Clinical trial NCT04555096
Conditions: Covid19 SARS-CoV-2 Infection
Keywords: COVID19 SARS-CoV-2 Infection
Sponsor: Galera Therapeutics, Inc.
Start date: 2020-09-09; Completion date: 2021-05-28
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Trial of GC4419 in Patients with Critical Illness due to COVID-19

Detailed description:

Arms: arm 1: Arm A arm 2: Arm B
Interventions: intervention 1: GC4419 intervention 2: Placebo
Intervention descriptions: intervention 1: 180 Minute IV Infusion intervention 2: 180 Minute IV Infusion

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
A Pilot, Randomized, Placebo-Controlled Trial of GC4419 
(avasopasem manganese) in Patients with Critical Illness 
Due to SARS-CoV-2 Infection (COVID-19)  
 
 
Sponsor: 
Galera Therapeutics, Inc. 
 
 
IND Number: 
150,065 
 
 
Protocol ID: 
COV-4419-201 
 
 
Medical Monitor: 
Jon T. Holmlund, MD 
 
Protocol Version/Date: 
Version 5.0/08 March 2021 
 
CONFIDENTIAL INFORMATION 
The information contained in this document is proprietary to Galera Therapeutics, Inc. 
The information is to be used only in connection with review of, or participation in, 
authorized clinical studies of the investigational drug described in the protocol. 
Disclosure of the information to others not under obligations to maintain this information 
in confidence is prohibited without written authorization from Galera Therapeutics, Inc. 
with the exception that, to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered, a general protocol description may be 
disclosed to such potential subjects. 
 
 


Clinical Study Protocol COV-4419-201 
 
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        Version 5.0; 08 March 2021 
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STUDY ACKNOWLEDGEMENT 
 
Study Title:  A Pilot, Randomized, Placebo-Controlled Trial of GC4419 (avasopasem 
manganese) in Patients with Critical Illness Due to SARS-CoV-2 Infection (COVID-19)   
 
Protocol No.  COV-4419-201  
 
 
 
 
 
 
 
Protocol Date:  08 March 2021 
This protocol has been approved by Galera Therapeutics, Inc. The following signature documents 
this approval. 
 
 
 
 
Investigator Statement 
I have read the attached protocol and appendices and agree to abide by all provisions set forth 
therein. I will provide copies of the protocol and other pertinent information to all individuals 
responsible to me who will assist with the study. 
I agree to comply with the International Conference on Harmonisation, Tripartite Guideline on Good 
Clinical Practice (ICH, GCP) and applicable global and local government regulations/guidelines 
including 21 Code of Federal Regulations (CFR) Parts 11, 50, 54, 56, and 312.   
I agree to ensure that Financial Disclosure Statements will be completed before study initiation, 
during the studies if there are changes that affect my financial disclosure status, and one year after 
study completion by: 
 myself (including, if applicable, my spouse [or legal partner] and dependent children) 
 my sub-investigators (including, if applicable, their spouses [or legal partners] and dependent 
children) 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of Galera Therapeutics. 
The Sponsor or its designee will have access to source documentation from which case report forms 
have been completed. 
 
__________________________________ 
__________________________ 
Signature of Principal Investigator 
Date (DD Month YYYY) 
 
__________________________________ 
Printed Name of Principal Investigator 
 
Jon T. Holmlund, MD 
Chief Medical Officer 
Galera Therapeutics, Inc. 


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REVISION HISTORY 
Revisions to Version 4.0 dated 08 February 2021 
Summary of Change  
Rationale  
Affected Protocol Sections 
Added statement that study drug 
infusions should not begin if the 
subject’s mean arterial pressure 
(MAP) is less than 65 mmHg 
DMC recommendation 
 
Synopsis 
 
Section 9.2 
 
Section 10.2.2 
 
Appendix 1 
Added clarification to SAE 
reporting 
To provide sites with further 
guidance on SAE reporting 
for this patient population 
 
Section 10.5.1 
Revisions to Version 3.0 dated 30 June 2020 
Summary of Change  
Rationale  
Affected Protocol Sections 
Updated estimated enrollment 
period and studied period 
To be accurate with current 
study status 
 
Synopsis 
Updated Inclusion Criteria #1 to 
allow sites to use their standard of 
care testing method for SARS-
CoV-2 Infection 
To be consistent with site’s 
standard practice 
 
Synopsis 
 
Section 7.1 
Revised Inclusion Criteria #3 to 
require FiO2  of >/= 50%  instead of 
>/= 60% 
To allow inclusion of 
additional subjects who still 
will fit the critically ill patient 
population 
 
Synopsis 
 
Section 7.1 
Added clarification to Exclusion 
Criteria #7 and prohibited 
medication section regarding 
subject participation in concurrent 
clinical trials 
To provide additional 
guidance to sites on subject 
inclusion 
 
Synopsis 
 
Section 7.2 
 
Section 8.2 
Added window of +/- 2 hours for 
study drug dosing 
To provide additional 
guidance for subject dosing  
 
Synopsis 
 
Section 6.1 
 
Section 6.2 
 
Section 10.2.2 
 
Appendix 1 
Revised CYP2D6 requirements and 
removed from prohibited 
medications 
To allow investigators to use 
their judgement in the use of 
these medications 
 
Synopsis 
 
Section 8.1 
 
Section 8.2 
Revised to require direct bilirubin, 
CRP, and triglycerides at baseline 
only unless clinically indicated. 
To be consistent with site’s 
standard practice 
 
Section 10.1.2 
 
Appendix 1 
Revised to require SOFA score only 
while subjects are in the ICU. 
To align with standard 
practice 
 
Synopsis 
 
Section 10.2.3 
 
Appendix 1 
Added language around timing of 
first two doses 
To provide additional 
guidance for subject dosing 
 
Appendix 1 
Revised to require 
Hematology/Chemistry samples 
To be consistent with site’s 
standard practice 
 
Appendix 1 


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Summary of Change  
Rationale  
Affected Protocol Sections 
after completion of treatment only 
if clinically indicated. 
Clarified PK collection timepoints 
To emphasize samples only 
need to be collected pre/post 
first infusion on Days 1 and 3 
 
Appendix 1 
Added language to allow post-
discharge follow-up visits to be 
done remotely (virtual/phone). 
To provide flexibility to study 
subjects depending on their 
post discharge status. 
 
Appendix 1 
Updated Schedule of Assessments: 
- 
to specify that Apache IV 
score only needs to be done 
once at screening/baseline 
and the worst value in the 
past 24 hours should be 
recorded. 
- 
to remove the collection of 
daily fluid balance after 
treatment discontinuation 
- 
to specify that if multiple 
labs are done in one day, 
the worst value should be 
recorded. 
- 
to revise requirement of 
viral load testing to 
screening/baseline, Day 7, 
and Day 14 
- 
to revise requirement of 
cytokine blood draw to 
screening/baseline, Day 7, 
and Day 14 
- 
to revise “each additional 
day in hospital” to “each 
additional day in ICU” 
- 
to revise “after discharge 
from hospital” to “after 
discharge from ICU” 
To provide additional 
guidance to sites 
 
Appendix 1 
Other editorial changes have been 
made throughout 
To correct administrative 
errors and ensure content 
accuracy and consistency. 
 
Throughout 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: 
Galera Therapeutics, Inc. 
Name of Investigational Product: 
GC4419 
Name of Active Ingredient: 
avasopasem manganese 
Title of Study:  
A Pilot, Randomized, Placebo-Controlled Trial of GC4419 (avasopasem manganese) in 
Patients with Critical Illness Due to SARS-CoV-2 Infection (COVID-19) 
Number of Study Center(s): up to 10  
Estimated Enrollment Period:  9-12 months 
Studied period:  
First patient enrolled:  September 2020 
Estimated date last patient completed assessment for 
primary endpoint:  September 2021 
Phase of development: 2 
 
Background:   
SARS-CoV-2/COVID-19: Approximately 20% of people with confirmed, symptomatic 
COVID-19 disease, due to infection with the SARS-CoV-2 virus, will develop viral 
pneumonia requiring hospitalization.  These patients exhibit respiratory compromise that can 
be characterized as severe (demonstrating dyspnea, hypoxia, and/or extensive lung opacities 
on chest x-ray); or critical, with respiratory failure, which may be accompanied by shock or 
multiorgan dysfunction).  Approximately 25% of hospitalized patients, comprising 
approximately 5% of all patients with symptomatic infection, will have critical disease as 
described herein.  Critical disease often manifests as a clinical picture consistent with the 
acute respiratory distress syndrome (ARDS), although information is still being obtained 
regarding the pathophysiology and pathophysiology of pulmonary compromise associated 
with SARS-CoV-2, compared with ARDS related to other causes.  Retrospective series 
suggest that, after a variable initial course of disease, dyspnea begins approximately 6-7 days 
after the first symptoms of infection, with swift progression to frank respiratory 
failure/ARDS 2-3 days thereafter.  Intensive care is often required for 14 days or more, and 
more than one attempt at ventilator weaning may be required before eventual extubation.  
Comorbidity among these critically ill patients includes renal, cardiac, and hepatic damage as 
well as hypotension requiring vasopressor treatment (Yang et al, 2020).   Mortality for 
critically ill patients, highest among the elderly or those with significant prior concomitant 
conditions, has been reported to be on the order of 50-60% (Yang et al, 2020; Wu et al 2020).  
The IHME has recently projected that, assuming full social distancing throughout the United 
States through May 2020, nationwide needs for hospital beds and ICU beds will exceed 
national capacity (https://covid19.healthdata.org/projections, accessed 15 April 2020, 12 
noon EDT)  Further, pending effective treatments or vaccine(s), potential remains for 
recurrent waves of infection and the attendant needs for hospital resources.   


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The proximate cause of ARDS in COVID-19 disease appears to be an inflammatory 
response, including a cytokine "storm," complicating the initial infection and producing 
pneumonitis.  Such responses are accompanied by production of large amounts of superoxide 
by activated macrophages and neutrophils.  It is this superoxide free radical which both 
initiates and sustains the inflammation, and which is produced in amounts sufficient to 
overwhelm the normal capacity of endogenous superoxide dismutase (SOD) enzymes to 
remove it.  Similarly, superoxide is critical to the development of shock characterized by 
hypotension that is non-responsive to vasopressor (catecholamines such as norepinephrine) 
therapy.   In the latter case, superoxide deactivates endogenous catecholamines, reacting with 
them via a free radical autoxidation cascade producing toxic products called 
"adrenochromes" (Macarthur et al, 2000).  This process also results in hyporeactivity to 
exogenously-administered catecholamines, producing hypotension that is refractory to 
vasopressor treatment.   
Avasopasem manganese (avasopasem): Avasopasem manganese is a highly selective, small 
molecule (MW 483) mimetic of naturally occurring superoxide dismutase (SOD) enzyme, 
which, like native SOD, converts superoxide to hydrogen peroxide and molecular oxygen 
specifically and selectively, at an enzymatic rate comparable to that of the native SOD.  In 
disease states characterized by excessive superoxide production, administration of 
avasopasem replaces or augments deficient or insufficient endogenous SOD capacity.  
Accordingly, avasopasem and related active dismutase mimetics have demonstrated ability to 
protect tissues from superoxide-mediated damage in laboratory studies and in the clinic.  
Results from in vivo models include: reduced zymosan-induced lung neutrophil infiltration, 
lipid peroxidation and lung injury, and mortality (Cuzzocrea et al, 2004); in the bleomycin 
intratracheal mouse model, reduced lung inflammatory infiltrates and alveolar epithelial 
apoptosis (Herzog, 2014); in a chronic asthma guinea pig model, reduced neutrophil 
infiltrate, lipid peroxidation and alveolar epithelia apoptosis (Masini et al, 2005); and in a 
lung focal irradiation mouse model, reduced late stage pulmonary fibrosis (Sishc et al, 2018).  
Results from animal studies also include reduction of E. coli-induced hypotension, vascular 
hyporeactivity to catecholamines, and mortality in septic shock (Macarthur et al, 2003), and 
decreased  levels of proinflammatory cytokines such as TNFα, IL-1β and IL-6 (Cuzzocrea et 
al 2004; Macarthur et al, 2003),  with increase in the anti-inflammatory cytokine IL-10 
(Macarthur et al, 2003).  In these studies, dismutase mimetic was administered continuously 
or repeatedly over several hours after challenge with zymosan or E. coli (Cuzzocrea et al 
2004; Macarthur et al, 2003).  In a hamster model, avasopasem reduced severe oral mucositis 
(Sonis, unpublished data, GC4419 Investigator's Brochure), supporting clinical trials of 
GC4419 to reduce radiation-induced severe oral mucositis.   In Phase 1-2b clinical trials 
(Anderson et al 2018; Anderson et al 2019), GC4419 reduced the incidence, severity, and 
duration of severe oral mucositis produced from the superoxide generated due to concurrent 
chemoradiotherapy for head and neck cancer,  with an acceptable safety profile, and a 
confirmatory Phase 3 trial (NCT03689712) in this indication is underway under 
Breakthrough Therapy Designation from FDA.   
GC4419 has been safely administered to over 300 human subjects, with the Phase 3 oral 
mucositis trial testing 90 mg by 60-minute IV infusion, repeated each weekday, prior to 
standard radiotherapy, for 7 weeks—a total of up to 35 doses.  Toxicity attributable to 
GC4419 has been limited to transient, infusion-related mild hypotension and postural 
symptoms, and mild circumoral paresthesia, attributable to reversible potentiation of nitric 


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oxide.  These effects appear to be related to the Cmax (which occurs at the end of the IV 
infusion), and are further limited with lower doses or prolonged infusion time at a given dose, 
with mild orthostatic lightheadedness reported in 6 of 72 healthy volunteers who have 
received 27 mg of GC4419 over 60 minutes, and 5 of 34 healthy volunteers who received 30 
or 51 mg of GC4419 IV over 15 minutes.  Adverse events observed in the oral mucositis 
trials have been those observed with the underlying standard regimen of radiation therapy 
plus cisplatin, and in a placebo-controlled randomized Phase 2b trial, the adverse event 
profiles for subjects receiving GC4419 or placebo were similar.  
No effect on the QT interval was found in a precision QT clinical trial of GC4419 at a dose 
of 51 mg IV over 15 minutes, a dose and schedule at which Cmax exceeds that produced after 
a 90 mg/60-minute infusion of GC4419.   
Nonclinical GLP toxicology studies of avasopasem in rats and dogs have shown no abnormal 
histopathologic findings except for injection-site reactions after subcutaneous administration.  
These studies include 6-month chronic toxicology in rats (final report pending).  A 9-month 
chronic toxicology study in dogs is in progress in the in-life phase.  Results of GLP 
toxicological studies support dosing of GC4419 at a total daily dose of up to 198 mg for up to 
14 days. 
GC4419 has a plasma half-life of approximately 2 hours, reaching maximum concentration at 
the end of IV infusion and declining in a bi-exponential fashion thereafter.  Plasma exposure 
is approximately dose-proportional.  In past clinical trials, GC4419 has been quantifiable in 
plasma up to approximately 24 hours after a 60-minute IV infusion, with minimal 
accumulation in plasma with repeated daily dosing.  Non-clinical data indicate a longer half-
life of GC4419 in tissues, with rapid entry into cells related to Cmax and slower release from 
cells. 
GC4419 is eliminated by GI and renal routes.  Human volunteer studies of GC4419 in the 
setting of compromised renal or hepatic function are in progress.  There has been no apparent 
nephrotoxicity or hepatotoxicity of GC4419 in human clinical trials.  
Rationale for the present study: The pathogenesis of severe-to-critical pulmonary disease 
complicating SARS-CoV-2 infection—and, when it occurs, the pathogenesis of attendant 
shock—along with the mechanism and available nonclinical and clinical data with GC4419, 
suggest that GC4419 could attenuate or reduce the risk of ARDS and the need for mechanical 
ventilation, and attenuate shock, in people suffering from them due to SARS-CoV-2. 
The present study is intended as an initial assessment to confirm the safety of GC4419 in 
COVID-19 patients with critical respiratory illness.  Hospitalized subjects whose respiratory 
function has deteriorated to the point where mechanical ventilation is needed will be studied.  
Subjects will be randomized in a 1:1 ratio to receive either GC4419 or placebo plus standard 
supportive care.   
Upon review of results from this trial, future trials to treat COVID-19 patients with GC4419 
earlier in the course of disease—e.g., in the setting of worsening hypoxemia and increasing 
requirement for supplemental oxygen short of mechanical ventilation—may be considered. 
Objectives:  
Primary: 
 
