Conditions: Snakebites Envenoming Envenoming, Snake Envenomation, Snake
Keywords: envenoming venom snakebite snakebite severity score varespladib snake antidote LY333013 sPLA2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 95
Healthy volunteers: no

Brief summary:
This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability and efficacy of varespladib-methyl, concurrently with standard of care (SOC), in subjects bitten by venomous snakes.

Detailed description:
This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability, and efficacy of varespladib-methyl, concurrently with SOC, in subjects bitten by venomous snakes.

Approximately 110 male and female eligible subjects will be enrolled and randomized to receive active varespladib-methyl or placebo (in addition to SOC) in a 1:1 ratio (approximately 36 per group). There will be no stratification by type of snakebite, though randomization will be stratified by age group (5 to 11 years, 12 to 17 years, and ≥ 18 years) and by the presence or absence of severe neurologic symptoms defined by yes/no neurologic system subscore of the snakebite severity score of ≥ 2.

Effective treatments for snakebite envenoming represents a deadly and unmet global medical need. While antivenoms comprise the SOC for treatment of snakebites, they suffer from several limitations including specificity of each antivenom for specific species of snake, limited access to antivenom in rural areas, practical storage requirements, and delays in administration. Treatment of snakebite envenoming with the small-molecule drug varespladib-methyl, which targets secreted phospholipase A₂ (sPLA₂) present in more than 95% of snake venoms, has the potential to overcome several limitations of serum-based antivenoms that underpin traditional SOC.

This study in the United States and India will provide coverage of a broad spectrum of venomous snake genera, including elapids, pit vipers, and potentially exotics such as vipers and colubrids if encountered over the course of the study. The study is designed to cover differing geographies and differing sPLA₂ structures. Study sites have been and will be selected based on demonstrated historical incidence of snake bites from species deemed relevant to this study, to ensure a broad range of envenoming toxins are expected to be encountered in potential study subjects.

The study design allows for both treatment arms (varespladib-methyl and placebo) to receive SOC (e.g., antivenom) concurrently. Thus, critically ill adult and pediatric subjects may receive emergency treatment in a timely manner while being evaluated for the potential clinical benefit associated with inhibition of venom sPLA₂ and inflammatory sPLA2s by varespladib-methyl.

Because subjects with severe snakebites are admitted to emergency departments, this study was designed to screen, enroll, and administer treatment in a single visit at the hospital upon admission. Because varespladib-methyl is administered orally, subjects who demonstrate substantial improvement and are eligible for discharge from the hospital may continue investigational product treatment in an outpatient setting.

Risks associated with the control (placebo) arm of this study include the same risks associated with SOC (antivenom).

Arms:
arm 1: Varespladib-methyl is an immediate-release (IR), oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration.

Scaled pediatric doses of varespladib-methyl are supplied as 50 mg IR capsules for oral administration.

Adult subjects will receive an initial loading dose of 500 mg (2 × 250 mg oral tablet) varespladib-methyl upon randomization, followed by dosing with 250 mg varespladib-methyl (1 × 250 mg oral tablet) approximately 12 hours later, and subsequent twice daily (BID) dosing with 1 × 250 mg varespladib-methyl oral tablets for the remainder of the 7-day treatment period. Tablets may be administered via naso- or orogastric tubes in patients requiring mechanical ventilation.

Pediatric subjects (5 to \< 18 years) will be administered doses of varespladib-methyl determined by allometric scaling, provided as 50 mg capsules. Age-appropriate capsules may be administered via naso- or orogastric tubes in patients requiring mechanical ventilation. arm 2: The oral placebo is supplied as a white film-coated oval tablet to match the appearance of the varespladib-methyl 250 mg tablet and contains a subset of the excipients present in the active tablet formulation: lactose monohydrate, microcrystalline cellulose, and magnesium stearate.

Placebo for scaled pediatric dosing is supplied as an immediate-release capsule to match the varespladib-methyl 50 mg capsule, and contains the excipients lactose monohydrate, microcrystalline cellulose, and magnesium stearate.

The dosing of placebo will match that of varespladib-methyl.

Interventions: intervention 1: Varespladib Methyl intervention 2: Placebo intervention 3: Standard of care (SOC)
Intervention descriptions: intervention 1: Varespladib-methyl (LY333013) is an IR, oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration. Scaled pediatric doses of varespladib-methyl (LY333013) are supplied as 50 mg IR capsules for oral administration. intervention 2: The oral placebo is supplied as a white film-coated oval tablet to match the appearance of the varespladib-methyl 250 mg tablet and contains a subset of the excipients present in the active tablet formulation: lactose monohydrate, microcrystalline cellulose, and magnesium stearate.

Placebo for scaled pediatric dosing is supplied as an IR capsule to match the varespladib-methyl 50 mg capsule, and contains the excipients lactose monohydrate, microcrystalline cellulose, and magnesium stearate. intervention 3: SOC (including antivenom) will continue to be administered throughout the subject's participation in the study according to the protocol and the judgment of the Investigator.

Protocol document:
Prot_000.pdf: 
 
 
 
Page 1 of 112 
 
 
PROTOCOL 
 
PRODUCT NAME: 
Varespladib-methyl 
PROTOCOL NUMBER: 
OPX-PR-01 
IND NUMBER: 
152097 
NCT NUMBER:  
CTRI NUMBER: 
04996264 
2021/07/045079 000062 
 
 
DEVELOPMENT PHASE: 
Phase 2 
PROTOCOL TITLE: 
Randomized, Double-Blinded, Placebo-Controlled Study to 
Evaluate the Safety, Tolerability, and Efficacy of a 
Multi-Dose Regimen of Oral Varespladib-Methyl in 
Subjects Bitten by Venomous Snakes 
(BRAVO study - Broad-spectrum Rapid Antidote: 
Varespladib Oral for snakebite) 
PROTOCOL DATE: 
Version 3.0, 5 May 2022 
SPONSORED BY: 
Ophirex, Inc. 
5643 Paradise Drive #2 
Corte Madera, CA 94925  
(415) 891-8682 
CONTRACT RESEARCH 
ORGANIZATION: 
 
 
This study will be performed in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices and applicable regulatory requirements, including the archiving of 
essential documents. Information contained in this protocol is confidential in nature, and may not 
be used, divulged, published, or otherwise disclosed to others except to the extent necessary to 
obtain approval of the institutional review board or independent ethics committee, or as required 
by law. Persons to whom this information is disclosed should be informed that it is confidential 
and may not be further disclosed without the express permission of Ophirex, Inc. 
 
 




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2 
PROTOCOL SUMMARY 
2.1 
Synopsis 
Number of Subjects 
Approximately 110 subjects (94 evaluable) enrolled 
Population 
Subjects ≥ 5 years of age and older 
Investigational Product 
Varespladib-methyl (LY333013), solid oral dosage forms 
Study Objectives 
Primary 
To evaluate the efficacy of a multiple-dose regimen of oral 
varespladib-methyl with standard of care (SOC) in subjects after 
venomous snakebite. 
 
Study Endpoints 
Primary Efficacy 
Change in the composite outcome of pulmonary, cardiovascular, 
hematologic, renal, and nervous system sections of the snakebite severity 
score (SSS) from Baseline (pre-dosing) to the average of the scores from 
6 and 9 hours after first dose.  
Secondary Efficacy 
• 
AUC of the pulmonary, cardiovascular, hematologic symptoms, 
renal, and nervous system sections of the SSS from Baseline 
through Day 7  
• 
Complete SSS from Baseline through Day 7  
• 
SSS neurologic system subscore from Baseline through Day 3 
• 
Coagulation abnormalities from Baseline through Day 7 
• 
Hemolysis markers from Baseline through Day 3 
• 
Levels of the myonecrosis marker, creatine kinase (CK), from 
Baseline through Day 3 
• 
Numeric Pain Rating Scale (NPRS) score in patients able to 
respond from Baseline through Day 28 
• 
Kidney function markers from Baseline through Day 28 
• 
Total differential antivenom requirement from Baseline through 
Day 28 
• 
Head-Lift duration from Baseline through Day 7 
• 
Total duration of ventilatory support from Baseline through Day 
28  
• 
Total duration of Intensive Care Unit (ICU) stay from Baseline 
through Day 28 
• 
Total duration of hospitalization from Baseline through Day 28 
• 
All-cause mortality from Baseline through Day 28 
• 
Clinical Global Impression-Improvement (CGI-I) from Baseline 
through Day 7 
• 
Patient Global Impression of Change (PGIC) from Baseline 
through Day 7 
• 
Patient-Specific Functional Scale (PSFS) total score from 
Baseline through Day 28  


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Exploratory Efficacy 
• 
Change in the SSS from Baseline through Day 7 using compressed 
SSS scale 
• 
SSS from Baseline through Day 28 after first dose 
• 
Grip strength pre-dosing through Day 28  
• 
SSS neurologic system subscore from Baseline through Day 7 
• 
Analgesic use from Baseline through Day 28  
• 
CGI-I from Baseline through Day 28 
• 
PGIC from Baseline through Day 28 
• 
Complete blood count (CBC) through all SSS evaluation days 
• 
Transfusion requirement from Baseline (Day 1) through Day 28 
• 
C-reactive protein (CRP) from Baseline through Day 14  
• 
D-dimer levels from Baseline through Day 14 
• 
Levels of myonecrosis marker (CK) from Baseline through Day 3 in 
patients presenting with and without tourniquets at enrollment 
• 
Secretory phospholipase A2 (sPLA2) in serum at specified timepoints 
on Days 1 to 7 in all subjects 
 
Pharmacokinetics 
• 
PK parameters of varespladib-methyl in plasma from a subset of 
adult and pediatric subjects at specified timepoints on Days 1 and 3 
followed by all subjects pre-dose on Day 7 
Safety 
• Incidence and severity of adverse events (AEs), serious AEs (SAEs), 
and AEs leading to discontinuation of Investigational Product (IP) 
• Safety of varespladib-methyl as assessed by the number and rates of 
reported treatment-emergent adverse events (TEAEs) from 
beginning of treatment until last Follow-Up Visit/Telephone Call at 
Day 28 
• Number of subjects with a treatment-related SAE from beginning of 
treatment until last Follow-Up Visit/Telephone Call at Day 28 
• Safety as assessed by 
− 
Vital signs 
− 
Clinical laboratory evaluations: CBC, urinalysis, liver function 
tests [LFTs], renal function tests (albumin, creatinine, blood 
urea nitrogen [BUN], estimated glomerular filtration rate 
[eGFR])  
− 
12-lead electrocardiogram (ECG) 
• Concomitant medications and therapies 
• Columbia-Suicide Severity Rating Scale (C-SSRS) evaluated at 
Baseline or at the earliest time point clinically allowable (ideally 
Day 1) and then at every study visit through Day 28 
Investigational Product 
Varespladib-Methyl: 
Tablet: Varespladib-methyl (LY333013) formulated as an 
immediate-release, white film-coated oval tablet (250 mg). 
Capsule: Varespladib-methyl (LY333013) formulated as an 
immediate-release capsule (50 mg). 


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Control Article 
Placebo: 
Tablet: The oral placebo is supplied as a white film-coated oval tablet to 
match the LY333013 250 mg tablet for oral administration and contains 
a subset of the excipients: lactose monohydrate, microcrystalline 
cellulose, and magnesium stearate. 
Capsule: Placebo is supplied as an immediate-release capsule to match 
the 50 mg IP, and contains the excipients lactose monohydrate, 
microcrystalline cellulose, and magnesium stearate. 
Route of Administration 
Oral 
Dose and Administration 
Adult subjects will receive an initial loading dose of 500 mg 
(2 x 250 mg oral tablets) varespladib-methyl upon randomization and an 
additional dose of 250 mg (1 x 250 mg oral tablet) approximately 
12 hours later, followed by dosing with 1 x 250 mg varespladib-methyl 
oral tablet twice daily (BID) for a total of 7 days from the first dose. 
Pediatric subjects (ages 5 to < 18) will be administered doses of 
varespladib-methyl determined by allometric scaling, provided as 50 mg 
capsules. Pediatric subjects will receive an initial loading dose of 
varespladib-methyl and an additional dose approximately 12 hours later 
(at the doses listed below), followed by the listed dose BID for the 
remainder of the 7-day treatment period. 
• 
Subjects 5 to < 11 years old will receive an initial loading dose of 
200 mg varespladib-methyl, an additional dose of 100 mg 
approximately 12 hours later, followed by 100 mg BID 
• 
Subjects 11 to < 18 years old will receive a loading dose of 400 mg 
varespladib-methyl, an additional dose of 200 mg approximately 
12 hours later, followed by 200 mg BID 
All patients will receive 14 doses total (i.e., one oral loading dose and 13 
additional oral doses).  
 
Follow-Up 
Subjects will be assessed on a regular schedule for a total of 28 days 
after administration of an initial dose of varespladib-methyl. 
 
 
 


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Eligibility 
To be eligible to participate in the study an individual must meet all 
listed inclusion criteria and none of the exclusion criteria.  The time 
between baseline and eligibility assessments, randomization, and IP 
administration should be minimized. 
 
Inclusion Criteria 
1. Is a male or female ≥ 5 years of age with venomous snakebite. 
2. Index event (snakebite) must be symptomatic and symptom onset 
must have occurred within 10 hours of eligibility assessment.  
3. Patients must meet one of two categories of inclusion criteria: 
Category 1: The patient has not yet completed first dose of 
antivenom:  
SSS inclusion score* of ≥2 in one system and ≥1 in another 
system (2+1) OR ≥3 in at least one system.  
OR 
Category 2: The patient has completed an initial dose of 
antivenom:  
SSS inclusion score* of ≥2 in one system and ≥1 in another 
system (2+1) OR ≥3 in at least one system AND CGI-I score of 
≥5 (i.e., minimally worse, much worse, or very much worse).  
 
4. Is willing (or legally authorized representative is willing) to provide 
informed consent prior to initiation of any study procedures. 
* Only local wound, pulmonary, cardiovascular, hematologic, or nervous 
system scores qualify for SSS inclusion criteria. GI and Renal scores 
are not used for inclusion. Hematologic score may be counted if 
available, but inclusion should not wait for laboratory results. Point of 
care tests (e.g., 20WBCT) may be used for enrollment, if used per site 
standard of care (see Appendix A). 
Exclusion Criteria 
1. Is considered by the Investigator to have a clinically significant 
upper GI bleed evidenced by hematemesis, “coffee-ground” emesis 
or nasogastric aspirate, or hematochezia thought to originate from 
upper GI tract. 
2. Has history of cerebrovascular accident or intracranial bleeding of 
any kind, acute coronary syndrome, myocardial infarction, or severe 
pulmonary hypertension. 
3. Has known history of inherited bleeding or coagulation disorder. 
4. Is, at Screening Visit, using the following anticoagulants: 
warfarin/coumadin, argatroban, bilvalirudin, lepirudin, apixaban, 
dabigatran, clopidogrel, prasugrel, ticlodipine or another 
anticoagulant agent not specifically listed, or has used heparin, 
enoxaparin, fondaparinux, or other low molecular weight heparin or 
antiarrhythmic drugs within 14 days prior to treatment. 
 


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5. Has a history of chronic liver disease such as chronic active viral 
hepatitis, alcohol-related liver disease, non-alcoholic steatohepatitis, 
non-alcoholic fatty liver disease, hemochromatosis, primary biliary 
cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis.  
6. Reports or has known pre-existing renal impairment or chronic 
kidney disease. 
7. Has a known allergy or significant adverse reaction to 
varespladib-methyl.  
8. Is considered by the Investigator to be unable to comply with 
protocol requirements due to geographic considerations, psychiatric 
disorders, or other compliance concerns. 
9. Is pregnant, has a positive urine or serum human chorionic 
gonadotropin (hCG) pregnancy test or not willing to use a highly 
effective method of contraception for 14 days after initial treatment, 
or is breast-feeding.  
Safety Follow-up 
Assessments 
Follow-up schedule: Day 14 and Day 28 after first dose of 
varespladib-methyl. If discharged before Day 7, follow-up will also be 
performed on Day 3 (if discharge prior to Day 3) and Day 7. 
Study Duration 
Approximately 12 months 
Sample Size 
The sample size for this study was determined by a formal power 
calculation. The total enrollment for this study will be approximately 
110 subjects (94 evaluable).  
The assumptions used to determine sample size are as follows: 
• 
2-sided alpha level 5% 
• 
Power 85% 
• 
Randomization Ratio 1:1. The randomization will be stratified by 
age group (5 to < 11 years, 11 to < 18 years, ≥ 18 years) and by the 
presence or absence of neurotoxicity (SSS nervous system subscore 
of 0–1 or ≥ 2) at Baseline, resulting in 6 strata in total 
• 
Withdrawal rate of 15% 
• 
The sample size also assumes: A minimum difference of change in 
SSS average of the 6- and 9-hour scores of 1.1 and a standard 
deviation of 1.75 
Statistical Analysis 
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 analysis are outlined in the study Statistical Analysis 
Plan. 
Efficacy 
All statistical testing for efficacy endpoints will be 2-sided and 
performed using a significance level of 0.05. All efficacy analyses will 
be performed on the analysis populations using descriptive statistics. 


