Protocol  Population, unless otherwise specified.   
• If the ITT, and PP populations are identical, or less than 10% different compared to the 
MITT population, then the selected efficacy analyses may not be repeated across the ITT 
and PP analysis population. 
• Enrolled Population includes all patients who were eligible and signed informed 
consent form (ICF). 
7.5 
Patient Disposition 
Descriptive statistics by treatment will be used to summarize the number of patients enrolled, the 
number of screening failures, the number of patients in Safety Population, ITT, MITT, and PP, 
number of patients who completed key study timepoints of interest (Days 1-5, Up to Day 6, Day 
14, Day 28, Day 58), and who completed treatment period, completed the study, withdrew from 
treatment, and withdrew from the study, and reasons for withdrawals from treatment and from 
study. The descriptive statistics will include numbers and percentages of patients in each 
identified category by treatment arms. A patient’s data listing will be provided for disposition 
that includes patients who are excluded from each analysis populations (and reasons for 
exclusion); who prematurely withdrew from the study and for early treatment discontinuation, 
along with the associated reasons. 
7.6 
Protocol Deviations 
All reported protocol deviations will be reviewed, and determined to be major or minor, based on 
the potential impact to efficacy and/or safety. 
A subject listing of protocol deviations data will be presented.  
The following general categories will be considered major deviations include, but are not limited 
to: 
• Deviation 1: Patients randomized but who did not receive study drug or standard of care 
(i.e., not treated) 
• Deviation 2: Patients who deviate from the following key entry criteria: 


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o Inclusion: 
o Exclusion: 
• Deviation 3: Patients randomized who received treatment other than that to which they 
were randomized to (i.e., received the other treatment). 
7.7 
Demographics and Baseline Disease Characteristics 
Demographic information for MITT Population will be summarized. The demographic data 
consists of age, gender, race, ethnicity, baseline height, body weight, body mass index (BMI), 
Body Surface Area (BSA). The baseline disease assessment scales, including the SOFA score 
(including categorization of <6 versus ≥ 6) , ordinal scale, and National Early Warning System 2 
Score will be summarized. The baseline COVID-19 diagnostic information will also be 
summarized. 
Individual demographics and other baseline factors will be listed by patient. 
Continuous variables (for example, age, height, body weight, body mass index, body surface 
area, disease assessment scales) will be summarized by n, means, medians, minimum, maximum, 
and 25th and 75th percentiles. Number of patients and percentages will be used to describe 
categorical (discrete) variables (for example, gender, race, ethnicity and SOFA score <6 versus 
≥ 6).  
If there is a difference between the MITT and the Safety Population, the summary of baseline 
and disease characteristics may be repeated on the Safety Population. 
7.8 
Medical History 
Medical condition and/or significant medical history will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) Version 23.0 or later, and listed by reported term, System 
Organ Class  and Preferred Term (PT). The number and percentage of patients will be 
summarized by System Organ Class and PT by treatment for MITT Population, and listed.  




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Treatment duration and treatment compliance will be summarized for the Safety Population. For 
each patient, the treatment duration is defined as the number of days from the first treatment date 
to the last treatment date, and can be calculated as:  
Treatment Duration (Days) = (Date and Time of Last Treatment – Date and Time of First 
Treatment)/24 +1. 
The result of treatment duration will be rounded to the nearest integer. For example, if the 
calculation results in 5.4 days, then the final result of treatment duration will be 5 days.  
See Section 7.1.4 for handling missing treatment times. Otherwise, if time of the last treatment is 
not available, the end time of the treatment duration will be imputed using the earliest of 1) End 
time of treatment Day 5; or 2) Time of patient’s early discontinuation from the treatment or from 
the study (where available). Treatment duration will be calculated for both treatment arms, and 
will include any treatment, sargramostim, and standard of care durations. 
For each patient who received sargramostim, the treatment compliance is defined as the actual 
treatment received as percentage of the planned treatment (K days). It can be calculated as: 
Treatment Compliance = 100*(Treatment Duration– Number of Days without Study 
Treatment)/K 
In this study, the prespecified treatment duration of sargramostim is 5 days (K=5).. For 
discontinued patients, K would be equal to the number of days from the date the sargramostim 
study drug is first received to the date of early discontinuation.  
K can be smaller than 5 1) if the end of the treatment/early discontinuation of treatment before 
Day 5; 2) if the patient has not completed 5 days of sargramostim treatment and has not 
discontinued treatment/study early by the time of the data cut. 
Since there is no planned or prespecified treatment duration for the standard of care therapies, 
compliance with standard of care cannot be determined or summarized. 


