Conditions: Coronavirus Disease 2019 Disease Caused by Severe Acute Respiratory Syndrome Coronavirus 2
Keywords: acute respiratory distress syndrome varespladib LY333013 severe acute respiratory syndrome coronavirus 2 coronavirus disease 2019 ARDS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 18
Healthy volunteers: no

Brief summary:
This is a 2-part, multi-center, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability, and efficacy of oral varespladib, in addition to standard of care, in patients hospitalized with severe COVID-19 caused by SARS-CoV-2.

Detailed description:
The goals of this 2-part, multi-center, randomized, double-blind, placebo-controlled, phase 2 study are to define a safe dose for the population and to assess the safety, tolerability, and efficacy of orally dosed varespladib to improve survival without respiratory failure in patients hospitalized with severe coronavirus disease 2019 (COVID-19), when given in addition to the institutional standard of care therapy.

Mortality rates of COVID-19 are strongly linked to acute respiratory distress syndrome (ARDS) which may be, additionally, correlated with elevations of secretory phospholipase 2 (sPLA2) and widespread loss of functioning lung tissue. Upregulation of sPLA2 is thought to be involved in the dysregulated inflammatory cascade pathways (increased markers of immune activation, also known as cytokine release syndrome) and enzymatic degradation of lung surfactant linked to the development of ARDS. It is believed that treatment with varespladib, a potent inhibitor of sPLA2, might prevent or mitigate progression of pulmonary dysfunction in COVID-19 patients by two mechanisms: suppression of sPLA2-induced inflammation and, uniquely, preservation of pulmonary surfactant by direct inhibition of the enzyme responsible for surfactant phospholipid degradation: sPLA2.

Data from previous phase 2 clinical trials of varespladib suggested it had potential to reduce mortality in severely septic patients with ARDS, particularly when treatment was initiated within 18 hours of identification of organ failure.

The study will be conducted in two parts. Both parts will be randomized and double-blind. Part 1 will be dose-finding in four parallel treatment groups randomized to treatment with varespladib (at 250 mg once daily \[QD\], twice daily \[BID\], or three times daily \[TID\] \[250, 500, or 750 mg/day\]) or placebo in a 5:5:5:3 ratio. After all participants in Part 1 have completed Day 28, a data safety monitoring board (DSMB) will review the safety results from Part 1, including all available safety data through Day 60, and will recommend the dose regimen to be used in Part 2. Part 2 will randomize an additional 72 participants to the dose regimen selected from Part 1 or placebo in a 1:1 ratio.

In both parts of the study, eligible participants will be enrolled and randomized to receive active varespladib or placebo in addition to institutional standard of care for 7 days.

Participants will be assessed daily per standard of care while hospitalized and on a regular basis after discharge. The Day 1, 4, 7, 14, and 28 visits will be performed in person (either at the hospital/site or via a home health provider) to assess safety, obtain blood and urine samples for laboratory tests, and obtain clinical outcome data. The Day 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 45, and 60 visits for discharged participants may be conducted by phone or via electronic patient-reported outcome (ePRO) devices.

Efficacy will be assessed by respiratory failure-free survival at Day 28. Safety will be assessed by evaluating adverse events (AEs), vital sign measurements, use of oxygen therapies, changes in levels of biomarkers, clinical laboratory test results, electrocardiograms (ECGs), physical examination findings, and concomitant medications and therapies. A DSMB will evaluate safety data at specified intervals during both parts of the trial.

Pharmacokinetic (PK) samples will be drawn from all participants in Part 1 and in a subset of approximately 14 participants in Part 2 in order to enable estimation of PK parameters in approximately 22 participants receiving active treatment with varespladib.

Arms:
arm 1: For 7 days, and in addition to institutional standard of care, participants will take 250 mg varespladib in the morning. In order to maintain the blind, they will also take 1 placebo tablet in the afternoon and 1 placebo tablet in the evening. arm 2: For 7 days, and in addition to institutional standard of care, participants will take 250 mg varespladib in the morning and in the evening. In order to maintain the blind, they will also take 1 placebo tablet in the afternoon. arm 3: For 7 days, and in addition to institutional standard of care, participants will take 250 mg varespladib in the morning, in the afternoon, and in the evening. arm 4: For 7 days, and in addition to institutional standard of care, participants will take 1 placebo tablet in the morning, in the afternoon, and in the evening. arm 5: Dose chosen for Part 2 was twice a day dosing. For 7 days, and in addition to institutional standard of care, participants will take 250 mg varespladib in the morning, and in the evening. arm 6: For 7 days, and in addition to institutional standard of care, participants will take 1 placebo tablet in the morning, and in the afternoon.

Interventions: intervention 1: Varespladib intervention 2: Placebo
Intervention descriptions: intervention 1: 250 mg immediate-release oblong, white, film-coated tablet for oral administration intervention 2: Oral formulation matched to the oral varespladib tablet

Protocol document:
Prot_000.pdf: 






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2. PROTOCOL SUMMARY 
2.1. Synopsis 
PRODUCT 
NAME/NUMBER 
Varespladib-methyl 
PROTOCOL 
NUMBER 
OPX-PR-02 
DEVELOPMENT 
PHASE 
2 
PROTOCOL TITLE 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Safety, Tolerability, and Efficacy of Varespladib in Patients Hospitalized with 
Severe COVID-19 Caused by SARS-CoV-2 
INDICATION 
Severe coronavirus disease 2019 (COVID-19) 
STUDY 
POPULATION 
Adult participants aged 18 to 80 years diagnosed with severe laboratory-confirmed 
COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
OBJECTIVES 
The objectives of this study are as follows: 
Primary: 
• 
To evaluate the safety, tolerability, and efficacy of varespladib in patients 
hospitalized with severe COVID-19 when given in addition to the institutional 
standard of care 
Secondary: 
• 
To evaluate the efficacy of varespladib in reducing the need for respiratory support 
• 
To evaluate the efficacy of varespladib in reducing the duration of hospitalization  
• 
To evaluate the efficacy of varespladib in improving time to recovery  
• 
To evaluate time to resolution of symptoms 
• 
To evaluate the efficacy of varespladib in reducing the incidence of morbidity and 
mortality 
Exploratory: 
• 
To assess the pharmacokinetics (PK) of varespladib in COVID-19 patients 
• 
To evaluate the overall effect of varespladib in suppression of secretory 
phospholipase A2 (sPLA2) with SARS-CoV-2 infection 
• 
To assess pharmacoeconomic outcomes 
STUDY DESIGN 
This is a 2-part, multi-center, randomized, double-blind, placebo-controlled, phase 2 
study designed to evaluate the safety, tolerability, and efficacy of oral varespladib, in 
addition to standard of care, in patients hospitalized with severe COVID-19 caused by 
SARS-CoV-2. 
The goals of this study are to define a safe dose for the population and to assess the 
safety, tolerability, and efficacy of orally dosed varespladib to improve survival 
without respiratory failure in patients hospitalized with severe COVID-19 when given 
in addition to the institutional standard of care therapy. 
The mortality rates of COVID-19 are strongly linked to acute respiratory distress 
syndrome (ARDS) which is correlated with elevations of sPLA2 and widespread loss 
of functioning lung tissue. Upregulation of sPLA2 has been shown to be involved in 
the dysregulated inflammatory cascade pathways (increased markers of immune 
activation, also known as cytokine release syndrome) and enzymatic degradation of 
lung surfactant linked to the development of ARDS. It is believed that treatment with 


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varespladib, a potent inhibitor of sPLA2, will prevent or mitigate progression of 
pulmonary dysfunction in COVID-19 patients by two mechanisms: suppression of 
sPLA2-induced inflammation and, uniquely, preservation of pulmonary surfactant by 
direct inhibition of the enzyme responsible for surfactant phospholipid degradation: 
sPLA2. 
Data from previous phase 2 clinical trials of varespladib suggest it was capable of 
reducing mortality in severely septic patients with ARDS, particularly when treatment 
was initiated within 18 hours of identification of organ failure.  
The study will be conducted in 2 parts. Both parts will be randomized and double-
blind. Part 1 will be dose-finding in 4 parallel treatment groups randomized to 
treatment with varespladib (at 250 mg once daily [QD], twice daily [BID], or three 
times daily [TID] [250, 500, or 750 mg/day]) or placebo in a 5:5:5:3 ratio. After all 
participants in Part 1 have completed Day 28, a data safety monitoring board (DSMB) 
will review results from Part 1, including all available safety data through Day 60, and 
will recommend the dose regimen to be used in Part 2. Part 2 will randomize an 
additional 72 participants to the dose regimen selected from Part 1 or placebo in a 1:1 
ratio.  
In both parts of the study, eligible participants will be enrolled and randomized to 
receive active varespladib or placebo in addition to institutional standard of care for 
7 days (7 complete days of study drug administration after randomization). 
Participants will be assessed daily per standard of care while hospitalized and on a 
regular basis after discharge. The Day 1, 4, 7, 14, and 28 visits will be performed in 
person (either at the hospital/site or via a home health provider) to assess safety, obtain 
blood and urine samples for laboratory tests, and obtain clinical outcome data. The Day 
2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 45, and 60 visits for discharged 
participants may be conducted by phone or via electronic patient-reported outcome 
(ePRO) devices. 
Efficacy will be assessed by respiratory failure-free survival at Day 28. Safety will be 
assessed by evaluating adverse events (AEs), vital sign measurements, use of oxygen 
therapies, changes in levels of biomarkers, clinical laboratory test results, 
electrocardiograms (ECGs), physical examination findings, and concomitant 
medications and therapies. A DSMB will evaluate safety data at specified intervals 
during both parts of the trial. 
Pharmacokinetic samples will be drawn from all participants in Part 1 and in a subset 
of approximately 14 participants in Part 2 in order to enable estimation of PK 
parameters in approximately 22 participants receiving active treatment with 
varespladib. The pharmacokinetic characterization of drug concentrations for each dose 
to be profiled will use noncompartmental analysis. Standard PK parameters assessed 
will include measures of the extent of absorption using estimates of the area-under-the-
curve (AUC) and rate-of-absorption using the maximum concentration (Cmax) and the 
time of Cmax (Tmax). 
 
 


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PLANNED NUMBER 
OF PARTICIPANTS 
Approximately 90 participants will be enrolled. Part 1 of the study will enroll 
18 participants; Part 2 of the study will enroll approximately 72 participants in a 1:1 
ratio. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria: 
1. Participant is hospitalized with severe COVID-19 illness, defined in accordance 
with the FDA Guidance for Industry – COVID-19: Developing Drugs and 
Biological Products for Treatment or Prevention (May 2020): 
a. 
Severe illness: 
i. Symptoms suggestive of severe systemic illness with COVID-19, 
which could include any symptom of moderate illness or shortness of 
breath at rest, or respiratory distress  
ii. Clinical signs indicative of severe systemic illness with COVID-19, 
such as respiratory rate ≥ 30 per minute, heart rate ≥ 125 per minute, 
SpO2 ≤ 93% on room air at sea level or partial pressure of oxygen 
PaO2/fraction of inspired oxygen FiO2 < 300  
2. Participant has a positive virologic nucleic acid amplification test (NAAT) 
indicating SARS-CoV-2 infection in a sample collected < 72 hours prior to 
randomization.  
3. Participant is between the ages of 18 and 80 years at the time of enrollment. 
4. Participant (or legally authorized representative) provides informed consent 
prior to initiation of any study procedures. 
5. Participant agrees to not participate in another clinical trial for the treatment of 
COVID-19 or SARS-CoV-2 through Day 28. 
6. Participant has adequate hematologic status (in the absence of transfusion and 
growth factor support for at least 28 days), defined as follows: 
a. Absolute neutrophil count (ANC) ≥1.5 × 109/L 
b. Platelet count ≥75 × 109/L 
c. Hemoglobin ≥9 g/dL 
7. Participant has an Eastern Cooperative Oncology Group (ECOG) performance 
score of 0-2. 
Exclusion criteria: 
1. Participant has mild, moderate, or critical COVID-19 defined in accordance with 
the FDA Guidance for Industry: 
a. 
Mild COVID-19: 
i. Symptoms of mild illness with COVID-19 that could include fever, 
cough, sore throat, malaise, headache, muscle pain, gastrointestinal 
symptoms, without shortness of breath or dyspnea  
ii. No clinical signs indicative of moderate, severe, or critical severity 
b. Moderate COVID-19: 
i. Symptoms of moderate illness with COVID-19, which could include 
any symptom of mild illness (fever, cough, sore throat, malaise, 
headache, muscle pain, gastrointestinal symptoms) or shortness of 
breath with exertion  
ii. Clinical signs suggestive of moderate illness with COVID-19, such as 
respiratory rate ≥ 20 breaths per minute, peripheral oxygen saturation 
(SpO2) > 93% on room air at sea level, heart rate ≥ 90 beats per minute  
iii. No clinical signs indicative of severe or critical illness  


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c. 
Critical COVID-19: 
i. Respiratory failure defined based on resource utilization requiring at 
least one of the following:  
• 
Endotracheal intubation and mechanical ventilation 
• 
Oxygen delivered by high-flow nasal cannula ([HFNC] heated, 
humidified, oxygen delivered via reinforced nasal cannula at flow 
rates > 20 L/min with fraction of delivered oxygen ≥ 0.5) 
• 
Noninvasive positive pressure ventilation 
• 
extracorporeal membrane oxygenation (ECMO), or  
• 
Clinical diagnosis of respiratory failure (i.e., clinical need for one 
of the preceding therapies, but preceding therapies not able to be 
administered in setting of resource limitation)  
ii. Shock (defined by systolic blood pressure < 90 mmHg, or diastolic 
blood pressure < 60 mmHg or requiring vasopressors)  
iii. Multi-organ dysfunction/failure  
2. Participant has taken investigational medications within 7 days or 5 half-lives 
prior to enrollment, whichever is shorter. 
3. Participant has required any new form of sedation, anxiolysis or central nervous 
system (CNS) depressant within the 48 hours prior to enrollment that would 
interfere with neurologic assessments at enrollment. 
4. Has history of cerebrovascular accident or intracranial bleeding of any kind, 
acute coronary syndrome, myocardial infarction, or severe pulmonary 
hypertension. 
5. Participant has chronic respiratory failure not associated with COVID-19, 
defined as prior need for home oxygen, need for home noninvasive positive-
pressure ventilation (NIPPV) for reasons other than isolated sleep apnea, or 
other signs of chronic respiratory failure, in the investigator’s judgment. 
6. Upper gastrointestinal (GI) bleed evidenced by hematemesis, “coffee-ground” 
emesis or nasogastric aspirate, or hematochezia thought to originate from 
upper GI tract. 
7. Participant has abnormal liver function defined as any 2 of the following at 
screening:  
a. 
Total bilirubin ≥ 2 × ULN 
b. Alanine aminotransferase (ALT) ≥ 3 × ULN 
c. 
Aspartate aminotransferase (AST) ≥ 3 × ULN 
d. Alkaline phosphatase (ALP) > 3× ULN 
e. 
Gamma-glutamyl transferase (GGT) > 3 × ULN 
8. Participant has an estimated glomerular filtration rate (eGFR) < 60 mL/min. 
9. Participant has a known allergy or significant adverse reaction to varespladib-
methyl or related compounds. 
10. Participant is considered by the investigator to be unable to comply with protocol 
requirements due to geographic considerations, psychiatric disorders, or other 
compliance concerns; or has any serious medical condition or clinically 
significant laboratory, ECG, vital sign, or physical examination abnormality that 
would prevent study participation or place the participant at significant risk, as 
judged by the Investigator. 
11. Participant is breast-feeding, pregnant, has a positive serum hCG pregnancy test, 
or is not willing to use a highly effective method of contraception for 14 days 
after treatment. Highly effective methods of contraception are as follows: 


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a. 
Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
b. Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable) 
c. 
Intrauterine device, intrauterine hormone-releasing system 
d. Bilateral tubal occlusion 
e. 
Vasectomized partner 
f. 
Sexual abstinence 
g. Double-barrier method (condoms, sponge, diaphragm, with spermicidal 
jellies, or cream) 
INVESTIGATIONAL 
PRODUCTS (IP) 
Test: varespladib-methyl (LY333013) 250 mg immediate-release, oblong, white, film-
coated tablet for oral administration 
LY333013 contains the excipients anhydrous lactose USP/National Formulary (NF), 
lactose monohydrate USP/NF, hydroxypropyl cellulose USP/NF, polysorbate 80 
(vegetable source) USP/NF, microcrystalline cellulose USP/NF, croscarmellose sodium 
USP/NF, magnesium stearate (vegetable source) USP/NF, and the film coat Opadry II 
85F18422 White. 
Reference: placebo 
Oral formulation matched to the oral varespladib tablet. 
TREATMENT 
REGIMENS 
Varespladib or placebo will be administered in addition to institutional standard of 
care for 7 days. 
Part 1: Participants will be randomized to receive varespladib (250 mg QD, BID, or 
TID [250, 500, or 750 mg/day]) or placebo in a 5:5:5:3 ratio.  
Part 2: Participants will be randomized to receive varespladib or placebo in a 1:1 
ratio. The varespladib dose for Part 2 will be the dose selected from Part 1. 
The written institutional standard of care at each site may change during the study. 
Other COVID-19 treatments currently approved or authorized for emergency use by 
the FDA are permitted if in the institution’s written standard of care.  
PLANNED STUDY 
SITES 
Approximately 5 to 10 study sites in the United States. 
CRITERIA FOR 
EVALUATION 
Efficacy endpoints: 
Primary efficacy endpoint: 
• Proportion of participants alive and free of respiratory failure at Day 28 (respiratory 
failure is defined in exclusion criterion 1.c.i) 
Secondary efficacy endpoints: 
• Clinical improvement as measured by the World Health Organization (WHO) 9-point 
ordinal scale from baseline through Day 60 
• Time to and proportion of subjects with all-cause mortality through Day 60 
• Proportion of participants who experienced respiratory failure within the first 28 days 
after randomization 
• Among patients that never experience respiratory failure in the first 28 days, time to 
initiation, duration, and proportion of subjects receiving supplemental oxygen or 
other respiratory support within the first 28 days after randomization   
• Among patients that experience respiratory failure in the first 28 days, time to 
initiation and duration of the forms of respiratory support meeting criteria outlined in 
critical COVID criteria (exclusion criteria 1.c.i) within the first 28 days after 
randomization  