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Safety 
Safety and tolerability will be evaluated by examining the occurrence of 
AEs, including TEAEs. AEs leading to discontinuation from the study 
drug, causality and severity will be summarized by treatment group. AEs 
will also be presented in listings. Summary statistics of clinical 
laboratory measures, vital signs, and ECG will be presented by treatment
group for each assessment. Number and percentage of subjects 
presenting at least one post-Baseline potentially clinically significant 
abnormality will be presented by treatment group for selected 
parameters. All safety analyses will be performed on the Safety 
Population set using descriptive statistics. 








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r 
Urinalysis should not delay care and should not be obtained by catheter unless patient already being catheterized (e.g., Russell’s viper). Urine from 
catheterized patients should not be collected from bag, but rather proximal port. 
s 
sPLA2 sampling will be performed for all subjects on Day 1 (pre-dose and 1, 3, 6, and 9 hours post-first dose), and on Day 2, Day 3, and Day 7 (pre-dose). 
sPLA2 in serum and PK samples will be processed and analyzed in a central laboratory, not at individual sites. 
t 
PK sampling will only be performed for a total of 20 adult and pediatric subjects on Days 1 and 3, and all subjects on Day 7. Once 20 subjects have provided 
PK samples for Days 1 and 3, sites will be notified by the sponsor to discontinue Day 1 and 3 PK sampling. Subjects will be enrolled for PK analysis as 
follows: Day 1 - 20 subjects, pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 (pre-second dose) hours; Day 3 - 20 subjects, pre-dose and 0.5, 1, 2, 4, 6 hours; Day 7 - 
all subjects, pre-dose.  


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Figure 1 
Study Schematic 
 
a. 
Because snakebite subjects are considered critically ill and will arrive in an emergency department setting, 
Screening, Baseline evaluation, randomization, and treatment must all take place on Study Day 1 
b. Assessments (see Schedule of Events) must be performed at the following times post-initial dose: 3 to 
4 hours, 5 to 6 hours, 8 to 10 hours, 2 days (12 to 18 hours after last Day 1 measurements), 3 days 
(approximately 24 hours after Day 2 measurements), 7 days ± 1 day, 14 days ± 2 days, and 28 days 
± 3 days 
c. 
The varespladib-methyl dosing for adult subjects is a 500 mg loading dose, a 250 mg dose approximately 
12 hours later, then 250 mg BID for the remainder of the study period; pediatric subjects (ages 5 to < 18) 
will be administered doses of varespladib-methyl determined by allometric scaling, provided as 50 mg 
capsules, depending on age (see Section 7.3). Abbreviations: BID = twice daily; SOC = standard of care; 
yr = years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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3 
TABLE OF CONTENTS 
1 
APPROVAL SIGNATURES ...................................................................................................2 
2 
PROTOCOL SUMMARY ........................................................................................................3 
2.1 
Synopsis 3 
2.2 
Schedule of Events ..........................................................................................................9 
3 
TABLE OF CONTENTS .......................................................................................................14 
3.1 
List of In-text Tables .....................................................................................................18 
3.2 
List of In-text Figures....................................................................................................18 
4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...........................................19 
5 
INTRODUCTION ..................................................................................................................20 
5.1 
Background and Rationale ............................................................................................20 
5.1.1 Scientific Rationale ...........................................................................................21 
5.1.2 Epidemiology of Snakebites in Children ...........................................................22 
5.2 
Clinical Experience .......................................................................................................22 
5.3 
Summary of Potential Risks and Benefits .....................................................................22 
6 
OBJECTIVES AND ENDPOINTS ........................................................................................25 
7 
STUDY DESIGN ...................................................................................................................28 
7.1 
Overall Study Design and Plan .....................................................................................28 
7.2 
Rationale and Discussion of Study Design ...................................................................29 
7.3 
Selection of Doses in the Study ....................................................................................30 
7.4 
Study Sites .....................................................................................................................32 
7.5 
End of Study Definition ................................................................................................32 
8 
STUDY POPULATION .........................................................................................................33 
8.1 
Selection of Study Population .......................................................................................33 
8.2 
Study Entry Criteria ......................................................................................................33 
8.2.1 Inclusion Criteria ...............................................................................................33 
8.2.2 Exclusion Criteria ..............................................................................................33 
8.3 
Early Subject Withdrawal .............................................................................................34 
8.4 
Discontinuation of Study Intervention ..........................................................................35 
8.5 
Subject Replacement Criteria ........................................................................................35 
9 
TREATMENTS ......................................................................................................................36 
9.1 
Identification of Investigational Products or Placebo ...................................................36 
9.2 
Selection of Timing of Dose for Each Subject..............................................................36 
9.3 
Dose Adjustment Criteria ..............................................................................................36 
9.4 
Treatment Compliance ..................................................................................................37 
9.5 
Method of Assigning Subjects to Treatment Groups ....................................................37 
9.6 
Blinding and Unblinding Treatment Assignment .........................................................37 
9.7 
Prohibited and Permitted Therapies ..............................................................................38 


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9.7.1 Prohibited Therapies ..........................................................................................38 
9.7.2 Permitted Therapies ...........................................................................................38 
9.8 
Treatment After End of Study .......................................................................................38 
9.9 
Dispensing and Storage .................................................................................................38 
9.10 Drug Accountability ......................................................................................................39 
9.11 Labeling and Packaging ................................................................................................39 
9.11.1 Labeling .............................................................................................................39 
10 STUDY PROCEDURES ........................................................................................................40 
10.1 Study Duration ..............................................................................................................40 
10.2 Study Periods and Visits ...............................................................................................40 
10.2.1 sPLA2 and Pharmacokinetics Sample Timing ...................................................40 
10.2.2 Screening (Enrollment and Baseline) ................................................................41 
10.2.3 Treatment Period ...............................................................................................43 
10.2.3.1 Day 1 (Dosing, 0 Hours) .......................................................................43 
10.2.3.2 Day 1 (1 Hour) ......................................................................................43 
10.2.3.3 Day 1 (2 Hours) .....................................................................................43 
10.2.3.4 Day 1 (3 to 4 Hours)..............................................................................43 
10.2.3.5 Day 1 (5 to 6 Hours)..............................................................................44 
10.2.3.6 Day 1 (8 to 10 Hours)............................................................................46 
10.2.3.7 Day 2 .....................................................................................................47 
10.2.3.8 Day 3 .....................................................................................................48 
10.2.3.9 Day 7 (7 Days ± 1 Day) ........................................................................50 
10.2.3.10 Day 14 (14 Days ± 2 Days) ...................................................................51 
10.2.3.11 Day 28 (End of Study Visit) .................................................................52 
10.3 Assessments ..................................................................................................................53 
10.3.1 Efficacy Assessments ........................................................................................53 
10.3.1.1 Composite Snakebite Severity Scale .....................................................54 
10.3.1.2 Clinical Global Impression-Improvement.............................................55 
10.3.1.3 Patient Global Impression of Change Scale ..........................................55 
10.3.1.4 Patient-Specific Functional Scale .........................................................55 
10.3.1.5 Numeric Pain Rating Scale ...................................................................56 
10.3.1.6 Columbia-Suicide Severity Rating Scale ..............................................56 
10.3.1.7 Additional Assessments on Endotracheally Intubated Subjects ...........56 
10.3.1.8 Grip Strength .........................................................................................57 
10.3.1.9 Head-Lift duration .................................................................................57 
10.3.1.10 Analgesic Use........................................................................................57 
10.3.2 Pharmacokinetics ...............................................................................................57 
10.3.2.1 Pharmacokinetic Analysis Methods ......................................................57 


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10.3.2.2 Pharmacokinetic Parameters .................................................................58 
10.3.2.3 Sample Collection .................................................................................58 
10.3.3 Safety Variables ................................................................................................58 
10.3.3.1 Clinical Laboratory Safety Assessments ...............................................59 
10.3.3.2 Clinical Examinations ...........................................................................59 
10.3.3.3 Adverse Events......................................................................................60 
11 ADVERSE EVENTS..............................................................................................................61 
11.1 Definitions .....................................................................................................................61 
11.1.1 Adverse Events ..................................................................................................61 
11.1.2 Unexpected Adverse Event ...............................................................................61 
11.1.3 Serious Adverse Events .....................................................................................62 
11.1.4 Treatment-Emergent Adverse Events ...............................................................62 
11.2 Event Assessment and Follow-Up of Adverse Events ..................................................62 
11.2.1 Assessment ........................................................................................................63 
11.2.2 Evaluation ..........................................................................................................63 
11.2.2.1 Severity of Adverse Events ...................................................................63 
11.2.2.2 Seriousness ............................................................................................64 
11.2.2.3 Action(s) Taken .....................................................................................64 
11.2.2.4 Outcome at the Time of Last Observation ............................................64 
11.2.2.5 Adverse Event Relationship to Investigational Product........................64 
11.2.3 Documentation ..................................................................................................65 
11.2.4 Treatment of Adverse Events ............................................................................65 
11.2.5 Follow-Up .........................................................................................................65 
11.2.6 Reporting ...........................................................................................................66 
11.2.6.1 Serious Adverse Events.........................................................................66 
11.3 Special Considerations ..................................................................................................67 
11.3.1 Adverse Events of Special Interest ....................................................................67 
11.3.2 Pregnancy ..........................................................................................................67 
11.3.3 Overdosage ........................................................................................................68 
12 DATA SAFETY MONITORING BOARD ...........................................................................69 
13 STATISTICS ..........................................................................................................................70 
13.1 Statistical Analysis ........................................................................................................70 
13.1.1 Analysis Populations .........................................................................................70 
13.1.2 Study Subjects and Demographics ....................................................................71 
13.1.2.1 Disposition and Withdrawals ................................................................71 
13.1.2.2 Protocol Deviations ...............................................................................71 
13.1.2.3 Demographics and Other Baseline Characteristics ...............................71 
13.1.3 Exposure and Compliance .................................................................................71 


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13.1.4 Efficacy Analysis ..............................................................................................71 
13.1.4.1 Primary Efficacy Endpoints ..................................................................71 
13.1.4.2 Secondary Efficacy Endpoints ..............................................................72 
13.1.4.3 Exploratory Endpoints ..........................................................................72 
13.1.4.4 Primary Analysis ...................................................................................73 
13.1.4.5 Secondary Analyses ..............................................................................74 
13.1.4.6 Exploratory, Corroborative, Sensitivity, and Other Analyses...............74 
13.1.5 Clinical Pharmacology Analyses .......................................................................74 
13.1.5.1 Pharmacokinetics ..................................................................................74 
13.1.6 Safety and Tolerability Analyses ......................................................................74 
13.1.6.1 Adverse Events......................................................................................75 
13.1.6.2 Clinical Laboratory Evaluations ...........................................................75 
13.1.6.3 Vital Signs .............................................................................................75 
13.1.6.4 12-lead Electrocardiograms ..................................................................75 
13.1.6.5 Physical Examination Findings .............................................................75 
13.1.6.6 Biomarkers ............................................................................................75 
13.2 Sample Size Determination ...........................................................................................76 
14 STUDY CONDUCT ...............................................................................................................77 
14.1 Sponsor and Investigator Responsibilities ....................................................................77 
14.1.1 Sponsor Responsibilities ...................................................................................77 
14.1.2 Investigator Responsibilities .............................................................................77 
14.1.3 Confidentiality and Privacy ...............................................................................77 
14.2 Site Initiation .................................................................................................................78 
14.3 Screen Failures ..............................................................................................................78 
14.4 Study Documents ..........................................................................................................79 
14.4.1 Informed Consent ..............................................................................................79 
14.4.2 Investigator’s Regulatory Documents ...............................................................79 
14.4.3 Case Report Forms ............................................................................................80 
14.4.4 Source Documents .............................................................................................80 
14.5 Data Quality Control .....................................................................................................81 
14.5.1 Monitoring Procedures ......................................................................................81 
14.5.2 Data Management ..............................................................................................82 
14.5.3 Quality Assurance/Audit ...................................................................................82 
14.6 Study Termination .........................................................................................................82 
14.6.1 Premature Study Termination ...........................................................................82 
14.7 Study Site Closure .........................................................................................................83 
14.7.1 Record Retention ...............................................................................................83 
14.8 Changes to the Protocol ................................................................................................84 


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14.9 Use of Information and Publication ..............................................................................84 
15 FINAL CLINICAL STUDY REPORT ..................................................................................85 
16 ETHICAL AND LEGAL CONSIDERATIONS ....................................................................86 
16.1 Good Clinical Practice ..................................................................................................86 
16.2 Subject Information and Informed Consent and/or Assent ...........................................86 
16.3 Approval by Institutional Review Board or Ethics Committee ....................................86 
16.4 Finance and Insurance ...................................................................................................86 
17 REFERENCES .......................................................................................................................87 
18 ATTACHMENTS ...................................................................................................................90 
18.1 Investigator’s Agreement ..............................................................................................90 
APPENDICES ...............................................................................................................................91 
Appendix A 
Scoring Sheet for Snakebite Severity Inclusion Criteria for Patients that 
Have not completed the First dose of antivenom ...................................................................92 
Appendix B 
Composite Snakebite Severity Score for Efficacy Endpoints .......................93 
Appendix C 
Study-specific Requirements ........................................................................94 
Appendix D 
COVID-19 Protocol Deviations ..................................................................111 
Appendix E 
Regulations and Good Clinical Practice Guidelines ...................................112 
 
3.1 
List of In-text Tables 
Table 1 
Schedule of Events ...................................................................................................9 
Table 2 
Comparison of Varespladib and Currently Available Serum-Based Antivenom 
Therapies ................................................................................................................23 
Table 3 
Summary of Adult and Pediatric Dosing ...............................................................31 
 
3.2 
List of In-text Figures 
Figure 1 
Study Schematic.....................................................................................................13 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ANCOVA 
Analysis of covariance 
AUC 
Area under the curve 
BUN 
Blood urea nitrogen 
CGI-I 
Clinical Global Impression - Improvement 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DDI 
Drug-drug interaction 
FDA 
Food and Drug Administration 
IC50 
Half-maximal inhibitory concentration 
IND 
Investigational New Drug application 
INR 
International normalized ratio 
IV 
Intravenous 
LFT 
Liver function test 
MOF 
Multiple organ failure 
MIP 
Maximum inspiratory pressure 
NIF 
Negative inspiratory force 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PLA2 
Phospholipase A2 
PSFS 
Patient-Specific Functional Scale 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PTSD 
Post-traumatic stress disorder 
Q12H 
Once every 12 hours 
QoL 
RASS 
Quality of life 
Richmond Agitation Sedation Scale 
SOC 
Standard of care 
sPLA2 
secreted phospholipase A2 
TEAE 
ULN 
Treatment-emergent adverse effect 
Upper Limit of Normal 
U.S. 
20WBCT 
United States 
20 minute whole blood clotting time 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 


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5 
INTRODUCTION 
5.1 
Background and Rationale 
The treatment of snakebite envenoming is an urgent, global unmet medical need. It is estimated 
that worldwide more than 5 million snakebite envenomings occur annually, causing significant 
morbidity (approximately 400,000 causing permanent deformities or amputation) and mortality 
(up to 138,000 causing death) (Gutierrez, et al., 2017; Longbottom, et al., 2018). Snakebite 
primarily affects poor, rural populations in tropical and sub-tropical regions of developing 
countries, where outcomes are adversely impacted by the snakebite victim’s lack of proximity 
and/or access to healthcare, including access to currently available antivenom therapies 
(Longbottom, et al., 2018). Although comparatively unusual in the U.S., snakebite envenoming 
incurs significant morbidity and occasional mortality with bad outcomes primarily associated 
with delays in care, young age, neurological deficit, thrombocytopenia and coagulation 
abnormalities (Gerardo, et al., 2019). 
Approximately 5.8 billion people live in regions that place them at risk for being bitten by a 
medically important snake (Longbottom, et al., 2018) and it is estimated that > 75% of deaths 
from snakebite occur outside the hospital setting before victims can reach medical care. While 
not all snakebites result in envenoming with morbidity and mortality, often by the time patients 
receive the appropriate medical care in a hospital setting it is far too late and the toxicities of 
snakebite envenoming have substantially progressed and are no longer amenable to effective 
treatment by antivenom therapy (Vaiyapuri, et al., 2013; Gerardo, et al., 2019). To underscore 
the urgency of the global public health crisis posed by snakebite envenoming, the World Health 
Organization (WHO) recently classified snakebite envenoming as a neglected tropical disease 
(Longbottom, et al., 2018). Furthermore, the WHO’s Snakebite Envenoming Working Group 
stated that “accelerating preclinical and clinical testing of promising prehospital adjunctive 
treatments, such as the phospholipase A2 inhibitor varespladib or varespladib-methyl, as part of 
the WHO snake bite envenoming research agenda may lead to early improvements in prehospital 
survival” (Williams, et al., 2019). 
Even when the standard of care (SOC) antivenom therapies are available, their use is associated 
with a number of challenges and limitations, many of which could potentially be overcome with 
a small-molecule therapeutic (Bulfone, et al., 2018) (summarized in Section 5.3). Indeed, 
because snake venom secreted phospholipase A2 (sPLA2) is involved in virtually every critical 
venom effect and exists as a major toxin in virtually all venomous snakes around the world 
(Tasoulis and Isbister, 2017), sPLA2 has been identified as a desirable target for a toxin-specific 
approach to the treatment of snakebite (Williams, et al., 2019). 
The objective of the development program by Ophirex is to advance varespladib, a high-potency 
small-molecule inhibitor of sPLA2, and its oral prodrug formulation (varespladib-methyl) for the 
treatment of snakebite envenoming. Varespladib-methyl (LY333013) is rapidly hydrolyzed into 
varespladib (LY315920). LY315920 is a potent inhibitor of sPLA2 (Snyder, et al., 1999). 
LY333013 is an orally bioavailable, methyl ester prodrug of the active sPLA2 inhibitor 
LY315920, which is administered intravenously (IV).  