To evaluate 28-day all-cause mortality/overall survival 


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Secondary (all through the same 28 days as for the primary endpoint): 
 
To evaluate the safety of avasopasem in the study population 
 
To evaluate the frequency of successful ventilator weaning 
 To evaluate the number days alive and intensive care-free  
 To evaluate the number of days alive and ventilator-free  
 To evaluate the number of days with minimum SpO2/FIO2 ratio or PaO2/FIO2 > 300  
 
To evaluate the number of days alive without vasopressor/catecholamine support 
 
To evaluate the incidence of mean arterial pressure < 65 mmHg on optimized 
vasopressor therapy 
 
To evaluate the number of days alive with a SOFA score of 6 or less 
 
To evaluate the percentage of subjects with an increase in mean arterial pressure of 
10 mm Hg or more at the end of more than one infusion of GC4419 
Exploratory: 
 
To assess levels of circulating cytokines IL-6, TNF-alpha, IL-1 beta, IL-10 
 
SARS-CoV-2 viral load by PCR testing for viral RNA 
 
To assess the plasma exposure to GC4419 in the study subjects 
Methodology:  
COV-4419-201 will be a randomized study to evaluate GC4419 administered IV to subjects 
with confirmed SARS-CoV-2 infection and critical pulmonary disease.   
To help ensure balanced randomization, subjects will be stratified at randomization for age < 
60 years vs >=60 years 
All subjects will receive standard supportive care according to the policies of the treating 
institution. 
Subjects will be randomized in a 1:1 ratio to receive either: 
 GC4419 by IV infusion q 12 hours (+/- 2 hours) for 7 days, plus standard supportive 
care, or 
 Placebo by IV infusion q 12 hours (+/- 2 hours) for 7 days, plus standard supportive 
care  
Rationale for GC4419 dosing plan: 
 Extensive clinical experience in cancer patients supports the safety of 90 mg of 
GC4419 administered over 60 minutes for 35 doses (M-F, up to 7 weeks) 
concurrently with chemoradiotherapy. 
 Cmax-related transient mild hypotension and orthostasis has been observed at the 
current 90 mg/60-minute infusion schedule, but this is less frequent with lower doses. 
 Therefore, administering 90 mg of GC4419 IV over 180 minutes (3 hours) is 
expected to provide an additional margin of safety. 
 The plasma half-life of GC4419 is approximately 2 hours. 
 Pharmacokinetic results to date do not indicate significant plasma accumulation of 
GC4419 with repeated dosing. 


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 Results of GLP animal toxicology studies support a total daily dose of GC4419 up to 
198 mg, administered for up to 14 days (compared with planned 7 days in the current 
study).  
 Administration of a related dismutase mimetic to rats in the zymosan and E. coli 
sepsis models was performed over a period of several hours after challenge with 
zymosan or E. coli.  Moreover, the persistent superoxide production is expected to be 
associated with the ongoing COVID-19 disease process.  Accordingly, a dosing 
schedule that maintains extracellular concentrations of GC4419 as much as possible 
and feasible may be desirable.   
In light of the above, subjects will receive, in a blinded fashion, either GC4419, 90 mg 
intravenously, or placebo, administered over 3 hours (180 minutes), repeated every 12 hours 
(+/- 2 hours) for 7 consecutive days.    
Subjects requiring renal dialysis should not have that procedure performed at any time during 
GC4419/placebo infusion and until at least 2 hours after infusion.  If continuous renal 
replacement therapy is required for >24 hours, dosing with blinded GC4419/placebo will be 
discontinued. 
Adverse Events and Serious Adverse Events will be assessed daily during dosing of 
GC4419/placebo, then daily during hospitalization and weekly after hospital discharge, for a 
total of 30 days after the last dose of GC4419/placebo.  Post-dosing AE assessment may be 
done on an outpatient basis for subjects who are discharged from the hospital.   
Ongoing safety results will be monitored by an independent Data Monitoring Committee 
(DMC) that will operate under a specific DMC charter separate from this protocol document.   
Number of patients (planned):  
Approximately 50 subjects, 25 receiving GC4419 and 25 receiving placebo.       
Diagnosis and main criteria for inclusion:  
Inclusion Criteria:  
1. Laboratory-confirmed SARS-CoV-2 infection as determined by a positive PCR test 
documented prior to randomization: 
a. Performed on a swab sample from the nasopharynx of a non-intubated subject or 
pulmonary secretions from an intubated subject per site’s standard practice 
b. Analyzed by a commercial, local, or public health laboratory 
c. A duplicate swab will be retained for subsequent confirmation at a Central 
Laboratory 
2. Requirement for intensive inpatient hospital care 
3. Acute hypoxemic respiratory failure typifying ARDS, as indicated by: 
a. PaO2/FiO2 ratio < 300 mm Hg, or SpO2 < 94% on FiO2 >/= 50% with bilateral 
pulmonary infiltrates along with respiratory distress and increased work of breathing 
requiring intubation and invasive mechanical ventilation, OR 
b. Non-invasive mechanical ventilation with SpO2 < 94% on FiO2 >/= 50% 
4. Adequate liver function as indicated by: 
a. Total bilirubin ≤ 1.5 x upper-normal limit (ULN) 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN 
5. Age 18 years or older 


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6. Serum or urine pregnancy test negative for females of childbearing potential 
7. Properly obtained informed consent obtained from subject or legally authorized 
representative 
Exclusion Criteria: 
1. Expected survival for less than 48 hours after randomization 
2. Child-Pugh stage C hepatic impairment and/or portal hypertension secondary to 
cirrhosis 
3. Stage IV chronic kidney disease or end-stage kidney disease on maintenance 
hemodialysis 
4. Requirement for extra-corporeal membrane oxygenation (ECMO) 
5. Acute Myocardial Infarction (AMI) 
6. Active bleeding requiring transfusion 
7. Concurrent participation in another clinical trial of experimental treatment for SARS-
CoV-2 
Note: Concurrent participation in any study of an approved treatment, or a product 
with Emergency Use Authorization for COVID treatment, is permitted if the Principal 
Investigator attests that the mechanism of the EUA product is not expected to 
interfere with the mechanism of GC4419 and that completion of study requirements 
for this protocol will not be compromised 
8. Female patients who are pregnant or breastfeeding 
9. Requirement for concurrent treatment with nitrates  
Investigational product, dosage and mode of administration:  
GC4419 (avasopasem manganese) is formulated as a clear solution at a concentration of 9 
mg/mL in 26 mM sodium bicarbonate-buffered 0.9 wt. % saline for parenteral administration 
(drug product).  GC4419 will be presented in single use vials.  Vials will be filled with 11 
mL of GC4419, of which 10 mL will be added to 170 mL of normal saline, for IV 
administration over 180 minutes every 12 hours (+/- 2 hours) for 7 consecutive days.   
Duration of treatment:  
Seven (7) days. 
Reference therapy, dosage and mode of administration:  
Placebo will be normal saline and will obtained from site stock.  
Placebo, 180 mL, will be administered in blinded fashion via IV administration over 180 
minutes every 12 hours (+/- 2 hours) for 7 consecutive days.  
Clinical Laboratory Assessment: Local clinical laboratories will be used for standard 
clinical laboratory assessment.  A reference laboratory will be designated for exploratory 
laboratory endpoints. 
Criteria for evaluation: 
 
Adverse Events and Serious Adverse Events—MedDRA classification 


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 Clinical observation of ON or OFF ventilator 
 Clinical observation: IN intensive care unit or NOT 
 Minimum SpO2/FIO2 ratio or PaO2/FIO2—recorded once per 24-hour period 
(midnight to midnight) 
 Clinical observation of ON or OFF vasopressors in any 24-hour period (midnight to 
midnight) 
 
Standard clinical evaluations of oxygenation and blood pressure 
o Mean arterial pressure  
o SpO2/FIO2 ratio or PaO2/FIO2 as clinically applicable 
 
Standard ventilatory parameters 
 
Sequential Organ Failure Assessment (SOFA) score (in ICU only) 
 
Apache IV score (at baseline only) 
 
Daily fluid balance 
 
Hematology and serum chemistry per standard of care 
 
The following assessments will be performed specifically for this research: 
 
Circulating cytokine levels: IL-6, IL-1beta, TNF-alpha, IL-10 
 
Quantitative PCR for viral load 
 
Safety Monitoring and Toxicity Management: 
Adverse/Serious Adverse Event assessments per GCP standards.  Severity of events will be 
graded according to the NCI-CTCAE v 5.0.   
For any given subject, study drug infusions should not begin if the subject’s mean arterial 
pressure (MAP) is less than 65 mmHg. 
For any given subject, hold blinded GC4419/placebo and reduce by 25% (from the initial 
dose) for all future infusions if: 
 During infusion or within 1 hour of completing infusion, the subject experiences an 
acute decrease in systolic blood pressure requiring bolus fluid resuscitation OR 
requiring initiation of vasopressor therapy OR increased vasopressor therapy. Hold 
GC4419/placebo until the dose of vasopressor therapy is stable and bolus fluid 
resuscitation is not required. 
 The subject develops serum creatinine > 5 mg/dL. Hold GC4419/placebo until the 
creatinine is =<5 mg/dL. 
 The subject develops serum total bilirubin > 6 mg/dL, or AST or ALT >10 times 
upper limit of normal.  Hold GC4419/placebo until the parameters in question are 
below these levels. 
 The subject experiences a serious or severe adverse event considered by the 
investigator to be related or possibly related to blinded GC4419/placebo. Hold 
GC4419/placebo until the event is no longer serious or severe. 
Up to two such dose reductions for a cumulative 50% from the initial dose of 
GC4419/placebo will be permitted for a given subject.  If a subject cannot tolerate 
GC4419/placebo infusion after a 50% dose reduction, all dosing with GC4419/placebo for 
that subject will be discontinued. 


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Patients unable to tolerate GC4419/placebo must discontinue treatment with GC4419/placebo 
but should continue with other protocol assessments at the discretion of the treating 
investigator and with the ongoing consent of the subject.   
An independent Data Monitoring Committee (DMC) will monitor ongoing safety results.  
The DMC will promptly receive all reports of Serious Adverse Events (SAEs).  The DMC 
will also be convened for review of available safety data after 20 subjects have completed 
blinded dosing of GC4419/placebo, and may convene other meetings at its discretion.  If 
upon review the DMC finds that more than 20% of experimental arm subjects require that 
GC4419 be discontinued according to the rules in this section, OR if the DMC finds an 
increase in serious or severe adverse events sufficient to constitute an unacceptable safety 
risk associated with GC4419, all dosing of GC4419/placebo for subjects on study will be 
discontinued, enrollment to the study will be terminated, and data reviewed with FDA prior 
to the sponsor considering additional dosing with GC4419 in this patient population.   
Concomitant Medications/Treatments: 
Investigators may prescribe any concomitant medication or supportive therapy deemed 
medically indicated for the care of the subject, with exception of the following prohibited 
medications/treatments:   
 
Nitrates, phosphodiesterase type 5 (PDE 5) inhibitors (e.g., sildenafil, tadalafil, or 
similar agents) or other concomitant drugs that in the judgment of the treating 
investigator could create a risk of a precipitous decrease in blood pressure are 
prohibited until at least 24 hours after the last dose of blinded GC4419/placebo.  
 
Concurrent participation in a clinical trial of investigational therapy for SARS-CoV-
2.   
o Other approved or unapproved agents for SARS-CoV-2, including drug or 
biologic therapy including immunomodulatory treatments, administered 
on an expanded access, compassionate care, off-label, or emergency 
access basis may be administered.  Use as part of another, concurrent 
clinical trial may be considered provided the site principal investigator 
determines that the mechanism of the other treatment is not expected to 
interfere with the mechanism of GC4419, and that completion of study 
requirements for this protocol will not be compromised.   
o Examples of acceptable concurrent medications under this provision 
include remdesivir, hydroxychloroquine (alone or with azithromycin) 
convalescent plasma, and other drug or biologic treatments for SARS-
CoV-2 as long as not part of a clinical trial other than the present trial. 
Statistical considerations: 
For this group with critical disease, the null hypothesis is that 50% of subjects will survive 
for 28 days.  The alternative hypothesis is that at least 90% of subjects receiving GC4419 
will survive for 28 days compared with the control survival of 50%.   A sample size of 50 
subjects, 25 in each group, is expected to provide approximately 80% power to detect this 
difference with a two-sided alpha of 0.05.      


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Subjects' treatment assignment will be stratified at randomization for age < 60 years vs ≥ 60 
years.    
The primary endpoint of 28-day mortality will be compared between the GC4419 and control 
group using an exact Cochran-Mantel-Haenszel (CMH) test stratified by age group (<60 vs 
≥60 years) at the two-sided 0.05 Type I error rate. The measure of association will be the 
CMH stratified relative risk of death by Day 28 along with an asymptotic 95% exact 
confidence interval. Secondary endpoints will be analyzed descriptively, and results 
tabulated.  As appropriate, percentages and 95% confidence intervals will be calculated. 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
CLINICAL STUDY PROTOCOL ..................................................................................................1 
1. 
SYNOPSIS ...............................................................................................................................5 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...........................14 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.........................................17 
4. 
INTRODUCTION ..................................................................................................................18 
4.1. 
Background ........................................................................................................................18 
4.1.1. 
COVID-19 and Associated Respiratory Disease .........................................................18 
4.1.2. 
Superoxide and Superoxide Dismutase Mimetics in Viral Pneumonia, ARDS 
and Septic Shock .........................................................................................................18 
4.1.3 
Dismutase Mimetic Nonclinical Pharmacology and Mechanism of Action ................20 
4.2. 
Avasopasem Manganese (GC4419) ...................................................................................22 
4.3. 
Rationale for the Present Trial ...........................................................................................24 
5. 
TRIAL OBJECTIVES AND PURPOSE ................................................................................26 
5.1. 
Primary Objective ..............................................................................................................26 
5.1.1. 
Rationale for Primary Endpoint Selection ...................................................................26 
5.2. 
Secondary Objectives.........................................................................................................26 
5.3. 
Exploratory Objectives ......................................................................................................26 
6. 
INVESTIGATIONAL PLAN .................................................................................................27 
6.1. 
Overall Study Design .........................................................................................................27 
6.2. 
Treatment Plan and Duration of Therapy ..........................................................................27 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..........................................................29 
7.1. 
Subject Inclusion Criteria ..................................................................................................29 
7.2. 
Subject Exclusion Criteria .................................................................................................29 
7.3. 
Rationale for Patient Population ........................................................................................30 
7.4. 
Screen Failures ...................................................................................................................30 
7.5. 
Subject Withdrawal Criteria ..............................................................................................30 
7.6. 
Study and Site Closure .......................................................................................................31 
8. 
INVESTIGATIONAL PRODUCT AND TREATMENT OF SUBJECTS ...........................32 
8.1. 
Concomitant Medications ..................................................................................................32 
8.1.1. 
Drug Interactions .........................................................................................................32 
8.2. 
Prohibited Medications ......................................................................................................32 
8.3. 
Description of Study Drug GC4419 ..................................................................................33 
8.3.1. 
GC4419 Drug Packaging and Labeling .......................................................................33 
8.3.2. 
Placebo Packaging and Labeling .................................................................................33 
8.3.3. 
Study Drug Storage ......................................................................................................34 
8.3.4. 
Study Drug Preparation................................................................................................34 
8.3.5. 
Administration .............................................................................................................34 
8.3.6. 
Accountability and Compliance ...................................................................................34 