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• Number of days of oxygen support through Day 28 after randomization 
• SpO2 through Day 28 after randomization 
• Number of ventilator-free days through Day 28 after randomization 
• Number of hospitalization days through Day 28 after randomization 
• Number of days without renal stabilization and/or replacement through Day 28 after 
randomization 
• Number of organ failure-free days through Day 28 after randomization 
• Number of days at elevated level of care (intensive care unit [ICU]) through Day 28 
after randomization 
• Number of healthcare encounters through Day 28 after randomization 
Exploratory endpoints: 
• sPLA2 within blood samples from treatment initiation to Day 28 after randomization 
Safety and tolerability endpoints: 
• Incidence and severity (based on National Cancer Institute [NCI] Common 
Terminology Criteria for Adverse Events [CTCAE] v5.0 grade) of AEs, serious AEs, 
and AEs leading to discontinuation of IP 
• Vital signs 
• Changes in levels of biomarkers: cardiac troponin, C-reactive protein, and ferritin 
• Clinical laboratory evaluations 
• 12-lead ECGs 
PK endpoints (exploratory): 
• PK parameters  
Pharmacoeconomic endpoints (exploratory): 
• Selected secondary endpoints to include number of healthcare encounters, number of 
hospitalization days, and number of days at elevated level of care (ICU), after 
randomization through Day 28. 
STATISTICAL 
METHODS 
Descriptive statistics (n, mean, median, standard deviation [SD], minimum, and 
maximum for continuous data; frequencies and percentages for categorical data) will be 
used to summarize study data and details of analyses as outlined in the study Statistical 
Analysis Plan (SAP). Quantitative outcomes (i.e., durations of interventions or 
healthcare events, ordinal scales, SpO2, and concentrations) will generally be analyzed 
via ANCOVA models for change from baseline. Dichotomous outcomes (i.e., 
occurrence of interventions or healthcare events) will generally be analyzed with 
logistic regression models, with risk differences presented and calculated via the delta 
method. Time-to-event outcomes (i.e., mortality, time till interventions or healthcare 
events) will generally be analyzed with Cox proportional hazards models. These 
analyses will control for covariates to be specified in the SAP. Pharmacokinetic and 
biomarker data will be summarized descriptively. Further details and specifications are 
provided in the SAP. 
SAMPLE SIZE 
DETERMINATION 
A total of approximately 90 participants will be randomized, 18 in Part 1 and 72 in 
Part 2. This is an exploratory proof of concept study and is not powered based on 
statistical assumptions. 
STUDY AND 
TREATMENT 
DURATION 
The overall study duration is expected to be approximately 18 months (6 months of 
active enrollment and 2 months of follow-up in Part 1; 2 to 4 weeks for DSMB review 
of Part 1 results at Day 28 and selection of the Part 2 dose; 6 months of active 
enrollment in Part 2; and 2 months of follow-up in Part 2). 
The sequence and approximate duration of the study periods will be as follows: 


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1. 
Screening: up to 72 hours 
2. 
Treatment: 7 days 
3. 
Follow-up: 28 days after randomization  
4. 
Safety follow-up: 45 and 60 days after randomization  
The maximum study duration for each participant is approximately 60 days. 
The treatment duration for each participant is 7 days from the point of randomization (7 
complete days of study drug administration after randomization). Screening/enrollment 
and baseline (Day 1) of the Treatment Period can take place on the same day if the 
required screening test results are available. 
 






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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES ...................................................................................................2 
2. 
PROTOCOL SUMMARY ........................................................................................................4 
2.1. Synopsis ..........................................................................................................................4 
2.2. Schedule of Events ........................................................................................................11 
3. 
TABLE OF CONTENTS .......................................................................................................13 
3.1. List of In-text Tables .....................................................................................................17 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...........................................18 
5. 
INTRODUCTION ..................................................................................................................21 
5.1. Background and Rationale ............................................................................................21 
5.2. Clinical Experience .......................................................................................................22 
5.3. Summary of Potential Risks and Benefits .....................................................................22 
6. 
OBJECTIVES AND ENDPOINTS ........................................................................................24 
7. 
STUDY DESIGN ...................................................................................................................26 
7.1. Overall Study Design and Plan .....................................................................................26 
7.2. Rationale and Discussion of Study Design ...................................................................27 
7.3. Selection of Doses in the Study ....................................................................................27 
7.4. Study Sites .....................................................................................................................28 
7.5. End of Study Definition ................................................................................................28 
8. 
PARTICIPANT POPULATION ............................................................................................29 
8.1. Selection of Study Population .......................................................................................29 
8.2. Study Entry Criteria ......................................................................................................29 
8.2.1 Inclusion Criteria ...............................................................................................29 
8.2.2 Exclusion Criteria ..............................................................................................29 
8.3. Participant Replacement................................................................................................31 
9. 
TREATMENTS ......................................................................................................................32 
9.1. Identification of Investigational Products .....................................................................32 
9.2. Timing of Dose for Each Participant ............................................................................32 
9.3. Dose Adjustment Criteria ..............................................................................................33 
9.4. Premature Participant Withdrawal ................................................................................33 
9.5. Discontinuation of Study Intervention ..........................................................................33 
9.5.1 Individual Participant Halting Criteria ..............................................................33 
9.5.2 Management of Acute Kidney or Liver Injury ..................................................34 
9.5.3 Study Halting Criteria .......................................................................................34 
9.6. Treatment Compliance ..................................................................................................35 
9.7. Method of Assigning Participants to Treatment Groups...............................................35 
9.8. Blinding and Unblinding Treatment Assignment .........................................................35 
9.9. Prohibited and Permitted Therapies ..............................................................................36 


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9.9.1 Prohibited Therapies ..........................................................................................36 
9.9.2 Permitted Therapies ...........................................................................................36 
9.10. Treatment After End of Study .......................................................................................36 
9.11. Dispensing and Storage .................................................................................................37 
9.12. Drug Accountability ......................................................................................................37 
9.13. Labeling.........................................................................................................................37 
10. STUDY PROCEDURES ........................................................................................................38 
10.1. Study Duration ..............................................................................................................38 
10.2. Study Periods and Visits ...............................................................................................38 
10.2.1 Screening ...........................................................................................................38 
10.2.2 Treatment Period ...............................................................................................39 
10.2.2.1 Day 1 .....................................................................................................39 
10.2.2.2 Day 2 .....................................................................................................40 
10.2.2.3 Day 3 .....................................................................................................40 
10.2.2.4 Day 4 .....................................................................................................40 
10.2.2.5 Day 5 .....................................................................................................41 
10.2.2.6 Day 6 .....................................................................................................41 
10.2.2.7 Day 7 .....................................................................................................41 
10.2.3 Follow-up Period ...............................................................................................42 
10.2.3.1 Days 8, 9, 10, 11, 12, and 13 .................................................................42 
10.2.3.2 Day 14 (±2) ...........................................................................................42 
10.2.3.3 Days 15, 16, 17, 18, 19, and 20 .............................................................42 
10.2.3.4 Day 21 (±2) ...........................................................................................42 
10.2.3.5 Day 28 (±2) or at time of Early Termination ........................................43 
10.2.3.6 Day 45 (±3) ...........................................................................................43 
10.2.3.7 Day 60 (±4) ...........................................................................................43 
10.3. Assessments ..................................................................................................................44 
10.3.1 Efficacy Assessments ........................................................................................44 
10.3.1.1 Oxygen Support ....................................................................................44 
10.3.1.2 WHO 9-point Ordinal Scale ..................................................................44 
10.3.1.3 Healthcare Encounters ..........................................................................44 
10.3.2 Pharmacokinetics ...............................................................................................45 
10.3.2.1 Pharmacokinetic Analysis Methods ......................................................45 
10.3.2.2 Pharmacokinetic Parameters .................................................................45 
10.3.2.3 Pharmacokinetic Sample Collection .....................................................45 
10.3.3 Safety Variables ................................................................................................45 
10.3.3.1 Clinical Laboratory Safety Assessments ...............................................45 
10.3.3.2 Clinical Examinations ...........................................................................46 


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10.3.3.3 Adverse Events......................................................................................47 
11. ADVERSE EVENTS..............................................................................................................48 
11.1. Definitions .....................................................................................................................48 
11.1.1 Adverse Events ..................................................................................................48 
11.1.2 Unexpected Adverse Event ...............................................................................48 
11.1.3 Serious Adverse Events .....................................................................................48 
11.1.4 Treatment-emergent Adverse Events ................................................................49 
11.2. Event Assessment and Follow-up of Adverse Events ..................................................49 
11.2.1 Assessment ........................................................................................................49 
11.2.2 Evaluation ..........................................................................................................49 
11.2.2.1 Severity of Adverse Events ...................................................................49 
11.2.2.2 Seriousness ............................................................................................50 
11.2.2.3 Action(s) Taken .....................................................................................50 
11.2.2.4 Outcome at the Time of Last Observation ............................................50 
11.2.2.5 Adverse Event Relationship to Investigational Product........................51 
11.2.3 Documentation ..................................................................................................51 
11.2.4 Treatment of Adverse Events ............................................................................51 
11.2.5 Reporting ...........................................................................................................52 
11.2.5.1 Serious Adverse Events.........................................................................52 
11.3. Special Considerations ..................................................................................................53 
11.3.1 Adverse Events of Special Interest ....................................................................53 
11.3.2 Pregnancy ..........................................................................................................53 
11.3.3 Overdose ............................................................................................................53 
12. DATA SAFETY MONITORING BOARD ...........................................................................54 
13. STATISTICS ..........................................................................................................................55 
13.1. Statistical Analysis ........................................................................................................55 
13.1.1 Analysis Populations .........................................................................................55 
13.1.2 Study Participants and Demographics ...............................................................56 
13.1.2.1 Disposition and Withdrawals ................................................................56 
13.1.2.2 Protocol Deviations ...............................................................................56 
13.1.2.3 Demographics and Other Baseline Characteristics ...............................56 
13.1.3 Exposure and Compliance .................................................................................56 
13.1.4 Efficacy Analysis ..............................................................................................56 
13.1.4.1 Efficacy Endpoints ................................................................................57 
13.1.4.2 Primary Analysis ...................................................................................58 
13.1.4.3 Secondary Analyses ..............................................................................58 
13.1.4.4 Exploratory Analyses ............................................................................59 
13.1.4.5 Clinical Pharmacology Analyses ..........................................................59 


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13.1.5 Safety and Tolerability Analyses ......................................................................59 
13.1.5.1 Adverse Events......................................................................................59 
13.1.5.2 Clinical Laboratory Evaluations, Vital Signs, Electrocardiograms, and 
Pulse Oximetry.......................................................................................................60 
13.1.5.3 Biomarkers ............................................................................................60 
13.1.6 Interim Analysis ................................................................................................60 
13.2. Sample Size Determination ...........................................................................................60 
14. STUDY CONDUCT ...............................................................................................................61 
14.1. Sponsor and Investigator Responsibilities ....................................................................61 
14.1.1 Sponsor Responsibilities ...................................................................................61 
14.1.2 Investigator Responsibilities .............................................................................61 
14.1.3 Confidentiality and Privacy ...............................................................................61 
14.2. Site Initiation .................................................................................................................62 
14.3. Screen Failures ..............................................................................................................62 
14.4. Study Documents ..........................................................................................................62 
14.4.1 Informed Consent ..............................................................................................63 
14.4.2 Investigator’s Regulatory Documents ...............................................................63 
14.4.3 Case Report Forms ............................................................................................63 
14.4.4 Source Documents .............................................................................................64 
14.5. Data Quality Control .....................................................................................................64 
14.5.1 Monitoring Procedures ......................................................................................64 
14.5.2 Data Management ..............................................................................................65 
14.5.3 Quality Assurance/Audit ...................................................................................65 
14.6. Study Termination .........................................................................................................66 
14.6.1 Premature Study Termination ...........................................................................66 
14.7. Study Site Closure .........................................................................................................66 
14.7.1 Record Retention ...............................................................................................67 
14.7.2 Sample Retention ..............................................................................................67 
14.8. Changes to the Protocol ................................................................................................67 
14.9. Use of Information and Publication ..............................................................................67 
14.10. 
Impact of COVID-19 on Current Conduct of Clinical Trials ...........................68 
15. ETHICAL AND LEGAL CONSIDERATIONS ....................................................................69 
15.1. Good Clinical Practice ..................................................................................................69 
15.2. Participant Information and Informed Consent and/or Assent .....................................69 
15.3. Approval by Institutional Review Board ......................................................................69 
15.4. Finance and Insurance ...................................................................................................69 
16. REFERENCES .......................................................................................................................70 
17. ATTACHMENTS ...................................................................................................................71 


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17.1. Investigator’s Agreement ..............................................................................................71 
APPENDICES ...............................................................................................................................72 
A. 
Study-specific Requirements ........................................................................................73 
B. 
Regulations and Good Clinical Practice Guidelines .....................................................74 
 
 
3.1. List of In-text Tables 
Table 2-1: 
Schedule of Events ............................................................................................11 
Table 10-1: 
WHO 9-point Ordinal Scale ..............................................................................44 
 
 
 


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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
EXPLANATION 
ACS 
acute coronary syndrome 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase  
ANCOVA 
analysis of covariance model 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate aminotransferase 
AUC 
area-under-the-curve 
BID 
twice daily 
BUN 
blood urea nitrogen  
CBC 
complete blood count 
CFR 
code of federal regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
cerebrovascular accident 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate  
ePRO 
electronic patient-reported outcome 
ET 
early termination 
FDA 
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 


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ABBREVIATION 
EXPLANATION 
hCG 
human chorionic gonadotropin  
HFNC 
high-flow nasal cannula 
HRPO 
Human Research Protection Office  
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
intensive care unit 
IND 
investigational new drug 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous 
IWRS 
interactive web response system  
MI 
myocardial infarction  
MMRM 
mixed-model repeated measures  
NAAT 
nucleic acid amplification test 
NCI 
National Cancer Institute (United States) 
NF 
national formulary 
NIPPV 
noninvasive positive-pressure ventilation 
PaO2 
partial pressure of oxygen  
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PP 
per protocol 
Q12H 
every 12 hours 
QD 
once daily 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
sPLA2 
secretory phospholipase 2 
SpO2 
peripheral oxygen saturation 
TEAE 
treatment-emergent adverse event 
TID 
three times daily 
Tmax  
time of maximum concentration 
ULN 
upper limit of normal 


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ABBREVIATION 
EXPLANATION 
USP 
United States Pharmacopeia 
WHO 
World Health Organization  


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5. INTRODUCTION 
5.1. Background and Rationale 
Evaluation and management of coronavirus disease 2019 (COVID-19) depends on the severity of 
the disease; patients with mild disease typically recover at home. Patients with severe or critical 
COVID-19 are usually hospitalized for observation and supportive care. While most people with 
COVID-19 develop only mild (40%) or moderate (40%) disease, approximately 15% develop 
severe disease that requires oxygen support, and 5% develop critical disease with complications 
such as respiratory failure, acute respiratory distress syndrome (ARDS), sepsis and septic shock, 
thromboembolism, and/or multiorgan failure, including acute kidney injury and cardiac injury.1 
Despite decades of research and therapeutic development, mortality due to ARDS remains high, 
at approximately 25% to 40% in most studies.2 There is significant comorbidity and reduced 
quality of life in patients who survive.2 ARDS is a life-threatening, clinical complex of signs and 
symptoms resulting in respiratory failure. The most common clinical disorders associated with the 
development of ARDS are pneumonias of bacterial or viral origin. Among other reasons, ARDS 
is also commonly associated with sepsis due to non-pulmonary sources, trauma (including 
iatrogenic), and aspiration of gastric contents, and less commonly with pancreatitis and drug 
reactions. ARDS is characterized by rapid-onset pulmonary failure, often preceded by a 
dysregulated inflammatory response, with preceding or resulting pulmonary surfactant destruction 
resulting in a need for supplemental oxygen, extracorporeal membrane oxygenation, or varying 
degrees of mechanical respiratory support.3 These cycles of inflammation and surfactant 
destruction act synergistically to the point at which the innate immune response to insult becomes 
lethally maladaptive. Once pulmonary edema fluid accumulates in the interstitium and air spaces 
of the lungs, it causes difficulty in the mechanical work of breathing and impaired gas exchange, 
causing the sensation of impending doom associated with oxygen starvation. This can result in 
hypoxemia, reduced carbon dioxide excretion, and ultimately, respiratory failure.4 The reduction 
of the inflammation cascade that leads to deteriorating pulmonary function is crucial to the 
prevention of worsening disease and the development of ARDS. 
Several therapeutic agents have failed to improve ARDS outcomes; the current treatment strategy 
is largely supportive and based on optimized ventilator settings (defined by the ratio of arterial 
oxygen tension [partial pressure of oxygen] to fraction of inspired oxygen [PaO2/FiO2]).5 It is, 
therefore, critical to identify novel targeted therapies for ARDS that is related to, or induced by, 
COVID-19. 
Mild and moderate COVID-19 cases are usually defined as those without pneumonia, ARDS, or 
intensive care unit (ICU) admission.6 Data suggest that patients with moderate disease may have 
dyspnea, but the peripheral oxygen saturation (SpO2) saturation is often, paradoxically, within 
normal range on ambient air.7,8,9 Indicators of severe disease are marked tachypnea (respiratory 
rate ≥ 30 breaths per minute), hypoxemia (SpO2 ≤ 93%), PaO2/FiO2 < 300), and lung infiltrates 
(> 50% of the lung field involved within 24 to 48 hours).10 Among patients with severe disease, 
the median time to dyspnea from the onset of illness or symptoms ranges from 5 to 8 days and the 
median time to ARDS from the onset of illness or symptoms ranges from 8 to 12 days.11  
The mortality rates of COVID-19 are strongly linked to deteriorating pulmonary function, which, 
in turn, is also strongly correlated with the elevation of secretory phospholipase A2 (sPLA2) and 
widespread loss of functioning lung tissue. Upregulation of sPLA2 has been shown to be involved 
in the dysregulated inflammatory cascade pathways and enzymatic degradation of lung surfactant, 


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both of which are linked to ARDS. It is believed that treatment with varespladib, a potent inhibitor 
of sPLA2, will prevent or mitigate progression of ARDS in COVID-19 patients by two 
mechanisms: suppression of sPLA2-induced inflammation and, uniquely, preservation of 
pulmonary surfactant by direct inhibition of the enzyme responsible for surfactant phospholipid 
degradation: sPLA2. 
Data from previous phase 2 clinical trials suggest varespladib could be capable of reducing 
mortality in severely septic patients with ARDS, particularly when treatment was given within 
18 hours of identification of organ failure.12 This population corresponds with COVID-19 patients 
with severe disease as defined by the FDA.13 
The goal of treatment with varespladib in COVID-19 patients is to improve survival without 
respiratory failure from COVID-19. The goals of this study are to define a safe dose for the 
population and to assess the safety, tolerability, and efficacy of orally dosed varespladib to improve 
survival without respiratory failure in patients hospitalized with severe COVID-19, when given in 
addition to the institutional standard of care therapy.  
5.2. Clinical Experience 
Multiple clinical studies were previously performed by Eli Lilly and Anthera to characterize the 
safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of varespladib. The 
inflammatory conditions studied clinically by the previous sponsors for varespladib include sepsis, 
rheumatoid arthritis, ulcerative colitis, asthma, atherosclerosis, acute chest syndrome in at-risk 
patients with sickle cell disease, and psoriasis. Previous clinical studies are summarized in the 
current version of the varespladib investigator’s brochure (IB). 
5.3. Summary of Potential Risks and Benefits 
The potential benefits of study participation are improvement in survival and respiratory signs and 
symptoms. Study participants may experience fewer hospitalizations, fewer hospitalization days, 
and a more rapid recovery. It is hoped that this study will demonstrate oral varespladib to be a 
cost-effective and procedurally simplified treatment for patients with COVID-19.  
All subjects, regardless of arm randomized, will benefit from participation in this study through 
safety monitoring beyond the standard of care. Other benefits include added clinical oversight from 
local study physician(s), providers, nurses, and research staff, as well as medical personnel at the 
Sponsor and the Contract Research Organization. Continued monitoring/oversight starting with 
the subject entering the study, through day 60, from health professionals as part of the Post-
Treatment Observation Period will provide subjects clinical monitoring well beyond hospital 
discharge and normal follow up. Vital sign monitoring is a key aspect of this study, and due to the 
increased frequency of monitoring any trending of the subject status decreasing will potentially be 
identified earlier. All subjects will receive a total of six 12-lead electrocardiograms. Additional 
laboratory tests to monitor liver function, cardiac function, renal function, coagulation, and 
hematology in addition to standard of care will increase safety monitoring of all subjects. Because 
of the high-level of monitoring and oversight for patients within the study, these patients, including 
those randomized to placebo, will likely have more timely access to resources including clinician 
evaluation, procedures, and escalation of care if warranted.  
 