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7.11 Efficacy Evaluations 
The primary and secondary efficacy endpoints of the study (as defined above in Sections 5.2.1 
and 5.2.2 above) will be analyzed as specified below.  If the primary and secondary efficacy 
endpoints show meaningful results, then the exploratory efficacy endpoints (Section 5.2.3 above) 
will be summarized. 
Key timepoints of interest for endpoints include Days 1-6, Day 14, and Day 28, where data are 
assessed and/or available, unless otherwise specified. All available efficacy data will be tabulated 
and presented for all patients in the Modified Intent-to-Treat (MITT) Population; see Section 7.4. 
7.11.1 Primary Efficacy Evaluations 
For primary efficacy measures based on oxygenation parameters, the main timepoints of interest 
for analyses are baseline, up to Day 6 for P(A-a)O2 gradient, and by Day 14 for rate of 
intubation, where data are available, unless otherwise specified.   
See Sections 7.1.2, 7.1.3, and 7.1.4 for algorithm on determining assessments to be used for 
analysis.  
As ABG was required only at baseline and at Day 6/Post-Treatment visit (or day of discharge if 
earlier), the number of patients with complete data at all study visit days is expected to quite 
limited.  Therefore, the primary timepoint for analyses for data based on ABG will be up to Day 
6. 
 Oxygenation Up to Day 6 
The P(A-a)O2 gradient will be derived using arterial blood gas assessment via arterial puncture at 
baseline and up to Day 6, or day of discharge whichever is earlier. See Sections 7.1.2, 7.1.3, and 
7.1.4 for algorithm on determining assessments to be used for analysis. 
The change from baseline and percentage from baseline is defined as: 
Percentage Change from Baseline= Change from Baseline/ Baseline 
The P(A-a)O2 gradient, the percent change from baseline up to Day 6 will be tabulated based on 
“unchanged or deteriorated” [no difference or positive percent change from baseline] and 
“improved” [negative percent changer from baseline] by 10% change increments.  In addition, 


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the percentage of patients with a ≥ 33% improvement for each treatment arm will be provided.  
For both of these analyses, a Chi-square, or Fisher’s exact test (or stratified logistic model) will 
be generated to compare the treatment arms.  Alternative cutoffs for defining meaningful 
improvement may be used (e.g., 25%, 50%), with similar analyses methods as above. 
The maximum change from baseline and maximum percentage change from baseline will be 
summarized up to Day 6 , and for  the study duration.  
Maximum percentage change from baseline is defined as: 
Maximum Percentage Change from Baseline= Maximum Change from Baseline/ Baseline 
For these analyses, the baseline is defined as the last available assessment prior to administration 
of study drug (see Section 7.1.2 above). Except as noted in Section 7.1.1, unscheduled records 
will be excluded from the summaries at specific timepoints but will be included in the maximum 
change from baseline.  
A listing of all P(A-a)O2 gradient measurements will be provided.  
A Mixed Model Repeated Measures (MMRM) model will be used to evaluate the change in P(A-
a)O2 gradient, in which the change of P(A-a)O2 gradient from baseline on each study day up to 
Day 6 (or day of discharge) will be included as dependent variable and treatment, study day 
(categorical), and treatment-by-study-day as fixed effects, patient as random effect, and the 
baseline value as a continuous covariate. An unstructured covariance matrix will be used for the 
MMRM analysis, unless the model does not converge, in which case the compound symmetry 
will be used. The change in P(A-a)O2 gradient up to Day 6 will be evaluated by this MMRM 
model.   
Change in oxygenation/respiratory parameter of P(A-a)O2 gradient will also be presented by 
waterfall plot.  
 Rate of Intubation, and any other Respiratory Support 
Another key primary endpoint will be the rate of intubation by Day 14. That is, any occurrence 
of intubation (mechanical ventilation, or ECMO) at any point time in time between Days 1 and 