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Varespladib and varespladib-methyl were originally developed as sPLA2 inhibitors for treating 
multiple diseases with an underlying inflammatory component (e.g., sepsis, rheumatoid arthritis, 
and cardiovascular disease) (Adis, 2011). These previous development efforts were terminated 
because of lack of efficacy or futility in diseases studied, but they have provided a substantial 
amount of clinical safety and bioavailability data, with > 4,600 subjects exposed to both 
varespladib and varespladib-methyl.  
5.1.1 
Scientific Rationale 
sPLA2 enzymes represent a family of enzymes implicated in the activation of the inflammatory 
process that produces multiple organ failure (MOF) in sepsis (Anderson, et al., 1994). In 
mammals, sPLA2 originates from a variety of cells including macrophages, neutrophils, and 
inflamed synovial tissue. In snake venom it originates from modified salivary glands and is a key 
toxin not reliably neutralized by antibody-based products such as antivenom (Prasarnpun, et al., 
2005). A defining characteristic of snakebite envenoming is that snake venom sPLA2 proteins are 
injected in high concentrations directly into the victim with potentially rapid lethality or 
morbidity effects (Gutierrez, et al., 2017).  
sPLA2s are the most pharmacologically active component of snake venoms, and one of the 
components most responsible for lethality and long-term morbidity (Gutierrez, et al., 2017). 
Virtually all snake venoms—even those commonly associated with coagulopathy—may also 
have neurotoxic and blood pressure lowering effects because the primary purpose of the venom 
is to weaken and immobilize prey so that the snake can ingest it. While it is the sPLA2-mediated 
neurotoxicity of snake venom that often causes rapid lethality in humans, snake venom sPLA2 
toxins are also responsible for hemolysis, coagulopathy, myonecrosis and kidney damage 
(Arce-Bejarano, et al., 2014; Gutierrez, et al., 2017; Bryan-Quiros, et al., 2019). Thus, inhibition 
of sPLA2 could address several limitations of antivenom therapies that lead to adverse outcomes, 
including delays in care, the ability to reverse neurological effects not effectively mitigated by 
antivenom, and coagulation parameters and platelet dysfunction that can be severely provoked 
by venom sPLA2 toxins (Bittenbinder, et al., 2018; Lewin, Gilliam, et al., 2018; Lewin, 
Gutierrez, et al., 2018; Alangode, et al., 2020; Albulescu, et al., 2020; Fontana Oliveira, et al., 
2020; Gutierrez, et al., 2020; Xie, et al., 2020; Zinenko, et al., 2020; Kazandjian, et al., 2021). 
In vitro, LY315920 and its prodrug LY333013 potently inhibit snake venom sPLA2, with 
half-maximal inhibitory constant (IC50) values in the nano- and sub-nanomolar range, including 
sPLA2 enzymes from pit vipers such as copperhead, cottonmouth, several rattlesnakes and 
elapids including coral snake (Lewin, et al., 2016). As an example, M. fulvius (Eastern coral 
snake) has a well-characterized venom causing both neurotoxic and hemotoxic effects 
(Arce-Bejarano, et al., 2014) and the toxicity of coral snake venom, as for other elapids (snakes 
related to cobras and kraits) around the world, is mediated by sPLA2 (Fernandez, et al., 2018). 
Several in vivo studies show that both the orally-administered LY333013 and IV-administered 
LY315920 rescue mice, rats and pigs from 100% lethal doses of coral snake venom, even when 
antivenom was no longer of benefit to the animals, returning platelet function to normal and 
reversing venom-induced hemolysis (Lewin, Gilliam, et al., 2018). The structural basis for 
LY315920 inhibition of snake venom sPLA2 has recently been established, as well, through 
crystallographic study (Salvador, et al., 2019). 


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5.1.2 
Epidemiology of Snakebites in Children 
Children anywhere in the world are at great risk for severe snakebite because they are small, 
naturally curious, frequently play outdoors and often reach or step into areas blindly, such as 
when picking up rocks or gathering firewood. Their small size puts them at greater risk of severe 
bites because of the weight-based dosage effect of snake venom toxins (Gerardo, et al., 2019; 
Pach, et al., 2020). In many countries, older children are often bitten when participating in 
agricultural work or while playing or walking close to their homes. In sub-Saharan Africa, 
approximately 30% of envenomings occur in children (Chippaux, 2011). Pediatric cases are 
particularly challenging to manage clinically and too often the result of a bite is life-long 
complications from tissue damage, necrosis, neurological deficits, social and educational burdens 
(Sankar, et al., 2013; Gerardo, et al., 2019). Additionally, the long-term effects of amputations 
and post-traumatic stress disorder (PTSD) account for a significant part of the burden of 
snakebite envenoming in children (Halilu, et al., 2019). 
Similar to the situation in low- and middle-income countries, snakebite envenoming in the 
United States (U.S.) is over-represented in pediatric population compared to percentage of the 
total population (Parrish, 1965; Seifert, et al., 2009). For example, in a series of 450 cases 
identified, 28.2% were children age 12 and under (Ruha, et al., 2017). In contrast, children aged 
12 years or younger make up only about 16% of the U.S. population 
(U.S. Census Bureau, 2019). The U.S., the pediatric population is at a significant risk of 
hospitalizations, admissions to ICUs or death following snakebite envenoming (Schulte, et al., 
2016). As with other places in the world, envenoming in the pediatric population is 
disproportionately more severe due to smaller body mass and higher concentration of venom 
delivered with young age being one of the main factors in snakebite severity (Gerardo, et al., 
2019).  
5.2 
Clinical Experience 
Multiple clinical studies have been performed by the previous sponsors for LY333013 
(varespladib-methyl) and LY315920 (varespladib), Eli Lilly and Anthera, to characterize the 
safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of LY315920 or 
LY333013. The inflammatory conditions studied clinically included sepsis, rheumatoid arthritis, 
ulcerative colitis, asthma, atherosclerosis, and acute chest syndrome in at-risk patients with 
sickle cell disease. Previous clinical studies have been 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 that subjects suffering from snakebite 
envenoming may receive improved outcome in terms of snakebite severity and quality of life 
(QoL) assessments. Table 2 describes the limitations of current serum-based antivenoms, and the 
potential advantages of varespladib or varespladib-methyl. 


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Table 2 
Comparison of Varespladib and Currently Available Serum-Based 
Antivenom Therapies 
Challenge or 
Limitation 
Limitations of Serum-Based 
Antivenom Therapy 
Potential Advantages of Oral 
Varespladib 
Ease of Use 
Must be administered IV in a clinical 
setting: cannot be self-administered at 
the time of snakebite 
 
Intensive monitoring for antivenom 
induced complications required 
In the clinic, oral and IV formulations 
can be administered in combination with 
antivenom therapies. 
 
If proven effective, an oral varespladib 
formulation could eventually be 
administered at the time of the 
snakebite—before reaching a hospital 
Species 
Specificity 
Generally specific to one species or 
closely related species of venomous 
snakes and sPLA2 is poorly antigenic 
Varespladib is a potent, broad-spectrum 
inhibitor of snake venom sPLA2 
Tissue 
Penetration 
Large proteinaceous molecules with 
limited or no ability to penetrate 
tissues 
Small molecules with the ability to 
penetrate tissues to neutralize or reverse 
sPLA2-mediated venom toxicities 
Potential for 
Allergenicity 
High 
Low (no documented allergies) 
Cost to 
Manufacture 
Higher 
Lower 
Requirement for 
Refrigeration 
Yes (most formulations) 
No refrigeration 
Available Global 
Supply 
Current and anticipated long-term 
global shortage (Williams, et al., 
2019) 
Potential for a comparably broader, more 
cost-effective, global distribution 
Abbreviations: IV = intravenous; sPLA2 = secreted phospholipase A2. 
 
The proposed dosing of varespladib-methyl for adult subjects consists of an initial loading dose 
of 500 mg (2 × 250 mg oral tablet), an additional 250 mg dose (1 x 250 mg oral tablet) 
approximately 12 hours later, and then 250 mg (1 x 250 mg tablet) twice daily (BID) for the 
remainder of the study period. Pediatric subjects (ages 5 to < 18) will be administered doses of 
varespladib-methyl determined by allometric scaling, provided as 50 mg capsules (Section 7.3). 
The doses proposed for this study are anticipated to be safe and tolerable for adult and pediatric 
subjects. 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 subjects. In a total of 
seven phase 1 and three phase 2 studies, IV varespladib was administered to 733 subjects. In a 
total of twelve phase 1 and five phase 2 studies oral varespladib-methyl was administered to a 
total of 3,679 subjects. 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 several subjects. Treatment with varespladib or varespladib-methyl was not 


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associated with changes in heart rate or blood pressure and there was no evidence of an effect on 
ventricular repolarization (QT interval prolongation). SAEs including cerebrovascular accident 
(CVA) and myocardial infarction (MI) have been observed in some acutely ill subjects in clinical 
studies for indications such as severe sepsis and acute coronary syndrome. Patients with 
conditions such as these are excluded from participation in this study.  
In subjects receiving continuous IV varespladib (LY315920) infusion, plasma drug 
concentrations up to 800 ng/mL for 6 hours were tolerated well and treatment-related AEs were 
mild to moderate and were not clinically significant. No AEs were reported with short-term 
dosing with IV varespladib infusion, resulting in plasma concentrations of up to 1,200 ng/mL for 
30 minutes; 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 subjects, dosing with varespladib or varespladib-methyl for up 
to 7 days and at doses up to 77 mg/kg or 500 mg Q12H, respectively, did not induce SAEs. In 
subjects 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, oral dosing with 250 mg varespladib-methyl BID is not anticipated to induce 
AEs, even in severely ill subjects such as those with snakebite envenoming. 
A summary of the pharmaceutical properties and known potential risks of varespladib or 
varespladib-methyl is provided in the current version of the Varespladib-Methyl IB. The 
Investigator must become familiar with all sections of the IB before the start of the study. 


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6 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary Objective 
Primary Efficacy Endpoint 
• To evaluate the efficacy of a 
multi-dose regimen of oral 
varespladib-methyl with standard 
of care (SOC) in subjects after 
venomous snakebite 
• 
Change in the composite outcome of pulmonary, 
cardiovascular, hematologic symptoms, renal, and 
nervous system sections of the snakebite severity score 
(SSS) from Baseline (pre-dosing) to the average of the 
scores from 6 and 9 hours after first dose.  
Secondary Objectives 
Secondary Efficacy Endpoints 
• To evaluate efficacy of 
varespladib-methyl as treatment for 
sPLA2-induced venom toxicities 
• 
AUC of the pulmonary, cardiovascular, hematologic 
symptoms, renal, and nervous system sections of the 
SSS from Baseline through Day 7  
• 
Complete SSS from Baseline through Day 7  
• 
SSS neurologic system subscore from Baseline 
through Day 3 
• 
Coagulation abnormalities from Baseline through 
Day 7 
• 
Hemolysis markers from Baseline through Day 3 
• 
Levels of the myonecrosis marker, creatine kinase 
(CK), from Baseline through Day 3 
• 
Numeric Pain Rating Scale (NPRS) score in patients 
able to respond from Baseline through Day 28 
• 
Kidney function markers from Baseline through Day 
28 
• 
Total differential antivenom requirement from 
Baseline through Day 28 
• 
Head-Lift duration from Baseline through Day 7 
• 
Total duration of ventilatory support from Baseline 
through Day 28  
• 
Total duration of Intensive Care Unit (ICU) stay 
from Baseline through Day 28 
• 
Total duration of hospitalization from Baseline 
through Day 28 
• 
All-cause mortality from Baseline through Day 28 
• 
Clinical Global Impression-Improvement (CGI-I) 
from Baseline through Day 7 
• 
Patient Global Impression of Change (PGIC) from 
Baseline through Day 7  
• 
Patient-Specific Functional Scale (PSFS) total score 
from Baseline through Day 28 
Exploratory Objectives 
Exploratory Endpoints 
• To assess the efficacy of 
varespladib-methyl as evaluated by 
a compressed SSS scale 
• 
Change in the SSS from Baseline through Day 7 using a 
compressed SSS scale 
• To assess the efficacy of 
varespladib-methyl as evaluated by 
SSS 
• 
SSS from Baseline through Day 28 after first dose 


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Objectives 
Endpoints 
• To assess the effect of varespladib-
methyl on neurological function as 
evaluated by grip strength 
• Grip strength pre-dosing through Day 28 
• To assess the effect of varespladib-
methyl on neurotoxicity 
• 
SSS neurologic system subscore from Baseline through 
Day 7 
• To assess the effect of varespladib-
methyl on analgesic use 
• 
Analgesic use from Baseline through Day 28  
• To evaluate the effect of 
varespladib-methyl on clinician- 
based impression of improvement 
• 
CGI-I from Baseline through Day 28 
• To evaluate the effect of 
varespladib-methyl on the PGIC 
• 
PGIC from Baseline through Day 28 
• To assess the effect of varespladib-
methyl on complete blood count 
(CBC) 
• 
CBC through all SSS evaluation days 
• To assess the effect of varespladib-
methyl on transfusion requirement 
in patients with hemolysis 
• 
Transfusion requirement from Baseline through Day 28 
• To evaluate the effect of 
varespladib-methyl on the levels of 
C-reactive protein (CRP) 
• 
CRP from Baseline through Day 14  
• To assess the safety biomarker D-
dimer 
• 
D-dimer levels from Baseline through Day 14 
• To assess the effect of varespladib-
methyl on myonecrosis marker 
(CK) in subjects with and without 
tourniquets at enrollment 
• 
Levels of CK in patients from Baseline through 
Day 3 in patients presenting with and without 
tourniquets at enrollment 
• To evaluate the levels of secretory 
phospholipase A2 (sPLA2) in 
serum 
• 
sPLA2 in serum at specified timepoints on Days 1 
to 7 in all subjects 
Pharmacokinetics Evaluation 
• To assess pharmacokinetics (PK) 
of varespladib-methyl in subjects 
with snakebite envenoming 
• 
PK parameters of varespladib-methyl in plasma from a 
subset of adult and pediatric subjects at specified 
timepoints on Days 1 and 3 followed by all subjects 
pre-dose on Day 7 
Safety  
Safety and Tolerability Endpoints 
 
• Incidence and severity of adverse events (AEs), serious 
AEs (SAEs), and AEs leading to discontinuation of 
Investigational Product (IP) 
• Safety of varespladib-methyl as assessed by the number 
and rates of reported treatment-emergent adverse events 
(TEAEs) from beginning of treatment until last 
Follow-Up Visit/Telephone call at Day 28 
• Number of subjects with a treatment-related SAE from 
beginning of treatment until last Follow-Up 


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Objectives 
Endpoints 
Visit/Telephone call at Day 28 
• Safety as assessed by 
− 
Vital signs 
− 
Clinical laboratory evaluations: CBC, 
urinalysis, liver function tests [LFTs], renal 
function tests (albumin, creatinine, blood 
urea nitrogen [BUN], estimated glomerular 
filtration rate [eGFR]) 
− 
12-lead electrocardiogram (ECG) 
• Concomitant medications and therapies 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
evaluated at Baseline or at the earliest time point 
clinically allowable (ideally Day 1) and then at every 
study visit through Day 28 
 


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7 
STUDY DESIGN 
7.1 
Overall Study Design and Plan 
This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to 
evaluate the safety, tolerability and efficacy of varespladib-methyl, concurrently with SOC, in 
subjects bitten by venomous snakes.  
• Approximately 110 male and female subjects (94 evaluable) will be randomized to receive 
active varespladib-methyl or placebo (in addition to SOC) in a 1:1 ratio. There will be no 
stratification by type of snakebite, though randomization will be stratified by age group (5 to 
< 11, 11 to < 18, and ≥ 18 years old) and by the presence or absence of neurotoxicity (SSS 
nervous system subscore of 0–1 or ≥ 2) at Baseline, resulting in 6 strata in total. 
 