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The doses proposed for this study are anticipated to be safe and tolerable for adult participants. 
The potential risks of study participation include those associated with varespladib, including 
adverse events (AEs) and serious adverse events (SAEs) as well as the risks of medical evaluation 
and treatment, including the minimal possibility of allergic reaction from the study drug. Across 
clinical studies, varespladib was tolerated well and generally did not induce AEs beyond those 
observed in placebo treatment groups, even in severely ill participants. A total of seven Phase 1 
and three phase 2 studies were performed with varespladib, with a total of 733 participants 
receiving study drug by intravenous (IV) infusion. A total of twelve phase 1 and five phase 2 
studies were performed with varespladib-methyl, with a total of 3,679 participants receiving study 
drug as an oral tablet formulation. Common AEs observed included rhinitis, nausea, and diarrhea. 
No clinically meaningful varespladib or varespladib-methyl treatment-related effects were noted 
for biochemical and hematologic parameters other than modest transient increases in liver enzymes 
that occurred in a number of participants. Treatment with varespladib or varespladib-methyl was 
not associated with changes in heart rate or blood pressure and there was no evidence of an effect 
on ventricular repolarization (QT interval). SAEs including cerebrovascular accident (CVA) and 
myocardial infarction (MI) have been observed in some acutely ill participants in clinical trials for 
indications such as severe sepsis and acute coronary syndrome. Patients with conditions such as 
these are excluded from participation in the trial.  
In participants receiving varespladib (LY315920) by continuous IV infusion, plasma drug 
concentrations up to 800 ng/mL for 6 hours were tolerated well and treatment-related AEs were 
not prevalent. Short-term dosing with varespladib by IV infusion, resulting in plasma 
concentrations of up to 1,200 ng/mL for 30 minutes, did not induce any AEs; similarly, infusion 
of varespladib at doses up to 0.323 mg/kg/hour for 4 hours was well-tolerated with no treatment-
emergent adverse events (TEAEs) observed. Multiple oral doses of varespladib-methyl tablets 
(LY333013) up to 500 mg once every 12 hours (Q12H) were tolerated well. Thus, short-term 
treatment with varespladib or varespladib-methyl (e.g., up to 1 hour) at doses exceeding 0.2 
mg/kg/hr (IV) or 500 mg Q12H (oral) is not anticipated to induce AEs, TEAEs, or SAEs. In healthy 
participants, dosing with varespladib or varespladib-methyl for up to 7 days and at doses up to 
77 mg/kg (over 7 days IV) or 500 mg Q12H (orally for up to 12 weeks) did not induce SAEs. In 
participants with severe sepsis, continuous IV dosing with varespladib for up to 7 days at plasma 
concentrations of up to 800 ng/mL did not induce substantially more SAEs than were observed 
with placebo. Thus, administration of varespladib at the proposed doses for this protocol is not 
anticipated to induce AEs, even in severely ill participants such as those with severe COVID-19. 
A summary of the pharmaceutical properties and known potential risks of varespladib and 
varespladib-methyl is provided in the current version of the varespladib IB. The Investigator must 
become familiar with all sections of the varespladib IB before the start of the study.  






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7. STUDY DESIGN 
7.1. Overall Study Design and Plan 
This is a 2-part, multi-center, randomized, double-blind, placebo-controlled, phase 2 study 
designed to evaluate the safety, tolerability, and efficacy of oral varespladib, in addition to standard 
of care, in patients hospitalized with severe COVID-19 caused by SARS-CoV-2. 
Approximately 90 participants will be randomized, 18 in Part 1 and 72 in Part 2. Participants must 
be 18 to 80 years of age and have severe laboratory-confirmed COVID-19.  
The study will be conducted in 2 parts. Both parts will be randomized and double-blind. Part 1 
will be dose-finding in 4 parallel treatment groups randomized to treatment with varespladib (at 
250 mg once daily [QD], twice daily [BID], or three times daily [TID] [total doses of 250, 500, or 
750 mg/day]) or placebo in a 5:5:5:3 ratio. After all participants in Part 1 have completed Day 28, 
a data safety monitoring board (DSMB) will review results from Part 1 and will recommend the 
dose regimen to be used in Part 2. Part 2 will randomize an additional 72 participants to the dose 
regimen selected from Part 1 or placebo in a 1:1 ratio.  
In both parts of the study, eligible participants will be enrolled and randomized to receive either 
varespladib or placebo in addition to institutional standard of care for 7 days (7 complete days of 
study drug administration after randomization). 
Participants will be assessed daily per standard of care while hospitalized and on a regular basis 
after discharge. The Day 1, 4, 7, 14, and 28 visits will be performed in person (either at the 
hospital/site or via a home health provider) to assess safety, obtain blood and urine samples for 
laboratory tests, and obtain clinical outcome data. The Day 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 
17, 18, 19, 20, 21, 45, and 60 visits for discharged participants may be conducted by phone or via 
electronic patient-reported outcome (ePRO) devices. 
Efficacy will be assessed by respiratory failure-free survival at Day 28. For the purposes of this 
protocol, respiratory failure is defined as a subject requiring: 
• Endotracheal intubation and mechanical ventilation 
• Oxygen delivered by high-flow nasal cannula ([HFNC] heated, humidified, oxygen 
delivered via reinforced nasal cannula at flow rates > 20 L/min with fraction of delivered 
oxygen ≥ 0.5) 
• Noninvasive positive pressure ventilation 
• extracorporeal membrane oxygenation (ECMO), or  
• Clinical diagnosis of respiratory failure (i.e., clinical need for one of the preceding 
therapies, but preceding therapies not able to be administered in setting of resource 
limitation) 
Safety will be assessed by evaluating AEs, vital sign measurements, use of oxygen therapies, 
changes in levels of biomarkers, clinical laboratory test results, ECGs, physical examination 
findings, and concomitant medications and therapies. A DSMB will evaluate safety data at 
specified intervals during both parts of the trial. 


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All AEs observed by the study personnel or reported by the participant during the study (from the 
time of the signing of the informed consent through Day 60) will be documented. 
PK samples will be drawn from all participants in Part 1 and in a subset of approximately 
14 participants in Part 2 in order to enable estimation of PK parameters in approximately 
22 participants receiving active treatment with varespladib. 
7.2. Rationale and Discussion of Study Design 
The available nonclinical and clinical data are sufficient to support a small, phase 2, proof-of-
concept trial in adult participants with COVID-19. The initial dose-ranging part of the study will 
be used to select the safest dose that is likely to demonstrate clinical efficacy in Part 2 of the study 
and later trials. Safety reviews of data from Part 1 and interim data from Part 2 are designed to 
ensure participant safety prior to enrollment and treatment of a substantial number of participants.  
The use of a placebo control will enable interpretation of safety and efficacy data. The study design 
requires that both treatment arms (varespladib and placebo) receive standard of care concurrently. 
Thus, participants will receive treatment in a timely manner while being evaluated for the potential 
clinical benefit of varespladib. 
This study is designed to exclude as few potentially critically ill COVID-19 patients as possible. 
However, restricting the study population to severe patients and excluding the critical population 
will better enable interpretation of safety and toxicity data. In addition, excluding patients who 
already meet clinical criteria of chronic respiratory failure or who already require oxygen support 
will allow for clearer measurement of progression of acute respiratory failure and consistency with 
our underlying hypothesis.  
Given the safety concern for cerebrovascular accidents (CVA) and myocardial infarction (MI) due 
to COVID-19, patients at risk of CVA and acute coronary syndrome (ACS) are excluded, and 
patients requiring any form of sedation, anxiolysis, or central nervous system (CNS) depressant 
within the 48 hours prior to enrollment that would interfere with neurologic assessments at 
enrollment are excluded. Given the known modest, transient increases in liver enzymes with 
varespladib, patients with liver abnormalities are excluded. Given the predominantly renal 
clearance of varespladib, patients with renal insufficiency are excluded. 
The efficacy endpoints for this study were selected to demonstrate superiority of varespladib over 
placebo. The primary endpoint was selected to evaluate clear clinical benefit based on survival 
without respiratory failure, whereas secondary and exploratory endpoints were selected to evaluate 
a range of potential effects of varespladib over the course of treatment that may inform later trials. 
7.3. Selection of Doses in the Study 
The proposed dosing regimens of LY333013 (varespladib methyl) for the treatment of COVID-19 
infection are based on the available PK/PD from previous clinical studies. 
LY333013, which is administered orally, is the prodrug of LY315920, which is administered 
intravenously. LY333013 is rapidly absorbed and hydrolyzed to LY315920; therefore, only 
LY315920 is detected in the systemic circulation and LY333013 pharmacokinetics are based 
solely on concentrations of LY315920. Both formulations have been investigated in clinical 
studies in healthy participants and participants with various disease states.  


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The pharmacokinetics of LY315920 and LY333013 was investigated in 3 studies in participants 
with rheumatoid arthritis (Studies J4A-LC-EZZC, J4A-LC-EZZG, and H5P-MC-BWWC). 
Plasma clearance, steady-state volume of distribution, and drug elimination rates for LY315920 in 
participants with active rheumatoid arthritis are essentially similar to those observed in healthy 
participants.  
The dose regimens in this study are supported by efficacy and safety data from clinical studies 
conducted by Eli Lilly in severe sepsis, including multiple organ failure. Two of the studies 
(J4A-LC-EZZE and J4A-LC-EZZF) support a specific dosing strategy in patients with severe 
sepsis. This strategy is based on a target plasma concentration of 800 ng/mL using the IV 
formulation of varespladib (LY315920), which was shown to be an effective concentration for 
inhibition of sPLA2. Studies in various indications indicated that this target concentration may be 
achieved with a dosing regimen of 500 to 1000 mg per day when given with food (Studies H5P-
LC-BWWC, H5P-LC-BWXC, H5P-LC-BWWE, NCT00533039 [SPIDER-PCI], NCT00455546 
[PLASMA 1], NCT00525954 [PLASMA 2], NCT01130246 [VISTA-16], and NCT00743925 
[FRANCIS-ACS]).  
The dose regimen for participants in Part 2 will be selected based on Part 1 of this study.  
7.4. Study Sites 
The study will take place at approximately 5 to 10 sites in the United States. Each site is anticipated 
to screen a sufficient number of participants to randomize approximately 5 to 15 participants. Sites 
will be selected to ensure access to a representative cross-section of the US population. A study 
site with a high recruitment rate may be allowed to recruit more participants if other sites have 
slow enrollment. 
7.5. End of Study Definition 
The clinical trial is considered completed when the last participant’s final study visit has occurred. 


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8. PARTICIPANT POPULATION 
8.1. Selection of Study Population  
Investigators or their designees will maintain a screening log of all candidates who are considered 
for participation in this study, including reasons for ineligibility or refusal to participate. Consent, 
screening, randomization, and dosing may occur on the same day if test results are available. 
Participants who do not meet all of the eligibility criteria will not be enrolled. Approximately 
90 participants will be randomized. 
8.2. Study Entry Criteria 
8.2.1 Inclusion Criteria 
A participant will be eligible for study participation if he or she meets all of the following criteria: 
1. Participant is hospitalized with severe COVID-19 illness, defined in accordance with the 
FDA Guidance for Industry – COVID-19: Developing Drugs and Biological Products for 
Treatment or Prevention (May 2020): 
a. Severe illness: 
i. Symptoms suggestive of severe systemic illness with COVID-19, which could 
include any symptom of moderate illness or shortness of breath at rest, or 
respiratory distress  
ii. Clinical signs indicative of severe systemic illness with COVID-19, such as 
respiratory rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on 
room air at sea level or partial pressure of oxygen PaO2/fraction of inspired 
oxygen FiO2 < 300  
2. Participant has a positive virologic nucleic acid amplification test (NAAT) indicating 
SARS-CoV-2 infection in a sample collected < 72 hours prior to randomization.  
3. Participant is between the ages of 18 and 80 years at the time of enrollment. 
4. Participant (or legally authorized representative) provides informed consent prior to 
initiation of any study procedures. 
5. Participant agrees to not participate in another clinical trial for the treatment of 
COVID-19 or SARS-CoV-2 through Day 28. 
6. Participant has adequate hematologic status (in the absence of transfusion and growth 
factor support for at least 28 days), defined as follows: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
b. Platelet count ≥ 75 × 109/L 
c. Hemoglobin ≥ 9 g/dL 
7. Participant has an Eastern Cooperative Oncology Group (ECOG) performance score of 
0-2. 
8.2.2 Exclusion Criteria 
A participant will be excluded from the study if he or she meets any of the following criteria: 
1. Participant has mild, moderate, or critical COVID-19 defined in accordance with the FDA 
Guidance for Industry: 


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a. Mild COVID-19: 
i. Symptoms of mild illness with COVID-19 that could include fever, cough, sore 
throat, malaise, headache, muscle pain, gastrointestinal symptoms, without 
shortness of breath or dyspnea  
ii. No clinical signs indicative of moderate, severe, or critical severity 
b. Moderate COVID-19: 
i. Symptoms of moderate illness with COVID-19, which could include any 
symptom of mild illness (fever, cough, sore throat, malaise, headache, muscle 
pain, gastrointestinal symptoms) or shortness of breath with exertion  
ii. Clinical signs suggestive of moderate illness with COVID-19, such as 
respiratory rate ≥ 20 breaths per minute, peripheral oxygen saturation (SpO2) 
> 93% on room air at sea level, heart rate ≥ 90 beats per minute  
iii. No clinical signs indicative of severe or critical illness  
c. Critical COVID-19: 
i. Respiratory failure defined based on resource utilization requiring at least one of 
the following:  
• Endotracheal intubation and mechanical ventilation 
• Oxygen delivered by high-flow nasal cannula ([HFNC] heated, humidified, 
oxygen delivered via reinforced nasal cannula at flow rates > 20 L/min with 
fraction of delivered oxygen ≥ 0.5) 
• Noninvasive positive pressure ventilation 
• ECMO, or  
• Clinical diagnosis of respiratory failure (i.e., clinical need for one of the 
preceding therapies, but preceding therapies not able to be administered in 
setting of resource limitation)  
ii. Shock (defined by systolic blood pressure < 90 mmHg, or diastolic blood 
pressure < 60 mmHg or requiring vasopressors)  
iii. Multi-organ dysfunction/failure  
2. Participant has taken investigational medications within 7 days or 5 half-lives prior to 
enrollment, whichever is shorter. 
3. Participant has required any new form of sedation, anxiolysis or central nervous system 
(CNS) depressant within the 48 hours prior to enrollment that would interfere with 
neurologic assessments at enrollment. 
4. Has history of cerebrovascular accident or intracranial bleeding of any kind, acute 
coronary syndrome, myocardial infarction, or severe pulmonary hypertension. 
5. Participant has chronic respiratory failure not associated with COVID-19, defined as 
prior need for home oxygen, need for home noninvasive positive-pressure ventilation 
(NIPPV) for reasons other than isolated sleep apnea, or other signs of chronic 
respiratory failure, in the investigator’s judgment. 
6. Upper gastrointestinal (GI) bleed evidenced by hematemesis, “coffee-ground” emesis or 
nasogastric aspirate, or hematochezia thought to originate from upper GI tract. 


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7. Participant has abnormal liver function defined as any 2 of the following at screening:  
a. Total bilirubin ≥ 2 × ULN 
b. Alanine aminotransferase (ALT) ≥ 3 × ULN 
c. Aspartate aminotransferase (AST) ≥ 3 × ULN 
d. Alkaline phosphatase (ALP) > 3× ULN 
e. Gamma-glutamyl transferase (GGT) > 3 × ULN 
8. Participant has an estimated glomerular filtration rate (eGFR) < 60 mL/min. 
9. Participant has a known allergy or significant adverse reaction to varespladib-methyl or 
related compounds. 
10. Participant is considered by the investigator to be unable to comply with protocol 
requirements due to geographic considerations, psychiatric disorders, or other compliance 
concerns; or has any serious medical condition or clinically significant laboratory, ECG, 
vital sign, or physical examination abnormality that would prevent study participation or 
place the participant at significant risk, as judged by the Investigator. 
11. Participant is breast-feeding, pregnant, has a positive serum hCG pregnancy test, or is not 
willing to use a highly effective method of contraception for 14 days after treatment. 
Highly effective methods of contraception are as follows: 
a. Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
b. Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, or implantable) 
c. Intrauterine device, intrauterine hormone-releasing system 
d. Bilateral tubal occlusion 
e. Vasectomized partner 
f. Sexual abstinence 
g. Double-barrier method (condoms, sponge, diaphragm, with spermicidal jellies, or 
cream) 
8.3. Participant Replacement  
Withdrawn participants will not be replaced.  
Randomized participants withdrawn from the study may not reenter. The participant number for a 
withdrawn participant will not be reassigned to another participant. 