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14, will be considered to be an event. In addition, any intubation at any point during the study 
will be tabulated.  The treatment arms will be compared using a Fisher’s Exact or Chi2 test. 
Furthermore, the various types of respiratory support will be summarized as specified below, 
including invasive ventilation (ventilator or ECMO), non-invasive ventilation by CPAP or 
BiPAP, high flow oxygen, low flow oxygen or no oxygen support required. 
The durations of respiratory support (days) are defined as: 
Duration of respiratory support 
= ෍(End Date time
⁄
on Day 𝑘𝑘𝑖𝑖–  Start Date time
⁄
on Day𝑘𝑘𝑖𝑖) 24
⁄
𝑁𝑁𝑖𝑖
𝑘𝑘𝑖𝑖=0
 
Where, 𝑁𝑁𝑖𝑖 is the total number of available study days for any patient 𝑖𝑖. Respiratory support 
includes invasive ventilation, non-invasive ventilation and supplemental oxygen. Duration of 
oxygen support will be summarized by treatment arm;  p-values generated from t-tests will 
compare the differences in the mean values between two treatment arms.  These analyses will be 
generated for any oxygenation support, and for invasive ventilation separately.  
Status of requiring respiratory support of each patient, including durations of any respiratory 
support (by type) will be listed. 
 Sensitivity analysis 
To evaluating the sensitivity and robustness of the primary analyses using the MITT population, 
the above analyses may be repeated in the ITT and PP Populations.  Baseline factors, including 
demographics, disease characteristics, medical history, concomitant medication may be repeated 
for each analysis population.  See Section 7.4 for further discussion on analyses populations. 
 Subgroup analysis 
For the purpose of evaluating the sensitivity and robustness of the primary analyses, subgroup 
analyses including, but not limited to, the following subgroups may be performed: 
• Age 
• Gender 
• Race 


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• Investigational sites 
• COVID-19 standard of care treatments received: 
o systemic steroids such as dexamethosone 
o remdesivir 
Baseline factors, including demographics, disease characteristics, medical history, concomitant 
medication may be repeated for each subgroup evaluated.  If warranted, safety analysis may be 
repeated across subgroups. 
7.11.2 Secondary Efficacy Evaluations 
For secondary efficacy measures. the main timepoints of interest for analyses are baseline, Days 
6, 14, 28, where data is available, unless otherwise specified.   
 Change in Ordinal Scale 
Ordinal scale will be assessed at the Screening/Baseline, during the 5 days of treatment 
administration, and at any days where the patients are hospitalized through Day 28 and at Day 
90. Baseline for the following analyses is defined as the last ordinal scale prior to administration 
of study drug. The number of patients with an improvement in the ordinal scale, defined as a 
change from baseline of ≥ 2 points, will be tabulated. 
A MMRM model will be used to evaluate the change in ordinal scale, in which the change of 
ordinal scale from baseline on each timepoint of interest will be included as dependent variable 
and treatment, timepoint (categorical), and treatment-by-timepoint as fixed effects, patient as 
random effect, and the baseline value as a continuous covariate. An unstructured covariance 
matrix will be used for the MMRM analysis, unless the model does not converge, in which case 
the compound symmetry will be used. 
Descriptive statistics for the overall treatment effect based on the MMRM model will include the 
least-squares (LS) mean difference, LS mean change from baseline for each treatment arm, their 
corresponding 95% CIs, and the p-values associated with the treatment difference compared to 
SOC. In addition, LS Means for the treatment differences at each timepoint of interest between 
treatment arms may also be provided with the same set of statistics derived from the same 
MMRM model defined above based on the MMRM estimates.  