Patients eligible for the study must be male or female ≥ 5 years of age with venomous snakebite. 
The index event (snakebite) must be symptomatic and symptom onset must have occurred within 
10 hours of eligibility assessment and the patient must be willing (or legally authorized 
representative is willing) to provide informed consent prior to initiation of any study procedures.  
Patients must meet one of two categories of inclusion criteria: 
Category 1: The patient has not yet completed first dose of antivenom:  
SSS inclusion score* of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at 
least one system.  
OR 
Category 2: The patient has completed an initial dose of antivenom:  
SSS inclusion score* of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at 
least one system AND CGI-I score of ≥5 (i.e., minimally worse, much worse, or very 
much worse).  
 
* Only local wound, pulmonary, cardiovascular, hematologic, or nervous system scores qualify 
for SSS inclusion criteria. GI and Renal scores are not used for inclusion. Hematologic score 
may be counted if available, but inclusion should not wait for laboratory results. Point of care 
tests (e.g., 20WBCT) may be used for enrollment, if used per site standard of care (see 
Appendix A). 
 
One group will be treated with the SOC plus placebo and the other treated with SOC plus 
varespladib-methyl. The time between baseline and eligibility assessments, randomization, and 
IP administration should be minimized. 
There should be no delay in providing the SOC, nor should there be a delay in administration of 
study drug after randomization.  
Primary efficacy outcome will be assessed by comparing the change in the combined pulmonary, 
cardiovascular, hematologic, renal, and nervous system subscores of the SSS from Baseline 


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(pre-dosing) to the average of the scores 6 and 9 hours post-Baseline for the treatment and 
control groups. Additional details will be provided in the SAP. 
Safety and tolerability will be assessed by evaluating AEs, vital sign measurements, clinical 
laboratory test results, ECGs, physical examination findings, and concomitant medications and 
therapies. 
All AEs observed by the study personnel or reported by the subject during the study (from the 
time of the signing of the informed consent and/or assent through the End of Study (EOS) visit) 
will be documented. 
Pharmacokinetic sampling will be performed for a subset of subjects on Days 1 and 3 and on all 
subjects on Day 7. 
7.2 
Rationale and Discussion of Study Design 
Snakebite envenoming represents a deadly and unmet global medical need. While antivenoms 
comprise the SOC for treatment of snakebites, they suffer from several limitations including 
specificity of each antivenom for specific species of snake, limited access to antivenom in rural 
areas, practical storage requirements, and delays in administration. Treatment of snakebite 
envenoming with the small-molecule drug varespladib-methyl, which targets sPLA2 present in 
approximately 95% of snake venoms, has the potential to overcome several limitations of 
serum-based antivenoms that underpin traditional SOC.  
The proposed study in the United States and India will provide coverage of a broad spectrum of 
venomous snake genera, including elapids, vipers, and pit vipers in differing geographies and 
differing sPLA2 structures. Study sites will be selected based on demonstrated historical 
incidence of snake bites from species deemed relevant to this study, to ensure a broad range of 
envenoming toxins are expected to be encountered in potential study subjects. 
This study was designed to exclude as few critically ill subjects as possible. The primary criteria 
for participation are that subjects must be ≥ 5 years of age, must present with an initial SSS of 
(A) 2 points in any SSS category other than GI or Renal and 1 or more additional point in any 
other SSS category other than GI or Renal or (B) an initial SSS score of ≥ 3 in any SSS category 
other than GI or Renal, must not be pregnant or breast-feeding, are not taking excluded 
medications, and have not been previously administered antivenom at another facility.  
The study design allows for both treatment arms (varespladib-methyl and placebo) to receive 
SOC (e.g., antivenom) concurrently. Thus, critically ill adult and pediatric subjects may receive 
emergency treatment in a timely manner while being evaluated for the potential clinical benefit 
associated with inhibition of venom sPLA2 by varespladib-methyl. 
Because subjects with severe snakebites are admitted to emergency departments, this study was 
designed to screen, enroll, and administer treatment in a single visit at the hospital upon 
admission. Because varespladib-methyl is administered orally, subjects who demonstrate 
substantial improvement and are eligible for discharge from the hospital may continue 
investigational product (IP) treatment in an outpatient setting. 


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Risks associated with the control (placebo) arm of this study include the same risks associated 
with SOC (antivenom). 
The efficacy endpoints for this study were selected to evaluate if varespladib-methyl plus SOC is 
superior to SOC alone. The primary endpoint was selected to evaluate clear clinical benefit based 
on SSS, whereas secondary and exploratory endpoints were selected to evaluate improvements in 
each subject’s snakebite severity and QoL over the course of treatment. PK analysis will be 
performed at specified timepoints throughout the treatment period, including in pediatric subjects 
enrolled. 
7.3 
Selection of Doses in the Study 
LY333013 (varespladib-methyl) is formulated in an immediate-release film-coated oval tablet at 
a unit dosage strength of 250 mg for oral administration. Ophirex is developing 
varespladib-methyl (LY333013) for oral administration for 7 days total for the treatment of 
venomous snakebites. LY333013 is a prodrug that is rapidly metabolized to LY315920; 
LY315920 is a potent inhibitor of sPLA2 in vitro and in vivo.  
This study evaluates the safety, tolerability, and efficacy of varespladib-methyl in subjects bitten 
by venomous snakes from diverse regions and snake genera, including (but not limited to) pit 
vipers (e.g., rattlesnake, copperhead), vipers (e.g., Russell’s viper and saw-scaled viper), and 
elapids (e.g., coral snake, cobra, krait).  
The proposed dosing of varespladib-methyl for adult subjects consists of an initial loading dose 
of 500 mg (2 × 250 mg oral tablet) varespladib-methyl upon randomization, followed by dosing 
with 250 mg varespladib-methyl (1 x 250 mg oral tablet) approximately 12 hours later, followed 
by BID dosing with 1 x 250 mg varespladib-methyl oral tablets for the remainder of the 7-day 
treatment period. 
Pediatric subjects (ages 5 to < 18) will be administered doses of varespladib-methyl determined 
by allometric scaling, provided as 50 mg capsules, depending on age. Pediatric doses were 
determined based on the 250 mg BID adult dose. Median weights from the Centers for Disease 
Control (CDC) growth charts were used for the allometric scaling, with weights averaged for 
male and female pediatric subjects. Subjects 5 to < 11 years old will receive an initial loading 
dose of 200 mg varespladib-methyl, an additional dose of 100 mg approximately 12 hours later, 
followed by 100 mg BID. Subjects 11 to < 18 years old will receive a loading dose of 400 mg 
varespladib-methyl, an additional dose of 200 mg approximately 12 hours later, followed by 
200 mg BID. Including the loading dose, subjects will receive a total of 14 doses of study 
medication. Dosing may occur on 7 or 8 calendar days, depending on whether the first dose of 
study medication is in the morning or the afternoon. 
Initial loading dose may be taken with or without food to accommodate the need to provide 
treatment as soon as possible following enrollment. The status of food consumption at the time 
of administration of the initial loading dose should be recorded in the case report form (CRF). 
All scheduled doses following the initial dose should be taken with food for the remainder of the 
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A summary of formulations and dosing for adult (age ≥ 18 years) and pediatric (ages ≥ 5 to 
< 18 years) subjects is provided in Table 3. 
Table 3 
Summary of Adult and Pediatric Dosing 
 
Age ≥ 18 yr (Adult) 
Age 11 to < 18 yr 
Age 5 to < 11 yr 
Oral Formulation 
Tablet 
Capsule 
Capsule 
Loading Dose 
500 mg  
(2 x 250 mg) 
400 mg 
(8 x 50 mg) 
200 mg 
(4 x 50 mg) 
Second Dose 
(approximately 12 hours 
after loading dose) 
250 mg  
(1 x 250 mg) 
200 mg 
(4 x 50 mg) 
100 mg 
(2 x 50 mg) 
BID Dose (for remainder 
of 7-day treatment 
period) 
250 mg  
(1 x 250 mg) 
200 mg 
(4 x 50 mg) 
100 mg 
(2 x 50 mg) 
Abbreviations: BID = twice daily; yr = year 
 
Serum sPLA2 levels may exceed 3 µg/mL in patients with severe sepsis or septic shock (whereas 
normal levels of sPLA2 are approximately 2 to 5 ng/mL), but 3 µg /mL can be rapidly exceeded 
with direct injection of snake venom. In vitro data suggest that complete inhibition of sPLA2 by 
LY315920 may occur when the molar concentration of the inhibitor exceeds that of the enzyme 
by approximately 5- to 7-fold (Sorensen, et al., 1994; Uhl, et al., 1995). PK/PD models of 
envenoming suggest that a catastrophic snakebite injecting 200 mg total sPLA2 (e.g., from the 
bite of an extremely large taipan with venom composed of > 80% sPLA2) may result in plasma 
sPLA2 concentrations up to almost 15 µg/mL in humans, whereas envenoming with a coral snake 
bite (i.e., 2.5 mg total sPLA2) may result in sPLA2 concentrations nearly 1000-fold lower 
(BSSA Modeling Report). According to these PK/PD calculations, a 500 mg loading dose and a 
subsequent 250 mg dose (total of 750 mg) on Day 1 of treatment, followed by 250 mg BID daily 
an additional 6 days, would be anticipated to result in clinically significant inhibition of sPLA2 
from most snakebite envenomings throughout the total venom exposure (including initial plasma 
sPLA2 concentrations up to 200 mg total venom sPLA2) (BSSA Modeling Report). In addition, 
the single 500 mg doses and 250 mg BID daily dosages used for adult subjects throughout the 
clinical development of LY333013 were safe and tolerated well. In sum, the proposed dose for 
adult subjects balances the predicted clinically significant inhibition of sPLA2 in venom with the 
well documented safety profile of the 250 mg BID daily dosage. 
Children often present with more severe effects of snakebite owing to their smaller size, 
weight-based dosage effect of snake venom toxins and lower volume of distribution relative to 
the mass of injected venom (Gerardo, et al., 2019; Pach, et al., 2020; Le Geyt, et al., 2021). The 
doses of antivenom used in children are the same as adult doses, as the volume of venom injected 
does not depend on the size of the victim (Le Geyt, et al., 2021), but small-molecule inhibitors 
whose venom binding is based on enzyme and drug concentrations are not subject to 
venom-antibody variability. Allometric scaling of adult doses of varespladib based on pediatric 
age-weight tables supports dosing in subjects 5 to < 11 years old and 11 to < 18 years old.  


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7.4 
Study Sites 
The study will take place at approximately 10 to 20 sites in the United States and India. Each site 
is anticipated to screen enough subjects to randomize approximately 5 to 20 subjects. No 
stratification or selection for type of snakebite will be made. Study site activation and enrollment 
periods will be planned to allow maximum enrollment during the most active seasonal snakebite 
months in each region. A study site with a high recruitment rate may be allowed to recruit more 
subjects if other sites have slow enrollment.  
7.5 
End of Study Definition 
The EOS is the date when the last subject’s last study visit occurs. 


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8 
STUDY 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 will occur on the same day. Subjects 
who do not meet all the eligibility criteria will not be enrolled. This study is estimated to enroll 
and randomize 110 male and female subjects equally into 2 groups. At least 94 evaluable 
subjects are expected to be available, allowing for up to 15% loss to follow-up. 
8.2 
Study Entry Criteria 
8.2.1 
Inclusion Criteria 
A subject will be eligible for study participation if he or she meets all the following criteria: 
1. Is a male or female ≥ 5 years of age with venomous snakebite. 
2. Index event (snakebite) must be symptomatic and symptom onset must have occurred within 
10 hours of eligibility assessment.  
3. Patients must meet one of two categories of inclusion criteria: 
Category 1: The patient has not yet completed first dose of antivenom:  
SSS inclusion score* of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at 
least one system.  
OR 
Category 2: The patient has completed an initial dose of antivenom:  
SSS inclusion score* of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at 
least one system AND CGI-I score of ≥5 (i.e., minimally worse, much worse, or very 
much worse).  
 
4. Is willing (or legally authorized representative is willing) to provide informed consent prior 
to initiation of any study procedures. 
 
* Only local wound, pulmonary, cardiovascular, hematologic, or nervous system scores qualify 
for SSS inclusion criteria. GI and Renal scores are not used for inclusion. Hematologic score 
may be counted if available, but inclusion should not wait for laboratory results. Point of care 
tests (e.g., 20WBCT) may be used for enrollment, if used per site standard of care (see 
Appendix A). 
 
8.2.2 
Exclusion Criteria 
A subject will be excluded from the study if he or she meets any of the following criteria: 


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1. Is considered by the Investigator to have a clinically significant upper GI bleed evidenced by 
significant hematemesis, “coffee-ground” emesis or nasogastric aspirate, hematochezia 
thought to originate from upper GI tract. 
2. Has history of CVA or intracranial bleeding of any kind, acute coronary syndrome, MI, or 
severe pulmonary hypertension. 
3. Has known history of inherited bleeding or coagulation disorder. 
4. Is, at Screening Visit, using the following anticoagulants: warfarin/coumadin, argatroban, 
bilvalirudin, lepirudin, apixaban, dabigatran, clopidogrel, prasugrel, ticlodipine or another 
anticoagulant agent not specifically listed, or has used heparin, enoxaparin, fondaparinux, or 
other low molecular weight heparin or antiarrhythmic drugs within 14 days prior to 
treatment. 
5. Has a history of chronic liver disease such as chronic active viral hepatitis, alcohol-related 
liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, 
hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune 
hepatitis.  
6. Reports or has known pre-existing renal impairment or chronic kidney disease. 
7. Has a known allergy or significant adverse reaction to varespladib-methyl.  
8. Is considered by the Investigator to be unable to comply with protocol requirements due to 
geographic considerations, psychiatric disorders, or other compliance concerns. 
9. Is pregnant, has a positive serum human chorionic gonadotropin (hCG) pregnancy test or not 
willing to use a highly effective method of contraception for 14 days after initial treatment, or 
is breast-feeding.  
 
8.3 
Early Subject Withdrawal 
All subjects are free to withdraw from participation in this study at any time, for any reason. The 
Investigator should make every reasonable attempt to keep subjects in the study; however, 
subjects must be withdrawn from the study if they withdraw consent to participate. Investigators 
must attempt to contact subjects who fail to attend scheduled visits by telephone or other means 
to capture any AEs and determine whether a subject should be withdrawn. Every possible 
attempt should be made to collect and report AEs upon withdrawal, as described in Section 11.2. 
The sponsor reserves the right to withdraw a subject due to protocol deviations or other reasons. 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
study 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 should be performed at the time of withdrawal. 
The reason for subject discontinuation from study medication or withdrawal from the study will 
be recorded on the eCRF. Subjects who sign the informed consent form and are randomized but 
do not receive the study intervention may be replaced. Subjects who sign the informed consent 
form, are randomized and receive the study intervention, and subsequently withdraw or are 
withdrawn or discontinued from the study will not be replaced. 


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8.4 
Discontinuation of Study Intervention 
An Investigator may discontinue a subject from study treatment for the following reasons: 
• Pregnancy 
• Significant study intervention or study procedure noncompliance  
• If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the subject 
(if there is reasonable evidence of clinical benefit to justify continuation on the protocol, this 
must be discussed with the Ophirex medical monitor) 
• If the subject meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
If a clinically significant finding is identified (including, but not limited to, changes from 
Baseline) after enrollment, the Investigator or qualified designee will determine if any change in 
subject management is needed. Specifically, this includes withdrawal of subjects who were 
initially enrolled but whose history of chronic liver disease, renal laboratory tests, or pregnancy 
tests suggest they are subject to exclusion criteria 6, 7, or 10.  
Discontinuation from IP does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  
Section 14.6 describes procedures in the event of suspension or termination of the study for all 
subjects. 
8.5 
Subject Replacement Criteria 
Withdrawn subjects will not be replaced. If a substantial number of subjects are withdrawn from 
the study, the sponsor will evaluate the need for developing replacement criteria. 
Randomized subjects 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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9 
TREATMENTS 
9.1 
Identification of Investigational Products or Placebo 
The IP used in this study is varespladib-methyl along with matching placebo. 
Varespladib-methyl will be provided as an oral formulation. 
• Varespladib-methyl  
- 
Varespladib-methyl (LY333013) is an immediate-release, oval, white, film-coated tablet 
at a dosage strength of 250 mg for oral administration. 
- 
Scaled pediatric doses of varespladib-methyl (LY333013) are supplied as 50 mg 
immediate-release capsules for oral administration. 
• Placebo  
- 
The oral placebo is supplied as a white film-coated oval tablet to match the appearance of 
the LY333013 250 mg tablet and contains a subset of the excipients present in the active 
tablet formulation: lactose monohydrate, microcrystalline cellulose, and magnesium 
stearate. 
- 
Placebo for scaled pediatric dosing is supplied as an immediate-release capsule to match 
the LY333013 50 mg capsule, and contains the excipients lactose monohydrate, 
microcrystalline cellulose, and magnesium stearate. 
 