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8.3.7. 
Study Drug Handling and Disposal .............................................................................35 
9. 
TOXICITY MANAGEMENT ................................................................................................36 
9.1. 
Anticipated toxicities of GC4419 ......................................................................................36 
9.2. 
Dose Delays and Dose Modifications for Toxicity............................................................36 
9.3. 
Supportive Care Guidelines ...............................................................................................36 
10. ASSESSMENTS.....................................................................................................................38 
10.1. Safety Assessments ............................................................................................................38 
10.1.1. 
Clinical Assessments ...................................................................................................38 
10.1.2. 
Laboratory Assessments ..............................................................................................38 
10.2. Schedule of Time and Events ............................................................................................39 
10.2.1. 
Screening Phase ...........................................................................................................39 
10.2.2. 
Hospitalization/Treatment Phase .................................................................................39 
10.2.3. 
Post ICU Discharge......................................................................................................40 
10.3. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..........................................40 
10.4. Definitions..........................................................................................................................40 
10.4.1. 
Adverse Event (AE) .....................................................................................................41 
10.4.2. 
Serious Adverse Event (SAE) ......................................................................................41 
10.5. Adverse Event Reporting Requirements ............................................................................42 
10.5.1. 
Serious Adverse Events ...............................................................................................42 
10.5.2. 
All Adverse Events (AEs) Regardless of Seriousness .................................................42 
10.5.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs 
and SAEs ....................................................................................................................42 
10.5.4. 
Grading of Adverse Events ..........................................................................................43 
10.6. Relationship to Study Drug ................................................................................................43 
10.7. Recording Adverse Events .................................................................................................44 
10.8. Follow-up of AEs and SAEs ..............................................................................................45 
10.9. Post-Study Reporting Requirements ..................................................................................45 
10.10. Pregnancy ...........................................................................................................................45 
10.10.1. 
Time Period for Collecting Pregnancy Information ....................................................46 
10.10.2. 
Action to be Taken if Pregnancy Occurs in a Female Partner of a Male Patient ........46 
10.11. Regulatory Reporting of Adverse Events ..........................................................................46 
11. STATISTICS ..........................................................................................................................48 
11.1. General Considerations ......................................................................................................48 
11.2. Sample Size ........................................................................................................................48 
11.3. Randomization and Stratification ......................................................................................48 
11.4. Analysis Populations ..........................................................................................................48 
11.5. Definition of Endpoints......................................................................................................48 
11.5.1. 
Primary Endpoint .........................................................................................................48 
11.5.2. 
Secondary Efficacy Endpoints .....................................................................................48 
11.5.3. 
Exploratory Endpoints .................................................................................................49 
11.6. Safety Analysis ..................................................................................................................49 


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11.6.1. 
Interim Safety Analysis................................................................................................49 
11.7. Primary Efficacy Analysis .................................................................................................49 
11.7.1. 
Primary Analysis ..........................................................................................................49 
11.7.2. 
Secondary and Exploratory Analyses ..........................................................................49 
12. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.....................................................50 
12.1. Study Monitoring ...............................................................................................................50 
12.2. Audits and Inspections .......................................................................................................50 
12.3. Protocol Compliance ..........................................................................................................51 
12.4. Protocol Modifications.......................................................................................................51 
12.5. Information Disclosure ......................................................................................................51 
12.5.1. 
Ownership ....................................................................................................................51 
12.5.2. 
Confidentiality .............................................................................................................51 
12.5.3. 
Publication ...................................................................................................................52 
13. QUALITY CONTROL AND QUALITY ASSURANCE .....................................................53 
14. ETHICS ..................................................................................................................................54 
14.1. Ethical Conduct of the Study .............................................................................................54 
14.2. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/Research 
Ethics Board (REB) Approval .........................................................................................54 
14.3. Written Informed Consent .................................................................................................54 
14.4. Data Monitoring Committee ..............................................................................................54 
15. DATA HANDLING AND RECORDKEEPING ...................................................................56 
15.1. Case Report Forms .............................................................................................................56 
15.2. Retention/Inspection of Records ........................................................................................56 
16. LIST OF REFERENCES ........................................................................................................57 
APPENDIX 1. 
SCHEDULE OF ASSESSMENTS ..................................................................58 
APPENDIX 2. 
SEQUENTIAL ORGAN FAILURE ASSESSMENT .....................................60 
APPENDIX 3. 
GLASOW COMA SCALE SCORE CRITERIA ............................................61 
APPENDIX 4. 
EXAMPLES OF CYP2D6-SUBSTRATE DRUGS ........................................62 
 
LIST OF TABLES 
Table 1. 
Abbreviations and Specialist Terms ......................................................................17 
Table 2 
Comparison of PK/TK Results Among Human Volunteers, Rat and Dog 
Studies ....................................................................................................................23 
Table 3:           Adverse Event Severity .........................................................................................43 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1. 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
APACHE 
Acute Physiology and Chronic Health Evaluation 
BED 
biologically equivalent dose 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CRF 
case report form 
Dmax 
maximum dose 
Dmean 
mean dose 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
intravenous 
MAP 
Mean arterial (blood) pressure 
SOFA 
Sequential organ failure assessment score 
OM 
oral mucositis 
PDE 
phosphodiesterase type 5 
PK  
Pharmacokinetic 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SOD 
superoxide dismutase 
SOM 
severe oral mucositis 


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4. 
INTRODUCTION 
4.1. 
Background 
4.1.1. 
COVID-19 and Associated Respiratory Disease 
Approximately 20% of people with confirmed, symptomatic COVID-19 disease, due to infection 
with the SARS-CoV-2 virus, will develop viral pneumonia requiring hospitalization.  These 
patients exhibit respiratory compromise that can be characterized as severe (demonstrating 
dyspnea, hypoxia, and/or extensive lung opacities on chest x-ray); or critical, with respiratory 
failure, which may be accompanied by shock or multiorgan dysfunction).  Approximately 25% 
of hospitalized patients, comprising approximately 5% of all patients with symptomatic 
infection, will have critical disease as described herein.  Critical disease often manifests as a 
clinical picture consistent with the acute respiratory distress syndrome (ARDS), although 
information is still being obtained regarding the pathophysiology and pathophysiology of 
pulmonary compromise associated with SARS-CoV-2, compared with ARDS related to other 
causes.  Retrospective series suggest that, after a variable initial course of disease, dyspnea 
begins approximately 6-7 days after the first symptoms of infection, with swift progression to 
frank respiratory failure/ARDS 2-3 days thereafter.  Intensive care is often required for 14 days 
or more, and more than one attempt at ventilator weaning may be required before eventual 
extubation.  Comorbidity among these critically ill patients includes renal, cardiac, and hepatic 
damage as well as hypotension requiring vasopressor treatment (Yang et al, 2020).   Mortality 
for critically ill patients, highest among the elderly or those with significant prior concomitant 
conditions, has been reported to be on the order of 50-60% (Yang et al, 2020; Wu et al 2020).  
The IHME has recently projected that, assuming full social distancing throughout the United 
States through May 2020, nationwide needs for hospital beds and ICU beds will exceed national 
capacity (https://covid19.healthdata.org/projections, accessed 15 April 2020, 12 noon EDT)  
Further, pending effective treatments or vaccine(s), potential remains for recurrent waves of 
infection and the attendant needs for hospital resources.    
4.1.2. 
Superoxide and Superoxide Dismutase Mimetics in Viral Pneumonia, ARDS and 
Septic Shock 
Superoxide (O2•-) plays a central role in initiation of numerous pathologic processes. Under 
normal circumstances O2•- is a by-product of mitochondrial cellular respiration and is also 
produced by activated phagocytes. Since O2•- is extremely reactive with biological molecules, it 
is quite toxic to cells. In all studied species, this potentially toxic O2•- burden is normally 
contained by a complement of superoxide dismutase (SOD) enzymes. In vertebrates, SOD 
enzymes are present in the cytoplasm (SOD1 Cu/Zn based), mitochondria (SOD2, Mn based) 
and extracellular spaces (SOD3, Cu/Zn based). Superoxide dismutases are a class of 
oxidoreductase enzymes that convert superoxide into molecular oxygen and hydrogen peroxide.  
The control of the free radical flux derived from oxygen is jeopardized in many circumstances in 
which superoxide production is excessive or if the breakdown of superoxide is compromised. 
This over-production of superoxide can overwhelm the body’s ability to eliminate it via catalytic 
dismutation and lead to a variety of superoxide initiated or mediated disease states, including 
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Normal cells counter the damaging effects of O2•- by detoxifying ROS via their intact redox 
protective enzyme systems (SOD, catalase, glutathione peroxidase), converting hydrogen 
peroxide into water and molecular oxygen, and by the activation of DNA repair mechanisms.  
Extensive literature suggests that O2•- may play multiple roles in viral infection and related 
pulmonary pathologies, including for the respiratory influenza and coronaviruses.  The exact 
mechanisms involved are still debated.  For example, does the virus elevate O2•- levels to aid 
virus proliferation, does O2•- via a hyperactivated immune response drive airway damage, is it 
both or are there other mechanisms also involved?  At the same time, it can be hypothesized that 
other non-pulmonary inflammatory pathologies in severe respiratory viral disease are similarly 
driven or exacerbated by O2•-.  Not surprisingly then, overexpression of superoxide dismutases 
(SOD), the enzymes which remove O2•- by converting it to hydrogen peroxide (H2O2) have also 
been shown in several studies to inhibit viral infection and pulmonary damage. 
 
A number of researchers have reported various ways that O2•- can play one or more roles in viral 
infections including HIV [1-5], HCV [6-10], hemorrhagic fevers [11], influenza [12-25] and 
coronaviruses [25-26].  For some virus classes O2•- may play a direct role in virus proliferation, 
aiding replication [2,15-18,23-24,26] or cell to cell spread [4].  And there is evidence that virus 
proteins may directly increase O2•- levels in infected or bystander cells to enlist these pathways 
[1,3-4,6-10,13-14,17-19].   
 
For all these classes, host response to infection and organ damage clearly involves O2•-. 
Researchers report that viral infection appears to elevate intracellular O2•-, perhaps as part of a 
proliferative role, directly driving host cell apoptosis [1,7-8.11,19].  In fact, the production of 
substantial amounts of O2•- by influenza infection is so well-known that it has been demonstrated 
as a robust way to assay infection in egg-based avian flu vaccine production [21]. Incidentally, 
this intracellular elevation might explain part of the reason older patients, without other underlying 
co-morbidities, disproportionately suffer more severe disease, as recent research has shown that 
accumulating mitochondrial dysfunction with age renders cells from older humans more 
susceptible to damage by intracellular O2•- [27].   
 
Most significantly, especially in respiratory viral disease, the immune response to extensive 
infection produces massive O2•- bursts from various monocytic and polymorphonuclear 
leukocytes.  These O2•- bursts may be an essential part of the immune response to viral infection, 
either for immune cell recruitment or, when further converted to H2O2 and hypochlorous acid 
(HOCl), for direct action against the virus [28,29].  However, when this inflammatory production 
of O2•- is excessive and prolonged it leads to host cell death and tissue damage [20,23,28,29].  
This excessive and prolonged production of O2•- then can become part of a vicious cycle 
sometimes referred to as cytokine storm, as superoxide not only damages host tissue, but also 
drives release of pro-inflammatory cytokines such as TNF, IL-1 & IL-6 [16,18,20,23] and other 
chemotractants at the site.  In the process membrane lipid oxidation also occurs, leading to 
activation of TLR4 and via that of NADPH oxidase (NOX) enzymes which produce even more 
O2•- [25,28-29].  In turn this exacerbates the hyperactive immune response leading to increased 
generation of O2•- [28].  For respiratory-targeting viruses this leads to and exacerbates acute lung 
injury and ARDS. 
 


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As O2•- has been shown to drive similar tissue injury and inflammatory damage patterns in other 
organs [6,30-35] it is possible that similar biology is involved in viral pathologies in these other 
sites, such as kidney or heart.  
 
By a somewhat different mechanism, O2•- has also been shown to be at least partially responsible 
for the inability to maintain blood pressure and adequate perfusion in so-called (bacterial) “septic 
shock” [36-38].  In this situation, O2•- generated by the hyperinflammatory response to septicemia 
initiates the auto-oxidation of catecholamines such as epinephrine, norepinephrine & dopamine, 
leading to self-perpetuating refractory hypotension.  In animal models of LPS and live bacteria-
induced refractory hypotension, the oxidation of the catecholamines produces a characteristic set 
of toxic end-products, adrenochromes [36], which a clinical observation study also strongly 
correlated to the presence of septic shock [39].  While some case reports suggest a similar 
refractory hypotension, it is unclear whether this is an issue for many critically ill COVID-19 
patients. 
 
Given the role of O2•-, it is not surprising that superoxide dismutases (SOD), enzymes which 
remove O2•- by converting it to H2O2, inhibit the viral infection roles attributed to O2•-. Via 
overexpression, exogenous administration and knock-down, the SOD enzymes have been shown 
to inhibit viral infection [2,4,15,17-18,24], and even more so to robustly decrease inflammatory 
cell infiltration, pro-inflammatory cytokine release, lung damage and related pulmonary 
pathologies in response to viral infection [18,22-24].  Much of this work has been done with 
Influenza A, though parallel results have been shown in avian flu and even coronaviruses.  Using 
exogenous or recombinant SOD enzymes, however, is limited by the challenges facing 
pharmacologic use of large, multi-subunit proteins as therapeutics, as well as the fact that they can 
be inactivated under the very conditions they may be intended to treat. 
 
Interestingly, the product of O2•- dismutation, H2O2, is well established as a very effective viral 
disinfectant and even antiviral [40-45].  In fact, it was first reportedly used successfully against 
influenza in patients in 1920 [40], and subsequent studies suggest that both influenza and 
coronaviruses may be particularly susceptible to it [41-42,44].  As a result, the conversion O2•- to 
H2O2 in a patient with advanced viral pulmonary involvement should not interfere with controlling 
their infection.  It should be noted, however, that its use directly has been thwarted by the portfolio 
of enzymes, particularly abundant catalase that make it difficult to maintain a therapeutic systemic 
concentration [45]. 
 
4.1.3 
Dismutase Mimetic Nonclinical Pharmacology and Mechanism of Action 
Galera’s manganese pentaaza-macrocycles (MnPAMs) are small molecule dismutase mimetics 
that can overcome the limitations to using SOD enzymes.  They have a similar ability to rapidly 
convert O2•- to H2O2 as MnSOD [46], on the order of 107 molecules of O2•- per second per 
dismutase molecule, which is essential to dispose of superoxide before it can initiate tissue 
damage.  Just like the SOD enzymes, they only dismutate O2•- to H2O2, a feature critical to 
avoiding off-target activity of the dismutase mimetics [47]. As such, they may offer an attractive 
option to pharmacologically curb O2•- and treat the severe consequences of SARS-CoV2 
pneumonia. 
 