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Additionally, the non-model based descriptive statistics for the corresponding change from baseline 
(overall) in the ordinal scale at each visit or timepoint of interest, change from baseline and 
maximum change from baseline will be evaluated and summarized by treatment arm.  Except as 
noted in Section 7.1.1, unscheduled records will be excluded from the summaries at specific 
timepoints but will be included in the maximum change from baseline. 
All available values of the ordinal scale, including change from baseline and maximum change 
from baseline will be listed by arm and patient.  Refer to Appendix C of the Study Protocol for 
the ordinal scale categories. 
 Mortality 
Survival status will be collected up to Day 90 +/- 30 days. Death is considered as an event. All 
the mortality events and cause of death will be listed by treatment arm and by patient.  
Patients who did not experience death within the first 90 days will be censored on the date of 
Day 90 visit or the date of last contact from the study which ever is earlier.   
The number of patients who died and survival time will be summarized by treatment arm. 
Survival time will also be listed by patient. The probability function of death will be estimated 
by Kaplan-Meier method. The median time and its 95% confidence interval for each group will 
be reported. Cumulative progression rates estimated by the KM method for up to day 6, 14, 28, 
90 and the 95% confidence intervals will be reported.  
The hazard ratio will be estimated by the Cox proportional hazards model with treatment arm as 
a covariate in the model.  Relevant hazard rates, hazard ratio between treatment arms and 
associated p-values will be tabulated. 
 Time to Improvement in Oxygenation 
The secondary endpoint of time to improvement in oxygenation will be assessed in terms of the 
analysis in oxygenation parameters by visit.  That is, evaluation of an improvement in 
oxygenation parameters will be assessed on the basis of the change from baseline analysis at the 
study timepoints of interest. 


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Oxygenation parameters including PaO2/FiO2 ratio, SpO2/ FiO2 ratio and P(A-a)O2 gradient 
(alveolar-arterial) will be measured at the Screening visit, any days the patient is hospitalized 
(and where data is available) from Day 1 through Day 28 and at Day 90.  On days where arterial 
blood gas test data is not available, PaO2 may be estimated using pulse oximetry when required 
for calculating the PaO2/FiO2 ratio.  
Oxygen saturation (SpO2), SpO2/FiO2 ratio, and PaO2/FiO2 ratio will be summarized, along with 
the change from baseline and percentage change from baseline, and at all available study visits 
during Days 1-6, Day 14, Day 28, and Day 90 (where available).  See Sections 7.1.2, 7.1.3, and 
7.1.4 for algorithm on determining assessments to be used for analysis. 
Percentage change from baseline is defined as: 
Percentage Change from Baseline= Change from Baseline/ Baseline 
For the percent change from baseline in these parameters, deterioration is defined as a negative 
percent change from baseline, while improvement is a positive percent change from baseline. 
Change in PaO2/FiO2 ratio will also be presented by waterfall plot.  
 Nosocomial Infections 
A listing of nosocomial infections identified through adverse events will be produced.  
 Hospitalization 
The duration of hospitalization (days) is defined as:  
Duration of hospitalization (Days) = Date of Discharge – Date of Randomization + 1.  In this 
context, the date of hospital discharge is the earliest hospitalization discharge date on/after the 
treatment completion/discontinuation date from the Treatment Disposition CRF page.  Moving a 
patient from ICU to a regular hospital ward, would not be considered as a hospital discharge 
date, in this case. 
However, duration of ICU (days) = Date of ICU Discharge – Date of ICU admission + 1.  In this 
context, moving a patient from ICU to a regular hospital ward, would be considered as ICU 
discharge date.  