9.2 
Selection of Timing of Dose for Each Subject 
Varespladib-methyl or placebo will be administered, concurrently with institutional SOC, to 
subjects with suspected or confirmed snakebite envenoming: 
• Adult subjects will receive an initial loading dose of 500 mg (2 x 250 mg oral tablet) 
varespladib-methyl upon randomization, followed by dosing with 250 mg varespladib-methyl 
(1 x 250 mg oral tablet) approximately 12 hours later, and subsequent BID dosing with 
1 x 250 mg varespladib-methyl oral tablets for the remainder of the 7-day treatment period.  
• Pediatric subjects (ages 5 to < 18) will be administered doses of varespladib-methyl 
determined by allometric scaling, provided as 50 mg capsules. 
 
Tablets and age appropriate capsules may be administered via feeding tube (e.g. naso- or 
orogastric tubes) in patients requiring mechanical ventilation. 
9.3 
Dose Adjustment Criteria 
Dose adjustment is not planned for this study. 


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9.4 
Treatment Compliance 
All hospitalized subjects will receive the IP or placebo at the study site under the surveillance of 
appropriate study personnel until discharged from the hospital. Tablet and capsule administration 
details will be recorded by the site. Subjects who are discharged during the 7-day treatment 
period will be asked to record the date and time of each dose.  
9.5 
Method of Assigning Subjects to Treatment Groups 
In this parallel-group randomized study, subjects who meet study entry criteria will be randomly 
assigned in a 1:1 ratio to varespladib-methyl or placebo. The randomization schedule 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 subjects are entered into the study. The 
randomization schedule will be stratified by age group (5 to < 11 years, 11 to < 18 years, and 
≥ 18 years) and by the presence or absence of neurotoxicity (SSS nervous system subscore of 
0−1 or ≥ 2) at Baseline, resulting in 6 strata in total. Study center will not be a blocking factor in 
the randomization schedule. No one involved in the study performance will have access to the 
randomization schedule before official unblinding of treatment assignment. 
The randomization schedule will be prepared by the study contract research organization (CRO) 
before the start of the study. No subject will be randomized into this study more than once. 
9.6 
Blinding and Unblinding Treatment Assignment 
All subjects, Investigators, and study personnel involved in the conduct of the study, including 
data management, will be blinded to treatment assignment except for a specified unblinded 
statistician and programmer from the study CRO who will have access to the randomization 
code. 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. If an 
interim analysis is conducted, then unblinded personnel who are not otherwise involved in the 
study will prepare the data for review. 
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 subject’s treatment assignment. 
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 subject’s treatment assignment.  
Unblinding for an individual subject will not result in unblinding the treatment assignments for 
the remaining subjects in the study. Thus, the overall study blind will not be compromised. If a 
subject’s treatment assignment is unblinded, he/she may or may not be asked to withdraw from 
the study. The Investigator will make this decision after consultation with the medical monitor. 


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9.7 
Prohibited and Permitted Therapies 
All concomitant medications (including over-the-counter medications and herbal supplements as 
well as sedatives and paralytics for intubated patients) and concomitant therapies used will be 
recorded in the source document and on the appropriate eCRF. 
9.7.1 
Prohibited Therapies 
The prohibited therapies prior to enrollment are described in Section 8.2.2.  
9.7.2 
Permitted Therapies 
All medications and therapies for snakebite envenoming, including SOC, are allowed after 
enrollment in this study. No other experimental therapies are permitted during participation in 
this study. 
Initial inhibition/induction potential of varespladib towards major human CYP450 enzymes have 
been performed. Data suggest that the active form of varespladib-methyl does not inhibit or 
induce major CYP450 enzymes. Although varespladib-methyl has been given to over 
3,600 subjects with few AEs, limited in vitro data exists regarding the potential of varespladib to 
act as an inducer for P450-mediated metabolism or impact major human transporters. Therefore, 
the sponsor recommends avoiding use of CYP450 inducers and substrates or inhibitors of major 
human transporters (but their use is not prohibited) during the period of IP administration based 
on the Investigator assessment of risk. A list of transporters is included on the FDA.gov Drug 
Development and Drug Interactions website in Table 5-1 and 5-2 of the Table of Substrates, 
Inhibitors and Inducers document (FDA, 2020): 
• Table 3-3, “Examples of clinical inducers for P450-mediated metabolisms (for concomitant 
use clinical DDI studies and/or drug labeling) (12/03/2019)” 
• Table 5-1, “Examples of clinical substrates for transporters (for use in clinical drug-drug 
interaction [DDI] studies and/or drug labeling) (12/03/2019)” 
• Table 5-2, “Examples of clinical inhibitors for transporters (for use in clinical drug-drug 
interaction [DDI] studies and drug labeling) (9/26/2016).” 
 
9.8 
Treatment After End of Study 
After the end of the study, each subject will be treated according to standard clinical practice. 
9.9 
Dispensing and Storage 
The IP and placebo supplied by Ophirex is to be used exclusively in the clinical study according 
to the instructions in this protocol. The Investigator is responsible for dispensing the IP and 
placebo according to the dosage scheme and for ensuring proper storage of the products. 


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Until the IP is dispensed to the subjects, it must be stored in a securely locked area that is not 
generally accessible. The oral IP and placebo 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 and placebo are in the study 
manual. 
9.10 
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 IP, including the date, quantity, batch or code number, and 
identification of subjects who received the IPs. The Investigator will not supply the IP to any 
person except those named as sub-Investigators on the Food and Drug Administration 
(FDA) form 1572, designated study personnel, and subjects in this study. The Investigator will 
not dispense the IPs from any study sites other than those listed on the FDA Form 1572. IP may 
not be relabeled or reassigned for use by other subjects. 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 (partly used, unused, and empty packaging, e.g., vials and 
tablet bottles) must be left in the original packaging and destroyed on site. 
9.11 
Labeling and Packaging 
Labeling and packaging of IP and placebo will be performed by Alcami, Inc., 1726 North 23rd 
Str, Wilmington, NC 28405. 
9.11.1 
Labeling 
Kits will have labels affixed that meet the applicable regulatory requirements and may include 
the kit or randomization number, IP, dosage strength, lot number, protocol number, volume or 
number of tablets/capsules, caution statement, storage, and sponsor identification. 


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10 
STUDY PROCEDURES 
Subjects who are able must provide written informed consent and/or assent before any 
study-related procedures are initiated, including the cessation of prohibited concomitant therapy. 
As snakebites may constitute life-threatening medical conditions that necessitate urgent 
intervention, a legally authorized representative may provide consent for subjects who are not 
able to provide informed consent because of the severity of their condition. 
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 
subject. If a subject misses a study visit for any reason, the visit should be rescheduled as soon as 
possible. In the event that subjects are unable to respond to study visit assessments (i.e., CGI-I, 
PGIC, PSFS, NPRS, C-SSRS), data from those study visits will be handled as described in 
Section 10.3.1. 
10.1 
Study Duration 
The overall study duration is expected to be approximately 12 months. 
The sequence and duration of the study periods will be as follows: 
1. Screening/Enrollment/Treatment Duration: 7 days. As subjects are admitted to ED, screening, 
enrollment, and treatment will take place on the same day. 
2. Follow-up: approximately 21 days (28 days after initial study intervention).  
 
10.2 
Study Periods and Visits 
10.2.1 
sPLA2 and Pharmacokinetics Sample Timing 
Note that the sPLA2 and PK sample collection will be performed with a different timing than the 
other assessments, as described in the Schedule of Events (Table 1).  
Specifically, PK sampling will only be performed for a subset of adult and pediatric subjects on 
Days 1 and 3 and all subjects on Day 7 as described in Section 10.3.2.1. Subjects will be enrolled 
for PK analysis as follows: Day 1 - 20 subjects, pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 
(pre-second dose) hours; Day 3 - 20 subjects, pre-dose and 0.5, 1, 2, 4, 6 hours; Day 7 - all 
subjects, pre-dose. Special attention should be paid to collection of PK samples on Day 1 of this 
protocol. 
sPLA2 sampling will be performed for all subjects on Day 1 (pre-dose and 1, 3, 6, and 9 hours 
post-first dose), and on Day 2, Day 3, and Day 7 (pre-dose). 


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10.2.2 
Screening (Enrollment and Baseline) 
Because patients are enrolled after a snakebite with envenoming, each subject must be screened, 
and treated within the first day (Day 1) of the study. Following completion of all assessments 
and confirmation of eligibility, the subject will be randomized via the IWRS.  
The following critical assessments/procedures must be performed at enrollment, prior to 
initiation of IP treatment: informed consent, inclusion/exclusion criteria review, medical history, 
physical examination, vital signs, SSS, Head-Lift, NPRS, and pre-dose laboratory blood draws. 
The following noncritical assessments should be performed as early as possible, but may be 
performed after randomization and initiation of study drug and SOC if required due to patient 
condition: demographic information, height/body weight, 12-lead ECG, grip strength, PGIC, 
CGI-I, and C-SSRS.  
The following procedures will be performed at Screening: 
• Baseline: 
- 
Obtain informed consent, either from the subject or a legally authorized representative  
- 
Review inclusion/exclusion criteria 
- 
Record prehospital tourniquet use as a snakebite treatment 
- 
Record hospitalization details 
- 
Record pulmonary support interventions 
- 
Perform physical examination  
- 
Measure vital signs per institutional practice 
- 
Perform individual assessments pertaining to the SSS (A scoring sheet for use by study 
personnel is provided in Appendix A; clinical evaluation of the overall SSS [Appendix B] 
will be performed after completion of the study): 
i. 
Local wound severity 
ii. 
Pulmonary severity 
iii. 
Cardiovascular severity 
iv. 
Gastrointestinal severity 
v. 
Hematologic severity (do not wait for laboratory results) 
vi. 
Renal severity (do not wait for laboratory results) 
vii. 
Nervous system severity 
- 
Measure Head-Lift duration (0 to 5 seconds) 
- 
Perform NPRS 
- 
Collect blood and urine for the following laboratory assessments:  
i. 
CBC 


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ii. 
Serum chemistry 
iii. 
CK 
iv. 
LFTs 
v. 
eGFR 
vi. 
Hemolysis (Free hemoglobin, haptoglobin, lactate dehydrogenase [LDH]) 
vii. 
Prothrombin time (PT), partial thromboplastin time (PTT), thrombin time, INR 
viii. 
Absolute fibrinogen 
ix. 
Urinalysis 
x. 
sPLA2 (see Section 10.2.1) 
xi. 
Urine pregnancy 
xii. 
Serum pregnancy test (subjects of childbearing potential only) 
xiii. 
Biomarkers (C-reactive protein [CRP], and D-dimer) 
- 
Collect samples for PK analysis from subset of subjects (see Section 10.3.2.1) 
- 
Confirm and record details of snakebite envenoming. Obtain photographic documentation 
where feasible 
- 
Assess and record demographic information (may be performed after randomization 
treatment should not be delayed) 
- 
Assess and record medical history, including time of bite, current medications 
(e.g., prescription and nonprescription medications) and therapies including antivenom 
use and analgesics (may be performed after randomization, treatment should not be 
delayed) 
- 
Measure weight and height (may be performed after randomization treatment should not 
be delayed) 
- 
12-lead ECG (may be performed after randomization treatment should not be delayed) 
- 
Measure grip strength (may be performed after randomization, treatment should not be 
delayed) 
- 
Perform PGIC (may be performed after randomization, treatment should not be delayed) 
- 
Perform C-SSRS (Baseline/Screening Form; if subject is unable to respond, perform 
C-SSRS as early as clinically possible on Day 1, screening and randomization should not 
be delayed for C-SSRS performance) 
- 
In sedated, endotracheally intubated subjects, perform additional assessments according 
to instructions in Section 10.3.1.7. 
- 
Perform baseline CGI-I. Baseline CGI-I should be assessed compared to patient’s 
previous clinical status. 
- 
Randomize subjects and assign IP to treatment and placebo arms 
 


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Procedures for rescreening prospective subjects who initially fail to meet study entry criteria are 
described in Section 14.3. 
10.2.3 
Treatment Period 
The treatment period is defined as the time of first dose on Day 1 through Day 7. Treatment 
should be initiated as soon as possible after snakebite envenoming. 
The following procedures will be performed on Day 1 of the Treatment Period:  
10.2.3.1 
Day 1 (Dosing, 0 Hours) 
• Administer IP (oral loading dose) (Day 1, 0 Hours) in treatment and placebo arms 
• Record time to SOC and IP intervention 
• Record details (type, brand, number of vials) of antivenom use from the point of the index 
snakebite through the completion of all antivenom use for this patient  
• Record hospitalization details 
• Record pulmonary support interventions 
• Record any concomitant therapy 
• Assess and record any AEs 
 
10.2.3.2 
Day 1 (1 Hour) 
• Perform CGI-I (assess compared to Baseline CGI-I) 
 
10.2.3.3 
Day 1 (2 Hours) 
• Perform CGI-I (assess compared to Baseline CGI-I) 
 
10.2.3.4 
Day 1 (3 to 4 Hours) 
• Perform CGI-I (assess compared to Baseline GGI-I) 
• Measure vital signs per institutional practice 
• Perform individual assessments pertaining the SSS, prior to administration of repeat doses of 
antivenom, if required (clinical evaluation of the actual SSS point score will be performed 
after completion of the study): 
- 
Local wound severity 


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- 
Pulmonary severity 
- 
Cardiovascular severity 
- 
Gastrointestinal severity 
- 
Hematologic severity 
- 
Renal severity 
- 
Nervous system severity 
• Measure Head-Lift duration (0 to 5 seconds) 
• Perform NPRS 
• Measure grip strength 
• Collect blood and urine for the following laboratory assessments:  
- 
CBC 
- 
Serum chemistry 
- 
Hemolysis (Free hemoglobin, haptoglobin, LDH) 
- 
PT, PTT, thrombin time, INR 
- 
Absolute fibrinogen 
- 
CK 
- 
sPLA2 levels at 3 hours post-dose as described in Section 10.2.1 
• Record concomitant medications and therapies (e.g., prescription and nonprescription 
medications, pain medications) 
• Perform PGIC 
• In sedated, endotracheally intubated subjects, perform additional assessments according to 
instructions in Section 10.3.1.7. 
• Collect PK samples from subset of subjects as described in Section 10.3.2.1 
• Record SOC treatment 
• Record hospitalization details 
• Record pulmonary support interventions 
• Assess and Record AEs 
 
10.2.3.5 
Day 1 (5 to 6 Hours) 
• Measure vital signs per institutional practice 


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• Perform individual assessments pertaining the SSS, prior to administration of repeat doses of 
antivenom, if required (clinical evaluation of the actual SSS point score will be performed 
after completion of the study): 
- 
Local wound severity 
- 
Pulmonary severity 
- 
Cardiovascular severity 
- 
Gastrointestinal severity 
- 
Hematologic severity 
- 
Renal severity 
- 
Nervous system severity 
• Measure Head-Lift duration (0 to 5 seconds) 
• Perform NPRS 
• Measure grip strength  
• Collect blood and urine for the following laboratory assessments:  
- 
CBC 
- 
Serum chemistry 
- 
LFTs 
- 
Hemolysis (Free hemoglobin, haptoglobin, LDH) 
- 
PT, PTT, thrombin time, INR 
- 
Absolute fibrinogen 
- 
CK 
- 
sPLA2 levels at 6 hours post-dose as described in Section 10.2.1 
• Record concomitant medications and therapies (e.g., prescription and nonprescription 
medications, pain medications) 
• Perform CGI-I 
• Perform PGIC 
• In sedated, endotracheally intubated subjects, perform additional assessments according to 
instructions in Section 10.3.1.7. 
• Collect PK samples from subset of subjects as described in Section 10.3.2.1 
• Continue SOC treatment 
• Record hospitalization details 


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• Record pulmonary support interventions 
• Assess and record AEs 
 
10.2.3.6 
Day 1 (8 to 10 Hours) 
• Measure vital signs per institutional practice 
• Perform individual assessments pertaining the SSS, prior to administration of repeat doses of 
antivenom, if required (clinical evaluation of the actual SSS point score will be performed 
after completion of the study): 
- 
Local wound severity 
- 
Pulmonary severity 
- 
Cardiovascular severity 
- 
Gastrointestinal severity 
- 
Hematologic severity 
- 
Renal severity 
- 
Nervous system severity 
• Measure Head-Lift duration (0 to 5 seconds) 
• Perform NPRS 
• 12-lead ECG 
• Measure grip strength  
• Collect blood and urine for the following laboratory assessments:  
- 
CBC 
- 
Serum chemistry 
- 
Hemolysis (Free hemoglobin, haptoglobin, LDH) 
- 
PT, PTT, thrombin time, INR 
- 
Absolute fibrinogen 
- 
CK 
- 
sPLA2 levels as described in Section 10.2.1 
- 
Biomarkers (CRP, and D-dimer) 
• Perform CGI-I 
• Perform PGIC 