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9. TREATMENTS 
9.1. Identification of Investigational Products 
The investigational products (IPs) in this study are varespladib and matching placebo.  
• Varespladib-methyl (LY333013) 
o 250 mg immediate-release oblong, white, film-coated tablet for oral administration 
• Placebo  
o Oral formulation matched to the oral varespladib tablet 
LY333013 contains the excipients anhydrous lactose United States pharmacopeia (USP)/National 
Formulary (NF), lactose monohydrate USP/NF, hydroxypropyl cellulose USP/NF, polysorbate 80 
(vegetable source) USP/NF, microcrystalline cellulose USP/NF, croscarmellose sodium USP/NF, 
magnesium stearate (vegetable source) USP/NF, and the film coat Opadry II 85F18422 White. 
9.2. Timing of Dose for Each Participant 
In Part 1, varespladib or placebo will be administered in addition to institutional standard of care 
for 7 days at a dosage of 250 mg QD, BID, or TID (total doses of 250, 500, or 750 mg/day). The 
doses should be taken at the same times each day (+/- 2 hours for medication scheduling); ideally 
at least 5 hours apart. In Part 1, each participant will take 3 tablets per day with food. If IP is 
administered via nasogastric tube, it should be taken with food if possible. 
Part 1 
Randomized Treatment 
Morning 
Afternoon 
Bedtime 
250 mg QD  
250 mg 
placebo 
placebo 
250 mg BID 
250 mg 
placebo 
250 mg 
250 mg TID 
250 mg 
250 mg 
250 mg 
placebo 
placebo 
placebo 
placebo 
 
In Part 1, any dose that is missed should not be taken later that day. This includes Day 1; if a 
participant is enrolled in the afternoon or evening, only the afternoon and/or evening doses should 
be taken. If 7 complete days of dosing have not been completed by the end of Day 7, then the 
remaining doses will be administered on the appropriate schedule on Day 8. Examples: 
• On Day 1, a participant who is enrolled in the morning should take the morning dose in the 
morning, the afternoon dose in the afternoon, and the bedtime dose at bedtime. No doses 
will be taken on Day 8. 
• On Day 1, a participant who is enrolled in the afternoon should take the afternoon dose in 
the afternoon and the bedtime dose at bedtime. The last morning dose will be taken in the 
morning on Day 8, completing study treatment. 
• On Day 1, a participant who is enrolled in the evening should take the bedtime dose at 
bedtime. The last morning and afternoon doses will be taken in the morning and afternoon, 
respectively, on Day 8, completing study treatment. 


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In Part 2, varespladib or placebo will be administered in addition to institutional standard of care 
for 7 days using the dose regimen selected from Part 1. For Part 2, the dose regimen for placebo 
will match the treatment regimen. The dose regimen selected for Part 2 will not include placebo 
doses used to maintain the blinding in Part 1. For example, if BID dosing is selected for Part 2, 
then the afternoon dose will be eliminated, and only morning and evening doses will be given for 
7 days. If QD dosing is selected for Part 2, then only one dose will be administered per day for 7 
days.  
The doses should be taken at the same times each day (+/- 2 hours for medication scheduling), 
with food. As in Part 1, if IP is administered via nasogastric tube, it should be taken with food if 
possible. For Part 2, missed doses should be taken as soon as possible. Doses should be spaced 
evenly, but if a dose is missed, an interval of at least 5 hours between doses is recommended. If 7 
complete days of dosing have not been completed by the end of Day 7 for Part 2 patients, then the 
remaining doses will be administered on the appropriate schedule on Day 8. 
9.3. Dose Adjustment Criteria 
Dose adjustment is not allowed in this study. 
9.4. Premature Participant Withdrawal 
All participants will be advised that they are free to withdraw consent from participation in this 
study at any time, for any reason, and without prejudice. The investigator should make every 
reasonable attempt to keep participants in the study, even if IP is discontinued; however, 
participants must be withdrawn from the study if they withdraw consent to participate. Participants 
should be listed as having withdrawn consent only when they no longer wish to participate in the 
study and no longer authorize the investigators to make efforts to continue to obtain their outcome 
data. Investigators must attempt to contact participants who fail to attend scheduled visits by 
telephone or other means to exclude the possibility of an AE being the cause of withdrawal. Should 
this be the cause, the AE must be documented, reported, and followed as described in Section 11.2. 
If a participant withdraws consent before completing the study, the reason for withdrawal of 
consent and the date of discontinuation will be recorded on the appropriate page of the electronic 
case report form (eCRF). Whenever possible and reasonable, the evaluations that were to be 
conducted at the completion of the study (see Section 10.2.3.5) should be performed at the time of 
premature discontinuation from the study, regardless of whether the participant has received study 
drug or not. 
9.5. Discontinuation of Study Intervention 
9.5.1 Individual Participant Halting Criteria 
If a clinically significant finding is identified (including, but not limited to, deterioration from 
baseline) after enrollment, the investigator or qualified designee will determine if any change in 
participant management is needed. Every effort should be made to administer the planned doses. 
Dosing should be held for a participant who experiences any of the following toxicities: 
• Any Grade ≥ 2 creatinine increase (> 1.5 × baseline or ULN) 
• Any new, treatment-emergent occurrence of any of the following adverse events of special 
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o Cerebrovascular accident  
o Acute coronary syndrome  
o Supraventricular arrhythmia requiring urgent medical intervention 
o Any ventricular tachycardia/fibrillation including Torsade de Pointes 
o Hepatic toxicity with AST and/or ALT ≥ 3 × ULN for 2 days or > 5 × ULN on one 
occasion 
If a participant becomes unable to swallow the IP due to worsening of their condition, nasogastric 
administration or a dose delay may be considered in consultation with the medical monitor. In 
general, treatment with IP should continue for the full 7 days unless the participant is unable to 
continue treatment or if it is the participant’s best interest to discontinue treatment. If a participant 
must discontinue IP, every effort will be made to continue the participant in the study through Day 
60. If a participant experiences an SAE judged to be related to the IP, the treatment for that 
participant will be permanently discontinued from the IP, but every effort will be made to continue 
the participant in the study through Day 60. 
Any new clinically relevant adverse finding will be reported as an adverse event (AE) as defined 
in Section 11.1. 
Discontinuation from IP does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  
9.5.2 Management of Acute Kidney or Liver Injury 
Acute kidney/liver injury has been reported as a possible complication during the disease 
progression of COVID-19. 
Extra caution and monitoring will be exercised when treating patients with COVID-19-induced 
hepatic dysfunction. Given the relatively short duration of treatment (7 days) compared to previous 
studies with varespladib and the transient nature of hepatic enzyme elevation, subjects with acute 
liver injury will continue IP and be closely monitored with clinic visits and repeated blood work 
including liver function tests on Days 14 and 28. If hepatic enzymes exceed the hepatic toxicity 
limits specified in Section 9.5.1, IP should be discontinued. However, every effort will be made to 
continue the participant in the study through Day 60. 
In the event of acute kidney injury secondary to COVID-19, the subsequent dose of the study drug 
will be withheld and will be recommenced once renal parameters become normal and an interval 
of at least 5 hours is available before the next dose. Once recommenced, IP will be given through 
the original 7-day treatment period and the missed dose will not be taken. If renal function is 
persistently abnormal and the participant misses study drug more than 24 hours, their IP treatment 
should be discontinued. 
9.5.3 Study Halting Criteria 
Any of the following criteria will trigger a review by the DSMB and a potential halt in IP 
administration or enrollment of new participants: 
• Any participant death or SAE in which there a reasonable possibility that the IP caused the 
death or SAE, as judged by the investigator. 


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Section 14.6 describes procedures in the event of suspension or termination of the study for all 
participants. The DSMB charter will include details of the procedures they will follow when 
reviewing study data (see Section 12). 
9.6. Treatment Compliance 
While hospitalized, participants will receive the IP at the study site under the surveillance of 
appropriate study personnel. Tablet administration details will be recorded by the site. Participants 
who are discharged during the 7-day treatment period will be provided with the remainder of their 
assigned study drug and asked to record the date and time of each dose and whether it was taken 
with food. 
9.7. Method of Assigning Participants to Treatment Groups 
In Part 1, 18 participants will be randomized in a double-blind manner in 4 parallel treatment 
groups to treatment with varespladib (at 250 mg QD, BID, or TID [total doses of 250, 500, or 750 
mg/day]) or placebo in a 5:5:5:3 ratio. After all participants in Part 1 have completed Day 28, a 
DSMB will review the results from Part 1, including all available safety data through Day 60, and 
will recommend the dose regimen to be used in Part 2.  
Part 2 will randomize up to an additional 72 participants to the dose regimen selected from Part 1 
versus placebo in a 1:1 ratio.  
The randomization schedules will be computer generated using a permuted block algorithm and 
will randomly allocate IP to randomization numbers. The randomization numbers will be assigned 
sequentially through a central interactive web response system (IWRS) as participants are entered 
into the study. Study center will be a blocking factor in the randomization schedules. 
The randomization schedules will be prepared by the CRO before the start of the study. No one 
involved in the study performance will have access to the randomization schedules before official 
unblinding of treatment assignment. No participant will be randomized into this study more than 
once. 
9.8. Blinding and Unblinding Treatment Assignment 
All participants, investigators, and study personnel involved in the conduct of the study, including 
data management, will be blinded to treatment assignment with the exception of a specified 
unblinded statistician and programmer from the CRO who will have access to the randomization 
code, and the DSMB. One secondary pharmacist at each site participating in Part 1 only will be 
unblinded to ensure the correct cartons are assigned to morning, noon, and evening. This unblinded 
pharmacist will have no other study participation or activities. Details are provided in the 
Pharmacist Manual. The unblinded study personnel will not participate in study procedures or data 
analysis prior to unblinding of the study data to all study-related personnel upon database lock. 
The unblinded personnel who are not otherwise involved in the study will prepare the data for 
DSMB review. The DSMB charter will include procedures to prevent unblinding of the other 
study-related personnel. 
Study personnel will make every effort to safeguard the integrity of the study blind to minimize 
bias in the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 


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participant’s treatment assignment. Study personnel will not be unblinded to determine if an event 
is related to IP. 
Unblinding should be discussed in advance with the medical monitor, if possible. For emergency 
unblinding, study personnel will use the IWRS. If the investigator is not able to discuss treatment 
unblinding in advance, they must notify the medical monitor as soon as possible about the 
unblinding incident without revealing the participant’s treatment assignment.  
The investigator or designee must record the date and reason for treatment unblinding on the 
appropriate CRF for that participant.  
Unblinding for an individual participant will not result in unblinding the treatment assignments for 
the remaining participants in the study. Thus, the overall study blind will not be compromised. If 
a participant’s treatment assignment is unblinded, he/she may be discontinued from IP 
administration, and every effort will be made to continue the participant in the study through 
Day 60. The investigator will make this decision after consultation with the medical monitor. 
9.9. Prohibited and Permitted Therapies 
All concomitant medications (including over-the-counter medications and herbal supplements) 
and concomitant therapies used will be recorded in the source document and on the appropriate 
eCRF. 
No potential drug interactions or overlapping toxicities with current standard-of-care treatments 
for COVID-19 have been identified. In vitro cytochrome P450 enzyme interaction studies showed 
that varespladib would not cause clinically significant inhibition of the metabolic clearance of 
drugs metabolized by CYP3A (such as dexamethasone), and no effect of varespladib on 
p-glycoprotein. 
Participants may receive supportive care according to the written standard of care policy or 
guidance for the trial site hospital. The written institutional standard of care at each site may change 
during the study.  
9.9.1 Prohibited Therapies 
Experimental treatment or off-label use of marketed medications intended as specific treatment for 
COVID-19 is prohibited from Day 1 through Day 28 unless such treatments are outlined by the 
institution’s written standard of care. Dialysis before the study is prohibited. Prospective 
participants on mechanical ventilation or ECMO at the time of enrollment are not eligible, but 
these therapies may be started during the study. 
9.9.2 Permitted Therapies 
All concomitant medications and therapies not prohibited in Section 9.9.1 are allowed.  
Other COVID-19 treatments currently approved or authorized for emergency use by the FDA are 
permitted if in the institution’s written standard of care.  
9.10. Treatment After End of Study 
After the end of the study, each participant will be treated according to standard clinical practice. 


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9.11. Dispensing and Storage 
The IP (varespladib and placebo) supplied by Ophirex, Inc. is to be used exclusively in the clinical 
study according to the instructions of this protocol. The investigator is responsible for dispensing 
the IP according to the dosage scheme and for ensuring proper storage of the products.  
Until the IP is dispensed to the participants, it must be stored in a securely locked area that is not 
generally accessible. The IP may be stored at room temperature. The key to the storage area is to 
be kept by the investigator or designee responsible for the IP. The store will be accessible only to 
those persons authorized by the investigator to dispense the products. 
Detailed instructions for selecting and dispensing each dose of IP are in the study manual. 
9.12. Drug Accountability 
The investigator or designee must confirm the receipt of the IP with his or her signature. A copy 
of this receipt must be kept by the investigator and another copy will be stored at Ophirex, Inc. or 
designee.  
The investigator or designee must maintain adequate records showing the receipt, dispensing, 
return, or other disposition of the IPs, including the date, quantity, batch or code number, and 
identification of participants who received the IPs. The investigator will not supply the IP to any 
person except those named as subinvestigators on the FDA form 1572, designated study personnel, 
and participants in this study. The investigator will not dispense the IPs from any study sites other 
than those listed on the FDA form 1572. Investigational product may not be relabeled or reassigned 
for use by other participants. If any of the IP is not dispensed, or is lost, stolen, spilled, unusable, 
or received in a damaged container, this information must be documented and reported to the 
sponsor and appropriate regulatory agencies, as required. 
Upon completion of the study, the IP (including unused, partly used, and empty packaging) must 
be left in the original packaging and retained in a securely locked area until instructed by the 
sponsor. 
9.13. Labeling  
Investigational product supplies will have labels that meet the applicable regulatory requirements 
including the protocol number, a caution statement, storage, and sponsor identification. 


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10. STUDY PROCEDURES 
Participants must provide written informed consent and/or assent before any study-related 
procedures are initiated, including the cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the study, refer to the Schedule of Events 
(Section 2.2). Throughout the study, every reasonable effort should be made by study personnel to 
follow the timing of assessments and procedures in the Schedule of Events for each participant. If 
a participant misses a study visit for any reason, the visit should be rescheduled as soon as possible. 
10.1. Study Duration 
The overall study duration is expected to be approximately 18 months (6 months of active 
enrollment and 2 months of follow-up in Part 1; 2 to 4 weeks for DSMB review of Part 1 results 
at Day 28 and selection of the Part 2 dose; 6 months of active enrollment in Part 2; and 2 months 
of follow-up in Part 2). 
The sequence and approximate duration of the study periods will be as follows: 
1. Screening: up to 72 hours 
2. Treatment: 7 days 
3. Follow-up: 28 days after randomization  
4. Safety follow-up: 45 and 60 days after randomization 
The maximum study duration for each participant is approximately 60 days. 
The treatment duration for each participant is 7 days from the point of randomization (7 complete 
days of study drug administration after randomization). Screening/enrollment and baseline (Day 
1) of the Treatment Period can take place on the same day if the required screening test results are 
available. 
10.2. Study Periods and Visits 
Participants will be assessed daily per standard of care while hospitalized and on a regular basis 
after discharge. The Day 1, 4, 7, 14, and 28 visits will be performed in person (either at the 
hospital/site or via a home health provider) to assess safety, obtain blood and urine samples for 
laboratory tests, and obtain clinical outcome data. The Day 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 
17, 18, 19, 20, 21, 45, and 60 visits for discharged participants may be conducted by phone or via 
ePRO devices. 
10.2.1 Screening  
The participant should be screened within 1 day before enrollment in the study; screening and 
enrollment could occur on the same day. Procedures and local laboratory results collected within 
72 hours of signed consent may be used for screening, although it is preferential to conduct 
screening activities within 24 hours, as long as they are collected within allowable study windows 
and meet all other study criteria.  
The following procedures will be performed at screening: 
• Obtain informed consent in writing 


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• Review inclusion/exclusion criteria 
• Collect demographic information 
• Record medical history, including current medications and therapies (e.g., prescription and 
nonprescription medications) 
• Measure vital signs and SpO2 per institutional practice 
• Measure weight and height 
• 12-lead ECG 
• Physical examination 
• Neurological assessment 
• Nasopharyngeal swab for virologic testing, if not collected within the previous 72 hours; 
NAAT confirmation of COVID-19 in a sample collected < 72 hours prior to randomization 
is required 
• Collect blood and urine for the following tests (see Section 10.3.3.1 for details on the 
components included in CBC, chemistry, coagulation, urinalysis and biomarker testing):  
o clinical laboratory tests including complete blood count (CBC), blood chemistry, 
coagulation tests, and urinalysis 
o sPLA2 enzyme activity  
o serum pregnancy test (participants of childbearing potential only) 
o biomarkers (cardiac troponin, CRP, and ferritin) 
• Evaluate the participant using the WHO 9-point ordinal scale 
• Record concomitant medications and concomitant therapies 
• Assess and record any AEs occurring after informed consent was signed 
Procedures for rescreening prospective participants who initially fail to meet study entry criteria 
are described in Section 14.3. 
10.2.2 Treatment Period 
The treatment period is defined as baseline (Day 1) through the completion of 7 days of study drug 
dosing which is expected on Day 7, but which may occur on calendar day 8, depending on the 
dosing regimen and timing of first dose of study drug. 
10.2.2.1 Day 1 
Following completion of all assessments and confirmation of eligibility, the participant will be 
randomized via the IWRS. The following procedures will be performed on Day 1 of the Treatment 
Period:  
• Measure vital signs and SpO2 per institutional practice 