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For patients who died in hospital prior to Day 28, alternative methods to account for these cases, 
such as assigning the duration of hospitalization as 28 days, may be considered. 
Duration of hospitalization will be listed for each patient, and summarized by treatment arm.  
 Normalization of WBC and Lymphocytes 
White Blood Cell (WBC) count and lymphocytes counts will be performed at the Screening visit 
and any days the patient is hospitalized from Day 1 through Day 28  and at Day 90.  
Normalization of WBC and lymphocyte count is defined as whether WBC and lymphocyte count 
results are normal or below normal or above normal ranges at available visits. A summary table 
and listing will be generated for normalization of WBC and lymphocytes. 
7.11.3 Exploratory Efficacy Evaluations 
For exploratory efficacy measures. the main timepoints of interest for analyses are baseline, 
Days 6, 14, 28, where data are available, unless otherwise specified.   
 National Early Warning Score (NEWS-2) 
The calculated total National Early Warning Score (NEWS-2) (See the scoring in Appendix D of 
the Study Protocol) will be summarized by treatment arm for each available timepoint of interest 
using descriptive analyses. Individual measures and overall score will be provided in patient data 
listing. 
 Sequential Organ Failure Assessment (SOFA) 
Sequential Organ Failure Assessment (SOFA) are based on six different scores, including 
respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. The overall 
calculated SOFA score will be summarized by treatment arm for each available timepoint.  
Individual SOFA scores and its components such as the Glasgow Coma Score will be provided 
in a patient data listing. 
The Glasgow Coma Score and the SOFA Scores are defined in Appendices A and B of the Study 
Protocol, respectively. 
 ROX Index 
The ROX Index assessment is described in Appendix E of the Study Protocol.  


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ROX Index calculation = SpO₂/FiO₂ ratio/ Respiratory rate (breaths/min).  
The ROX Index will be summarized by treatment arm .  The ROX Index Score and its 
components will be listing by patient. 
 ARDS progression and Changes on Chest X-ray or CT 
The exploratory endpoints of progression to ARDS and changes on chest x-ray or CT will be 
evaluated in terms of determining ARDS progression. 
Chest X-ray or CT may be performed at the Screening visit, Treatment period Days 1-5, Post-
treatment period at Day 6 or day of discharge (whichever is earlier), Days 7-27 (or until hospital 
discharge), Day 28, and Day 90.  
Percentage of patients in whom ARDS or ARDS progression is documented post-baseline will 
be summarized.  Potential available data sources for the diagnosis of ARDS/ARDS progression 
include adverse events, physical examination findings, imaging studies such as Chest X-ray, CT, 
treatment or study discontinuation reasons, etc. 
7.12 Safety Evaluations 
Safety assessments will include monitoring of available assessments of vital signs, adverse 
events (AEs), clinical laboratory tests, and physical examinations. The main analysis period would 
be the Treatment Emergent period which is defined as the period from the date of the first dose until 
the end of earliest of the following 1) date of Study Day 58 for AEs and date of Study Day 90 for the 
rest; or 2) date of early discontinuation from study; or 3) data cutoff date. This analysis period will be 
used for all treatment emergent adverse event, laboratory evaluations. However, serious adverse 
events analysis will include all the serious adverse events collected after the first dose. 
Safety variables will be tabulated and presented for all patients in the Safety Population.  
7.12.1 Adverse Event 
All adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 23.0 (or later). Adverse events will be categorized as prior events, treatment emergent 
adverse events, and post treatment adverse events: 