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• In sedated, endotracheally intubated subjects, perform additional assessments according to 
instructions in Section 10.3.1.7. 
• Perform PSFS 
• Collect PK samples from subset of subjects as described in Section 10.3.2.1 
• Record concomitant medications and therapies (e.g., prescription and nonprescription 
medications, pain medications) 
• Continue SOC treatment 
• Record hospitalization details 
• Record pulmonary support interventions 
• Assess and record AEs 
 
10.2.3.7 
Day 2 
• Continue BID oral treatment with the IP 
• Perform physical examination  
• Measure vital signs per institutional practice 
• Perform individual assessments pertaining the SSS (clinical evaluation of the actual SSS 
point score will be performed after completion of the study): 
- 
Local wound severity 
- 
Pulmonary severity 
- 
Cardiovascular severity 
- 
Gastrointestinal severity 
- 
Hematologic severity 
- 
Renal severity 
- 
Nervous system severity 
• Measure Head-Lift duration (0 to 5 seconds) 
• Perform NPRS 
• Measure grip strength  
• Collect blood and urine for the following laboratory assessments:  
- 
CBC 
- 
Serum chemistry 


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- 
LFTs 
- 
Hemolysis (Free hemoglobin, haptoglobin, LDH) 
- 
PT, PTT, thrombin time, INR 
- 
Absolute fibrinogen 
- 
CK 
- 
Urinalysis  
- 
sPLA2 levels as described in Section 10.2.1 
- 
Biomarkers (CRP, and D-dimer) 
• Perform CGI-I 
• Perform PGIC 
• Perform PSFS 
• Assess C-SSRS (Frequent Screening Form) 
• In sedated, endotracheally intubated subjects, perform additional assessments according to 
instructions in Section 10.3.1.7 
• Record concomitant medications and therapies (e.g., prescription and nonprescription 
medications, pain medications) 
• Continue SOC treatment 
• Record hospitalization details 
• Record pulmonary support interventions 
• Assess and Record AEs 
 
10.2.3.8 
Day 3 
• Continue BID oral treatment with the IP 
• Perform physical examination 
• Measure vital signs per institutional practice 
• Perform individual assessments pertaining the SSS (clinical evaluation of the actual SSS 
point score will be performed after completion of the study): 
- 
Local wound severity 
- 
Pulmonary severity 
- 
Cardiovascular severity 


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- 
Gastrointestinal severity 
- 
Hematologic severity 
- 
Renal severity 
- 
Nervous system severity 
• Measure Head-Lift duration (0 to 5 seconds) 
• Perform NPRS 
• Measure grip strength  
• Collect blood and urine for the following laboratory assessments:  
- 
CBC 
- 
Serum chemistry 
- 
LFTs 
- 
CK 
- 
Hemolysis (Free hemoglobin, haptoglobin, LDH) 
- 
PT, PTT, thrombin time, INR 
- 
Absolute fibrinogen 
- 
Urinalysis  
- 
sPLA2 levels as described in Section 10.2.1 
- 
Biomarkers (CRP, and D-dimer) 
• Collect PK samples from subset of subjects as described in Section 10.3.2.1 
• Perform CGI-I 
• Perform PGIC 
• Perform PSFS 
• Assess C-SSRS (Frequent Screening Form) 
• In sedated, endotracheally intubated subjects, perform additional assessments according to 
instructions in Section 10.3.1.7 
• Record concomitant medication and therapies (e.g., prescription and nonprescription 
medications, pain medications) 
• Continue SOC treatment 
• Record hospitalization details 
• Record pulmonary support interventions 


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• Assess and Record AEs 
 
10.2.3.9 
Day 7 (7 Days ± 1 Day) 
• Continue BID oral treatment with the IP 
• Perform physical examination  
• Measure vital signs per institutional practice 
• Perform individual assessments pertaining the SSS (clinical evaluation of the actual SSS 
point score will be performed after completion of the study): 
- 
Local wound severity 
- 
Pulmonary severity 
- 
Cardiovascular severity 
- 
Gastrointestinal severity 
- 
Hematologic severity 
- 
Renal severity 
- 
Nervous system severity 
• Measure Head-Lift duration (0 to 5 seconds) 
• Perform NPRS 
• 12-lead ECG 
• Measure grip strength  
• Collect blood and urine for the following laboratory assessments:  
- 
CBC 
- 
Serum chemistry 
- 
LFTs 
- 
PT, PTT, thrombin time, INR 
- 
Absolute fibrinogen 
- 
Urinalysis  
- 
sPLA2 levels as described in Section 10.2.1 
- 
Biomarkers (CRP, and D-dimer) 
• Collect PK samples from all subjects as described in Section 10.3.2.1 
• Perform CGI-I 


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• Perform PGIC 
• Perform PSFS 
• Assess C-SSRS (Since Last Visit Form) 
• In sedated, endotracheally intubated subjects, perform additional assessments according to 
instructions in Section 10.3.1.7 
• Record concomitant medications and therapies (e.g., prescription and nonprescription 
medications, pain medications) 
• Continue SOC treatment 
• Record hospitalization details 
• Record pulmonary support interventions 
• Assess and Record AEs 
 
10.2.3.10 
Day 14 (14 Days ± 2 Days) 
• Perform physical examination  
• Measure vital signs per institutional practice 
• Perform individual assessments pertaining the SSS (clinical evaluation of the actual SSS 
point score will be performed after completion of the study): 
- 
Local wound severity 
- 
Pulmonary severity 
- 
Cardiovascular severity 
- 
Gastrointestinal severity 
- 
Hematologic severity 
- 
Renal severity 
- 
Nervous system severity 
• Measure Head-Lift duration (0 to 5 seconds) 
• Perform NPRS 
• Measure grip strength  
• Collect blood and urine for the following laboratory assessments:  
- 
CBC 
- 
Serum chemistry 


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- 
PT, PTT, thrombin time, INR 
- 
Absolute fibrinogen 
- 
Biomarkers (CRP, and D-dimer) 
• Perform CGI-I 
• Perform PGIC 
• Perform PSFS 
• Assess C-SSRS (Since Last Visit Form) 
• Record medical history, including current medications and therapies (e.g., prescription and 
nonprescription medications, pain medications) 
• Continue SOC treatment 
• Record hospitalization details 
• Record pulmonary support interventions 
• Assess and Record AEs 
 
10.2.3.11 
Day 28 (End of Study Visit) 
• Perform physical examination  
• Measure vital signs per institutional practice 
• Measure body weight 
• Perform individual assessments pertaining the SSS (clinical evaluation of the actual SSS 
point score will be performed after completion of the study): 
- 
Local wound severity 
- 
Pulmonary severity 
- 
Cardiovascular severity 
- 
Gastrointestinal severity 
- 
Hematologic severity 
- 
Renal severity 
- 
Nervous system severity 
• Measure Head-Lift duration (0 to 5 seconds) 
• Perform NPRS 
• 12-lead ECG 


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• Measure grip strength  
• Collect blood and urine for the following laboratory assessments:  
- 
CBC 
- 
PT, PTT, thrombin time, INR 
- 
Absolute fibrinogen 
- 
Serum chemistry 
- 
LFTs 
- 
Urinalysis 
- 
Serum pregnancy test (subjects of childbearing potential only) 
• Perform CGI-I 
• Perform PGIC 
• Perform PSFS 
• Assess C-SSRS (Since Last Visit Form) 
• Record concomitant medications and therapies (e.g., prescription and nonprescription 
medications, pain medications) 
• Continue SOC treatment 
• Record hospitalization details 
• Record pulmonary support interventions 
• Assess and Record AEs 
 
10.3 
Assessments 
10.3.1 
Efficacy Assessments 
Assessments used in this protocol include additional bedside assessments for endotracheally 
intubated subjects, the SSS, the CGI-I, the PGIC, the PSFS, the NPRS, grip strength, Head-Lift 
duration, and analgesic use. Each study subject will be evaluated using the PGIC, PSFS, grip 
strength, or NPRS at the timepoints indicated in the Schedule of Events (Table 1). The SSS 
evaluation is provided as a checklist in Appendix A and B; all other forms and assessments are 
provided in Appendix C. 
Acute changes in a patient's clinical status that occur during the first 24 hours, including the 
period between enrollment and administration of IP, but outside of a "Scheduled Assessment" 
timepoint should be recorded as "Unscheduled Visit" in ePRO or EDC systems, as appropriate. 


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Individuals that cannot respond to assessments due to severity of snakebite envenoming will be 
given a score corresponding to the worst score available in the assessment. Specific assessments 
and unable to respond scores are: 
• PSFS = 0 (Unable to perform activity) 
• PGIC =10 (Feel much worse) 
• Grip Strength = 0 
 
Missing measurements of the SSS at 6 or at 9 hours won't be replaced for the purpose of 
calculating the primary outcome. If the SSS at one of these timepoints is missing, the average 
SSS will be based solely on the SSS recorded for the other time point.  
10.3.1.1 
Composite Snakebite Severity Scale 
The SSS (Dart RC et al., 1996) is a tool that was developed to measure the severity of 
envenoming based on 6 body system categories. The composite SSS score to be used, herein, is 
based on 7 categories and includes respiratory paralysis, acute renal failure, major thrombotic 
events, and death.  
The renal system category will be used to characterize the severity of acute renal injury (scoring 
provided in appendix B). The baseline value for serum creatinine will be defined as the most 
recent serum creatinine in the past year, if one is available, or as the normal expected value for 
the patient.  
Severe weakness or paralysis, including respiratory paralysis, will be scored a 3 in the nervous 
system section. Major thrombotic events will be scored in the appropriate SSS category as 
clinically presented. Death will be scored as the maximum score in each section.  
The seven body systems are included as follows: 
• Local wound (e.g., pain, swelling and ecchymosis) 
• Pulmonary 
• Cardiovascular 
• Gastrointestinal 
• Hematologic 
• Nervous system  
• Renal  
 


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Each of these 7 categories are graded at levels from Grade 0 to Grade 3 (pulmonary, 
cardiovascular, gastrointestinal, nervous, and renal systems) or Grade 0 to Grade 4 (local wound 
and hematologic symptoms). A higher score indicates worse signs or symptoms. SSS scores will 
be performed by study personnel using the scoring sheet provided in Appendix B. At each 
assessment timepoint, each of the 7 SSS subscores should be recorded and a justification for each 
score should be provided.  
10.3.1.2 
Clinical Global Impression-Improvement 
The CGI-I provides a clinician-based overall rating of the patient’s condition (i.e., severity, 
distress, impairment and impact on functioning) in comparison to previous clinical status. The 
CGI-I should be determined using all available information, such as interviews with patients and 
family members, reports from other providers (including prehospital and transfer reports), 
medical records, and prior laboratory data (Busner and Targum, 2007) (Appendix C1). Baseline 
rating should be in comparison to previous patient status. Additional CGI-I should be performed 
on Day 1 at 1, 2, and 3 hours post initial dose, then follow normal assessment schedule as 
provided in the Schedule of Events. All post-baseline CGI-I assessments should be compared to 
baseline CGI-I. 
The CGI-I is defined as a selection of one of the following at each assessment period: 
1 = very much improved since the initiation of treatment 
2 = much improved 
3 = minimally improved 
4 = no change from baseline (the initiation of treatment) 
5 = minimally worse 
6 = much worse 
7 = very much worse since the initiation of treatment 
 
10.3.1.3 
Patient Global Impression of Change Scale 
The PGIC (Appendix C2) is a short, widely used, qualitative metric to evaluate a subject’s belief 
regarding the efficacy of treatment. This metric consists of a question asking the subject to score 
their overall change in symptoms, followed by a question regarding the degree of change. 
 
10.3.1.4 
Patient-Specific Functional Scale 
The PSFS (Appendix C3) is a questionnaire that can be used to quantify activity limitation and 
measure functional outcome for patients. The clinician asks each subject to identify up to 
3 activities that they are unable to perform due to their medical condition, and asks the subject to 
rate their ability to perform that activity on a scale from 0 (unable to perform) to 10 (able to 
perform to the same ability as before the medical condition). 


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10.3.1.5 
Numeric Pain Rating Scale 
The NPRS is a numerical metric that is used by patients to evaluate pain they are experiencing. 
The NPRS may be adapted or replaced as necessary for pediatric subjects (Appendix C4). 
10.3.1.6 
Columbia-Suicide Severity Rating Scale 
The C-SSRS is a short questionnaire, available in 114 languages, that is designed to provide 
suicide risk assessment. Ultimately, the determination of the presence of suicidal ideation or 
behavior depends on the judgment of the individual administering the scale and patients 
indicating ideation of self-harm at any point in the study should be evaluated and treated per 
institutional practice. 
Generally, the C-SSRS should be administered at Baseline, or at the earliest time point clinically 
allowable (ideally on Day 1) and then at every study visit through Day 28. For the sake of this 
clinical study, modified versions of the C-SSRS will be administered at different study visits to 
minimize burden on study subjects. The modified C-SSRS forms are provided in Appendix C5 
as the “C-SSRS Baseline/Screening Form” and the “C-SSRS Since Last Visit Form.” These 
modified C-SSRS forms should be administered to subjects as follows: 
• The C-SSRS Baseline/Screening Form should be administered at Baseline (on Day 1) or as 
early as clinically allowable, performance should not delay care, 
• The C-SSRS Since Last Visit Form should be administered for the remaining visits on Days 
2, 3, 7, 14, and 28. 
 
10.3.1.7 
Additional Assessments on Endotracheally Intubated Subjects  
For SSS nervous system examination in endotracheally intubated patients: 
1. Record current mechanical ventilation modes and all relevant ventilator settings; 
e.g. control mode ventilation, weaning mode ventilation, or independent breathing 
without any support. Commonly used ventilatory modes are listed in Appendix C7. 
2. Remove sedation (and if applicable, paralytics) sufficiently early for awake examination 
(e.g. until patient is sufficiently awake to follow commands) per institutional practice 
3. In subjects able to respond and follow commands 
a. Once subject is sufficiently alert, record time from removal of sedation to 
examination and describe the level of alertness/sedation per institutional practice. 
If a sedation score is typically used, it should be recorded and the scoring system 
used should be specified.  
b. Measure Head-Lift duration in the same manner as for non-intubated subjects. 
With the patient supine on a flat bed, ask the subject to raise head approximately 


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8 cm off the bed. Record the duration of time that the subject can lift and hold 
head approximately 8 cm off the bed, up to a maximum of 5 seconds.  
c. Perform and record the SSS. 
4. In subjects who are unable to achieve an acceptable level of alertness 60 minutes after 
discontinuation of sedation (and if applicable, paralytics), record SSS and Head-Lift 
duration.  
5. In subjects who meet institutional weaning criteria, record mode and settings of 
mechanical ventilation as listed in Appendix C7 to indicate the level of 
support/independence to which they have progressed. 
6. In subjects who meet institutional criteria for immediate extubation but deferred or 
postponed as per institutional practice (e.g., meets criteria for extubation at night but not 
extubated until the next day), note patient status and record mode and settings of 
mechanical ventilation (see Appendix C7). 
7. If used per institutional practice, record negative inspiratory force (NIF)/maximum 
inspiratory pressure (MIP). 
 
10.3.1.8 
Grip Strength 
Grip strength will be evaluated using a dynamometer, as a measure of the severity of the 
neurological effects of snakebite. Grip strength should be measured in affected hand if the bite 
occurred in upper extremity or the dominant hand if bite occurred elsewhere. 
10.3.1.9 
Head-Lift duration 
Patient should be supine on flat bed. Ask patient to lift their head approximately 8 cm off of bed. 
Measure the duration in seconds that the patient can hold their head approximately 8 cm off of 
the bed. Stop after 5 seconds (i.e. maximum duration is 5 seconds). 
10.3.1.10 
Analgesic Use 
For each assessment time point, the patient’s current analgesic use will be characterized by the 
clinical research team based on the strongest category of analgesic taken to treat snakebite-
related pain. 
10.3.2 
Pharmacokinetics 
10.3.2.1 
Pharmacokinetic Analysis Methods  
The concentration of varespladib-methyl in plasma will be evaluated in a subset of both adult 
and pediatric subjects on Days 1 and 3 and in all subjects on Day 7. PK sampling will only be 
performed for a total of 20 adult and pediatric subjects on Days 1 and 3, and all subjects on Day 
7. Once 20 subjects have provided PK samples for Days 1 and 3, sites will be notified by the 


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sponsor to discontinue Day 1 and 3 PK sampling. Efforts will be made to include at least 
4 pediatric subjects from each age tier (5 to < 11, 11 to < 18 years old) in the PK analysis. PK 
samples will be collected on Days 1 and 3 as follows: 
• Day 1 (20 adult and pediatric subjects): pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 (pre-second 
dose) hours post-dose. 
• Day 3 (20 adult and pediatric subjects): pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose. 
• Day 7 (all 110 subjects): pre-dose. 
 