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Consistent with the biology described above for O2•- and SODs, the MnPAM dismutase mimetics 
have shown potent protective activity in multiple acute lung injury models.  In the zymosan i.p. 
rat model, Galera’s MnPAM dismutase mimetic GC4401 reduced zymosan-induced lung 
neutrophil infiltration, lipid peroxidation and lung injury, TNFa and IL-1b plasma levels, and 
mortality [34]. Similarly, in the bleomycin i.t. mouse model, another dismutase mimetic, 
avasopasem, reduced lung inflammatory infiltrates and alveolar epithelial apoptosis [48].  In other 
lung inflammatory injury models, GC4403 (the enantiomer of avasopasem) reduced neutrophil 
infiltrate, lipid peroxidation and alveolar epithelia apoptosis in a chronic asthma guinea pig model 
[49], and also reduced neutrophil infiltrate and lipid peroxidation in a splanchnic artery reperfusion 
inflammatory shock model [50] while GC4419 blocked late stage pulmonary fibrosis in a lung 
focal radiation mouse model [51].  Intriguingly, GC4419 worked in this model both when given 
around the time of the irradiation or starting after the injury, suggesting that it can inhibit an 
ongoing inflammatory damage cycle.  In a related model oral mucosa focal radiation hamster 
model, both GC4403 & GC4419 reduced tissue damage in the form of severe oral mucositis (OM) 
[35, 52].  Importantly this OM result has now been reproduced in clinical studies, which likely 
involves reducing both the initial tissue insult and resulting inflammatory response [53,54]. 
 
Galera’s MnPAM dismutase mimetics have also demonstrated the ability to reduce key pro-
inflammatory cytokines in ARDS including TNFa, IL-1b & IL-6.  In addition to suppressing 
zymosan-induced increases in TNFa and IL-1b plasma levels [34], they blocked production of 
TNFa and IL-6 in LPS-stimulated rat alveolar macrophages while also suppressing NF-kB 
activation [55].  Similar results have been demonstrated in live E. coli-induced refractory 
hypotension with plasma TNFa, IL-1b & IL-6 being reduced while the anti-inflammatory cytokine 
IL-10 was increased [37], collagen-induced arthritis with TNFa & IL-1b being reduced [56], 
splanchnic artery occlusion/reperfusion with TNFa & IL-1b being reduced [56], and in several 
other models of inflammatory disease and tissue damage.  Whatever the initiating insult or target 
organ, these inflammatory models consistently show that Galera’s dismutase mimetics, reduce 
inflammatory cell infiltration (including lung, even if not the target organ), lipid peroxidation, key 
cytokines, cell apoptosis and organ injury, and where appropriate increase survival. 
 
Based on case reports from the current COVID-19 outbreak, three additional nonclinical findings 
may also be important in subsets of patients.  First, based on the understanding that in the 
hyperinflammatory state, O2•- can initiate the auto-oxidation of catecholamines, leading to self-
perpetuating refractory hypotension, the MnPAM dismutase mimetics have been shown in 
multiple models to restore response to vasopressor therapy and maintain mean arterial blood 
pressure [36-38].  It is unclear how broadly refractory hypotension is an issue for critically ill 
COVID-19 patients, however renal failure does seem to be a substantial issue.  While renal failure 
may be due to compromised circulation (perhaps stemming from refractory hypotension), acute 
kidney injury has also been linked directly to O2•- and such injury is reduced by the MnPAM 
dismutase mimetics in models of direct injury by cisplatin and of the zymosan-induced 
inflammatory response [30,34].  In addition, in a randomized Phase 2 setting, post hoc analysis 
suggests that GC4419 reduces chronic kidney disease in cisplatin-treated patients [57].  Finally, 
analogous to lung injury models discussed above, in myocardial injury models, GC4403 reduced 
O2•-, neutrophil infiltrate, lipid peroxidation and myocardial damage, while significantly 
improving cardiac function post-ischemia/reperfusion, transplant or hyperglycemia [58-61], 
suggesting that a MnPAM dismutase mimetic might also reduce cardiac myopathy seen in some 


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critically ill COVID-19 patients. Further, MnSOD overexpression reverses pulmonary 
hypertension (PAH) in the fawn-hooded rat [62].  In alignment with that MnPAM dismutase 
mimetics have been shown to reduce PAH in hypoxic piglet and bleomycin rat models [63-66], 
which could also be a beneficial activity in patients with myocardial injury.  Thus, beyond treating 
or preventing ARDS, in critically ill COVID-19 patients may offer help with refractory 
hypertension, renal impairment and heart failure co-morbidities. 
 
While it can be debated what the best animal models of ARDS or of critically ill COVID-19 
patients are, the nonclinical data above argue strongly for assessing the MnPAM dismutase 
mimetics in this indication, as well as for protection of other organs targeted by cytokine storm.   
 
Since viral disease has not previously been a development focus for the MnPAM dismutase 
mimetics, there has been very little prior testing in viral disease models, either for host tissue 
protection or for anti-viral activity.  In the one exception, GC4403 was shown to protect astrocytes 
from HIV-driven apoptosis, and reported to demonstrate potent antiviral activity [33,67].  
 
Testing in SARS-CoV2-specific in vitro and in vivo models is now being planned or underway.  
Until such model results are available, interpolation must be made between O2-/SOD viral model 
and MnPAM dismutase mimetic non-viral model experimental data. 
4.2. 
Avasopasem Manganese (GC4419) 
Avasopasem manganese (avasopasem) is a highly-selective, small molecule (MW 483) mimetic 
of naturally occurring superoxide dismutase (SOD) enzyme, which, like native SOD, converts 
superoxide to hydrogen peroxide and molecular oxygen specifically and selectively, at an 
enzymatic rate comparable to that of the native SOD.  It is being developed for reduction of the 
incidence and severity of SOM (severe oral mucositis) induced by RT, without systemic therapy, 
in patients with head and neck malignancies, under IND 111,539 with the Division of 
Dermatology and Dental Products, United States Food and Drug Administration (FDA). 
In disease states characterized by excessive superoxide production, administration of 
avasopasem replaces or augments deficient or insufficient endogenous SOD capacity.  
Accordingly, avasopasem and related active dismutase mimetics have demonstrated ability to 
protect tissues from superoxide-mediated damage in laboratory studies and in the clinic.  As 
noted in Section 4.1.3, relevant non-clinical studies include: reduced zymosan-induced lung 
neutrophil infiltration, lipid peroxidation and lung injury, and mortality (Cuzzocrea et al, 2004);   
in the bleomycin intratracheal mouse model, reduced lung inflammatory infiltrates and alveolar 
epithelial apoptosis (Herzog, 2014); in a chronic asthma guinea pig model, reduced neutrophil 
infiltrate, lipid peroxidation and alveolar epithelia apoptosis (Masini et al, 2005); and in a lung 
focal irradiation mouse model, reduced late stage pulmonary fibrosis (Sishc et al, 2018).  Results 
from animal studies also include reduction of E. coli-induced hypotension, vascular 
hyporeactivity to catecholamines, and mortality in septic shock (Macarthur et al, 2003), and 
decreased  levels of proinflammatory cytokines such as TNFα, IL-1β and IL-6 (Cuzzocrea et al 
2004; Macarthur et al, 2003),  with increase in the anti-inflammatory cytokine IL-10 (Macarthur 
et al, 2003).  In these studies, dismutase mimetic was administered continuously or repeatedly 
over several hours after challenge with zymosan or E. coli (Cuzzocrea et al 2004; Macarthur et 
al, 2003).  In a hamster model, avasopasem reduced severe oral mucositis (Sonis, unpublished 


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data, GC4419 Investigator's Brochure), supporting clinical trials of avasopasem to reduce 
radiation-induced severe oral mucositis.   In Phase 1-2b clinical trials (Anderson et al 2018; 
Anderson et al 2019), GC4419 reduced the incidence, severity, and duration of severe oral 
mucositis produced from the superoxide generated due to concurrent chemoradiotherapy for 
head and neck cancer,  with an acceptable safety profile, and a confirmatory Phase 3 trial 
(NCT03689712) in this indication is underway under Breakthrough Therapy Designation from 
FDA.   
GC4419 has been safely administered to over 300 human subjects, with the Phase 3 oral 
mucositis trial testing 90 mg by 60-minute IV infusion, repeated each weekday, prior to standard 
radiotherapy, for 7 weeks—a total of up to 35 doses.  Toxicity attributable to GC4419 has been 
limited to transient, infusion-related mild hypotension and postural symptoms, and mild 
circumoral paresthesia, attributable to reversible potentiation of nitric oxide.  These effects 
appear to be related to the Cmax (which occurs at the end of the IV infusion), and are further 
limited with lower doses or prolonged infusion time at a given dose, with mild orthostatic 
lightheadedness reported in 6 of 72 healthy volunteers who have received 27 mg of GC4419 over 
60 minutes, and 5 of 34 healthy volunteers who received 30 or 51 mg of GC4419 IV over 15 
minutes.  Adverse events observed in the oral mucositis trials have been those observed with the 
underlying standard regimen of radiation therapy plus cisplatin, and in a placebo-controlled 
randomized Phase 2b trial, the adverse event profiles for subjects receiving GC4419 or placebo 
were similar.  
No effect on the QT interval was found in a precision QT clinical trial of GC4419 at a dose of 51 
mg IV over 15 minutes, a dose and schedule at which Cmax exceeds that produced after a 90 
mg/60-minute infusion of GC4419.   
Nonclinical GLP toxicology studies of avasopasem in rats and dogs have shown no abnormal 
histopathologic findings except for injection-site reactions after subcutaneous administration.  
These studies include 6-month chronic toxicology in rats (final report pending).  A 9-month 
chronic toxicology study in dogs is in progress in the in-life phase.   
A 14-day repeat dose GLP toxicology study in Sprague-Dawley rats with GC4419 administered 
as a 15-minute intravenous infusion resulted in a bi observed adverse effect level (NOAEL) of 
15 mg/kg/day and a calculated HED of 145 mg/day [(15 mg/kg/ 6.2) x 60 kg].  A similarly 
designed study in beagle dogs resulted in a NOAEL of 5 mg/kg/day and a calculated HED of 167 
mg/day [(5 mg/kg/1.8) x 60 kg].   
Additionally, toxicokinetic results from the 14-day rat study resulted in GC4419 plasma 
exposures  (Cmax and AUClast) that when compared to the GC4419 plasma exposures from the 
Sponsor clinical study GT-001 (90 mg /day), resulted in a AUC-based safety margin of 2.2, 
further supporting an HED of 198 mg/day (Table 2). 
Table 2 
Comparison of PK/TK Results Among Human Volunteers, Rat and Dog Studies  
Species 
Dose 
HED 
(mg/kg) 
HED 
 (mg) 
Cmax  
(ng/mL) 
AUClast  
(ng*hr/mL) 
AUC vs AUC Margin 
HED 
(mg) 
1Human 
90 mg 
- 
 
3650 
7160 
- 
- 
2Rat 
15 mg/kg 
2.4 
145 
17,100 
15,980 
2.2 
198 
1Human data from: Phase 1b/2a trial GT-001, Week 3, Day 3  
2Rat data from 14d repeat dose (15 min infusion): Day 1 (M + F).  Dose reported was the NOAEL. 
 


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The Sponsor has also conducted 60-day GLP repeat dose toxicology studies (60-minute 
infusions) in rat and dog which yield HED of 77 mg/day and 333 mg/day, respectively, based on 
preliminary assessment of NOAELs based on in-life reports of reduced weight gain and food 
consumption (full reports pending).  
Avasopasem has a plasma half-life of approximately 2 hours, reaching maximum concentration 
at the end of IV infusion and declining in a bi-exponential fashion thereafter.  Plasma exposure is 
approximately dose-proportional.  In past clinical trials, has been quantifiable in plasma up to 
approximately 24 hours after a 60-minute IV infusion, with minimal accumulation in plasma 
with repeated daily dosing.  Non-clinical data indicate a longer half-life of avasopasem in tissues, 
with rapid entry into cells related to Cmax and slower release from cells. 
Pharmacokinetic modeling based on human data for a 60-minute IV infusion of 90 mg of 
GC4419 predicts no increase in Cmax provided the second dose in a day occurs at least four hours 
after the first dose, important since the primary acute toxicity associated with GC4419 appears to 
be related to Cmax related hypotension. 
Avasopasem is eliminated by GI and renal routes.  Human volunteer studies of GC4419 in the 
setting of compromised renal or hepatic function are in progress.  There has been no apparent 
nephrotoxicity or hepatotoxicity of avasopasem in human clinical trials.  
See the Investigator's Brochure for additional background information about GC4419. 
4.3. 
Rationale for the Present Trial 
The pathogenesis of severe-to-critical pulmonary disease complicating SARS-CoV-2 infection—
and, when it occurs, the pathogenesis of attendant shock—along with the mechanism and 
available nonclinical and clinical data with avasopasem, suggest that GC4419 could attenuate or 
reduce the risk of ARDS and the need for mechanical ventilation, and attenuate shock, in people 
suffering from them due to SARS-CoV-2. 
With the same extraordinarily fast and specific activity in converting O2- to H2O2 as the SOD 
enzymes, avasopasem and other manganese pentaaza-macrocycles (MnPAMs) being developed 
by Galera are true small molecule dismutase mimetics.  As such, they may offer an attractive 
option to pharmacologically harness this biology and treat the severe consequences of viral 
pneumonia, such as in the current COVID-19 pandemic. Aligned with the O2- and SOD 
experimental reports, nonclinical models with the MnPAM dismutase mimetics demonstrate 
potent protective activity in acute lung injury models perhaps representative of acute respiratory 
distress syndrome (ARDS).  Nonclinical data and mechanism also support a potential role for 
these candidates in addressing other co-morbidities such as kidney injury and cardiac myopathy, 
and the refractory hypotension and hemodynamic instability that present in some late-stage 
patients.   
The MnPAM dismutase mimetics have seen only limited testing in viral disease models, either 
for host tissue protection or for anti-viral activity.  Such testing is now being planned or 
underway.  Until such model results are available, interpolation must be made between O2-/SOD 
viral model and MnPAM dismutase mimetic non-viral model experimental data.  
Galera has identified several potential clinical applications of GC4419 in the setting of SARS-
CoV2 infection/COVID-19 in hospitalized patients.  First among these is the 
prevention/reduction of ARDS and long-term related lung pathologies, based on protection of 
airway tissue from inflammatory injury demonstrated in multiple models (along with reduction 


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in inflammatory cytokines including TNFa, IL-1b & IL-6), as well as SOD data in influenza 
pulmonary models.  The second application is in an overlapping population displaying 
hemodynamic instability for the treatment of hypotension refractory to vasopressor therapy, 
based on LPS and live E. coli challenge models.  Third, emerging reports of significant kidney 
injury and cardiac myopathy among critically ill COVID-19 patients suggest further potential 
roles for GC4419 in preventing inflammatory damage to these organs, based on the known 
action of O2- in driving myocardial ischemia/reperfusion injury and doxorubicin cardiotoxicity, 
as well as cisplatin kidney injury.   
For the oral mucositis indication, at the intended dose and schedule of 90 mg by 60-minute IV 
infusion M-F for 7 weeks, GC4419 demonstrated efficacy in the proposed indication in a 
randomized, double-blind, three-arm Phase 2b trial in which patients receiving standard 
chemoradiotherapy for locally advanced head and neck cancer received either 90 mg or 30 mg of 
GC4419 or placebo.  GC4419 did not increase the known adverse effects of the chemoradiotherapy 
in this trial; the adverse event profiles for each active arm and the placebo control arm were similar.   
 
Adverse effects attributable to GC4419 in clinical development are limited, with the principal 
adverse effect being mild, transient postural symptoms or hypotension at the end of the one-hour 
infusion, and to mild circumoral paresthesia, both attributable to transient potentiation of nitric 
oxide (NO).  Data in humans and animals have demonstrated that these effects, which are related 
to Cmax, are further limited by lowering the dose or prolonging the infusion time of GC4419.  
 