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• Prior Events includes all adverse events with a start date before the first dose of the study 
drug regardless of the end date.  
• Treatment-emergent adverse events (TEAE) are defined as adverse events with a start 
date (or date of worsening) on or after the first dose of the study drug and no later than 
the earliest of the following 1) the date for the Day 58; 2) date of early discontinuation 
from study, or 3) data cutoff date.  
• All adverse event started after study day 58 will be considered post-treatment. 
All TEAE will be summarized by  treatment arm and presented by: 
1) system organ classification and preferred term (PT);  
2) PT;  
3) system organ classification, PT and the maximum severity.  
Treatment-related TEAE, serious TEAE and treatment-related serious TEAE will be summarized 
by MedDRA System Organ Class and PT , and the maximum severity. SAEs and deaths will be 
listed by patient. 
For patients at sites where Aerogen devices were supplied by PTX, the following analyses will 
be performed: 
• All device-related TEAEs will be summarized by treatment arm; 
• All device-related TE-SAEs will be summarized by treatment arm; 
• All device-related AEs will be listed by patient. 
The frequency of treatment-emergent serious adverse events (TESAEs) will be summarized by 
arm, SOC, and preferred term.  Severity (using CTCAE) and relationship of TEAEs to treatment 
(sargramostim, sargramostim inhalation device or standard of care) will be analyzed as recorded 
on eCRF  (also refer to Section 8 of the Study Protocol for definitions).  
Clinically significant adverse drug reactions (ADRs) are treatment-emergent drug-related AEs 
and SAEs (as discussed above). 
If a patient experiences more than one TEAE within a preferred term, the patient will be counted 
only once in the calculation of incidence of TEAE within that preferred term. Similarly, if a 


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patient experiences more than one TEAE within a system organ class, the patient will be counted 
only once in the calculation of incidence of TEAE within that system organ class. If a patient 
experiences more than one TEAE within a preferred term (or system organ class), the occurrence 
with the highest severity will be used in the calculation of the incidence of TEAE within that 
preferred term (or system organ class) with regards to severity. If a patient experiences more than 
one TEAE within a preferred term (or system organ class), the occurrence considered most 
closely related to study drug will be used in the calculation of the incidence of TEAE with that 
preferred term (or system organ class) with regards to relationship . 
Data listings for all AEs, and for serious AEs, will be provided with flags for TEAE, relatedness 
and CTCAE severity. 
7.12.2 Laboratory data 
Laboratory data, as performed and collected as part of SOC in both arms (see Section 10 in the 
Study Protocol), 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-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 
Descriptive statistics for baseline value, actual value at a given visit, and change from baseline to 
each scheduled postbaseline visit will be provided by arm for the clinical hematology, chemistry 
laboratory, ferritin, d-dimer, CRP, and immune profiling (where available) tests described above.  
In addition, the neutrophil/lymphocyte ratio will also be summarized and listed. Baseline for 
these tests is defined as the last assessment prior to administration of study drug (see Section 
7.1.2). Conventional Units will be used for reporting the laboratory test results.  


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Serum pregnancy test results will be listed. Values for any chemistry, hematology, ferritin, d-
dimer, CRP, and immune profiling values outside the clinical reference ranges (where available) 
will be flagged on the individual patient data listings.  
7.12.3 Physical Examination 
Physical examination findings will be listed by arm and patient. 
7.12.4 Vital Signs 
Vital signs (including temperature, respiratory rate, and blood pressure and pulse) will be 
measured during the Screening visit, Treatment period Days 1-5, Post-treatment period at Day 6 
or day of discharge (whichever is earlier), Day 28, and Day 90.  
Baseline for vital signs is defined as the last assessment prior to administration of study drug (see 
Section 7.1.2).  
All vital sign data including unscheduled records will be listed. Unscheduled records will be 
excluded from the summary statistics. Vital sign data including baseline value, actual value at a 
given visit, and change from baseline to each post-baseline visit will be summarized by arm and 
timepoint. 
7.12.5 Electrocardiogram (ECG) 
Electrocardiogram examination findings for ECGs will be listed by arm and patient for each 
ECG parameter.  
7.12.6 Patient Profiles 
Key lab parameters for patients with SAEs, discontinuation due to AE, and deaths will be 
presented in patient profiles, in which the demographics and treatment data will be included. 
Additional profiles may be generated for any identified suspected unexpected serious adverse 
reactions (SUSARs). 


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8 Data Presentation 
8.1  Insufficient Data for Presentation 
Some of the TFLs may not have sufficient numbers of patients or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the table, such as, “None 
reported”. 
9 Revision History 
10  Reference