The PK characterization of drug concentrations for each dose to be profiled will use 
noncompartmental analysis (NCA). Additional details of the parameters and their calculation and 
evaluation is included in the Statistical Analysis Plan (SAP). 
10.3.2.2 
Pharmacokinetic Parameters 
Standard PK parameters assessed will include measures of the extent of absorption using 
estimates of the area under the curve (AUC), maximum plasma concentration and 
rate-of-absorption using the maximum concentration (Cmax), and the time of Cmax (Tmax), 
respectively. 
10.3.2.3 
Sample Collection 
Samples will be collected at the time points specified in Section 10.3.2.1 and the Schedule of 
Events (Section 2.2).  
Blood 
The total amount of blood to be collected will include samples for CBC, renal function tests, 
liver function test, coagulation profile, and biomarkers, sPLA2 levels, and plasma drug levels. 
Blood volumes should be adjusted as necessary for pediatric subjects. 
Urine 
Mid-stream or catheter urine collected for dipstick urinalysis. Urinalysis should not delay care 
and should not be obtained by catheter unless patient already being catheterized. Urine should 
not be collected from a bag, but rather from proximal port. 
10.3.3 
Safety Variables 
Safety will be assessed by evaluating AEs, vital sign measurements, clinical laboratory test 
results, 12-lead ECGs, physical examination findings, and concomitant medications and 
therapies. 


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10.3.3.1 
Clinical Laboratory Safety Assessments 
 
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 1). 
Complete blood 
count (CBC): 
White blood cell count including differential, hemoglobin/hematocrit, 
platelets  
Liver function: 
Albumin, total and indirect bilirubin, alkaline phosphatase, alanine 
aminotransferase, aspartate aminotransferase, LDH  
Serum chemistry: 
Sodium, potassium, chloride, bicarbonate, creatinine, BUN, eGFR 
Hemolysis 
Free hemoglobin, haptoglobin, LDH 
Myonecrosis 
CK 
Coagulation: 
PT, PTT, absolute fibrinogen, INR 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones 
Other: 
sPLA2 and biomarkers (CRP, D-dimer) 
Serum pregnancy 
test: 
evaluated for subjects of childbearing potential only 
 
Routine laboratory specimens will be analyzed at local laboratories, as specified in the study 
laboratory manual. A central laboratory will be used for nonstandard assays. 
 
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 11.2.5. 
10.3.3.2 
Clinical Examinations 
 
Vital Signs 
Vital signs will be assessed and recorded at the timepoints indicated in the Schedule of Events 
(Table 1) per institutional practice. In addition, body temperature will be measured and recorded 
every 4 to 8 hours during hospitalization.  
 
 
 


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Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed at the timepoints indicated in the Schedule of Events 
(Table 1) per institutional practice. All ECG recordings will be identified with the subject 
identification, date, and time of the recording and will be attached to the subject’s eCRF. 
 
Physical Examination 
A physical examination will be performed at the timepoints indicated in the Schedule of Events 
(Table 1) per institutional practice. 
 
Neurological Assessment 
For sedated, endotracheally intubated subjects, a separate neurological assessment will be 
performed according to Section 10.3.1.7. 
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 
subject administered an IP 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, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether related to the medicinal product, or not.  
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. Abnormal laboratory values related to liver and renal 
function that are deemed clinically significant by the investigator will always be considered as 
AEs if they have worsened from baseline. Any other laboratory values that are judged by the site 
investigator to be wholly caused by the snakebite envenoming will be regarded as AEs at the 
discretion of the investigator. 
Events that occur in subjects treated with control product (SOC), 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. For 
a marketed product, the known information is contained in the current package insert for the 
product. 
An unexpected adverse event (UAE) is one for which the nature or severity of which is not 
consistent with the applicable product information (e.g., IB for an unapproved IP or package 
insert/summary of product characteristics for an approved product). For example, hepatic 
necrosis would be unexpected (greater severity) if the IB only listed elevated hepatic enzymes or 
hepatitis. Likewise, cerebral vasculitis would be unexpected (greater specificity) if the IB only 
listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, 
already documented adverse reaction constitute unexpected events. Examples would be (a) acute 
renal failure as an expected adverse reaction with a subsequent new occurrence of interstitial 
nephritis (interstitial nephritis would be unexpected) and (b) hepatitis with a first occurrence of 
fulminant hepatitis (fulminant hepatitis would be unexpected.) 


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11.1.3 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to 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 
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 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP during pregnancy is an 
SAE. However, a newly diagnosed pregnancy in a subject that has received an IP is not considered an SAE 
unless it is suspected that the IP(s) interacted with a contraceptive method and led to the pregnancy.  
• 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 that do not result in hospitalization, 
development of drug dependency, or drug abuse.  
 
11.1.4 
Treatment-Emergent Adverse Events 
An AE is defined as treatment-emergent if the first onset or worsening is during or after the 
first administration of IP and not more than 30 days after the last administration of IP. 
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 study 
visits and interviews of a study subject presenting for medical care or upon review by a study 
monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate CRF. Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (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 or stabilization. 


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Any medical condition that is present at the time that the subject is screened will be considered 
as Baseline and not reported as an AE. However, if the study subject’s condition deteriorates at 
any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE, or an AE that is intermittent, will be documented as separate 
AEs to allow an assessment of the duration of the event at each level of severity to be performed. 
AEs characterized as intermittent require documentation of onset and duration of each episode. 
Site staff will record all reportable AEs with start dates occurring any time after informed 
consent is obtained until 28 days after the last day of study participation. At each study visit, the 
Investigator will inquire about the occurrence of AE/SAEs since the last visit.  
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. At each visit, the subject 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 as: 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
 
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. 


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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. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
 
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 
*Fatal should only be selected as an outcome when the AE results in death. If more than one AE is judged to be 
possibly related to the subject’s death, the outcome of death should be indicated for each such AE. Although “fatal” 
is usually an event outcome, events such as sudden death or unexplained death should be reported as SAEs. 
 
11.2.2.5 
Adverse Event Relationship to Investigational Product 
The Investigator must assess each AE’s relationship to the IP. The Investigator must carefully 
consider possible manifestations of snakebite when assigning a relationship of specific AEs to 
study drug. 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. 


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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 
AEs 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 subject 
may continue in the study will be made by the sponsor after consultation with the Investigator 
and/or medical monitor. 
If AEs occur in a subject that are not tolerable, the Investigator must decide whether to stop the 
subject’s involvement in the study and/or treat the subject. Special procedures may be 
recommended for the specific IP, such as the collection of a serum sample for determining blood 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate. 
For double-blinded studies, it is not necessary to unblind a subject’s treatment assignment in 
most circumstances, even if an SAE has occurred. If unblinding is necessary, see Section 9.6 for 
a description of the unblinding procedures. 
11.2.5 
Follow-Up 
Any AE will be followed (up to a maximum of 30 days after the last dose of IP) to a satisfactory 
resolution, until it becomes stable, or until it can be explained by another known cause(s) 
(i.e., concurrent condition or medication) and clinical judgment indicates that further evaluation 
is not warranted. All findings relevant to the final outcome of an AE must be reported in the 
subject’s medical record and recorded on the eCRF page.  




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AEs, date of occurrence, subject identification (ID), study ID, 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 study CRO using a follow-up request form or via 
email communication. 
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 associated with varespladib treatment, 
including cerebrovascular accident (CVA; stroke), MI, and malignant cardiac arrhythmias. 
However, these AEs may also be associated with many snakebites. 
11.3.2 
Pregnancy 
All subjects 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 
treatment. Subjects should be instructed to contact the Investigator or study staff immediately if 
pregnancy occurs or is suspected. 
Participants of reproductive potential must agree to use a highly effective method of 
contraception from the time of consent and for 14 days following his or her last dose of IP. 
Highly effective methods of contraception are as follows: 
• combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, or transdermal) 
• progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, or implantable) 
• intrauterine device, intrauterine hormone-releasing system 
• bilateral tubal occlusion 
• vasectomized partner 
• sexual abstinence 
• double-barrier method (condoms, sponge, diaphragm, with spermicidal jellies, or cream). 
 


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Pregnancy testing will be conducted prior to administration of the IP on every subject of 
childbearing potential. A subject who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a screening failure. 
A subject who becomes pregnant during IP treatment will be immediately discontinued from 
receiving the study drug. The Investigator must report the pregnancy within 72 hours of learning 
of the pregnancy, to the study CRO pharmacovigilance team 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. 
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 
Overdosage 
As with any overdose, patients should be monitored closely and observed for expected and 
unexpected clinical and laboratory effects. 
No specific antidote to varespladib or varespladib-methyl exists, so treatment should be directed 
at supportive care. 
In the presence of normal hepatic and renal function, blood levels of varespladib would be 
expected to rapidly diminish. Clinical and laboratory effects of varespladib overdose, however, 
may be delayed and patients should be monitored until all such effects have resolved. 
Based on preclinical toxicology studies, acute renal failure may result from high plasma levels of 
varespladib. Renal toxicity studies performed in rats suggest that forced diuresis may diminish 
the extent of renal injury following bolus administration of varespladib-methyl. No data in 
humans are available to support forced diuresis as a potential therapy. However, as the toxicity 
of many potential nephrotoxins can be diminished by increased urine flow rates, fluid or 
mannitol administration to promote diuresis may be reasonable in the setting of a 
varespladib-methyl overdose. In circulation, varespladib is highly (approximately 90%) protein 
bound. Studies to determine if hemodialysis or hemoperfusion would be of benefit in patients 
with varespladib-methyl overdose have not been performed. 


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12 
DATA SAFETY MONITORING BOARD 
The data safety monitoring board (DSMB) will operate under a charter that will be finalized 
prior to the start of the study. The DSMB will evaluate the safety data, including summaries 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 stopping recruitment in a 
particular dose group. If toxicity is observed, the treatment assignment for the subject(s) 
involved may be unblinded by the DSMB at its discretion. 


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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.  
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 subjects (n), mean, median, 
standard deviation (SD), 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.  
P-values of less than 0.05 will be considered statistically significant based on a 2-sided test 
unless otherwise specified. 
All statistical analyses will be conducted with the SAS® System, version 9.3 or higher. 
13.1.1 
Analysis Populations 
The following analysis populations are planned for this study:  
• Safety Population (SAF): The Safety Population includes all subjects who receive any 
amount of IP. Subjects who are members of the SAF population will be analyzed according 
to the treatment received. This population will be used for analysis of demographics, baseline 
characteristics, and all safety analyses. 
• Intent-To-Treat Population (ITT): The ITT population includes all subjects who have been 
randomized. Subjects included in the ITT population will be analyzed as randomized. The 
ITT population will be used for analysis of demographics, baseline characteristics, and all 
efficacy analyses. 
• Per-Protocol Population (PP): The PP population includes all subjects in the ITT without 
any significant protocol deviation. Subjects who are members of the PP population will be 
analyzed as randomized. This will be a secondary supporting population for the primary 
efficacy analysis. 
• Pharmacokinetic Population (PK): The PK Population includes all subjects in the SAF 
Population who provide at least 1 evaluable post-dose PK measurement. Subjects who are 
members of the PK population will be analyzed according to the treatment received.  
 
Assignment of subjects to populations will be confirmed at a blinded data review meeting to be 
held before the study database is locked. 


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13.1.2 
Study Subjects and Demographics 
13.1.2.1 
Disposition and Withdrawals 
The numbers of subjects randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of subjects 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 subjects from the PP population. Due to the Coronavirus 
Disease 2019 (COVID-19) global health crisis, study visits and protocol-defined procedures may 
be impacted; COVID-19-related protocol deviations are discussed in Appendix D.  
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 subject characteristics will include 
medical history and physical examination findings. 
Prior and concomitant medications will be summarized by treatment group, by the number and 
percentage of subjects taking each medication, classified using World Health Organization Drug 
Dictionary (WHO-DD) 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 subject. 
13.1.4 
Efficacy Analysis 
13.1.4.1 
Primary Efficacy Endpoints 
Statistical analysis of efficacy will be assessed by an improvement in the composite SSS (See 
SAP for SSS scale; Individual Category Severity Assessments: Pulmonary, Cardiovascular, 
Hematologic Symptoms, Renal, and Nervous Systems) from Baseline (pre-dosing) to 6 and 9 
hours after first dose, where the average of the 6- and 9-hour scores are used as the post 
treatment value: Change = (Baseline – [6hr + 9hr]/2). Subjects that die before recording a 6 or 9 
hour SSS measurement will be assigned the worst possible score when analyzing the primary 
endpoint. Missing measurements of the SSS at 6 or at 9 hours won't be replaced for the purpose 
of calculating the primary outcome. If the SSS at one of these timepoints is missing, the average 
SSS will be based solely on the SSS recorded for the other time point.  


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13.1.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are to evaluate the: 
• AUC of the pulmonary, cardiovascular, hematologic symptoms, renal, and nervous system 
sections of the SSS from Baseline through Day 7  
• Complete SSS from Baseline through Day 7  
• SSS neurologic system subscore from Baseline through Day 3 
• Coagulation abnormalities from Baseline through Day 7 
• Hemolysis markers from Baseline through Day 3 
• Levels of the myonecrosis marker, creatine kinase (CK), from Baseline through Day 3 
• Numeric Pain Rating Scale (NPRS) score in patients able to respond from Baseline through 
Day 28 
• Kidney function markers from Baseline through Day 28 
• Total differential antivenom requirement from Baseline through Day 28 
• Head-Lift duration from Baseline through Day 7 
• Total duration of ventilatory support from Baseline through Day 28  
• Total duration of Intensive Care Unit (ICU) stay from Baseline through Day 28 
• Total duration of hospitalization from Baseline through Day 28 
• All-cause mortality from Baseline through Day 28 
• Clinical Global Impression-Improvement (CGI-I) from Baseline through Day 7 
• Patient Global Impression of Change (PGIC) from Baseline through Day 7 
• Patient-Specific Functional Scale (PSFS) total score from Baseline through Day 28  
 
13.1.4.3 
Exploratory Endpoints 
The exploratory efficacy endpoints are to evaluate the: 
• Change in the SSS from Baseline through Day 7 using compressed SSS scale 
• SSS from Baseline through Day 28 after first dose 
• Grip strength pre-dosing through Day 28  
• SSS neurologic system subscore from Baseline through Day 7 


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• Analgesic use from Baseline through Day 28  
• CGI-I from Baseline through Day 28 
• PGIC from Baseline through Day 28 
• Complete blood count (CBC) through all SSS evaluation days 
• Transfusion requirement from Baseline (Day 1) through Day 28 
• C-reactive protein (CRP) from Baseline through Day 14  
• D-dimer levels from Baseline through Day 14 
• Levels of myonecrosis marker (CK) from Baseline through Day 3 in patients presenting with 
and without tourniquets at enrollment 
• Secretory phospholipase A2 (sPLA2) in serum at specified timepoints on Days 1 to 7 in all 
subjects 
 
13.1.4.4 
Primary Analysis 
The ITT and PP analysis populations will be used to analyze the primary efficacy endpoint. The 
ITT population will be the primary population for the efficacy analyses. 
Descriptive statistics for the SSS score will be tabulated by treatment group. A detailed scoring 
algorithm of the SSS score will be given in the SAP. 
The SSS score will be compared between treatment groups within an analysis of covariance 
model (ANCOVA) with the baseline SSS score, age group (5 to < 18 and ≥ 18 years), 
neurological system score ≥2 (Yes or No), and completion of the initial dose of antivenom prior 
to initiation of study drug (Yes or No) as covariates. The comparison of varespladib-methyl to 
placebo (varespladib-methyl vs placebo) will be tested at 5% two-sided significance level, the 
corresponding 95% two-sided confidence intervals will be presented. The null hypothesis for the 
ANCOVA model is given below. 
• H0: There is no difference in the change from baseline SSS (based on the Pulmonary, 
Cardiovascular, Hematologic, Renal and Nervous System subscores) to the SSS (based on 
those same 5 subscores) average at the 6- and 9-hour timepoints for subjects receiving SOC 
plus varespladib-methyl vs subjects receiving SOC plus placebo. 
 
Summary statistics and ANCOVA model results will also be presented separately within 
pediatric (5 to < 18 years) and adult (≥ 18 years) subjects. Additional pediatric subgroups may be 
considered in a posthoc analysis depending on the total number of pediatric subjects that enroll 
in the study. For the subgroup analyses, age group will not be included as a covariate in the 
ANCOVA model. If an adequate number of pediatric subjects do not enroll in the study to fit an 
ANCOVA model, only summary statistics will be presented.  