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• Part 1 participants only: collect a PK blood sample prior to the first dose of IP (NOTE: 
Vital signs collection is not required prior to collection of PK blood samples, and daily 
vital signs may be collected before or after PK blood samples as local procedures allow.) 
• Initiate IP dosing  
After initiating treatment with the IP: 
• Physical examination 
• Part 1 participants only: collect a PK blood sample at the following times after the first 
dose: 30 minutes and 1, 2, 3, 4, 6, 8, and 12 hours 
• Neurological assessment 
• Evaluate the participant using the WHO 9-point ordinal scale  
• Record concomitant medications and concomitant therapies 
• Assess and record AEs 
10.2.2.2 Day 2 
• Part 1 participants only: collect a PK blood sample prior to the morning dose of IP 
• Continue IP dosing  
• If hospitalized, measure vital signs and SpO2 per institutional practice 
• 12-lead ECG 
• Evaluate the participant using the WHO 9-point ordinal scale  
• Record concomitant medications and concomitant therapies 
• Assess and record AEs 
10.2.2.3 Day 3 
• Continue IP dosing  
• If hospitalized, measure vital signs and SpO2 per institutional practice 
• Part 1 (all participants) and Part 2 (PK participants): collect a PK blood sample prior to the 
morning dose of IP and at the following times after the morning dose: 30 minutes and 1, 2, 
3, 4, 6, 8, and 12 hours 
• Evaluate the participant using the WHO 9-point ordinal scale  
• Record concomitant medications and concomitant therapies 
• Assess and record AEs 
10.2.2.4 Day 4 
• Continue IP dosing  
• If hospitalized, measure vital signs and SpO2 per institutional practice 
• 12-lead ECG 


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• Physical examination 
• Neurological assessment 
• Collect blood and urine for the following tests:  
o clinical laboratory tests including CBC, blood chemistry, coagulation tests, and 
urinalysis 
o sPLA2 enzyme activity 
o biomarkers (cardiac troponin level, CRP, and ferritin) 
• Evaluate the participant using the WHO 9-point ordinal scale  
• Record concomitant medications and concomitant therapies 
• Assess and record AEs 
10.2.2.5 Day 5 
• Continue IP dosing  
• Measure vital signs and SpO2 per institutional practice 
• Evaluate the participant using the WHO 9-point ordinal scale  
• Record concomitant medications and concomitant therapies 
• Assess and record AEs 
10.2.2.6 Day 6 
• Continue IP dosing 
• If hospitalized, measure vital signs and SpO2 per institutional practice 
• Evaluate the participant using the WHO 9-point ordinal scale  
• Record concomitant medications and concomitant therapies 
• Assess and record AEs 
10.2.2.7 Day 7 
• Continue IP dosing through the end of 7 complete days of study drug dosing (this may end 
on calendar Day 8) 
• Measure vital signs and SpO2 per institutional practice 
• 12-lead ECG 
• Physical examination 
• Neurological assessment 
• Collect blood and urine for the following tests:  
o clinical laboratory tests including CBC, blood chemistry, coagulation tests, and 
urinalysis 


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o sPLA2 enzyme activity 
o biomarkers (cardiac troponin level, CRP, and ferritin) 
• Evaluate the participant using the WHO 9-point ordinal scale  
• Record concomitant medications and concomitant therapies 
• Assess and record AEs 
10.2.3 Follow-up Period  
10.2.3.1 Days 8, 9, 10, 11, 12, and 13 
• If hospitalized, measure vital signs and SpO2 per institutional practice 
• Evaluate the participant using the WHO 9-point ordinal scale  
• Record concomitant medications and concomitant therapies 
• Assess and record AEs 
10.2.3.2 Day 14 (±2) 
At 14 (±2) days after randomization, the following procedures will be performed: 
• Measure vital signs and SpO2 per institutional practice  
• 12-lead ECG 
• Collect blood and urine for the following tests:  
o clinical laboratory tests including CBC, blood chemistry, coagulation tests, and 
urinalysis 
o sPLA2 enzyme activity 
o biomarkers (cardiac troponin level, CRP, and ferritin) 
• Evaluate the participant using the WHO 9-point ordinal scale  
• Record concomitant medications and concomitant therapies 
• Assess and record AEs 
10.2.3.3 Days 15, 16, 17, 18, 19, and 20 
• If hospitalized, measure vital signs and SpO2 per institutional practice 
• Evaluate the participant using the WHO 9-point ordinal scale  
• Record concomitant medications and concomitant therapies 
• Assess and record AEs 
10.2.3.4 Day 21 (±2) 
At 21 (±2) days after randomization, the following procedures will be performed: 
• If hospitalized, measure vital signs and SpO2 per institutional practice 


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• Evaluate the participant using the WHO 9-point ordinal scale 
• Record concomitant medications and concomitant therapies 
• Assess and record AEs 
10.2.3.5 Day 28 (±2) or at time of Early Termination 
• Measure vital signs and SpO2 per institutional practice 
• Measure weight  
• 12-lead ECG 
• Physical examination 
• Neurological assessment 
• Collect blood and urine for the following tests:  
o clinical laboratory tests including CBC, blood chemistry, coagulation tests, and 
urinalysis 
o sPLA2 enzyme activity 
o serum pregnancy test (participants of childbearing potential only) 
o biomarkers (cardiac troponin level, CRP, and ferritin) 
• Evaluate the participant using the WHO 9-point ordinal scale 
• Record concomitant medications and concomitant therapies 
• Assess and record AEs  
10.2.3.6 Day 45 (±3) 
• If hospitalized, measure vital signs and SpO2 per institutional practice 
• Evaluate the participant using the WHO 9-point ordinal scale 
• Assess and record AEs  
10.2.3.7 Day 60 (±4) 
• If hospitalized, measure vital signs and SpO2 per institutional practice 
• Evaluate the participant using the WHO 9-point ordinal scale 
• Assess and record AEs  


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10.3. Assessments 
10.3.1 Efficacy Assessments 
10.3.1.1 Oxygen Support  
The investigator will assess the participant’s need for oxygen support throughout the study per 
institutional practice. Endpoints pertaining to oxygenation, non-invasive ventilation/high flow 
oxygen, and invasive mechanical ventilation/ECMO will be assessed using these data.  
10.3.1.2 WHO 9-point Ordinal Scale 
The investigator will assess the participant’s clinical status using the WHO 9-point ordinal scale. 
Table 10-1: 
WHO 9-point Ordinal Scale 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence of infection 
0 
Ambulatory 
No limitations on activities 
1 
Limitation on activities 
2 
Hospitalized; mild 
disease 
No oxygen therapy 
3 
Oxygen by mask or nasal prongs 
4 
Hospitalized; 
severe disease 
Noninvasive ventilation or high-flow oxygen 
5 
Intubation and mechanical ventilation 
6 
Ventilation plus additional organ support (pressors, renal 
replacement therapy (RRT), extracorporeal membrane 
oxygenation (ECMO) 
7 
Dead 
Death 
8 
 
The timepoints are indicated in the Schedule of Events (Table 2-1).  
Endpoints pertaining to hospitalization and mortality will be assessed using these data and 
post-discharge eCRF questions. 
10.3.1.3 Healthcare Encounters 
All healthcare encounters through Day 60 will be documented for each participant using 
participant reports and medical records. A healthcare encounter is defined as an interaction 
between a participant and a healthcare provider for the purpose of providing healthcare services or 
assessing the health status of a patient. An escalation in level of care for a hospitalized patient will 
also be included as a healthcare encounter for purposes of analysis. 


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10.3.2 Pharmacokinetics 
10.3.2.1 Pharmacokinetic Analysis Methods  
Pharmacokinetic samples will be drawn in all participants in Part 1 and in a subset of 
approximately 14 participants in Part 2 in order to enable estimation of PK parameters in 
approximately 22 participants receiving active treatment with varespladib. Samples should be 
drawn within windows for each timepoint: ± 15 minutes for 0.5 hour timepoint, ± 30 minutes for 
1, 2, 3 and 4 hour timepoints, and ± 1 hour for 6, 8 and 12 hour timepoints. The pharmacokinetic 
characterization of drug concentrations for each dose to be profiled will use noncompartmental 
analysis. Standard PK parameters assessed will include measures of the extent of absorption using 
estimates of the area-under-the-curve (AUC) and rate-of-absorption using the maximum 
concentration (Cmax) and the time of Cmax (Tmax). Additional details of the parameters and their 
calculation and evaluation will be included in the PK analysis plan.  
10.3.2.2 Pharmacokinetic Parameters 
The PK parameter estimates will be completed using WinNonlin (Pharsight Corporation). Actual 
sampling times will be used for all parameter estimation. 
10.3.2.3 Pharmacokinetic Sample Collection 
Blood samples for PK analysis will be collected at the time points specified in the Schedule of 
Events (Section 2.2). Blood sample collection, processing, and shipping instructions will be 
provided in the study laboratory manual. Samples should be drawn within windows for each 
timepoint: ± 15 minutes for 0.5 hour timepoint, ± 30 minutes for 1, 2, 3 and 4 hour timepoints, and 
± 1 hour for 6, 8 and 12 hour timepoints. 
10.3.3 Safety Variables 
Safety will be assessed by evaluating AEs, vital sign measurements, pulse oximetry, use of oxygen 
therapies, changes in levels of biomarkers, clinical laboratory test results, ECGs, physical 
examination findings, and concomitant medications and therapies. 
10.3.3.1 Clinical Laboratory Safety Assessments 
10.3.3.1.1 Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points indicated in the 
Schedule of Events (Table 2-1). 
 
Complete blood 
count: 
hemoglobin, hematocrit, red blood cell (RBC) count, red cell distribution 
width (RDW), mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), mean corpuscular volume (MCV), 
platelet count (or estimate), white blood cell count including differential 
(percentage 
and 
absolute: 
basophils, 
eosinophils, 
lymphocytes, 
monocytes, neutrophils) 
Blood chemistry: 
albumin, creatinine, blood urea nitrogen (BUN), eGFR, total bilirubin, 
total protein, alkaline phosphatase, alanine aminotransferase, aspartate 


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aminotransferase, lactate dehydrogenase, gamma-glutamyl transferase, 
lipase, lactate, blood glucose 
Coagulation: 
international normalized ratio (INR), prothrombin time, partial 
thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones 
Other: 
sPLA2 enzyme activity and biomarkers (cardiac troponin, C-reactive 
protein [CRP], and ferritin) 
Serum pregnancy 
test: 
for participants of childbearing potential only 
Routine laboratory specimens will be analyzed at local laboratories, PK and sPLA2 samples will 
be analyzed by a central laboratory. Specimens must be prepared for analysis according to the 
instructions provided in the study laboratory manual before shipment to the central laboratory. 
10.3.3.1.2 Evaluation of Clinical Laboratory Values 
Each local laboratory will provide the normal ranges of values for the clinical laboratory 
assessments in this study, and the local ranges will be regarded as the reference ranges on which 
decisions will be made by each investigator. 
If a laboratory value is out of the reference range, it is not necessarily clinically relevant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
relevance in the appropriate eCRF. 
All clinical laboratory values that in the investigator’s opinion show clinically relevant or 
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 11.2. 
10.3.3.2 Clinical Examinations 
10.3.3.2.1 Vital Signs and Peripheral Oxygen Saturation (SpO2) 
Vital signs (including body temperature) and peripheral oxygen saturation (SpO2) will be assessed 
at the timepoints indicated in the Schedule of Events (Table 2-1) per institutional practice.  
If the participant has multiple vital sign or SpO2 assessments on a given day, an assessment 
measured between 6 am-noon should be recorded in the eCRF, if possible, for consistency. 
10.3.3.2.2 Twelve-lead Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) will be performed at the timepoints indicated in the 
Schedule of Events (Table 2-1) per institutional practice. All ECG recordings will be identified 
with the participant identification, date, and time of the recording and will be attached to the 
participant’s eCRF. 
10.3.3.2.3 Physical Examination 
A physical examination will be performed at the timepoints indicated in the Schedule of Events 
(Table 2-1) per institutional practice. 


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10.3.3.2.4 Neurological Assessment 
A neurological assessment will be performed at the timepoints indicated in the Schedule of Events 
(Table 2-1) per institutional practice.  
10.3.3.3 Adverse Events 
The definitions and management of AEs, and any special considerations for AEs, are provided in 
Section 11. 


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11. ADVERSE EVENTS 
11.1. Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
participant administered an investigational product that 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, physical examination finding, or neurological finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
related to the medicinal product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity or a change in the quality of the disease or condition. Worsening of a 
pre-existing condition is considered an AE. Worsening or progression of the COVID-19 disease 
under study will not automatically be considered an AE unless the investigator believes that the 
progression is related to study drug. In that case, the worsening or progression of COVID-19 
disease under study will be reported as an AE / SAE as appropriate. 
Events that occur in participants treated with placebo, or during treatment-free periods of the study, 
are also considered AEs. 
11.1.2 Unexpected Adverse Event 
An expected AE is one for which the nature or severity is consistent with the known AE profile of 
the product. For a pre-approval test product, the known information is contained in the IB. An 
unexpected adverse event is one for which the nature or severity is not consistent with the IB. All 
AEs whether expected or unexpected will be recorded. 
11.1.3 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: An elective hospital admission to treat a condition present before exposure to the 
IP, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the 
condition or event as an SAE.  
• results in persistent or significant disability/incapacity 
• is a congenital anomaly in an infant born to a mother who was exposed to the IP during 
pregnancy (a newly diagnosed pregnancy in a participant that received IP is not considered 
an SAE unless it is suspected that the IP interacted with a contraceptive method and led to 
the pregnancy) 


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• is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias, or convulsions.  
11.1.4 Treatment-emergent Adverse Events 
An AE is defined as treatment-emergent if the first onset or worsening is after the first 
administration of IP and within the study’s AE reporting period. 
11.2. Event Assessment and Follow-up of Adverse Events 
The occurrence of an AE or SAE may come to the attention of study personnel during 
hospitalization and at outpatient visits or via telephone.  
All AEs will be captured on the appropriate case report form (CRF). Information to be collected 
includes event description, time of onset, clinician’s assessment of severity, relationship to IP 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
Site staff will record all reportable events with start dates occurring any time after informed 
consent is obtained through Day 60. At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit. Events will be followed for outcome information until 
resolution or stabilization. 
11.2.1 Assessment 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. During hospitalization and at each outpatient 
visit or telephone visit, the participant will be allowed time to spontaneously report any issues 
since the last visit or evaluation. The investigator will then monitor and/or ask about or evaluate 
AEs using nonleading questions, such as 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
11.2.2 Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified by the investigator using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Specific 
conditions and symptoms have values or descriptive comments for each grade. The CTCAE grades 
are based on this general guideline: 


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Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living. 
Grade 3  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
  
Changes in the severity of an AE will be documented. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.3. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.3. 
11.2.2.3 Action(s) Taken 
Action(s) taken may consist of: 
IP interrupted 
IP schedule was modified by temporarily terminating the prescribed 
regimen of IP. 
IP withdrawn 
IP schedule was modified through termination of IP. 
11.2.2.4 Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*Only select fatal as an outcome when the AE results in death. If more than one AE is judged to 
be possibly related to the participant’s death, the outcome of death should be indicated for each 
such AE.  


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11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must assess each AE’s relationship to the IP. Infection with SARS-CoV-2 
resulting in severe COVID-19 is associated with broad, complex, and significant pathophysiology. 
The Investigator should carefully consider the list of possible manifestations of COVID-19 when 
assigning a relationship of specific AEs to the study drug. The categories for classifying the 
investigator’s opinion of the relationship are as follows: 
The investigator must assess each AE’s relationship to the IP. The categories for classifying the 
investigator’s opinion of the relationship are as follows: 
Definitely 
A definite probability exists of a relationship between the AE and IP. 
Probably 
A reasonable probability exists of a relationship between the AE and IP. 
Possibly 
A possibility exists of a relationship between the AE and IP. 
Unrelated 
No reasonable possibility exists of a relationship between the AE and IP. 
11.2.3 Documentation 
All AEs that occur within the period of observation for the study must be documented in the CRF 
with the following information, where appropriate. (The period of observation for the study is 
described in Section 11.2.) 
• AE name or term 
• When the AE first occurred (start date and time) 
• When the AE stopped (stop date and time or an indication of “ongoing”) 
• Severity of the AE 
• Seriousness (hospitalization, death, etc.) 
• Actions taken 
• Outcome 
• Investigator opinion regarding the AE relationship to the IP 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. If such treatment constitutes a deviation from the protocol, the decision about whether the 
participant may continue treatment with IP will be made by the sponsor after consultation with the 
investigator and/or medical monitor. 
For double-blinded studies, it is not necessary to unblind a participant’s treatment assignment in 
most circumstances, even if an SAE has occurred. If unblinding is necessary, see Section 9.8 for a 
description of the unblinding procedures. 


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11.2.5 Reporting 
11.2.5.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to 
 within 24 hours 
of first becoming aware of the event by completing, signing and dating the SAE Report Form, 
verifying the accuracy of the information recorded in the form with the source documents and 
eCRF, and sending the SAE form to 
 by one of the following methods:  
Email: 
 
This written report should be submitted on the SAE form provided for this purpose. At the time of 
first notification, the investigator or designee should provide the following information, if 
available: 
• Protocol number 
• Reporter (study site and investigator) 
• Participant’s identification number 
• Participant’s year of birth 
• Participant’s gender 
• Date of first dose of IP 
• Date of last dose of IP, if applicable 
• AE term 
• Date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
• The seriousness criteria that were met 
• Concomitant medication at onset of the event 
• Relevant medical history information 
• Relevant laboratory test findings 
• Investigator’s opinion of the relationship to IP (“Is there a reasonable possibility that the 
IP caused the SAE? Yes or No?”) 
• Whether and when the investigator was unblinded as to the participant’s treatment 
assignment  
Any missing or additional relevant follow-up information concerning the SAE should be sent to 
the sponsor/sponsor representative via the same contact details above as soon as possible on a 
follow-up SAE Report Form, together with the following minimal information (initial report, AEs, 
date of occurrence, participant identification number, study number, IP, and site number); this will 
allow the follow-up information to be linked to the initial SAE report.  
Specific information may be requested by the 
 Pharmacovigilance Department 
using a follow-up request form or via email communication. 