In the present trial, fifty (50) subjects with respiratory failure and documented SARS-CoV-2 
infection will be randomized, 1:1, to receive either GC4419 or placebo plus standard supportive 
care or standard supportive care alone.  The 90 mg dose currently being tested in the Phase 3 OM 
trial will be used, but with GC4419/placebo infused over 180 minutes rather than 60 minutes to 
limit the potential for NO-related adverse events.  Twice daily (q12 hour) infusion is proposed for 
a duration of 7 days, supported by results from animal toxicology, human pharmacokinetic data 
indicating little if any potential for drug accumulation in plasma, and relevant animal 
pharmacology studies employing drug administration over a several hour period to maintain 
extracellular exposure.  A double-blind design will be employed.  
 
The primary endpoints will be 28-day all-cause mortality, which is expected to be 50% or more 
for the control group, and safety of GC4419 in the study population.  Secondary endpoints will 
assess safety of GC4419, ability to wean study subjects from ventilator support, ventilator-free 
and ICU-free days, days of minimum PaO2/FiO2 days < 300, days of vasopressor/catecholamine 
support, effects on SOFA score, and effects of GC4419 on mean arterial blood pressure.  
Exploratory endpoints will include SARS-CoV2 viral load, circulating cytokine levels and plasma 
exposure to GC4419 in study subjects.  
 
Based on initial results from this first study, one or more subsequent trials following a similar 
design (randomized, double-blind, placebo-controlled) may be considered and separately 
proposed in the future.   
 
 


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5. 
TRIAL OBJECTIVES AND PURPOSE 
5.1. 
Primary Objective 
The primary objective of this study is to evaluate 28-day all-cause mortality/overall survival. 
5.1.1. 
Rationale for Primary Endpoint Selection 
Based on available reports, the target study population has a high risk of mortality and other 
morbidity.  28-day all-cause mortality is a standard and readily assessed primary endpoint in 
critically ill subjects.  Additional, related outcomes (see secondary objectives) are also 
appropriate for observation but insufficient data exist to base a null hypothesis on those. 
GC4419 has not yet been studied in this patient population, so an initial assessment of the safety 
of GC4419 is required. 
5.2. 
Secondary Objectives 
The following secondary objectives will be assessed through a 28-day period to align with the 
primary objective: 
 To assess the safety of avasopasem in the study population 
 To evaluate the frequency of successful ventilator weaning 
 To evaluate the number of days alive and intensive care-free  
 To evaluate the number of days alive and ventilator-free  
 To evaluate the number of days of minimum SpO2/FIO2 ratio or PaO2/FIO2 > 300 
 To evaluate the number of days alive without vasopressor/catecholamine support  
 To evaluate the incidence of mean arterial pressure < 65 mmHg on optimized vasopressor 
therapy 
 To evaluate the number of days alive with a SOFA score of 6 or less 
 To evaluate the percentage of subjects with an increase in mean arterial pressure of 10 
mm Hg or more at the end of more than one infusion of GC4419 
 
5.3. 
Exploratory Objectives 
 To assess levels of circulating cytokines IL-6, TNF-alpha, IL-1 beta, IL-10 before, 
during, and after treatment 
 To assess SARS-CoV-2 viral load by PCR testing for viral RNA 
 To assess the plasma exposure to GC4419 in the study subjects 
 Lung compliance to be calculated from clinical data for exploratory purposes 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
COV-4419-201 will be a randomized study to evaluate GC4419 administered IV to subjects with 
documented SARS-CoV-2 infection and critical pulmonary disease.   
Subjects will be randomized in a 1:1 ratio to receive either: 
 GC4419 by IV infusion q 12 hours (+/- 2 hours), plus standard supportive care, or 
 Placebo by IV infusion q 12 hours (+/- 2 hours), plus standard supportive care  
To help ensure balanced randomization at a 1:1 ratio, subjects will be stratified at randomization 
for age < 60 years vs >=60 years  
All subjects will receive standard supportive care according to the policies of the treating 
institution. 
Adverse Events and Serious Adverse Events will be assessed daily during dosing of 
GC4419/placebo, then daily during hospitalization and weekly after hospital discharge, for a 
total of 30 days after the end of treatment.  Post-treatment AE assessment may be done on an 
outpatient basis for subjects who are discharged from the hospital.   
Ongoing safety results will be monitored by an independent Data Monitoring Committee.    
6.2. 
Treatment Plan and Duration of Therapy 
Subjects in the present trial will receive, in a blinded fashion, either GC4419, 90 mg 
intravenously, or placebo, administered over 3 hours (180 minutes), repeated every 12 hours (+/- 
2 hours) for 7 consecutive days.    
Rationale for GC4419 dosing plan: 
 Extensive clinical experience in cancer patients supports the safety of 90 mg of GC4419 
administered over 60 minutes for 35 doses (M-F, up to 7 weeks) concurrently with 
chemoradiotherapy. 
 Cmax-related transient mild hypotension and orthostasis has been observed at the current 
90 mg/60-minute infusion schedule, but this is less frequent with lower doses. 
 Therefore, administering 90 mg of GC4419 IV over 180 minutes (3 hours) is expected to 
provide an additional margin of safety. 
 The plasma half-life of GC4419 is approximately 2 hours. 
 Pharmacokinetic results to date do not indicate significant plasma accumulation of 
GC4419 with repeated dosing. 
 Results of GLP animal toxicology studies support a total daily dose of GC4419 up to 198 
mg, administered for up to 14 days; this is greater than the planned 180 mg per day (90 
mg q 12 hours) for 7 days.  
 Administration of a related dismutase mimetic to rats in the zymosan and E. coli sepsis 
models was performed over a period of several hours after challenge with zymosan or E. 
coli.  Moreover, the persistent superoxide production is expected to be associated with 
the ongoing COVID-19 disease process.  Accordingly, a dosing schedule that maintains 


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extracellular concentrations of GC4419 as much as possible and feasible may be 
desirable.   


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Approximately 50 total subjects from up to 10 investigational sites in the US will be enrolled.  
Subjects appropriate for this trial will be identified by the institutional Principal Investigator (or 
designee) who will make a preliminary determination of the patient’s eligibility for the trial in 
accordance with the provisions of the study protocol. Once a patient is enrolled to the study, the 
Sponsor or designee will assign a unique patient identification number that does not contain any 
Personal Health Information that will be used to reference the patient and corresponding data that 
is collected. 
7.1. 
Subject Inclusion Criteria 
Subjects are required to meet the following inclusion criteria before entering the trial: 
1. Laboratory-confirmed SARS-CoV-2 infection as determined by a positive PCR test 
documented prior to randomization: 
a. Performed on a swab sample from the nasopharynx of a non-intubated subject or 
pulmonary secretions from an intubated subject per site’s standard practice 
b. Analyzed by a commercial, local, or public health laboratory 
c. A duplicate swab will be retained for subsequent confirmation at a Central 
Laboratory 
2. Requirement for intensive inpatient hospital care 
3. Acute hypoxemic respiratory failure typifying ARDS, as indicated by: 
a. PaO2/FiO2 ratio < 300 mm Hg, or SpO2 < 94% on FiO2 >/= 50% with bilateral 
pulmonary infiltrates along with respiratory distress and increased work of breathing 
requiring intubation and invasive mechanical ventilation, OR 
b. Non-invasive mechanical ventilation with SpO2 < 94% on FiO2 >/= 50% 
4. Adequate liver function as indicated by: 
a. Total bilirubin ≤ 1.5 x upper-normal limit (ULN) 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN 
5. Age 18 years or older 
6. Serum or urine pregnancy test negative for females of childbearing potential 
7. Properly obtained informed consent obtained from subject or legally authorized 
representative 
7.2. 
Subject Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria: 
1. Expected survival for less than 48 hours after randomization 
2. Child-Pugh stage C hepatic impairment and/or portal hypertension secondary to cirrhosis 
3. Stage IV chronic kidney disease or end-stage kidney disease on maintenance 
hemodialysis 
4. Requirement for extra-corporeal membrane oxygenation (ECMO) 
5. Acute Myocardial Infarction (AMI) 
6. Active bleeding requiring transfusion 
7. Concurrent participation in another clinical trial of experimental treatment for SARS-
CoV-2 


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Note: Concurrent participation in any study of an approved treatment, or a product with 
Emergency Use Authorization for COVID treatment, is permitted if the Principal 
Investigator attests that the mechanism of the EUA product is not expected to interfere 
with the mechanism of GC4419 and that completion of study requirements for this 
protocol will not be compromised 
8. Female patients who are pregnant or breastfeeding 
9. Requirement for concurrent treatment with nitrates 
 
7.3. 
Rationale for Patient Population 
COVID-19 is associated with respiratory failure and other organ failure.  The mechanism and 
preclinical data with avasopasem indicate that it may attenuate respiratory failure; severe 
hypotension requiring vasopressor support; or renal, cardiac, or hepatic damage, all of which are 
mediated by superoxide.  Based on prior clinical data, the risks of a short course of GC4419 to 
human subjects appears to be low, but for a first clinical trial of GC4419 in COVID-19 patients, 
the benefit-risk appears to be most appropriate for critically ill patients at high risk of mortality 
or severe morbidity from COVID-19.  
7.4. 
Screen Failures 
A subject is considered to be a screen failure if the subject signs the informed consent form (ICF) 
but withdraws consent or is deemed ineligible prior to Day 1 investigational product 
administration. The reason why the subject was precluded from the clinical study will be 
collected. All subjects who sign the ICF for this study, including screening failures, will be 
logged into the IRT system. 
7.5. 
Subject Withdrawal Criteria 
In accordance with the Declaration of Helsinki, a subject has the right to withdraw from the 
study at any time for any reason. The Investigator may also, at his/her discretion, discontinue a 
subject from participating in this study at any time. Additionally, study treatment may be 
discontinued for any of the following reasons: 
 AE 
 Medical requirement to administer a contra-indicated medication 
 Subject non-compliance 
 Subject has a confirmed positive serum pregnancy test 
 Discontinuation of the study at the request of the Sponsor 
The primary reason for ceasing treatment will be clearly documented in the subject’s medical 
record and recorded on the appropriate CRF page. A subject who permanently discontinues 
treatment with GC4419/placebo will not be allowed to be retreated. 
If a subject discontinues study drug as a result of an AE or serious adverse event (SAE), every 
attempt should be made to keep the subject in the study and continue to perform the required 


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study-related follow-up and procedures. If this is not possible or acceptable to the subject, the 
subject may be withdrawn from the study. 
If a subject withdraws consent, additional details about the reasons for that decision will be 
sought and documented. 
Withdrawn subjects will not be replaced.  
7.6. 
Study and Site Closure 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures. In terminating the study, 
the Sponsor and the Investigator will assure that adequate consideration is given to the protection 
of the subjects’ interests. 
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the Investigator or site staff, as appropriate: 
 Return of all study data to the Sponsor (as applicable) 
 Resolution of all data queries 
 Accountability, reconciliation, and arrangements for all unused GC4419 
 Review of site study records for completeness 
 Shipment of laboratory samples (as applicable) 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study either at a single site or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues or severe non-compliance. If the Sponsor determines such action is 
needed, the Sponsor will discuss this with the Investigator (including the reasons for taking such 
action) at that time. When feasible, the Sponsor will provide advance notification to the 
Investigator of the impending action prior to it taking effect. 
The Sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons and will also inform the regulatory 
authorities of the suspension or termination of the study and the reason(s) for the action. If 
required by applicable regulations, the Investigator must inform the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)/Research Ethics Board (REB) promptly and provide 
the reason for the suspension or termination. If the study is prematurely discontinued, all study 
data must be returned to the Sponsor. 
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the Investigator and the Sponsor. 


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8. 
INVESTIGATIONAL PRODUCT AND TREATMENT OF 
SUBJECTS 
8.1. 
Concomitant Medications 
All concomitant therapies (e.g., prescription and over-the-counter medications) taken by subjects 
from Baseline of Day 1 GC4419/placebo administration until 30 days following the last 
GC4419/placebo dose will be collected in the CRF. Additionally, any concomitant therapies if 
used to treat any serious or related AE will be recorded in the CRF.   
If a subject withdraws consent for the study or is removed from the study completely (i.e., the 
subject is no longer participating in any study procedures or follow-up) no further data should be 
collected after the date of the subject’s study discontinuation.  
8.1.1. 
Drug Interactions 
GC4419 is a strong inhibitor of CYP2D6.   
Concomitant use of GC4419 increases the concentration of drugs that are CYP2D6 substrates, 
which may increase the risk of toxicities of these drugs. Concomitant use of GC4419 with 
CYP2D6 substrates where minimal increases in concentration of the CYP2D6 substrate should 
be avoided if possible in situations where minimal increases may lead to serious or life-
threatening toxicities (substrates with a narrow therapeutic range). Such CYP2D6 substrates 
(Appendix 4) include certain  antidepressants (eg, tricyclics), antipsychotics (eg, phenothiazines 
and most atypicals), and antiarrhythmics (eg, propafenone, flecainide).  
Beta blockers that are CYP2D6 substrates (e.g. metoprolol) have been administered, with 
acceptable safety, concurrently with GC4419 to subjects in other clinical trials and may be 
administered in this study with careful monitoring of the subject. 
In addition, concomitant use of GC4419 may decrease the concentration of active metabolites of 
prodrugs that require CYP2D6 for activation. Concomitant use of GC4419 with CYP2D6 
prodrug substrates requiring functional CYP2D6 activity for their clinical benefit (eg, codeine, 
tramadol, taxomifen) may decrease their effectiveness.   
Subjects should receive concomitant administration of a CYP2D6-substrate drug only if the 
investigator judges that doing so, and continuing blinded GC4419/placebo, is warranted in an 
individual subject’s case.    
See the Investigator's Brochure for additional information. 
8.2. 
Prohibited Medications 
Investigators may prescribe any concomitant medication or supportive therapy deemed medically 
indicated for the care of the subject, with exception of the following prohibited 
medications/treatments:   
 
Nitrates, phosphodiesterase type 5 (PDE 5) inhibitors (e.g., sildenafil, tadalafil, or 
similar agents) or other concomitant drugs that in the judgment of the treating 


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investigator could create a risk of a precipitous decrease in blood pressure are 
prohibited until at least 24 hours after the last dose of blinded GC4419/placebo.  
 
Concurrent participation in a clinical trial of investigational therapy for SARS-CoV-2.   
o Other approved or unapproved agents for SARS-CoV-2, including drug or 
biologic therapy including immunomodulatory treatments, administered on an 
expanded access, compassionate care, off-label, or emergency access basis 
may be administered.  Use as part of another, concurrent clinical trial may be 
considered provided the site principal investigator determines that the 
mechanism of the other treatment is not expected to interfere with the 
mechanism of GC4419, and that completion of study requirements for this 
protocol will not be compromised.   
o Examples of acceptable concurrent medications under this provision include 
remdesivir, hydroxychloroquine (alone or with azithromycin) or convalescent 
plasma, and other drug or biologic treatments for SARS-CoV-2 as long as not 
part of a clinical trial other than the present trial. 
Subjects who receive prohibited medications will not automatically be removed from the study; 
however, administration of a prohibited medication is a significant deviation from the protocol 
and must be reported to the Medical Monitor as soon as possible and the presiding IRB/IEC/REB 
(per institutional guidelines). The decision for study continuation or discontinuation will be made 
at that time on a case-by-case basis and in consideration of the clinical requirement and 
circumstances.  
8.3. 
Description of Study Drug GC4419 
GC4419 is formulated as a sterile solution at the following concentration: 
 99 mg avasopasem manganese in 11mL: 9 mg/mL in 26 mM sodium bicarbonate-
buffered 0.9 wt. percentage saline for parenteral administration .   
8.3.1. 
GC4419 Drug Packaging and Labeling 
Open-label GC4419 will be provided as single-use vials for daily doses to be administered IV.   
GC4419 is packaged as an 11 mL ± 0.1 mL aliquot in a 10 mL glass vial of which 10 mL be 
added into 170 mL of normal saline, for daily IV administration over 180 minutes. Each bottle 
will be labeled with the appropriate language, including information required by local heath 
authority regulations. 
Further label details will be provided in a separate Pharmacy Manual.   
8.3.2. 
Placebo Packaging and Labeling 
 
Placebo will be normal saline for parenteral administration only and is to be provided by 
investigative site. 