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The investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, institutional review board 
(IRB), principal and coordinating investigators, study investigators, and institutions. Each 
investigator is obligated to learn about the reporting requirements for investigators in his/her 
country. The study monitor can assist with this. 
11.3. Special Considerations 
11.3.1 Adverse Events of Special Interest 
Investigators should specifically monitor several AEs potentially associated with varespladib 
treatment, including cerebrovascular accident (CVA; stroke), myocardial infarction (MI), and 
malignant cardiac arrhythmias. These AEs may also be associated with COVID-19. Investigators 
should carefully determine whether these AEs are potentially related to study drug. 
11.3.2 Pregnancy 
All participants of childbearing potential who participate in the study should be counseled on the 
need to practice adequate birth control and on the importance of avoiding pregnancy during study 
participation. Participants should be instructed to contact the investigator or study staff 
immediately if pregnancy occurs or is suspected. 
Pregnancy testing will be conducted prior to administration of the IP on every participant of 
childbearing potential. A participant who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a screening failure. 
A participant who becomes pregnant during IP treatment will be immediately discontinued from 
IP, but every effort will be made to continue the participant in the study through Day 60. The 
investigator must report the pregnancy within 72 hours of learning of the pregnancy, to 
 
Pharmacovigilance using the Pregnancy Data Collection Form via the same fax number 
and/or email address as for SAE reporting. The investigator should contact the designated 
individual(s) who receive SAE notification and record information related to the pregnancy on a 
pregnancy form provided by the sponsor or its designee. 
Safety assessments are required as soon as possible after learning of the pregnancy. The 
investigator is also responsible for following the pregnancy until delivery or termination. These 
findings must be reported on a pregnancy form and forwarded to the designated individual(s). The 
event meets the SAE criterion only if it results in a spontaneous abortion or a congenital anomaly. 
11.3.3 Overdose 
An overdose is the accidental or intentional use of a drug in an amount higher than the dose being 
studied. An overdose or incorrect administration of study treatment is not itself an adverse event, 
but it may result in an adverse event. Any AEs associated with an overdose or incorrect 
administration of study drug should be recorded on the AE CRF. If the associated adverse event 
fulfills seriousness criteria, the event should be reported to the Medical Monitor immediately (i.e., 
within 24 hours of learning of the event). 
No specific antidote to LY333013 exists, so treatment should be directed at supportive care. As 
with any overdose, participants should be monitored closely and observed for expected and 
unexpected clinical and laboratory effects. 


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12. DATA SAFETY MONITORING BOARD 
The DSMB will operate under a charter that will be finalized prior to the start of the study. After 
all participants in Part 1 have completed Day 28, the DSMB will review the safety results from 
Part 1, including all available safety data through Day 60, and will recommend the dose regimen 
to be used in Part 2. During Part 2, the DSMB will evaluate unblinded safety data, including data 
by group, at the intervals specified in the DSMB charter. In case of significant toxicity, the DSMB 
may choose to review the available safety data and recommend pausing or stopping recruitment in 
a particular dose group or the study as a whole. Efforts will be made to collect all follow-up and 
safety data through Day 60 for all patients enrolled in the study. 
 


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13. STATISTICS 
13.1. Statistical Analysis 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. The statistical analysis plan (SAP) with final planned analyses will be developed and 
finalized before database lock.  
Descriptive statistical methods will be used to summarize the data from this study with confidence 
intervals calculated for the primary and secondary efficacy endpoints. Unless stated otherwise, the 
term “descriptive statistics” refers to the number of participants (n), mean, median, standard 
deviation, minimum, and maximum for continuous data; and frequencies and proportions for 
categorical data. All data collected during the study will be included in data listings.  
Participants who die will have their data after death assigned as the worst possible value within a 
specific scale or with regard to duration or proportion as defined by the particular outcome. 
Participants who do not experience a particular event will not be excluded from the analysis of 
duration or time-to-event endpoints and will have an appropriate value assigned. Missing data for 
reasons other than death will, when possible, be derived from contemporaneous clinical data. If 
other clinical data are not available or not determinative of the outcome, data will be imputed based 
on the last available value (last observation carried forward). 
Unless otherwise indicated, comparative statistics between treatment and control group will report 
point estimates, p-values, and 95% confidence intervals with the goal of understanding the clinical 
importance of observed effects.  
This study is considered an exploratory study. Statistical tests will be interpreted in an exploratory 
sense only and will not be considered formal hypothesis tests. 
All efficacy variables will be summarized descriptively. Primary and secondary efficacy endpoints 
will be tabulated according to the “Observed Cases” approach. Exploratory hypothesis testing will 
also be conducted for the majority of endpoints. 
Part 2 efficacy summaries will be done by randomized treatment. Part 1 efficacy data will be listed 
only. Hypothesis testing will be evaluated in an exploratory manner in order to inform decisions 
about future trials. 
All statistical analyses will be conducted with the SAS® System, version 9.3 or higher. 
13.1.1 Analysis Populations 
The following 5 analysis populations are planned for this study:  
• Intent-to-treat (ITT): All randomized participants. 
• Safety: All participants who receive at least 1 dose of IP. 
• Per-protocol (PP): All randomized participants with at least 1 dose of IP with no key 
protocol deviations during the study that would affect the interpretation of the primary 
efficacy assessments. Inclusion in the PP population will be determined prior to database 
lock and unblinding of treatment assignment. 
• Pharmacokinetic (PK): All randomized participants who receive at least 1 dose of IP 
and provide at least 1 evaluable post-dose PK measurement. 


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• Combined Population: All participants in Part 2 and all participants in Part 1 assigned to 
the dose regimen selected for Part 2, who receive at least 1 dose of IP at the dose regimen 
used in Part 2. 
Assignment of participants to populations will be determined prior to database lock. 
The Safety Population will be used to analyze the safety endpoints, the ITT Population will be 
used to analyze the efficacy endpoints, and the PK population will be used to analyze the PK 
endpoints. In addition to the ITT Population, the PP and Combined Populations will be used to 
analyze the primary efficacy endpoint. 
Part 1 efficacy data will be listed. Part 1 participants receiving placebo or the dose regimen used 
in Part 2 will be included in the Combined Population. Safety and PK analyses will be based on 
actual treatment received. For the efficacy analyses, in the event that a participant is randomized 
incorrectly or is given the incorrect IP, analyses of the ITT, PP, and Combined populations will be 
based on the randomized treatment. 
13.1.2 Study Participants and Demographics 
13.1.2.1 Disposition and Withdrawals 
The numbers of participants randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of participants in each 
analysis population will be reported. 
13.1.2.2 Protocol Deviations 
Protocol deviations will be identified and classified as minor or major for statistical analysis 
purposes before unblinding and will be summarized or listed as appropriate. Key protocol 
deviations will be used to exclude participants from the PP population. 
13.1.2.3 Demographics and Other Baseline Characteristics 
These analyses will be conducted for the safety and ITT populations.  
Demographic variables will include age, sex, height, and weight. Information on race and ethnicity 
will be collected for any eventual analysis of differences in response to the IP, in accordance with 
local regulatory requirements. Baseline participant characteristics will include medical history and 
disease characteristics. 
Prior and concomitant medications will be summarized by treatment group, by the number and 
percentage of participants taking each medication, classified using World Health Organization 
Drug Dictionary Anatomical Therapeutic Chemical classes and preferred terms.  
13.1.3 Exposure and Compliance 
IP exposure and dosing information including the number of doses and amount of IP received will 
be listed for each participant. 
13.1.4 Efficacy Analysis 
Withdrawn participants will not be replaced. Randomized participants withdrawn from the study 
may not reenter. The subject number for a withdrawn subject will not be reassigned to another 
subject. 


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Missing data for reasons other than death will, when possible, be derived from contemporaneous 
clinical data. If other clinical data are not available or not determinative of the outcome, data will 
be imputed based on the last available value (last observation carried forward). 
Participants in the ITT population with missing data due to death will have their missing data 
imputed as the worst possible value within a specific scale or in regard to duration or proportion 
as defined by the particular outcome. Participants who do not experience a particular event will 
not be excluded from the analysis of duration or time-to-event endpoints and will have an 
appropriate value assigned. Specific assignments for death are provided in the SAP. 
 
 Efficacy data for Part 1 participants will be listed only. All statistical testing for endpoints will be 
2-sided and will be evaluated in an exploratory manner to inform decisions about future trials. 
13.1.4.1 Efficacy Endpoints 
The primary endpoint is the proportion of participants alive and free of respiratory failure at Day 28 
(respiratory failure is defined in exclusion criterion 1.c.i). 
The secondary efficacy endpoints are: 
• Clinical improvement, as measured by the World Health Organization (WHO) 9-point 
ordinal scale through Day 60 
• Time to and proportion of subjects with all-cause mortality through Day 60 
• Proportion of participants who experienced respiratory failure in the first 28 days 
• Among patients that never experience respiratory failure in the first 28 days, time to 
initiation, duration, and proportion of subjects receiving supplemental oxygen or other 
respiratory support within the first 28 days after randomization   
• Among patients that experience respiratory failure in the first 28 days, time to initiation 
and duration of the forms of respiratory support meeting criteria outlined in critical 
COVID criteria (exclusion criteria 1.c.i) within the first 28 days after randomization  
• Number of days of oxygen support through Day 28 after randomization 
• SpO2 through Day 28 after randomization 
• Number of ventilator-free days through Day 28 after randomization 
• Number of hospitalization days through Day 28 after randomization 
• Number of days without renal stabilization and/or replacement through Day 28 after 
randomization 
• Number of organ failure-free days through Day 28 after randomization 
• Number of days at elevated level of care (ICU) through Day 28 after randomization 
• Number of healthcare encounters through Day 28 after randomization 
The exploratory efficacy endpoints are: 
• sPLA2 within blood samples from treatment initiation to Day 28 after randomization 


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13.1.4.2 Primary Analysis 
The ITT, PP, and Combined populations will be used to analyze the primary efficacy endpoint. 
The ITT population will be considered to be the primary population for the efficacy analyses. 
The proportion of respiratory failure-free surviving participants in each Part 2 treatment group at 
Day 28 will be analyzed using logistic regression with treatment as a factor. Age, diabetes, body 
mass index, and baseline sPLA2 activity will be included as covariates. Risk differences between 
varespladib and placebo, the 95% CI for the risk difference, and p-values for differences in 
treatment will be presented and calculated via the delta method. Additional details will be provided 
in the SAP which will be finalized before unblinding of the data. 
The primary endpoint will be analyzed using the ITT, PP, and Combined Populations. 
13.1.4.3 Secondary Analyses 
Analysis of the secondary endpoints will be carried out for the ITT and Combined populations. 
Mean change from baseline in the WHO 9-point scale will be analyzed using an analysis of 
covariance model (ANCOVA); the model will include treatment and age, diabetes, body mass 
index, and baseline sPLA2 as covariates. Distribution of outcomes on the WHO ordinal scale will 
also be described via plots in supplemental analyses..  
Ventilator-free days; hospitalization days; organ failure-free days; days at elevated level of care 
[ICU]; number of days without renal stabilization; days of oxygen support; and number of 
healthcare encounters) during the 28-day study period will be analyzed using an analysis of 
covariance model (ANCOVA); the model will include treatment as a covariate. Additional 
covariates may be added to the model and full details will be given in the final SAP. 
Secondary time to event endpoints (all-cause mortality and respiratory support (in patients with 
and without respiratory failure)) will be analyzed using a Cox-Proportional hazard model. The 
number of participants who experience the event, median time to the event and 95% CI, and rate 
ratio and 95% CI will be presented. The p-value to test if the rate ratio between treatments differs 
from 1 will be presented. Additional covariates will be considered; full details will be given in the 
SAP. 
Additionally, the duration respiratory support in patients with and without respiratory failure will 
be analyzed using the same ANCOVA model as previously described. 
The absolute values and change from baseline of SpO2 will be tabulated by treatment arm and 
visit. An ANCOVA approach will be used to assess the treatment effect for SpO2 through Day 28. 
Additional details will be provided in the SAP. 
The proportion of participants who die, the proportion of participants with and without respiratory 
failure that receive respiratory support will be summarized using the same logistic regression 
method as the primary endpoint. In general, the proportions of subjects with an event on or before 
Day 28 will be analyzed unless otherwise specified in the SAP. 
No adjustment will be made for multiple comparisons. This is an exploratory pilot study that will 
be used to inform decisions about possible future trials. 
Additional details of the efficacy analyses can be found in the SAP. 


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13.1.4.4 Exploratory Analyses 
Change in sPLA2 from baseline through Day 28 will be analyzed using the same ANCOVA model 
as previously described for SpO2. The pharmacoeconomic impacts of varespladib treatment will 
be reviewed in an exploratory manner using results from secondary endpoints to include number 
of healthcare encounters, number of hospitalization days, and number of days at elevated level of 
care (ICU), all through Day 28. 
13.1.4.5 Clinical Pharmacology Analyses 
13.1.4.5.1 Pharmacokinetics 
For noncompartmental analysis, plasma concentrations will be listed and summarized at each time 
point using descriptive statistics; graphical representations will also be provided. The PK 
parameters will be summarized by dose using descriptive statistics. Testing of PK parameters will 
be outlined in the SAP. 
13.1.5 Safety and Tolerability Analyses 
All safety analyses will be performed on the Safety population. 
The variables for safety endpoints are TEAEs, vital signs, oxygen therapies, changes in biomarker 
levels, laboratory evaluations, 12-lead ECGs, physical examinations, and concomitant medications 
and therapies. 
Safety and tolerability will be evaluated by examining the occurrence of AEs, including treatment-
emergent AEs that begin with treatment. Adverse events leading to discontinuation from IP, 
causality, and severity (based on NCI CTCAE v5.0 grade) will be summarized by treatment group. 
Adverse events will also be presented in listings. Summary statistics of clinical laboratory 
measures will be presented by treatment group for each assessment. The number and percentage 
of participants with at least 1 post-baseline potentially clinically significant abnormality will be 
presented by treatment group for selected parameters. The same approach will be used for vital 
signs, ECGs, and pulse oximetry. Separate safety outputs will be produced for Part 1 and Part 2 
participants. 
An additional analysis will be done for Part 2 participants for AEs with a greater severity than mild 
as well as for AEs related to study treatment. The frequency and percentage of participants 
experiencing each type of event by Day 60 will be presented in each treatment arm. The difference 
in proportions, 95% CI derived, and p-value comparing varespladib and placebo from a  
2-proportion Z-test will also be presented.  
Additional details will be given in the SAP. 
13.1.5.1 Adverse Events 
Treatment-emergent AEs are defined as AEs that first occur or worsen in severity (based on NCI 
CTCAE v5.0 grade) after the first dose of IP and prior to the 30 days after last administration of 
IP. Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). For each treatment group, the number of TEAEs and incidence rates will be tabulated 
by preferred term and System Organ Class. 


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Treatment-emergent AEs leading to discontinuation from IP, causality, and severity will be 
summarized by treatment group. An additional analysis will be done for Part 2 participants for 
AEs with a greater severity than mild as well as for AEs related to study treatment. The frequency 
and percentage of participants experiencing each type of event by Day 60 will be presented in each 
treatment arm. The difference in proportions, 95% CI derived, and p-value comparing varespladib 
and placebo from a 2-proportion Z-test will also be presented. 
13.1.5.2 Clinical Laboratory Evaluations, Vital Signs, Electrocardiograms, and Pulse 
Oximetry 
Summary statistics of clinical laboratory measures will be presented by treatment group for each 
assessment. The number and percentage of participants with at least 1 post-baseline potentially 
clinically significant abnormality will be presented by treatment group for selected parameters. 
The same approach will be used for vital signs, ECGs, and pulse oximetry.  
13.1.5.3 Biomarkers 
Observed values and changes from baseline in biomarkers such as cardiac troponin level, CRP, 
and ferritin will be summarized using descriptive statistics by visit. 
13.1.6 Interim Analysis 
No interim analyses are planned.  
13.2. Sample Size Determination 
Approximately 90 participants are planned for this study. Eighteen participants will be randomized 
into Part 1 of the study in a 5:5:5:3 ratio with 3 varespladib arms and a placebo arm. In Part 2 of 
the study, 72 participants will be randomized in a 1:1 ratio with the selected varespladib arm from 
Part 1 of the study and a placebo arm. No stratification variables will be used. 
This is a pilot study and exploratory in nature. The sample size is not based on a formal power 
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14. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 15). The sponsor reserves the right to withdraw a participant from the study (Section 9.4), 
to terminate participation of a study site at any time (Section 14.7), and/or to discontinue the study 
(Section 14.6). 
Ophirex, Inc. agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 17.1), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol.  
The trial will be conducted in accordance with ICH GCP and applicable United States Code of 
Federal Regulations (CFR). The principal investigator will assure that no deviation from, or 
changes to, the protocol will take place without prior agreement from the Investigational New 
Drug (IND) sponsor, funding agency and documented approval from the IRB, except where 
necessary to eliminate an immediate hazard(s) to the trial participants.  
Investigators should ensure that all persons who are delegated study-related responsibilities are 
adequately qualified and informed about the protocol, the IPs, and their specific duties within the 
context of the study. Investigators are responsible for providing Ophirex, Inc. with documentation 
of the qualifications, GCP training, and research experience for themselves and their staff as 
required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.1.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the investigator, including, but not limited to, 


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medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, institutional policies, or sponsor 
requirements, at a minimum of three years. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the CRO. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study participant number. The study data entry and study management systems used 
by clinical sites and 
staff will be secured and password protected. At the end of the study, 
all study databases will be de-identified and archived. 
14.2. Site Initiation 
Study personnel may not screen or enroll participants into the study until after receiving 
notification from the sponsor or its designee that the study can be initiated at the study site. The 
study site will not be authorized for study initiation until: 
1. The study site has received the appropriate IRB approval for the protocol and the 
appropriate informed consent form (ICF). 
2. The study site Federal Wide Assurance has been verified. 
3. All regulatory documents have been submitted to and approved by the sponsor or its 
designee. (Department of Defense-supported research sites will require Human Research 
Protection Office (HRPO) review prior to initiation.) 
4. The study site has a Clinical Trial Agreement in place. 
5. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
14.3. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of an 
initially negative virologic test for COVID-19 can be rescreened upon new symptoms/new 
admission. Rescreened participants will be assigned a new participant number; the participant 
number from the initial screening will be recorded in the eCRF. 
14.4. Study Documents 
All documentation and material provided by Ophirex, Inc. for this study are to be retained in a 
secure location and treated as confidential material. 


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14.4.1 Informed Consent 
Consent forms describing in detail the study intervention, study procedures, and risks will be given 
to the participant, and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
IRB-approved and the participant will be asked to read and review the document. The investigator 
will explain the research study to the participant and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants. Participants 
will have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the ICF prior 
to any procedures being done specifically for the study. Participants must be informed that 
participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their 
records. The informed consent process will be conducted and documented in the source document 
(including the date) and the form signed before the participant undergoes any study-specific 
procedures. The rights and welfare of the participants will be protected by emphasizing to them 
that the quality of their medical care will not be adversely affected if they decline to participate in 
this study. 
14.4.2 Investigator’s Regulatory Documents 
The regulatory documents are listed in the study manual. 
The regulatory documents must be received from the investigator and reviewed and approved by 
Ophirex, Inc. or its designee before the study site can initiate the study and before Ophirex, Inc. 
will authorize shipment of IP to the study site. Copies of the investigator’s regulatory documents 
must be retained at the study site in a secure location. Additional documents, including a copy of 
the protocol and applicable amendment(s), the varespladib IB, eCRF completion guidelines, copies 
of regulatory references, copies of IRB correspondence, and IP accountability records will also be 
retained as part of the investigator’s regulatory documents. It is the investigator’s responsibility to 
ensure that copies of all required regulatory documents are organized, current, and available for 
inspection. 
14.4.3 Case Report Forms 
By signing the Investigator’s Agreement (Section 17.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all participants who sign 
an ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
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To ensure data accuracy, eCRF data for individual participant visits should be completed as soon 
as possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a designated sub-investigator. These signatures 
serve to attest that the information contained in the eCRF is accurate and true. 
14.4.4 Source Documents 
Information recorded in the EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. Source data permits not only reporting 
and analysis but also verification throughout the study for the purposes of confirmation, quality 
control, audit, or inspection. It is important that source data and the records that hold those data 
are:  
• Accurate  
• Legible  
• Contemporaneous  
• Original  
• Attributable  
• Complete  
• Consistent  
• Enduring  
• Available when needed  
Study monitors will perform ongoing source data verification to confirm that critical protocol data 
(i.e., source data) entered into the eCRFs by authorized site personnel are accurate, complete, and 
verifiable from source documents.  
Before study initiation, the types of source documents that are to be generated will be clearly 
defined in the study manual. Any protocol data that will be permitted to be entered directly into 
the eCRFs (i.e., with no prior written or electronic record of the data) will be specified.  
Source documents that are required to verify the validity and completeness of data entered into the 
eCRFs must not be obliterated or destroyed and must be retained per the policy for retention of 
records described below.  
14.5. Data Quality Control 
Ophirex, Inc. and its designees will perform quality control checks on this clinical study. 
14.5.1 Monitoring Procedures 
Ophirex, Inc. and/or its designee will conduct site visits remotely or onsite to monitor the study 
and ensure compliance with the protocol, GCP, and applicable regulations and guidelines. The 
assigned clinical research associate(s) (CRA[s]) will visit the investigator and study site at periodic 
intervals and maintain periodic communication. The investigator agrees to allow the CRA(s) and 


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other authorized Ophirex, Inc. personnel access. The CRA(s) will maintain current personal 
knowledge of the study through observation, review of study records and source documentation, 
and discussion of the conduct of the study with the investigator and staff. While on site, the CRA(s) 
will review 
• regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• consenting procedures 
• AE procedures 
• storage and accountability of IP and study materials 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF are described in the study manual. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 17.1), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow Ophirex, Inc. or designee auditors or inspectors from regulatory agencies to review 
records and to assist the inspectors in their duties, if requested.  
For additional information, please refer to the clinical monitoring plan. 
14.5.2 Data Management 
Ophirex, Inc. or designee will be responsible for activities associated with the data management 
of this study. The standard procedures for handling and processing records will be followed per 
GCP and the CRO’s standard operating procedures. A comprehensive data management plan will 
be developed, including a data management overview, description of database contents, annotated 
CRF, self-evident correction conventions, query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries are described in the study manual. 
14.5.3 Quality Assurance/Audit 
This study will be subject to audit by Ophirex, Inc. or its designee. Audits may be performed to 
check compliance with GCP guidelines and can include: 
• Site audits 
• Trial Master File audits 
• Database audits 
• Document audits (e.g., protocol and/or clinical study report) 
• Specific protocol training documents 


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Ophirex, Inc. or its designee may conduct additional audits on a selection of study sites, requiring 
access to participant notes, study documentation, and facilities or laboratories used for the study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Ophirex, Inc. immediately. 
14.6. Study Termination 
The study may be terminated at Ophirex, Inc.’s discretion at any time and for any reason. 
14.6.1 Premature Study Termination 
The study may be temporarily suspended or terminated prematurely is there is sufficient reasonable 
cause at any time by Ophirex, Inc., IRBs, regulatory authorities, respective steering committees, 
or the coordinating investigator.  
Written notification documenting the reason for study suspension or termination will be provided 
by the suspending or terminating party to study participants, investigator, funding agency, the IND 
sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the PI will 
promptly inform study participants, the IRB, and sponsor and will provide the reason(s) for the 
termination or suspension. Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
Study sites may be asked to have all participants currently participating in the study complete all 
of the assessments for the Early Termination Visit. 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or FDA. 
14.7. Study Site Closure 
At the end of the study, all study sites will be closed. Ophirex, Inc. may terminate participation of 
a study site at any time. Examples of conditions that may require premature termination of a study 
site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate participant enrollment 


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14.7.1 Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the study, 
specifically including, but not limited to, those defined by GCP as essential until: 
• At least 3 years after the last marketing authorization for the IP has been approved or the 
sponsor has discontinued its research with the IP, or 
• At least 3 years have elapsed since the formal discontinuation of clinical development of 
the IP 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor has 30 days to respond to the investigator’s notice, and the 
sponsor has further opportunity to retain such materials at the sponsor’s expense. 
14.7.2 Sample Retention 
Samples may be used for purposes related to this research. The samples will be stored until the 
sponsor has determined that specimens are no longer needed, and the decision has been made that 
none of the samples needs to be reanalyzed. In addition, identifiable samples can be destroyed at 
any time at the request of the participant. 
Data collected for this study will be analyzed and stored at the CRO. After the study is completed, 
the de-identified, archived data will be transmitted to and stored at the CRO for use by other 
researchers, including those outside of the study. Permission to transmit data to the CRO will be 
included in the informed consent.  
14.8. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Ophirex, Inc. The protocol amendment must be signed by the 
investigator and approved by the IRB before it may be implemented. Protocol amendments will 
be filed with the appropriate regulatory agency(s) having jurisdiction over the conduct of the study. 
Any changes to the protocol will have written approval prior to implementation. 
14.9. Use of Information and Publication 
All information concerning varespladib, Ophirex, Inc.’s operations, patent applications, formula, 
manufacturing processes, basic scientific data, and formulation information supplied by Ophirex, 
Inc. or its designee to the investigator, and not previously published, is considered confidential and 
remains the sole property of Ophirex, Inc. Case report forms also remain the property of Ophirex, 
Inc. The investigator agrees to use this information for purposes of study execution through 
finalization. 
The information developed in this study will be used by Ophirex, Inc. in connection with the 
continued development of varespladib and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. 
The information generated by this study is the property of Ophirex, Inc. Publication or other public 
presentation of varespladib data resulting from this study requires prior review and written 


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approval of Ophirex, Inc. Abstracts, manuscripts, and presentation materials should be provided 
to Ophirex, Inc. for review at least 30 days prior to the relevant submission deadline.  
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition, or publication by the investigator until Ophirex, Inc. has reviewed and commented on 
such a presentation or manuscript for publication. If applicable, this study will be registered at 
ClinicalTrials.gov, and results from this study will be submitted to ClinicalTrials.gov. 
14.10. 
Impact of COVID-19 on Current Conduct of Clinical Trials 
To mitigate the possible risks associated with study conduct during the COVID-19 pandemic, 
measures and procedures based on the advice issued by local authorities should be followed by 
study participants and site staff (e.g., social distancing, use of personal protective equipment and 
disinfectants). Investigators should use medical judgment and current evidence as well as 
consultation with their IRB/IEC, as appropriate, to determine the risks and benefits of participation 
in the study, and investigators are encouraged to communicate with participants to ensure safety.  
The sponsor, its designees, and investigators will conduct the appropriate study monitoring 
activities to ensure study integrity; if on-site monitoring visits are not possible, alternative 
procedures will be established. 


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15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1. Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry 
GCP E6 (including archiving of essential study documents), the Integrated Addendum to 
ICH E6 (R2) of November 2016, and the applicable regulations of the country in which the study 
is conducted. 
15.2. Participant Information and Informed Consent and/or Assent 
A properly constituted, valid IRB must review and approve the protocol, the investigator’s ICF, 
and related participant information and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that written informed consent and/or assent is 
obtained from the participant before any activity or procedure is undertaken that is not part of 
routine care. 
If any enrolled participant becomes a prisoner and thus a vulnerable subject, the investigator must 
promptly report this information to their IRB and to the sponsor, who will report the information 
to the HRPO of the US Army Medical Research and Development Command. 
15.3. Approval by Institutional Review Board  
For Investigational New Drug studies, the minimum standards of conduct and requirements for 
informed consent and/or assent are defined in the FDA regulations. 
A valid IRB must review and approve this protocol before study initiation. Written notification of 
approval is to be provided by the investigator to the sponsor’s designated contact before shipment 
of IP supplies, and will include the date of the committee’s approval and the chairperson’s 
signature.  
Until written approval by the IRB has been received by the investigator, no participant may 
undergo any procedure not part of routine care for the participant’s condition. 
Protocol amendments must also be reviewed and approved by the IRB. Written approval from the 
IRB or a designee must be received by Ophirex, Inc. before implementation. 
Prior to implementation of any actions, HRPO approval is required. In addition, any amendments 
will also require HRPO approval prior to implementation.  
15.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 


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16. REFERENCES 
1. 
World Health Organization. COVID-19 Clinical management: living guidance. Published 
27 May 2020; updated 25 January 2021. https://www.who.int/publications/i/item/WHO-
2019-nCoV-clinical-2021-1. 
2. 
Rezoagli E, Fumagalli R, Bellani G. Definition and epidemiology of acute respiratory 
distress syndrome. Annals of Translational Medicine. 2017;5(14):282-282. 
3. 
Englert JA, Bobba C, Baron RM. Integrating molecular pathogenesis and clinical 
translation in sepsis-induced acute respiratory distress syndrome. JCI Insight. 
2019;4(2):e124061. 
4. 
Mirastschijski U, Dembinski R, Maedler K. Lung surfactant for pulmonary barrier 
restoration in patients with COVID-19 
pneumonia. Frontiers in Medicine. 
2020;7(254):Published online ahead of print on 22-May-2020. 
5. 
Griffiths MJD, Mcauley DF, Perkins GD, et al. Guidelines on the management of acute 
respiratory distress syndrome. BMJ Open Respiratory Research. 2019;6(1):e000420. 
6. 
Michelen M, Jones N, Stavropoulou C. In patients of COVID‑19, what are the symptoms 
and clinical features of mild and moderate cases? https://www.cebm.net/covid-19/in-
patients-of-covid-19-what-are-the-symptoms-and-clinical-features-of-mild-and-
moderate-case/. 01‑Apr‑2020. 
7. 
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel 
coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. 
8. 
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 
novel Coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-
1069. 
9. 
Yang X, Yu Y, 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 Medicine. 2020;8(5):475-481. 
10. 
Gandhi RT, Lynch JB, Del Rio C. Mild or moderate Covid-19. N Engl J Med.Published 
online ahead of print on 25‑Apr‑2020. 
11. 
Interim clinical guidance for management of patients with confirmed coronavirus disease 
(COVID‑19). 
Centers 
for 
Disease 
Control 
and 
Prevention 
website. 
https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-
patients.html. Updated 10‑Sep‑2020. Accessed 09‑Oct‑2020. 
12. 
Abraham E, Naum C, Bandi V, et al. Efficacy and safety of LY315920Na/S-5920, a 
selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with 
suspected sepsis and organ failure. Critical Care Medicine. 2003;31(3):718-728. 
13. 
Food and Drug Administration. Guidance for Industry on COVID-19: Developing Drugs 
and Biological Products for Treatment or Prevention, May 2020. 
14. 
Ware J, Jr., Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of 
scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220-233. 
 
 
 


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17. ATTACHMENTS 
17.1. Investigator’s Agreement 
PROTOCOL 
NUMBER: 
OPX-PR-02 
PROTOCOL TITLE: 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Safety, Tolerability, and Efficacy of Varespladib in 
Patients Hospitalized with Severe COVID-19 Caused by 
SARS-CoV-2 
CURRENT VERSION 
DATE: 
v3.0, 28-Feb-2022 
I have read this protocol and agree to conduct this clinical study as outlined herein. I will ensure 
that all sub-investigators and other study staff members have read and understand all aspects of 
this protocol. I agree to cooperate fully with Ophirex, Inc. during the study. I will adhere to all 
FDA, ICH, and other applicable regulations and guidelines regarding clinical studies on an IP 
during and after study completion. 
Principal Investigator: 
 
Printed Name: 
 
 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 


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APPENDICES 
A. Study-specific Requirements 
B. Regulations and Good Clinical Practice Guidelines 
 
 


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A. Study-specific Requirements 
• WHO 9-point Ordinal Scale 
• WHO guideline for the clinical management of COVID-19 (living guidance: 
https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1) 
 
 


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B. Regulations and Good Clinical Practice Guidelines 
1. Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
2. Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URLs: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf 
 
 

SAP_001.pdf: 






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Table of Contents
Approvals........................................................................................................................................ 1
Document History........................................................................................................................... 3
Table of Contents............................................................................................................................ 4
List of Abbreviations ...................................................................................................................... 7
1.
Overview............................................................................................................................. 9
2.
Study Objectives and Endpoints......................................................................................... 9
2.1.
Study Objectives........................................................................................................... 9
2.1.1. Primary Objective......................................................................................................... 9
2.1.2. Secondary Objectives.................................................................................................... 9
2.1.3. Exploratory Objectives ............................................................................................... 10
2.2.
Study Endpoints.......................................................................................................... 10
2.2.1. Efficacy Endpoints...................................................................................................... 10
2.2.2. Safety Endpoints......................................................................................................... 11
2.2.3. Pharmacokinetic Variables (Exploratory)................................................................... 11
2.2.4. Pharmacokinetic Variables (Exploratory)................................................................... 11
3.
Overall Study Design and Plan......................................................................................... 12
3.1.
Overall Design ............................................................................................................ 12
3.2.
Sample Size and Power............................................................................................... 12
3.3.
Study Population......................................................................................................... 12
3.4.
Treatments Administered............................................................................................ 12
3.5.
Method of Assigning Participants to Treatment Groups ............................................ 12
3.6.
Blinding and Unblinding............................................................................................. 13
3.7.
Schedule of Events...................................................................................................... 13
4.
Statistical Analysis and Reporting.................................................................................... 13
4.1.
Introduction................................................................................................................. 13
4.2.
Interim Analysis and Data Monitoring ....................................................................... 14
5.
Analysis Populations......................................................................................................... 14
6.
General Issues for Statistical Analysis.............................................................................. 15
6.1.
Statistical Definitions and Algorithms........................................................................ 15
6.1.1. Baseline....................................................................................................................... 15
6.1.2. Adjustments for Covariates......................................................................................... 15
6.1.3. Multiple Comparisons................................................................................................. 15
6.1.4. Handling of Dropouts or Missing Data....................................................................... 16




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9.
Safety and Tolerability Analysis....................................................................................... 26
9.1.
Adverse Events ........................................................................................................... 27
9.1.1. Adverse Events Leading to Withdrawal of the Study Drug ....................................... 27
9.1.2. Deaths and Serious Adverse Events ........................................................................... 28
9.2.
Clinical Laboratory Evaluations ................................................................................. 28
9.3.
Biomarkers.................................................................................................................. 28
9.4.
Vital Signs and Pulse Oximetry.................................................................................. 28
9.5.
12-Lead Electrocardiogram ........................................................................................ 28
9.6.
Physical Examination.................................................................................................. 29
9.7.
Concomitant Medication............................................................................................. 29
10.
Changes from Planned Analysis ....................................................................................... 29
11.
Other Planned Analysis..................................................................................................... 30
11.1.
Pharmacokinetic Analysis........................................................................................... 30
12.
References......................................................................................................................... 30


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List of Abbreviations
ABBREVIATION
EXPLANATION
AE
adverse event
ANCOVA
analysis of covariance model
AUC
area-under-the-curve
BID
twice daily
CI
confidence interval
Cmax
maximum concentration
COVID-19
coronavirus disease 2019
CRF
case report form
DSMB
data safety monitoring board
ECG
electrocardiogram
ECMO
extracorporeal membrane oxygenation
eCRF
electronic case report form
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HFNC
high-flow nasal cannula
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICU
intensive care unit
IND
investigational new drug
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
ITT
intent-to-treat
PD
pharmacodynamic


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ABBREVIATION
EXPLANATION
PK
pharmacokinetic
PP
per protocol
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
sPLA2
secretory phospholipase 2
SpO2
peripheral oxygen saturation
TEAE
treatment-emergent adverse event
TID
three times daily
Tmax
time of maximum concentration
WHO
World Health Organization 




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To evaluate time to resolution of symptoms
To evaluate the efficacy of varespladib in reducing the incidence of morbidity and 
mortality.
2.1.3. Exploratory Objectives
The exploratory objectives are:
To assess the pharmacokinetics of varespladib in COVID-19 patients
To evaluate the overall effect of varespladib in suppression of sPLA2 with severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
To assess pharmacoeconomic endpoints
2.2.
Study Endpoints
2.2.1. Efficacy Endpoints
2.2.1.1.
Primary Efficacy Endpoint
The primary efficacy endpoint of this study is a proportion of participants alive and free of 
respiratory failure at Day 28.
The primary estimand for the primary efficacy endpoint of this study is a proportion of 
participants alive and free of respiratory failure at Day 28.
2.2.1.2.
Secondary Efficacy Endpoint(s)
The secondary efficacy endpoints of this study include the following:
Clinical improvement as measured by the World Health Organization (WHO) 9-point 
ordinal scale from baseline through Day 60
Time to and proportion of participants with all-cause mortality through Day 60
Proportion of participants who experienced respiratory failure within the first 28 days 
after randomization
Among patients that never experience respiratory failure in the first 28 days, time to 
initiation, duration, and proportion of subjects receiving supplemental oxygen or other 
respiratory support within the first 28 days after randomization  
Among patients that experience respiratory failure in the first 28 days, time to initiation 
and duration of the forms of respiratory support meeting criteria outlined in critical 
COVID criteria (exclusion criteria 1.c.i) within the first 28 days after randomization 
Number of days of oxygen support through Day 28 after randomization
SpO2 through Day 28 after randomization