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8.3.3. 
Study Drug Storage 
GC4419 should be stored in a blinded fashion and refrigerated at 2°C-8°C in a secured and 
controlled area with restricted access. Temperature excursions above freezing and up to 25°C or 
down to 0.1°C for four hours are accepted; however, the Sponsor, or its designee must be 
notified immediately of the temperature excursion to ensure proper oversight.  
Once prepared, the IV bags containing GC4419/placebo mixtures must also be stored at 2°C to 
8°C until use and must be administered to subjects within 24 hours of preparation. GC4419 
dosing solutions must not be frozen at any time. If freezing of the material is evident, that supply 
must be quarantined per institutional guidelines and Galera Therapeutics, Inc. or its designee 
must be notified immediately. 
8.3.4. 
Study Drug Preparation 
GC4419 will be provided to the study site in single use, sterile, pyrogen-free vials ready for dose 
preparation. Proper mixing with normal saline is required. Standard aseptic techniques will be 
used to maintain sterility. Infusions should be prepared using a sterile 0.22 micron syringe filter 
prior to introduction into the infusion bag. 
To prepare IV solutions, investigational pharmacists will extract 10 mL GC4419 from a single 
vial and add to 170 mL of normal saline. No additional modifications or adjustments are to be 
made to the infusion solution.   
To prepare placebo solution, sites are to prepare 180 mL of normal saline. 
IV bags should be prepared and labelled in a blinded manner. 
Further information and preparation details will be provided in a separate Pharmacy Manual. 
8.3.5. 
Administration 
Prepared GC4419/placebo will be administered intravenously at an infusion rate that totals 180 
min (± 6 min to account for saline overfill) for the total dose assigned. Infusions of 
GC4419/placebo must be administered using an infusion pump (i.e., not by drip rate). Infusion 
pump models are not specified and may be per institutional preference/standard. 
To facilitate administration of GC4419/placebo according to the study schedule, an indwelling 
venous access device may be used, at the discretion of the treating Investigator.  If port is to be 
used for other medications, a flush is required prior to GC4419/placebo administration, at 
minimum. 
8.3.6. 
Accountability and Compliance 
Compliance with GC4419/placebo dosing, including administration details (e.g., volume, start, 
stop times, etc.) should be documented in the source documents and recorded on the CRF. 
The Investigator is responsible for ensuring adequate accountability of all used and unused 
GC4419. This includes acknowledgment of receipt of each shipment of GC4419 (quantity and 
condition), subject dispensing records, and quantity of GC4419 vials returned or destroyed. 


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Dispensing records will document quantities received from the Sponsor and quantities dispensed 
to subjects, including container number or lot number, date dispensed, subject identifier number, 
subject initials, and the initials of the person dispensing the medication. Any GC4419 that is 
prepared but not used must also be recorded in the dispensing records. 
All GC4419 supplies and associated documentation will be reviewed and verified by an 
unblinded study monitor. All GC4419 and used containers are to be retained by the site until 
notified by the unblinded study monitor, who will instruct the site in the disposal and/or 
destruction of all used GC4419 supplies. Copies of all forms, documenting drug receipt at the 
study site, drug transportation to satellite sites, and drug return to the Sponsor, together with drug 
accountability records, will be retained according to the regulations governing record retention. 
The Investigator will not allow GC4419 to be given to any patient not included in the study or to 
any unauthorized person. 
8.3.7. 
Study Drug Handling and Disposal 
After completion of the study, all unused study drug will be inventoried and if possible, 
destroyed locally at the site. GC4419 should not be returned directly to Galera Therapeutics, Inc. 
unless specifically requested by Galera Therapeutics, Inc.. The study monitor will instruct the 
site in the disposal and/or destruction of all used and unused GC4419 supplies. Destruction of 
any GC4419 should be documented appropriately. 
 


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9. 
TOXICITY MANAGEMENT 
9.1. 
Anticipated toxicities of GC4419 
Based on the drug’s mechanism of action, adverse effects anticipated with GC4419 are 
attributable to transient potentiation of nitric oxide.  Clinical results with GC4419 to date are 
consistent with this.  These effects have been IV infusion related and transient, typically with 
onset during or at the end of infusion, resolving within 1-2 hours of cessation of GC4419 
administration. At the dose and schedule planned in this trial, these effects may include mild 
hypotension, postural lightheadedness/presyncope, and perioral/facial tingling or 
paresthesia.  Mild nausea and vomiting have also been observed in human subjects receiving 
GC4419.   
See the investigator’s brochure for additional details. 
9.2. 
Dose Delays and Dose Modifications for Toxicity 
For any given subject, study drug infusions should not begin if the subject’s mean arterial 
pressure (MAP) is less than 65 mmHg. 
For any given subject, hold blinded GC4419/placebo and reduce by 25% (from the initial dose) 
for all future infusions if: 
 During infusion or within 1 hour of completing infusion, the subject experiences an acute 
decrease in systolic blood pressure requiring bolus fluid resuscitation OR requiring 
initiation of vasopressor therapy OR increased vasopressor therapy. Hold 
GC4419/placebo until the dose of vasopressor therapy is stable and bolus fluid 
resuscitation is not required. 
 The subject develops serum creatinine > 5 mg/dL. Hold GC4419/placebo until the 
creatinine is =<5 mg/dL. 
 The subject develops serum total bilirubin > 6 mg/dL, or AST or ALT >10 times upper 
limit of normal.  Hold GC4419/placebo until the parameters in question are below these 
levels. 
 The subject experiences a serious or severe adverse event considered by the investigator 
to be related or possibly related to blinded GC4419/placebo. Hold GC4419/placebo until 
the event is no longer serious or severe. 
Up to two such dose reductions for a cumulative 50% from the initial dose of GC4419/placebo 
will be permitted for a given subject.  If a subject cannot tolerate GC4419/placebo infusion after 
a 50% dose reduction, all dosing with GC4419/placebo for that subject will be discontinued. 
Patients unable to tolerate GC4419/placebo must discontinue treatment with GC4419/placebo 
but should continue with other protocol assessments at the discretion of the treating investigator 
and with the ongoing consent of the subject.   
9.3. 
Supportive Care Guidelines 
Necessary supportive measures for optimal medical care will be given throughout the study.  
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Supportive care medications may be administered at the investigator's discretion and recorded in 
the CRF. However, medications are subjected to the exclusions listed in Section 8.2. 
Supportive care parameters such as ventilator settings will be collected in accordance with the 
Schedule of Events (Appendix 1).   
Supportive care for study subjects will be according to investigative sites' institutional protocols, 
but in all cases clinical respiratory practices for this critically ill study population with COVID-
19-associated ARDS are anticipated to conform to the recommendations and best practice 
guidelines of the Society of Critical Care Medicine [Surviving Sepsis Campaign; Guidelines on 
the Management of Critically Ill Patients with Coronavirus 2019 (COVID-19), published 
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10. 
ASSESSMENTS 
The study procedures to be conducted for each patient enrolled in the study are presented in 
Appendix 1. 
Any deviation from protocol procedures should be documented and explained in the source 
documents. The sponsor (or designee) and the site’s IRB (as required by the IRB’s policies and 
procedures) should be notified as soon as possible of any substantial deviations potentially 
affecting patient safety, study drug administration or the assessment of safety, efficacy, and 
tolerability parameters. 
10.1. 
Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs. Safety will be assessed on 
the basis of treatment-emergent AEs, physical examination findings, clinical laboratory tests, 
electrocardiogram (ECG) measurements, and vital sign measurements. 
10.1.1. 
Clinical Assessments 
See the following clinical assessments are defined when referenced in the schedule of events 
(Appendix 1) for a list of clinical assessments.   
10.1.2. 
Laboratory Assessments 
Clinical laboratory tests during the study will be performed by local laboratories to facilitate 
standard care of the study subjects.   
A laboratory abnormality reported by the local laboratory may meet the criteria to qualify as an 
AE or SAE as described in this protocol. In these instances, the AE corresponding to the 
laboratory abnormality will be recorded on the Adverse Event electronic CRF.  
For laboratory abnormalities meeting the criteria of SAEs, the site must fax or email the SAE 
report including the laboratory report (as regionally required) to the sponsor using the SAE form. 
The investigator must assess all abnormal clinical laboratory results for clinical significance in a 
timely fashion. A notation of clinically significant (CS) or non-clinically significant (NCS) with 
initials and date will be documented on the respective laboratory report next to any abnormal 
value. Information on laboratory AE reporting can be found in Section 10.2.3.  
The following laboratory assessments are defined as referenced in the schedule of events 
(Appendix 1) for this study: 
 Serum or urine pregnancy 
 Hematology/Serum Chemistry performed by local lab:  CBC with differential and 
platelet; sodium, potassium, chloride, CO2, BUN, creatinine, total protein/albumin, 
AST/ALT, and total bilirubin.  Direct bilirubin, triglycerides, C-reactive protein, and 
troponin to be assessed at baseline only unless clinically indicated.  If baseline troponin is 
above ULN, the highest post-baseline value during hospitalization and the value closest 
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 Pharmacokinetic sampling for central lab analysis 
 Cytokines collected for central lab analysis:  IL-1 beta, IL-6, TNF-alpha, IL-10  
 Viral load:  Testing by qPCR of sample collected by nasopharyngeal swab unless subject 
is intubated, in which case, pulmonary sample to be used  
o Initial testing by local lab for eligibility 
o Duplicate swab will be collected at enrollment for Central Laboratory analysis 
o All subsequent weekly viral load specimens will be run by the Central Laboratory 
 
10.2. 
Schedule of Time and Events 
A schedule of study assessments table is located in Appendix 1. Minor changes to the assessment 
schedule may be made to accommodate holidays, administrative closures, etc., which if 
necessary, are not considered as significant deviations by the Sponsor. Sites should contact the 
Sponsor (or its representative) prospectively to address rescheduling protocol assessments and 
data handling. 
10.2.1. 
Screening Phase 
The following screening observations and procedures will be completed prior to Day 1:  
 Obtain a signed IRB/IEC/REB-approved informed consent  
 Confirm patient eligibility by reviewing inclusion/exclusion criteria 
 Obtain medical history including comorbid conditions hypertension, diabetes, coronary 
artery disease, hyperlipidemia, asthma, other notable pre-existing conditions 
 Record predicted body weight  
 Record supplemental oxygen/ ventilation status and parameters 
 Blood Pressure/MAP/vasopressor use 
 Collect sample for laboratory assessments per Schedule of Assessments  
 12-lead ECG 
 Review of concomitant medications 
 Record SOFA and Apache IV score 
 Record previous day's Daily Fluid Balance, if available 
10.2.2. 
Hospitalization/Treatment Phase 
All subjects will receive standard supportive care according to the policies of the treating 
institution.  Subjects will be randomized in a 1:1 ratio to receive either: 
 GC4419 by IV infusion q 12 hours (+/- 2 hours), plus standard supportive care, or 
 Placebo by IV infusion q 12 hours (+/- 2 hours), plus standard supportive care only 


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Subjects will receive, in a blinded fashion, either GC4419, 90 mg intravenously, or placebo, 
administered over 3 hours (180 minutes), repeated every 12 hours (+/- 2 hours) for 7 consecutive 
days.  Study drug infusions should not begin if the subject’s mean arterial pressure (MAP) is less 
than 65 mmHg.  
The following observations and procedures will be completed per the schedule of assessments:  
 Supplemental oxygen/ventilation status and parameters 
 Blood Pressure/MAP 
 SaO2 or PaO2/FiO2 ratio 
 Collect sample for laboratory assessments per schedule of assessments  
 Review of concomitant medications and adverse events 
 SOFA scores 
 Daily Fluid Balance 
 Administer GC4419/placebo  
10.2.3. 
Post ICU Discharge 
The following observations and procedures will be completed per the schedule of assessments  
 Blood Pressure/MAP 
 SaO2 or PaO2/FiO2 ratio  
 Collect sample for laboratory assessments per schedule of assessments 
 Review of concomitant medications and adverse events 
 
10.3. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Adverse Events and Serious Adverse Events will be assessed daily during hospitalization and 
weekly after hospital discharge, for a total of 6 weeks after day 1 and encompassing at least 30 
days after end of GC4419/placebo dosing (experimental arm subjects).  Post-treatment AE 
assessments may be done on an outpatient basis for subjects who are discharged from the 
hospital.  
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE as provided in this protocol. Throughout the study, AEs will be 
recorded in the source documents and on the appropriate pages of the CRF regardless of whether 
the AEs are considered related to GC4419/placebo. To avoid confusion, the AE should be 
recorded in standard medical terminology. 
10.4. 
Definitions 
The following definitions of terms are guided by the International Conference on Harmonization 
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10.4.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
Examples of an AE include: 
 Significant or unexpected worsening or exacerbation of the condition/indication under 
study.   
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity (grade) of the condition. 
 New conditions detected or diagnosed after investigational product administration even 
though they may have been present prior to the start of the study. 
 Signs, symptoms, or the clinical sequelae associated with a suspected interaction of the 
investigational product with a concomitant medication. 
 Signs, symptoms, or the clinical sequelae associated with a suspected overdose of either 
investigational product or a concurrent medication. 
10.4.2. 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening – NOTE: The term ‘life-threatening’ in the definition of ‘serious’ refers 
to any adverse drug experience [adverse event] that places the patient or subject, in the 
view of the investigator, at immediate risk of death from the reaction as it occurred, ie, it 
does not include a reaction that, had it occurred in a more severe form, might have 
caused death.   
 Requires inpatient hospitalization or prolongation of hospitalization – NOTE: In general, 
hospitalization signifies that the patient or subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether “hospitalization” occurred or was necessary, the AE should be 
considered serious. Hospitalization for elective treatment of a pre-existing condition that 
did not worsen from baseline is not considered an AE. 
 Results in persistent or significant disability/incapacity – NOTE: The term disability 
means a substantial disruption of a person’s ability to conduct normal life functions. 
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 Is a congenital abnormality/birth defect. 
 Is an other important medical event 
10.5. 
Adverse Event Reporting Requirements 
10.5.1. 
Serious Adverse Events 
All events meeting the criteria for SAEs (see Section 10.4.2) must be reported by investigational 
sites within 24-hours of becoming aware of the event. The investigator may determine that the 
event is the natural progression of disease and therefore should be reported as an AE, but not a 
Serious AE.  Some examples are as follows: 
 Progression of respiratory failure to require artificial ventilation 
 Prolongation of hospitalization due to ventilator-associated pneumonia 
 Persistent oxygen requirement lasting beyond hospital discharge 
In order to determine the sponsor’s timeline for notifying regulatory authorities and investigators 
per Federal Regulations, an event term, serious criteria, and causality is required at the time of 
the initial report. Specific SAE reporting instructions are provided in a separate manual. 
The investigator is responsible for notifying the IRB/IEC/REB in writing of serious events as 
soon as is practical in accordance with the policy of the IRB/IEC/REB. 
10.5.2. 
All Adverse Events (AEs) Regardless of Seriousness 
Any adverse medical condition or laboratory abnormality with an onset date before the date of 
the baseline visit is considered to be pre-existing in nature, and part of a subject’s medical 
history. Adverse medical conditions that begin on or after date of baseline visit will be 
considered an AE, including SAEs, and followed for 30 days after end of treatment 
GC4419/placebo. Similarly, new events will be reported as AEs/SAEs if the start date is within 
30 Day Follow-up Period. Increases in toxicity grade of pre-existing conditions that occur on or 
after the date of the baseline visit are also considered an AE. 
All AEs must be recorded in the patient’s source documents and on the CRF regardless of 
frequency, severity (grade) or assessed relationship to study drug.  
10.5.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs 
and SAEs 
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
associated with the disease being studied, unless judged by the investigator as more severe than 
expected for the patient’s condition, or that are present or detected at the time of the baseline 
visit and do not worsen, will not be reported as AEs or SAEs.   
A laboratory abnormality reported by the local laboratory may meet the criteria to qualify as an 
AE or SAE as described in this protocol. Laboratory abnormalities should only be recorded in 
the AE section of the CRF if at least one of the following criteria is met: 
 Meets the criteria of an SAE 


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 Treatment is initiated specifically for the abnormality 
 Investigational product was discontinued 
 Grade 3 or Grade 4 abnormalities not present at baseline, and more severe than expected 
for the patient's condition in the judgment of the treating investigator 
For laboratory abnormalities meeting the criteria of SAEs, the site must complete and send the 
SAE report including the laboratory report (as regionally required) to the sponsor using the SAE 
form.  
Abnormal assessments (eg, ECGs) that are judged by the investigator as clinically significant 
will be recorded as AEs or SAEs if they meet the definitions as defined in Section 10.4.   
10.5.4. 
Grading of Adverse Events 
The severity of adverse events will be designated as mild, moderate, severe, life threatening, or 
fatal per NCI CTCAE version 5.0. If not specifically addressed in NCI CTCAE version 5.0, use 
Table 3 below: 
Table 3:  Adverse Event Severity 
Grade  
Criteria1 
Mild – Grade 1 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Moderate – Grade 2 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL2 
Severe – Grade 3 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL3 
Life Threatening – Grade 4 
Life-threatening consequences; urgent intervention indicated 
Death – Grade 5 
Death related to adverse event 
1  A semi-colon indicates ‘or’ within the description of the grade. 
2  Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
3  Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
10.6. 
Relationship to Study Drug 
All AEs will be categorized by the investigator with respect to their relationship to 
GC4419/placebo. The relationship between GC4419/placebo and the AE may be considered 
related, possibly related, or unrelated. The criteria for each category are listed below: 
 Related: It is likely that GC4419/placebo caused or contributed to the cause of the AE or 
laboratory abnormality, when the temporal sequence from the time of GC4419/placebo 
administration, the known consequences of the patient’s clinical/state condition or study 
procedures, the effects of discontinuing or re-introducing GC4419/placebo on the AE, 
and other medically relevant factors are considered.   


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 Possibly Related: There is a reasonable possibility that the AE or laboratory abnormality 
was caused by GC4419/placebo, when the temporal sequence from the time of 
GC4419/placebo administration, the known consequences of the patient’s clinical 
state/condition or study procedures, and other medically relevant factors are considered.   
 Unrelated: The investigator has a high level of certainty that the patient’s clinical 
state/condition, study procedures, or other medically relevant factors other than treatment 
with GC4419/placebo caused the AE or laboratory abnormality. This relationship 
category should only be used when a clear precipitating cause exists, and it is not 
reasonably possible that the event is caused by treatment with GC4419/placebo. 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possibly related” the event will be considered to be related to the investigational product for the 
purposes of expedited regulatory reporting. 
10.7. 
Recording Adverse Events 
All AEs must be recorded on the appropriate CRF regardless of the severity or relationship to 
GC4419/placebo. All AEs that meet the seriousness criteria should also be recorded on the SAE 
Report Form. All SAEs must be reported to the Sponsor or delegated organization within the 
timeline stated in Section 10.5. 
The recording of AEs will be based on data obtained from the following sources: 
 Medical and surgical history 
 Physical examinations including vital signs 
 Clinical laboratory test results 
 Subject verbal reports to the investigational staff and documented in the medical chart 
All clinical events, including both observed (such as any reaction at sites of application) and 
volunteered problems, complaints, or symptoms, are to be recorded. The need to capture this 
information is not dependent upon whether the clinical event is associated with GC4419/placebo 
use. AEs resulting from concurrent illnesses, reactions to concurrent medications are also to be 
recorded. 
The information to be recorded for AEs will include: 
 The specific type of event in standard medical terminology – diagnosis if known, is 
preferred over symptoms 
 Duration of the clinical event (start and stop dates) 
 Severity (Grade 1, 2, 3, 4, or 5) of the clinical event 
 Seriousness (SAE) criteria, if applicable 
 Relationship of the AE to GC4419/placebo as defined in Section 10.6 
 Management of GC4419/placebo administration and other action taken to alleviate the 
clinical events 


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 Clinical outcome of the AE 
10.8. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient 
and provide further information on the patient’s condition. The investigator will ensure that 
follow-up includes any supplemental investigations as may be indicated to elucidate the nature 
and/or causality of the AE or SAE. This may include additional laboratory tests or investigations, 
or consultation with other health care professionals. 
Non-serious AEs that have not resolved by the end of the prescribed Follow-up Period will be 
considered ongoing, and marked as such in the CRF. All SAEs will be followed until they 
resolve, or a new baseline is established, at which point the appropriate CRF page(s) or SAE 
Report Form(s) will be updated.   
Routine collection of AEs will stop 30 days after the end of treatment.   
As reasonably requested by the Sponsor, the investigator will perform or arrange for the conduct 
of supplemental measurements and/or evaluations to elucidate as fully as possible the nature 
and/or causality of the AE or SAE. If a patient dies during participation in the study or during a 
recognized follow-up period, Galera Therapeutics, Inc. will be provided with a copy of any 
post-mortem findings, including histopathology. 
10.9. 
Post-Study Reporting Requirements 
Although such information may not be routinely sought or collected by Galera Therapeutics, 
Inc., SAEs that occur after the patient has completed a clinical study may be reported. Such cases 
will be evaluated for expedited reporting. 
10.10. 
Pregnancy 
The risks of treatment with GC4419 during pregnancy have not been evaluated. Male subjects 
and female subjects of childbearing potential who engage in heterosexual intercourse should use 
a highly effective method of contraception starting at least on day prior to the first day of 
treatment and throughout the study and for 30 days (females) or 90 days (males) following the 
last dose of GC4419/placebo. 
All females will be considered to be of childbearing potential unless they are postmenopausal 
(eg, amenorrheic for at least 12 consecutive months, in the appropriate age group, and without 
other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, 
total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing). 
Subjects with a vasectomy or a vasectomized partner with confirmed azoospermia are eligible. 
Highly effective methods of contraception include any of the following: 
◦ 
total abstinence from heterosexual intercourse (per circumstances and lifestyle) 
◦ 
an intrauterine device or intrauterine hormone-releasing system (IUS) 


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◦ 
a contraceptive implant 
◦ 
an oral contraceptive at a stable dose of the same oral contraceptive product, begun at 
least 28 days before dosing and throughout the study and continued for 30 days after study 
drug discontinuation)   
Pregnant and/or lactating females are excluded. 
 
A subject who becomes pregnant must be withdrawn from the study. 
Pregnancies or exposure to study drug through breastfeeding must be reported as soon as 
possible but no later than 24 hours from the date the investigator becomes aware of the event. 
The contact information for the reporting of pregnancies and exposure to study drug through 
breastfeeding is provided in the Investigator Study File. The outcome of the pregnancy must be 
reported as soon as possible but no later than 24 hours from the date the investigator becomes 
aware of the outcome. 
10.10.1. 
Time Period for Collecting Pregnancy Information 
As permitted by IRB/EC/REB policies, any pregnancy that occurs from the baseline visit up to 
30 days after the last dose of GC4419/placebo should be reported using the appropriate form 
within 2 weeks of learning of the patient’s pregnancy. The patient will be followed throughout 
the course of the pregnancy. Generally, follow-up will be no longer than six to eight weeks 
following the estimated delivery date. Any premature termination of the pregnancy should be 
reported. If a pregnancy is identified outside the 30 days after last dose, the investigator may 
report using clinical judgment.  
10.10.2. 
Action to be Taken if Pregnancy Occurs in a Female Partner of a Male Patient 
The investigator will attempt to collect pregnancy information on any female partner of a male 
study patient who becomes pregnant while participating in this study. The investigator will 
record pregnancy information on the appropriate form and submit it to Galera Therapeutics, Inc. 
within 2 weeks of learning of the partner’s pregnancy. The partner will also be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and child will 
be forwarded to Galera Therapeutics, Inc.. Generally, follow-up will be no longer than six to 
eight weeks following the estimated delivery date. Any premature termination of the pregnancy 
will be reported. If a pregnancy is identified outside the 30 days after end of treatment, the 
investigator may report using clinical judgment. 
10.11. 
Regulatory Reporting of Adverse Events 
Galera Therapeutics, Inc. will have final determination of reportability and is responsible for 
notifying the relevant regulatory authorities of certain events. The investigator will report all 
SAEs that occur at his/her site to the IRB per the site’s IRB regulations. AEs will be reported to 
regulatory authorities in compliance with 21 Code of Federal Regulations (CFR) 312.32, local and 
regional law and established guidance by the Sponsor or its designee. The format of the reports 
will be dictated by the local and regional requirements.  


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Investigators will also be notified of all unexpected, serious, drug-related events (7/15 Day 
Safety Reports) that occur during the clinical trial. Each site is responsible for notifying its 
IRB/IEC/REB of these additional SAEs in accordance with local or central IRB/IEC/REB 
procedures. Copies of each report will be kept in the investigator’s files and adequate 
documentation will be provided to Galera Therapeutics, Inc. including documentation that the 
IRB/IEC/REB was notified of each safety report.  


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11. 
STATISTICS 
11.1. 
General Considerations 
A separate statistical analysis plan will provide technical details of the statistical analyses to be 
performed, in addition to the specifications in this protocol. 
11.2. 
Sample Size  
For this group with critical disease, the null hypothesis is that 50% of subjects will survive for 28 
days.  The alternative hypothesis is that at least 90% of subjects receiving GC4419 will survive 
for 28 days compared with the control survival of 50%.   A sample size of 50 subjects, 25 in each 
group, is expected to provide approximately 80% power to detect this difference with a 
two-sided alpha of 0.05.           
11.3. 
Randomization and Stratification 
Eligible subjects will be randomized 1:1 to the two treatment arms using a permuted block 
randomization schedule. Randomization will be stratified by age (<60 versus ≥60 years).  
11.4. 
Analysis Populations 
All randomized subjects who receive at least one dose of blinded GC4419/placebo will be 
included in the population to be analyzed for safety and efficacy. 
11.5. 
Definition of Endpoints 
11.5.1. 
Primary Endpoint 
 The primary endpoint is 28-day mortality 
11.5.2. 
Secondary Efficacy Endpoints 
 safety of avasopasem 
 frequency of successful ventilator weaning 
 days alive and intensive care-free  
 days alive and ventilator-free  
 days alive with minimum PaO2/FiO2 ≥ 300mmHg 
 days alive and without vasopressor/catecholamine support 
 incidence of mean arterial pressure < 65 mmHg on optimized vasopressor therapy 
 days alive with a SOFA score of 6 or less 
 percentage of subjects with an increase in mean arterial pressure of 10 mm Hg or more at 
the end of more than one infusion of GC4419 


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11.5.3. 
Exploratory Endpoints 
 Levels of circulating cytokines IL-6, TNF-alpha, IL-1 beta, IL-10 
 SARS-CoV-2 viral load 
 Plasma exposure to GC4419  
 Lung compliance to be calculated from clinical data for exploratory purposes 
11.6. 
Safety Analysis 
Adverse events will be grouped by system organ class, high level term, and preferred term 
according to the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. Incidence 
by subject will be tabulated for all treatment emergent, serious, severe, and treatment-related 
AEs. Detailed listings will be provided for all SAEs, deaths, and withdrawals due to AEs. 
Laboratory measurements, vital signs, and ECG parameters will be summarized by treatment 
group at each of the protocol specified time points.  
Further details will be provided in the trial’s statistical analysis plan.  
11.6.1. 
Interim Safety Analysis 
An independent Data Monitoring Committee (DMC) will perform an unblinded safety 
review while subjects in the study receive GC4419/Placebo (Section 14.4). 
 
11.7. 
Primary Efficacy Analysis 
11.7.1. 
Primary Analysis  
The primary endpoint of 28-day mortality will be compared between the GC4419 and control 
group using an exact Cochran-Mantel-Haenszel (CMH) test stratified by age group (<60 vs ≥60 
years) at the two-sided 0.05 Type I error rate. The measure of association will be the CMH 
stratified relative risk of death by Day 28 along with an asymptotic 95% exact confidence 
interval. For each age stratum, 28-day mortality will be presented descriptively. Should any 
chance imbalance occur between the groups for important baseline prognostic factors, the effect 
of these covariates on the inference on treatment may also be examined through logistic 
regression or similar methods. 
 
11.7.2. 
Secondary and Exploratory Analyses  
Secondary and exploratory endpoints will be analyzed descriptively, and results tabulated.  As 
appropriate, percentages and 95% confidence intervals will be calculated. 


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12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
12.1. 
Study Monitoring 
In accordance with International Conference on Harmonisation Good Clinical Practice (ICH 
GCP) guidelines, the study monitor must have direct access to the investigator’s source 
documentation in order to verify the consistency of the data recorded in the electronic CRFs. 
The monitor is responsible for routine review of the electronic CRFs at regular intervals 
throughout the study, to verify adherence to the protocol, and the completeness, consistency and 
accuracy of the data being entered on them. The monitor should have full access to any patient 
records needed to verify the entries on the electronic CRFs. The investigator agrees to cooperate 
with the monitor to assure that any follow-up items identified in the course of these monitoring 
visits are resolved. 
The investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any 
relevant issues. 
Due to the timing of this study, it will be necessary to allow monitor remote access to the 
electronic medical record in order to perform CRF review against source documents remotely. 
During site visits, the monitor will: 
 Check the progress of the study; 
 Review study data collected; 
 Conduct source document verification; 
 Identify any issues and address their resolution; 
 This will be done in order to verify that the: 
o Data are authentic, consistent, accurate, and complete; 
o Safety and rights of subjects are being protected; 
o Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements. 
12.2. 
Audits and Inspections 
Authorized representatives of Galera Therapeutics, Inc., a regulatory authority, an IEC or an IRB 
may visit the site to perform audits or inspections, including source data verification. The 
purpose of a Galera Therapeutics, Inc. audit or inspection is to systematically and independently 
examine all study-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to the protocol, 
GCP guidelines of the ICH, and any applicable regulatory requirements. The investigator should 
contact Galera Therapeutics, Inc. immediately if contacted by a regulatory agency about an 
inspection. 


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12.3. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
In general, major protocol deviations include deviations from inclusion/exclusion criteria, from 
concomitant medication restrictions, and from any other protocol requirement that could, at least 
hypothetically, result in significant risk to the subject and/or affect the outcome of the clinical 
trial. Major protocol deviations will be noted in the final Clinical Summary Report.   
A minor deviation is defined as non-adherence to the protocol procedures or schedule as defined 
by the protocol or the primary endpoint that does not place the subject at any added or significant 
risk or affect the data quality or the outcome of the clinical trial (eg, a missed procedure, an 
out-of-window site visit).   
Only subjects who meet protocol-defined eligibility criteria may be enrolled in this clinical trial. 
If any protocol eligibility criteria or procedures are unclear, the investigator or investigational 
site personnel should contact the Clinical Research Associate. If the question requires medical 
interpretation, the sponsor’s medical monitor should be consulted. All protocol deviations should 
be reported to the IRB/IEC according to the standard practices of the investigational site and 
applicable regulatory requirements.  
12.4. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Galera Therapeutics, Inc. or its representatives. All protocol modifications must be 
submitted to the IRB/IEC/REB and regulatory authorities in accordance with local requirements. 
Approval must be obtained before changes can be implemented. 
12.5. 
Information Disclosure 
12.5.1. 
Ownership 
All information provided by Galera Therapeutics, Inc. or its representatives, and all data and 
information generated by the site as part of the study (other than a subject’s medical records), are 
the sole property of Galera Therapeutics, Inc. 
12.5.2. 
Confidentiality 
All information provided by Galera Therapeutics, Inc. or its representatives, and all data and 
information generated by the site as part of the study (other than a subject’s medical records) will 
be kept confidential by the investigator and other site staff. Information related to this study is 
subject to the confidentiality provisions of the Clinical Research Agreement between the 
investigative site and Galera Therapeutics, Inc. 