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Number of ventilator-free days through Day 28 after randomization
Number of hospitalization days through Day 28 after randomization
Number of days without renal stabilization and/or replacement through Day 28 after 
randomization
Number of organ failure-free days through Day 28 after randomization
Number of days at elevated level of care (ICU) through Day 28 after randomization
Number of healthcare encounters through Day 28 after randomization
2.2.1.3.
Exploratory Efficacy Endpoint(s)
The exploratory efficacy endpoints of this study include the following:
sPLA2 within blood samples from baseline through Day 28 after randomization
2.2.2. Safety Endpoints
The safety endpoints of this study include the following:
Incidence and severity (based on National Cancer Institute [NCI] Common Terminology 
Criteria for Adverse Events [CTCAE] v5.0 grade) of AEs, SAEs, and AEs leading to 
discontinuation of IP
Vital signs
Changes in levels of biomarkers: cardiac troponin, C-reactive protein (CRP), and ferritin
Clinical laboratory evaluations
12-lead electrocardiograms (ECGs)
2.2.3. Pharmacokinetic Variables (Exploratory)
The PK endpoints for the study include PK parameters for varespladib:
PK Parameters
2.2.4. Pharmacokinetic Variables (Exploratory)
Selected secondary endpoints, to include number of healthcare encounters, number of 
hospitalization days, and number of days at elevated level of care (ICU), all through Day 
28


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3.
Overall Study Design and Plan
3.1.
Overall Design
This is a 2-part, multi-center, randomized, double-blind, placebo-controlled, phase 2 study 
designed to evaluate the safety, tolerability, and efficacy of oral varespladib, in addition to 
standard of care, in patients hospitalized with severe COVID-19 caused by SARS-CoV-2.
Approximately 90 participants will be randomized, 18 in Part 1 and 72 in Part 2. Participants
must be 18 to 80 years of age and have severe laboratory-confirmed COVID-19. 
The study will be conducted in 2 parts. Both parts will be randomized and double-blind. Part 1 
will be dose-finding in 4 parallel treatment groups randomized to treatment with varespladib (at 
250 mg once daily [QD], twice daily [BID], or three times daily [TID] [total doses of 250, 500, 
or 750 mg/day]) or placebo in a 5:5:5:3 ratio. After all participants in Part 1 have completed Day 
28, a data safety monitoring board (DSMB) will review the safety results from Part 1 and will 
recommend the dose regimen to be used in Part 2. Part 2 will randomize an additional 72 
participants to the dose regimen selected from Part 1 or placebo in a 1:1 ratio. 
In both parts of the study, eligible participants will be enrolled and randomized to receive either 
varespladib or placebo in addition to institutional standard of care for 7 days.
3.2.
Sample Size and Power
Approximately 90 evaluable participants are planned for this study. Eighteen participants will be 
randomized into Part 1 of the study in a 5:5:5:3 ratio with 3 varespladib arms and a placebo arm. 
In Part 2 of the study, 72 participants will be randomized in a 1:1 ratio with the selected 
varespladib arm from Part 1 of the study and a placebo arm. No stratification variables will be 
used.
This is a pilot study and exploratory in nature. The sample size is not based on a formal power 
calculation.
3.3.
Study Population
Participants will be adults aged 18 to 80 years diagnosed with severe laboratory-confirmed 
COVID-19 requiring hospitalization caused by severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2).
3.4.
Treatments Administered
Varespladib or placebo will be administered in addition to institutional standard of care. The 
written institutional standard of care at each site may change during the study.
3.5.
Method of Assigning Participants to Treatment Groups
In Part 1, varespladib or placebo will be administered in addition to institutional standard of care 
for 7 days at a dosage of 250 mg QD, BID, or TID (total doses of 250, 500, or 750 mg/day).


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Table 1: Treatment groups in Part 1
Randomized Treatment
Morning
Afternoon
Bedtime
250 mg QD 
250 mg
placebo
placebo
250 mg BID
250 mg
placebo
250 mg
250 mg TID
250 mg
250 mg
250 mg
placebo
placebo
placebo
placebo
Any dose that is missed should not be taken later that day. 
In Part 2, varespladib or placebo will be administered in addition to institutional standard of care 
for 7 days using the dose regimen selected from Part 1.
3.6.
Blinding and Unblinding
All participants, investigators, and study personnel involved in the conduct of the study, 
including data management, will be blinded to treatment assignment with the exception of a 
specified unblinded statistician and programmer who will have access to the randomization code, 
and the DSMB. In Part 1 only, secondary pharmacists, separate from other study staff, will be 
unblinded to ensure the correct cartons are assigned to morning, noon, and evening. Unblinded 
pharmacists will have no other study participation or activities.
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject
If a subject
may not be asked to withdraw from the study. The investigator will make this decision after 
consultation with the medical monitor.
3.7.
Schedule of Events
Please see the protocol Table 2-1 for a detailed schedule of events.
4.
Statistical Analysis and Reporting
4.1.
Introduction
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations except for PK parameter estimation will primarily use SAS (release 9.3
or later). All PK parameter estimations will use WinNonlin® version 6.4 or later. If the use of 
other software is warranted, the final CSR will detail what software was used for what purposes.




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Pharmacokinetic Population (PK): All randomized participants who receive at least 1 dose 
of IP and provide at least 1 evaluable post-dose PK measurement.
Combined Population: All participants who receive at least 1 dose of placebo or at least 1 
dose of IP at the dose regimen used in Part 2.
Assignment of participants to populations will be determined prior to the study database lock.
The Safety Population will be used to analyze the safety endpoints, the ITT Population will be 
used to analyze the efficacy endpoints, and the PK population will be used to analyze the PK 
endpoints. In addition to the ITT Population, the PP and Combined Populations will be used to 
analyze the primary efficacy endpoint. Secondary endpoints will also be analyzed using the 
Combined Population.
Part 1 efficacy data will be listed. Part 1 participants receiving placebo or the dose regimen used 
in Part 2 will be included in the Combined Population. Safety and PK analyses will be based on 
actual treatment received. For the efficacy analyses, in the event that a subject is randomized 
incorrectly or is given the incorrect IP, analyses of the ITT, PP, and Combined Populations will 
be based on the randomized treatment.
6.
General Issues for Statistical Analysis
6.1.
Statistical Definitions and Algorithms
6.1.1. Baseline
The last observation recorded before the first administration of IP will be used as the baseline 
observation for all calculations of change from baseline. 
6.1.2. Adjustments for Covariates
The adjustments for covariates will be performed for analyses of data from Part 2 and for 
analyses of the Combined Population.
An analysis of covariance (ANCOVA) with the treatment as covariate will be used. When the 
analysis is based on a continuous endpoint, the baseline value of the endpoint will be included as 
a covariate. Endpoint analyses will also be adjusted for the following, a priori specified 
covariates: diabetes (dichotomous), age (continuous), body mass index (continuous), baseline 
sPLA2 activity (continuous). Each of these variables is known to be associated with outcomes in 
patients with severe COVID-19 infection. Each of these variables will be assessed at baseline, 
prior to randomization. Additional covariates will be considered for inclusion in the adjusted 
models if there is significant imbalance between the two arms of the trial. 
6.1.3. Multiple Comparisons
This is an exploratory pilot study that will be used to inform decisions about possible future 






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Adverse events will be coded using the MedDRA version 24.0 thesaurus.
A treatment related AE is any AE with a relationship to the study drug assessed by the investigator.
The investigator should carefully consider the list of possible manifestations of COVID-19 when 
assigning a relationship of specific AEs to the study drug.
For partial start dates:
If the year is unknown, then do not impute the date but instead assign a missing value.
If the year is known, but the month or month and day is unknown, then:
o
If the year matches the year of first dose date and the end date (if present) is after 
first dose date, or the AE/medication is ongoing, then impute as the month and 
day of the randomization date. If this produces a date after the end date, assign 01 
January.
o
Otherwise, assign 01 January.
If the year and month are known, but the day is unknown, then:
o
If the month and year match the month and year of the first dose date, then impute 
as the day of the randomization date. If this produces a date after the 
AE/medication end date, assign 01.
o
Otherwise, assign 01.
For partial end dates:
If the year is unknown, then do not impute the date but assign as missing value.
If the year is known but the month or month and day is unknown, then:
o
If the year matches the year of the last date of the study (date of last contact if 
subject lost to follow-up; date of completion or early termination otherwise), then 
impute as the month and day of the last date of the study.
o
Otherwise, assign 31 December.
If the year and month are known, but day is unknown, then:
o
If the month and year match the month and year of the last date of the study, then 
impute as the day of the last date of the study.
o
Otherwise, assign the last day of the month.
In general, for quantitative laboratory
quantitation (LLOQ) will be used for analysis (i.e., the value of X will be used in the analysis for 




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7.4.
Exposure and Compliance
IP exposure and dosing information including the number of doses and amount of IP received 
will be listed for each subject.
8.
Efficacy Analysis
Efficacy data for Part 1 participants will be listed only, except for data from Part 1 participants 
that are included in the Combined Population. 
For Part 2 and the Combined Population, all statistical testing for endpoints will be 2-sided and 
will be evaluated in an exploratory manner to inform decisions about future trials. Tests 
comparing treatment and control group will report point estimates, p-values, and 95% confidence 
intervals. In Part 2 and the Combined Population, all efficacy variables will be summarized 
descriptively. The primary analytic method will include adjustment for a priori selected 
covariates as described in Section 6.1.2.
8.1.
Primary Efficacy Analysis
The primary efficacy endpoint is the proportion of participants alive and free of respiratory 
failure at Day 28.
The proportion of respiratory failure-free surviving participants in each Part 2 treatment group at 
Day 28 will be analyzed using logistic regression with treatment as a factor and age, diabetes, 
body mass index, and baseline sPLA2 activity included as covariates. Dummy/refence coding 
will be used in all logistic regression implementations. The risk difference between varespladib 
and placebo along with the 95% CI and p-value will be presented. Note that logistic regression 
typically involves calculation and testing of odds ratios, however, this analysis will focus on 
presenting and testing the risk difference via the delta method (Ge et al, 2011).
The ITT, PP and Combined populations will be used to analyze the primary efficacy endpoint. 
The ITT population will be the primary population for the efficacy analyses.
8.1.1. Sensitivity Analyses of the Primary and Key Secondary Efficacy Endpoints
Two types of sensivity analyses will be conducted for the primary efficacy endpoint and key 
secondary efficacy endpoints using the ITT population. The following sensitivity analysis will be 
conducted in Part 2 subjects only.
One sensitivity analysis will be to examine the effect of covariate selection. This work will 
include estimating (1) the effect of treatment on the outcome adjusted for only the a priori
specified model covariates (see section 6.2.1), and (2) and if significant imbalance is observed in 
other important covariates, then adjustment for the a priori specified covariates as well as other 
variables that are imbalanced between the treatment arms.






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the 95% CI associated with the treatment effect will be a Wald-type CI. 
Additionally, the proportion of participants who die will be analyzed using the same logistic 
regression and risk difference method with dummy coding as the primary endpoint (Ge et al, 
2011). In general, the proportions of participants with an event on or before Day 60 will be 
analyzed. 
8.2.3 Proportion of participants who experienced respiratory failure within the first 28 
days after randomization 
The proportion of participants experiencing respiratory failure from randomization through Day 
28 will be analyzed using the same logistic regression and risk difference method with dummy 
coding as the primary endpoint. Respiratory failure is defined as defined by requiring HFNC >20 
L/min, non-invasive positive pressure ventilation, mechanical ventilation, or ECMO, or clinical 
diagnosis of respiratory failure (exclusion criteria 1.c.i) at any time during the 28 days after 
randomization. Note that those who experience mortality after respiratory failure are still counted 
towards this analysis. Those who experience mortality without prior respiratory failure will not 
be counted towards this analysis. 
8.2.4 Among patients that do not experience respiratory failure in the first 28 days, time 
to initiation and duration of supplemental oxygen or other respiratory support within the 
first 28 days  
The number of days of supplemental oxygen or other respiratory support in patients not meeting 
the criteria for respiratory failure from randomization through Day 28 will be summarized 
descriptively and analyzed using ANCOVA. The LS means will be presented along with the 
associated 95% CI within each treatment group. In comparing treatments, LS mean differences 
between treatments will be presented along with associated 95% CIs and p-values. For Part 1 
analysis, this endpoint will be reported in all patients in the ITT population. 
The time to start of supplemental oxygen or other respiratory support from randomization 
through Day 28 will be analyzed using a Cox-Proportional hazard model. The number of 
participants who experience the event and rate ratio with 95% CI will be presented. The p-value 
to test if the rate ratio between treatments differs from 1 will be evaluated. Kaplan-Meier 
methodology will be used to estimate the median time to the event and 95% CI. Censoring 
events include loss to follow-up prior to Day 28. Mortality will not be considered a censoring 
event and instead will be analyzed as if this patient was on supplemental oxygen or other 
respiratory support for all days between randomization and Day 28. If mortality or the event of 
interest does not occur; all subjects will be censored at Day 28. Covariates will include those a 
priori specified in Section 6.1.2, and Efron’s method for handling tied time-to-events will be 
used. The p-value testing for non-zero treatment effect will be obtained from a Wald chi-square 
test, and the 95% CI associated with the treatment effect will be a Wald-type CI. 
Duration and time to supplemental oxygen or other respiratory support through Day 28 will be 
calculated according to Section 6.1.7 
 








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therapies.
All safety analyses will be performed on the Safety Population. Separate outputs will be 
produced for Part 1 and Part 2 of the study.
9.1.
Adverse Events
All AEs, TEAEs, and SAEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) v24.0.
Treatment-emergent AEs are defined as AEs that first occur or worsen in severity after the first 
dose of IP and prior to the 30 days after last administration of IP.
An overall summary of number and percentage of participants with at least one TEAE, severe 
TEAE, treatment-related TEAE, AE leading to discontinuation, AE leading to death, at least one 
SAE, and treatment-related SAE will be presented.
The number and percent of participants reporting treatment emergent TEAEs, grouped by 
MedDRA SOC and preferred term (coded using MedDRA v24.0) will be tabulated for the overall 
safety population and by treatment group. In the case of multiple occurrences of the same TEAE 
within the same subject, each subject will only be counted once for each preferred term.
Causality, and severity of TEAEs (by CTCAE v5.0 grade) will be tabulated. In the summaries 
showing severity and relationship to study medication the event with the maximum severity or 
strongest relationship will be reported. Although not anticipated, if a particular event is missing 
the severity and/or relationship, missing severities will be imputed as CTCAE Grade 3 and 
missing relationships will be imputed as related. CTCAE Grade 3 (i.e., Severe or medically 
significant but not immediately life-threatening) is chosen since higher grades (i.e., Grade 4 [life-
threatening] or Grade 5 [death]) are most unlikely to be unobserved and Grade 3 is considered 
sufficiently deleterious when the severity is in question. Related is chosen for missing 
relationships as it is the most conservative option. Missing data for severities and relationships 
will be reported with counts and percentages prior to this imputation.
An additional analysis will be done for Part 2 participants for AEs with a greater severity than 
mild and AEs related to study treatment. The frequency and percentage of participants
experiencing each type of event by Day 60 will be presented in each treatment arm. The 
difference in proportions, 95% CI derived, p-value comparing varespladib and placebo from a 2-
proportion Z-test will also be presented.
In the AE data listings, all AEs will be displayed. AEs that are not treatment-emergent will be 
flagged.
9.1.1. Adverse Events Leading to Withdrawal of the Study Drug
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study drug by system organ class, and preferred term will be prepared for the safety population
overall and treatment.


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A data listing of TEAEs leading to withdrawal of study drug will also be provided, displaying 
details of the event(s) captured on the CRF.
9.1.2. Deaths and Serious Adverse Events
Any deaths that occur during the study will be listed.
SAEs will be listed and also tabulated by system organ class and preferred term and presented by 
treatment.
9.2.
Clinical Laboratory Evaluations
Laboratory test results for chemistry, coagulation, hematology and urinalysis will be summarized 
descriptively by treatment and visit as both observed values and change from baseline values.
The number and percentage of participants with at least 1 post-baseline potentially clinically 
significant abnormality will be presented by treatment group for selected parameters. The number 
of participants with clinical laboratory values below, within, or above the normal range by visit
and in relation to baseline will be tabulated for each clinical laboratory analyte by treatment group
(shift table).
Individual data listings of laboratory results will be presented for each subject. Flags will be 
displayed for values
normal reference limits.
9.3.
Biomarkers
Observed values and changes from baseline in biomarkers such as cardiac troponin level, CRP, 
and ferritin will be summarized using descriptive statistics by visit. The safety biomarkers data 
will be provided in a listing.
9.4.
Vital Signs and Pulse Oximetry
Descriptive summaries of actual values and changes from baseline will be calculated systolic 
blood pressure, diastolic blood pressure, heart rate, respiratory rate, body temperature, and SpO2.
The number and percentage of participants with at least 1 post-baseline potentially clinically 
significant abnormality will be presented by treatment group for selected parameters.
Individual data listings of vital signs (observed and change from baseline) will be presented for 
each subject.
9.5.
12-Lead Electrocardiogram
Descriptive summaries of observed values and changes from baseline will be calculated for heart 
rate, PR interval, QRS interval, QT interval and QTcF by visit and treatment group. 






Statistical Analysis Plan, 
Sponsor Ophirex, Inc.
Protocol Number OPX-PR-02
AD-ST-33.06 Effective date: 12-Nov-2020
Version 2.0    |    Date 13-Jun-2022      |    
 Effective date: 17-Aug-2020
Page 31 of 31
ICH (1998). ICH Harmonised Tripartite Guideline. Statistical Principles for Clinical Trials E9; 
1998. https://database.ich.org/sites/default/files/E9_Guideline.pdf
RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014.
https://rss.org.uk/about/policy-and-guidelines/code-of-conduct/.