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12.5.3. 
Publication 
All publication or presentation rights for the findings of the clinical investigation under this 
protocol shall be governed by the appropriate terms of the Clinical Research Agreement between 
the investigational site and Galera Therapeutics, Inc. 


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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The study will be monitored and managed in accordance with ICH GCP E6. 
To ensure compliance with GCPs and all applicable regulatory requirements, Galera 
Therapeutics, Inc. or its representatives may conduct a quality assurance audit. 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. 


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14. 
ETHICS 
14.1. 
Ethical Conduct of the Study 
The investigator will ensure that this study is conducted in full compliance with the principles of 
the “Declaration of Helsinki” (version October 2008), ICH guidelines, in particular ICH GCP 
E6, or with the laws and regulations of the country in which the research is conducted, whichever 
affords the greatest protection to the study patient. The investigator will also assure that the basic 
principles outlined in “ICH Guideline for Good Clinical Practice” as published in the Federal 
Register May 9, 1997, and all applicable Federal regulations including 21 CFR parts 50, 54, 56, 
and 312 are adhered to. 
14.2. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Research Ethics Board (REB) Approval 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted, by the investigator, to an IRB/IEC/REB. Approval from the 
IRB/IEC/REB must be obtained and a copy must be provided to Galera Therapeutics, Inc. or its 
representatives before initiating the conduct of any study procedures including screening or 
enrolling any subjects into the trial. 
No modifications or deviations from this protocol other than those that are deemed medically 
necessary by the Principal Investigator or designated sub-investigator are to be made. Any 
protocol deviations will be reported to Galera Therapeutics, Inc. and to the IRB/IEC/REB in 
accordance with its reporting policy. 
Any modifications made to the protocol by the sponsor after receipt of IRB/IEC/REB approval 
must be submitted to the committee for approval prior to implementation. 
14.3. 
Written Informed Consent 
In accordance with regulatory and local IRB/IEC/REB requirements, before study procedures are 
performed, subjects will be informed about the study and required to sign the IRB/IEC/REB 
approved ICF. This form will be signed after adequate explanation of the aims, methods, 
objective and potential hazards of the study and prior to undertaking any study-related 
procedures. The Sponsor or its designee will provide an ICF template to the investigator. The 
Sponsor or its designee must approve changes to the ICF template prior to submission to the 
IRB/IEC/REB. Informed consent will be obtained according to the applicable IRB/IEC/REB 
requirements. No patient is to be screened or treated until an ICF, written in a language in which 
the patient or his/her legally authorized representative is fluent, has been obtained. The signed 
ICF will be retained with the study records. Each patient will also be given a copy of his/her 
signed ICF.  
14.4. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be responsible for safeguarding the 
interests of the subjects by reviewing study data and providing recommendations about whether 


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the study is safe to proceed with ongoing enrollment as written and whether a protocol 
modification is required. The DMC will receive weekly updates on SAEs considered to be at 
least possibly related to study drug and will make a recommendation based on monthly 
cumulative summaries of these possibly related SAEs.  The DMC will also be convened for 
review of available unblinded safety data and summaries of clinical data determined by the DMC 
to be relevant after 20 subjects have completed blinded dosing of GC4419/placebo, and may 
convene other meetings at its discretion.  The DMC may recommend that further dosing of study 
treatment be discontinued and enrollment be halted pending further review if it finds that either 
a) more than 20% of GC4419 subjects require treatment discontinuation because of the 
protocol’s criteria for dose reductions and discontinuation or b) the incidence of possibly related 
serious adverse events in the GC4419 arm constitute an unacceptable safety risk. 
 


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15. 
DATA HANDLING AND RECORDKEEPING 
15.1. 
Case Report Forms 
All required study data must be recorded on the electronic CRF provided by Galera 
Therapeutics, Inc. or its representatives. The data recorded onto the electronic CRF is derived 
from the source documents. The investigator shall ensure that all data in the electronic CRF is 
accurate and consistent with the source documents or that any discrepancies of the electronic 
CRF with source documents are explained (ICH E6 4.9.2).   
Electronic CRFs will be accessed by the study center for collection of all study data, and a copy 
of the electronic CRF will be provided to the site for the investigator files. For each patient who 
is randomized to the study, the electronic CRF must be completed by site staff and must be 
signed electronically by the principal investigator in a timely fashion after data collection. If a 
patient withdraws from the study, the electronic CRFs should be promptly completed and the 
reason for withdrawal must be noted. If a patient is withdrawn from the study because of a 
drug-related toxicity, thorough efforts should be made to clearly document the outcome. 
The sponsor will ensure that the electronic CRF selected meets the requirements per ICH E6 R2 
with regard to data collection and handling, system maintenance, system security measures, 
change control, data backup, recovery, contingency planning, and decommissioning. 
15.2. 
Retention/Inspection of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. 
Records of drug receipt and disposition, electronic file of CRFs, source documents, reports of 
this investigation and other study documentation must be maintained by the investigator for a 
period of at least two years following the date on which the investigational drug is approved by 
FDA or other applicable regulatory agency for marketing for the purposes that were the subject 
of the clinical investigations. If no application is to be filed, records must be retained until two 
years following the date that the study is discontinued and the FDA or other applicable 
regulatory agency is notified. If the application is not approved by the FDA or other applicable 
regulatory agency for such indication, records must be retained for two years after notification by 
Galera Therapeutics, Inc. of the FDA or other applicable regulatory agency decision. The records 
must be available for copying and inspection if requested by regulatory authorities.   
Galera Therapeutics, Inc. should be notified in writing at least 30 days prior to the disposal or 
transfer to another location or party of any study records related to this protocol. 


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16. 
LIST OF REFERENCES 
 
Anderson CM, Sonis ST, Lee CM, et al.  Phase 1b/2a trial of the superoxide dismutase mimetic 
GC4419 to reduce chemoradiotherapy-induced oral mucositis in patients with oral cavity or 
oropharyngeal carcinoma.  Int J Radiat Oncol Biol Phys 100:427-435, 2018. 
Anderson CM, Lee CM, Saunders DP, et al.  Phase IIb randomized, double-blind trial of 
GC4419 versus placebo to reduce severe oral mucositis due to concurrent radiotherapy and 
cisplatin for head and neck cancer.  J Clin Oncol 37:3256-3265, 2019. 
Cuzzocrea S, Mazzon E, Di Paola R, et al.  Protective effects of M40401, a selective superoxide 
dismutase mimetic, on zymosan-induced non-septic shock.  Crit Care Med 32:157-167, 2004. 
Herzog EL, unpublished data, 2014 
Macarthur H, Westfall DC, Riley DP, et al.  Inactivation of catecholamines by superoxide gives 
new insights on the pathogenesis of septic shock.  PNAS 97:9753-9758, 2000. 
Macarthur H, Couri DM, Wilken GH, et al.  Modulation of serum cytokine levels by a novel 
superoxide dismutase mimetic, M40401, in an Escherichia coli model of septic shock: 
Correlation with preserved circulating catecholamines.  Crit Care Med 31:237-245, 2003. 
Masini, et al, Free Rad Biol Med, 39:520-31, 2005. 
Sishc BJ, Polsdofer E, Bloom DA, et al. The radioprotector GC4419 ameliorates radiation 
induced lung fibrosis while enhancing the response of non-small cell lung cancer tumors to high 
dose per fraction radiation exposures.  AACR Ann Mtg 2018, abstract 667, 2018.  
Wu C, Chen X, Cai Y, et al.  Risk factors associated with acute respiratory distress syndrome 
and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.  JAMA 
Internal Medicine, published online March 13, 2020, doi.10.1001/jamainternmed.2020, 0994, 
accessed 8 April 2020 
Yang X, Yu U, Xu J et al.  Clinical course and outcomes of critically ill patients with SARS-
CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.  
Lancet Respiratory, published online February 21, 2020, doi.10.1016/S2213-2600(20)30079-5, 
accessed 8 April 2020 
COVID-19 Projections accessed 15Apr2020  Health Data, Institute for Health Metrics and 
Evaluations, https://covid19.healthdata.org/projections 
Galera Therapeutics, Inc.  ROMAN: A Study to Investigate the Effects of GC4419 on Radiation 
Induced Oral Mucositis in Patients with Head/Neck Cancer.  Available from 
https://clinicaltrials.gov/ct2/show/NCT03689712.  NLM identifier:  NCT03689712. 
 
 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS  
Assessments 
Screening/ 
Baseline 
In hospital 
After discharge from 
ICU 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Each 
additional 
Day in ICU 
Weekly until 30 days 
after last 
GC4419/placebo 
dose18 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
Inclusion/exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
Age/Medical history1 
X 
  
  
  
  
  
  
  
  
  
Predicted Body Weight 2 
X 
  
  
  
  
  
  
  
  
  
Supplemental oxygen/ventilation status and 
parameters 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Blood pressure/MAP/vasopressor use 4, 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum or urine pregnancy test 
X 
  
  
  
  
  
  
  
  
  
12-lead ECG  
X 
  
  
  
  
  
  
  
  
  
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X16 
SaO2 or PaO2 /FiO2 ratio 6 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
SOFA score 6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Apache IV score 7 
X 
 
 
 
 
 
 
 
 
  
Daily Fluid Balance 8 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
Hematology, serum chemistry 9 
X 
X 
X 
X 
X 
X 
X 
X 
X17 
X17 
GC4419/placebo administration 10 
  
X 
X 
X 
X 
X 
X 
X 
 
  
Blood for cytokines 11, 12 
X 
X 
  
  
  
  
  
 X 
X11 
  
Viral load testing 13 
X14 
X 
  
  
  
  
  
 X 
X13 
 
Pharmacokinetic blood testing 15 
 
X 
 
X 
 
 
 
 
 
 


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1 Include comorbid conditions hypertension, diabetes, coronary artery disease, hyperlipidemia, asthma, other notable pre-existing conditions 
2 Predicted body weight:  males—PBW in kg = 50 + 2.3 x (height in inches – 60).  Females—45.5 + 2.3 x (height in inches – 60)  
3 Record maximum support needed, once per 24 hour period: ON/OFF mechanical ventilation; high-flow O2, mask, non-rebreather mask, mechanical 
ventilation for each 24-hour period; also record the following daily before 10 am (but at least 30 minutes after any sedation vacation): tidal volume, minute 
ventilation, PEEP, peak inspiratory pressure, plateau pressure, prone positioning yes/no, hours per day of prone positioning.  Lung compliance to be 
calculated from clinical data for exploratory purposes. 
4  Once during screening, then q12 hours and also before each GC4419/placebo infusion, every 30 minutes during each GC4419/placebo infusion, at end of 
each GC4419/placebo infusion, and 1, 2, and 4 hours post GC4419/placebo  
5   Record vasopressor requirements once at screening and q12 hours while on vasopressors; record specific vasopressor and dose in 
mcg/minute; not applicable post discharge 
6   Record worst value once a day assessed 8am-6pm 
7  https://intensivecarenetwork.com/Calculators/Files/Apache4.html. Record worst value in past 24 hours at baseline visit only.   
8  Record highest value during any 24-hour period  
9  Performed locally.  CBC with differential and platelets; sodium, potassium, chloride, CO2, BUN, creatinine, total protein/albumin, AST/ALT, and total 
bilirubin. Include direct bilirubin, triglycerides, C-reactive protein, and troponin at baseline only unless clinically indicated.  If baseline troponin is above 
ULN, the highest post-baseline value during hospitalization and the value closest to date of discharged will also be collected.  Record Worst Value for 
Any Day When Multiple Labs are Drawn. 
10  Administer 90 mg IV over 180 minutes, Q 12 hours (+/- 2 hours) for 7 days.  It is acceptable for the timing of the first 2 doses to be modified in order to 
accommodate subsequent dosing on a Q12 hour schedule that meets institution’s standard of care procedures.  Study drug infusions should not begin if the 
subject’s mean arterial pressure (MAP) is less than 65 mmHg. 
11  Collected once during screening/baseline, at Day 7 and Day 14 (while in the hospital); blood sample to be stored on site for analysis by 
central lab at end of study 
12  IL-1 beta, IL-6, TNF-alpha, IL-10 
13  Screening sample to be performed by local lab with a duplicate sample collected for central lab analysis.  Subsequent samples collected at Day 7 and Day 
14 (while in the hospital) for central lab analysis.  Nasopharyngeal sample required unless subject is intubated, in which case pulmonary secretion 
collected.   
14  If viral load test has been performed within 7 days of baseline, no repeat is necessary at baseline 
15  Collected pre and post first infusion on Day 1 and Day 3 for central lab analysis  
16  Adverse Events will be assessed weekly after hospital discharge, for a total of 6 weeks from Day 1 and encompassing at least 30 days after end of 
GC4419/placebo dosing. Post-treatment AE assessments may be done on an outpatient basis for subjects who are discharged from the hospital.        
17  As Clinically Indicated, Record Worst Value for Any Day When Multiple Labs are Drawn. 
18  If subjects are not able to come into the hospital or clinic for an in-person visit, it is acceptable for a virtual visit or phone call to take place.  
 


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APPENDIX 2. SEQUENTIAL ORGAN FAILURE ASSESSMENT 
 
 
 


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APPENDIX 3. GLASOW COMA SCALE SCORE CRITERIA 
 
 
 
 


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APPENDIX 4. EXAMPLES OF CYP2D6-SUBSTRATE DRUGS 
Beta Blockers and 
Antiarrhythmics 
Antidepressant, 
Antipsychotics and 
Other Neurological 
Analgesics and 
Antiemetics 
Other 
 
Carvedilol 
Haloperidol 
Tramadol 
Dextromethorphan 
Metoprolol 
Desipramine 
Codeine 
Eliglustat 
Propafenone 
Nortriptyline 
Oxycodone 
Tolterodine 
Nebivolol 
Perphenazine 
Ondansetron 
Tamoxifen 
Propranolol 
Atomoxetine 
Metoclopramide 
Deutetrabenazine 
Timolol 
Venlafaxine 
 
Valbenazine 
Encainide 
Amitriptyline 
 
Tetrabenzine 
Flecainide  
Clomipramine 
 
 
Mexilitene 
Imipramine 
 
 
 
Trimipramine 
 
 
 
Aripiprazole 
 
 
 
Brexpiprazole 
 
 
 
Donepezil 
 
 
 
Doxepin 
 
 
 
Duloxetine 
 
 
 
Fluoxetine 
 
 
 
Fluvoxamine 
 
 
 
Paroxetine 
 
 
 
Risperidone 
 
 
 
Thioridazine 
 
 
 
Zuclopenthixol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Red: CYP2D6 substrates commonly prescribed in ICU setting (Zhuo et al Pharmagenomics of 
Medications Commonly Used in the Intensive Care Unit. Frontiers in Pharmacol, 2018; 9: 1436.) 
Bold: Sensitive index substrates that demonstrate an increase in AUC of ≥5-fold with 
strong CYP2D6 inhibitors in clinical DDI studies.