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13.1.4.5 
Secondary Analyses 
Analysis of the secondary endpoints will be carried out for the ITT population.  
All secondary endpoints will be summarized using frequencies and percentages for categorical 
endpoints, and numeric summary statistics for quantitative endpoints. 
Additional ANCOVA or a repeated measures model (MMRM) analyses will be considered for 
quantitative secondary endpoints. 
All-cause mortality will be analyzed using Kaplan-Meier methods. 
PGI-C and CGI-I responders will be summarized by frequency and percentage at each visit 
within treatment group. The difference in treatment response will be analyzed using a logistic 
regression model at each visit with  baseline SSS score, age group (5 to < 18 and ≥ 18 years), 
neurological system subscore ≥2 (Yes or No), and completion of the initial dose of antivenom 
prior to initiation of study drug (Yes or No) as covariates. 
Additional details of the efficacy analyses will be given in the final SAP. 
13.1.4.6 
Exploratory, Corroborative, Sensitivity, and Other Analyses 
Exploratory endpoint efficacy data will be summarized descriptively by visit within treatment 
groups. 
Endpoints will also be analyzed in the subset of study participants who are enrolled prior to the 
completion of the first dose of antivenom and in the subset of study participants who are enrolled 
after the completion of the first dose of antivenom. Additional details will be provided in the 
SAP. 
All sPLA2 from beginning of IP dosing to discharge will be presented and used to calculate 
maximum concentrations in both treatment groups and compare concentration-time curves using 
a nonlinear regression to quantify a change in the half-maximal effective concentration (EC50) 
and its confidence interval, and to compute a p-value that tests the null hypothesis that there is no 
difference between curves.  
13.1.5 
Clinical Pharmacology Analyses 
13.1.5.1 
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. 
13.1.6 
Safety and Tolerability Analyses 
All safety analyses will be performed on the Safety Population. 


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The variables for safety endpoints are TEAEs, vital signs, laboratory evaluations, 12-lead ECGs, 
physical examinations, and concomitant medications and therapies. 
13.1.6.1 
Adverse Events 
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. AEs will be coded using 
the Medical Dictionary for Regulator Activities (MedDRA). For each treatment group, the 
number of TEAEs and incidence rates will be tabulated by preferred term and System Organ 
Class. 
Treatment-emergent AEs will be summarized for each treatment group based on frequency, 
maximum severity, relationship to IP, SAEs, TEAEs leading to death, and TEAEs leading to 
discontinuation of IP. 
13.1.6.2 
Clinical Laboratory Evaluations 
All serum chemistry, hematology, urinalysis, liver function tests, coagulation profile 
measurements, biomarker levels, and sPLA2 levels will be summarized for each treatment group 
using descriptive statistics by visit for observed values and changes from Baseline. 
Shift tables for measurements described above, summarizing the shifts from Baseline (high; 
normal; low) at each post-Baseline visit, will be presented. 
13.1.6.3 
Vital Signs  
All vital signs will be summarized for each treatment group using descriptive statistics at each 
visit for raw numbers and change from Baseline. 
13.1.6.4 
12-lead Electrocardiograms 
All ECG measurements will be summarized for each treatment group using descriptive statistics 
by visit for raw numbers and change from Baseline. 
Additionally, frequencies and percentages of Investigator ECG interpretations by visit will be 
presented. 
13.1.6.5 
Physical Examination Findings 
The number and percentage of subjects with normal and abnormal findings in the complete 
physical examination will be displayed for each treatment group.  
13.1.6.6 
Biomarkers 
Observed values and changes from Baseline in biomarkers such as CK, CRP, D-dimer will be 
summarized using descriptive statistics by visit. 


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13.2 
Sample Size Determination 
• The planned approximate total enrollment is 110 patients (94 evaluable patients accounting 
for up to 15% loss to follow-up). The randomization scheme will be 1:1 with approximately 
one-half of subjects randomized to receive varespladib-methyl plus SOC and approximately 
one-half randomized to receive placebo plus SOC. The randomization will be stratified by 
age group (5 to < 11 years, 11 to < 18 years, ≥ 18 years) and by the presence or absence of 
neurotoxicity (SSS nervous system subscore of 0–1 or ≥ 2) at Baseline, resulting in 6 strata in 
total. 
 
The determination of the effectiveness of varespladib-methyl versus placebo will be based on the 
primary efficacy endpoint. The sample size for this phase 2 study was determined by a formal 
power calculation. This study was powered at greater than 85% to detect a statistically 
significant (2-sided alpha = 0.05) treatment effect. The assumptions are the following: 
• 2-sided Alpha level 5% 
• Power 85% 
• Randomization ratio 1:1 
• Withdrawal rate of 15%  
• A minimum difference in change from Baseline to the average of the 6- and 9-hour 
pulmonary, cardiovascular, hematologic, and nervous system subscores of the SSS of 
1.1 points and a SD of 1.75. 
 


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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 16). The sponsor reserves the right to withdraw a subject from the study (Section 8.3), 
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 18.1), 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 study will be conducted in accordance with ICH Good Clinical Practice (GCP) and 
applicable U.S. 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 
IND or Investigational Device Exemption sponsor, funding agency and documented approval 
from the IRB, except where necessary to eliminate an immediate hazard(s) to the study subjects. 
All personnel involved in the conduct of this study have completed Human Subjects Protection 
and ICH GCP training. 
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 
Subject confidentiality and privacy must be 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 subjects. Therefore, the study protocol, documentation, data, and all other 


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information generated must 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, medical records (office, clinic, or hospital) and pharmacy records for the subjects in this 
study. The clinical study site will permit access to such records. 
The study subject’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. 
Study subject research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the study CRO. This will not include the subject’s contact or 
identifying information. Rather, individual subjects and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by 
clinical sites and the study CRO 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 subjects 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 or Ethics Committee approval for the 
protocol and the appropriate informed consent form (ICF). 
2. All regulatory documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the Investigator, have participated in a study initiation 
meeting. 
 
14.3 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 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 subjects 
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. 


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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. 
14.4.1 
Informed Consent 
Consent forms describing in detail the study intervention, study procedures, and risks will be 
given to the subject, and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. As snakebites may constitute life-threatening 
medical conditions that necessitate urgent intervention, a legally authorized representative may 
provide consent for subjects who are not able to provide informed consent because of the 
severity of their condition. 
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 subject will be asked to read and review the document. The Investigator 
will explain the research study to the subject and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the subject’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research subjects. Subjects will 
have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The subjects should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The subject will sign the informed 
consent document prior to any procedures being done specifically for the study. Subjects 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 subjects 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 subject undergoes any 
study-specific procedures. The rights and welfare of the subjects 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 plan. 
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 
should 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. 


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14.4.3 
Case Report Forms 
By signing the Investigator’s Agreement (Section 18.1), the Investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign 
an ICF. 
Electronic case report forms are considered confidential documents and should be protected 
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 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject 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 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.  


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Before study initiation, the types of source documents that are to be generated will be clearly 
defined in the study plan. 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 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 
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 plan. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 18.1), 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. 


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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 study CRO’s standard operating procedures. A comprehensive data management 
plan will be developed, including a data management overview, description of database contents, 
annotated CRF, pre-entry review list, 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 plan. 
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 (TMF) audits 
• database audits 
• document audits (e.g., protocol and/or CSR) 
 
Ophirex, Inc. or its designee may conduct additional audits on a selection of study sites, 
requiring access to subject 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 at any time, for any reason, 
by Ophirex, Inc. 


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Written notification documenting the reason for study suspension or termination will be provided 
by the sponsor to Investigators, IRBs, and appropriate regulatory authorities. If the study is 
prematurely terminated or suspended, the Investigator will promptly inform study subjects. 
Study subjects 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 subjects 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Sponsor may terminate the study at any time for any reason. 
 
Study sites may be asked to have all subjects currently participating in the study complete all 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 appropriate regulatory authority. 
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 subject enrollment 
 
14.7.1 
Record Retention 
The Investigator shall retain and preserve 1 copy of all data generated during 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. 


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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. 
14.8 
Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment by 
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. 
14.9 
Use of Information and Publication 
All information concerning varespladib, varespladib-methyl, 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 or varespladib-methyl 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 or varespladib-methyl data resulting from this study requires 
prior review and written 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. 


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15 
FINAL CLINICAL STUDY REPORT 
Ophirex, Inc. will retain ownership of the data. 
The final CSR will be written within 6 months of completion of the clinical part of the study. 
This report will include a summary of the study results based on a statistical evaluation and 
clinical assessment of the protocol-defined endpoints. 
The final CSR will be submitted to the regulatory authorities.  


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16 
ETHICAL AND LEGAL CONSIDERATIONS 
16.1 
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. 
16.2 
Subject Information and Informed Consent and/or Assent 
A properly constituted, valid IRB or EC must review and approve the protocol, the Investigator’s 
ICF, and related subject 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 subject before any activity or procedure is undertaken that is not part of 
routine care. 
16.3 
Approval by Institutional Review Board or Ethics Committee 
For IND studies, the minimum standards of conduct and requirements for informed consent 
and/or assent are defined in the FDA regulations. 
A valid IRB or EC 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 or EC has been received by the Investigator, no subject may 
undergo any procedure not part of routine care for the subject’s condition. 
Protocol amendments must also be reviewed and approved by the IRB or EC. Written approval 
from the IRB or EC or a designee must be received by Ophirex, Inc. before implementation. 
16.4 
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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17 
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Bittenbinder MA, Zdenek CN, Op den Brouw B, et al. Coagulotoxic Cobras: Clinical 
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Bulfone TC, Samuel SP, Bickler PE, Lewin MR. Developing Small Molecule Therapeutics for 
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Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical 
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Chippaux JP. Estimate of the burden of snakebites in sub-Saharan Africa: a meta-analytic 
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Fernandez ML, Quartino PY, Arce-Bejarano R, et al. Intravascular hemolysis induced by 
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Fontana Oliveira IC, Gutierrez JM, Lewin MR, Oshima-Franco Y. Varespladib (LY315920) 
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Gerardo CJ, Vissoci JRN, Evans CS, Simel DL, Lavonas EJ. Does This Patient Have a Severe 
Snake Envenomation?: The Rational Clinical Examination Systematic Review. JAMA Surg. 
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Gutierrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA. Snakebite 
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Gutierrez JM, Lewin MR, Williams DJ, Lomonte B. Varespladib (LY315920) and Methyl 
Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting 
Neurotoxic Snake Venoms. Toxins (Basel). 2020;12(2). 
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Saharan Africa: estimates from 41 countries. Toxicon. 2019;159:1-4. 
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Le Geyt J, Pach S, Gutierrez JM, et al. Paediatric snakebite envenoming: recognition and 
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Lewin MR, Samuel S, Merkel J, Bickler P. Varespladib (LY315920) Appears to Be a Potent, 
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Lewin MR, Gilliam LL, Gilliam J, et al. Delayed LY333013 (Oral) and LY315920 
(Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of 
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Lewin MR, Gutierrez JM, Samuel SP, et al. Delayed Oral LY333013 Rescues Mice from Highly 
Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom. Toxins (Basel). 
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Parrish HM. Snake Venenation in Illinois. IMJ Ill Med J. 1965;127:671-677. 
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toxin inhibition by the synthetic compound Varespladib (LY315920). Sci Rep. 2019;9(1):17203.
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Schulte J, Domanski K, Smith EA, Menendez A, Kleinschmidt KC, Roth BA. Childhood 
Victims of Snakebites: 2000-2013. Pediatrics. 2016;138(5). 
Seifert SA, Boyer LV, Benson BE, Rogers JJ. AAPCC database characterization of native U.S. 
venomous snake exposures, 2001-2005. Clin Toxicol (Phila). 2009;47(4):327-335. 
Snyder DW, Bach NJ, Dillard RD, et al. Pharmacology of LY315920/S-5920, [[3-
(aminooxoacetyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl]oxy] acetate, a potent and selective 
secretory phospholipase A2 inhibitor: A new class of anti-inflammatory drugs, SPI. J Pharmacol 
Exp Ther. 1999;288(3):1117-1124. 
Sorensen J, Kald B, Tagesson C, Lindahl M. Platelet-activating factor and phospholipase A2 in 
patients with septic shock and trauma. Intensive Care Med. 1994;20(8):555-561. 
Tasoulis T, Isbister GK. A Review and Database of Snake Venom Proteomes. Toxins (Basel). 
2017;9(9). 
Uhl W, Beger HG, Hoffmann G, et al. A multicenter study of phospholipase A2 in patients in 
intensive care units. J Am Coll Surg. 1995;180(3):323-331. 
Vaiyapuri S, Vaiyapuri R, Ashokan R, et al. Snakebite and its socio-economic impact on the 
rural population of Tamil Nadu, India. PLoS One. 2013;8(11):e80090. 
Williams DJ, Faiz MA, Abela-Ridder B, et al. Strategy for a globally coordinated response to a 
priority neglected tropical disease: Snakebite envenoming. PLoS Negl Trop Dis. 
2019;13(2):e0007059. 
Xie C, Albulescu LO, Bittenbinder MA, et al. Neutralizing Effects of Small Molecule Inhibitors 
and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins. Biomedicines. 
2020;8(9). 
Zinenko O, Tovstukha I, Korniyenko Y. PLA2 Inhibitor Varespladib as an Alternative to the 
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Guidance Documents: 
Food and Drug Administration (FDA), 2020. Drug Development and Drug Interactions | Table 
of Substrates, Inhibitors and Inducers. Accessed 08 June 2021. https://www.fda.gov/drugs/drug-
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inducers. 


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18 
ATTACHMENTS 
18.1 
Investigator’s Agreement 
PROTOCOL 
NUMBER: 
OPX-PR-01 
PROTOCOL TITLE: 
Randomized, Double-Blinded, Placebo-Controlled Study to 
Evaluate the Safety, Tolerability, and Efficacy of a Multi-Dose 
Regimen of Oral Varespladib-Methyl in Subjects Bitten by 
Venomous Snakes 
FINAL PROTOCOL: 
Version 3.0, 5 May 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. Scoring Sheet for Snakebite Severity Score Inclusion Criteria 
B. Scoring Sheet for Composite Snakebite Severity Score Efficacy Endpoints 
C. Study-specific Requirements 
C1. Clinical Global Impression – Improvement (CGI-I) 
C2. Patient Global Impression of Change (PGIC) 
C3. Patient-Specific Functional Scale (PSFS) 
C4. Numeric Pain Rating Scale (NPRS) 
C5. Columbia-Suicide Severity Rating Scale 
C6. Neurological Evaluation (Grip Strength) 
C7. Modes of Mechanical Ventilation 
C8. Head-Lift Duration 
C9. Analgesic Use 
D. COVID-19 Protocol Deviations 
E. Regulations and GCP Guidelines 
 


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APPENDIX A 
SCORING SHEET FOR SNAKEBITE SEVERITY INCLUSION CRITERIA  
The inclusion criteria for this study require that each subject is hospitalized with a suspected or confirmed venomous snakebite. 
Regardless of previous antivenom administration, subjects should only be included if they present at the time of eligibility assessment 
with 2 points in any of the system scores shown below and 1 or more additional points in any other category below OR a 3 or greater 
in any category below. Subjects that have completed the initial dose of antivenom must also have a CGI-I score of ≥ 5 (i.e., minimally 
worse, much worse, or very much worse). This inclusion criteria scoring should not wait until hematologic laboratories are evaluated. 
Point of care testing (e.g., 20WBCT) may be used for enrollment determinations for the Hematologic system, if performed per site 
standard of care. Severe abnormalities of other coagulation parameter laboratory values, including 20WBCT, should be scored as a 4 
in the Hematologic system subscore for purposes of enrollment.    
 
Local wound 
  No signs/symptoms 
  Pain, swelling, or ecchymosis within 5–7.5 cm of bite site 
  Pain, swelling, or ecchymosis involving less than half the extremity (7.5–50 cm from bite site) 
  Pain, swelling, or ecchymosis involving half to all of extremity (50–100 cm from bite site) 
  Pain, swelling, or ecchymosis extending beyond affected extremity (more than 100 cm of bite site) 
 
0 
1 
2 
3 
4 
Pulmonary symptoms 
  No signs/symptoms 
  Dyspnea, minimal chest tightness, mild/vague discomfort, respirations of 20–25 breaths per minute 
  Moderate respiratory distress, 26–40 bpm 
  Cyanosis, air hunger, extreme tachypnea, or respiratory insufficiency /failure 
 
0 
1 
2 
3 
Cardiovascular system 
  No signs/symptoms 
  HR 100–125 BPM, palpitations, generalized weakness, benign dysrhythmia, or hypotension 
  HR 126–175 BPM, or hypotension with SBP > 100 mmHg 
  HR > 175 BPM, or hypotension with SBP < l00 mmHg, malignant dysrhythmia, or cardiac arrest 
 
0 
1 
2 
3 
Hematologic symptoms 
  No signs/symptoms 
  Coagulation parameters slightly abnormal: PT ULN–20 secs, PTT ULN–50 secs, platelets 100–150K/mL, or fibrinogen 100–150 mcg/mL 
  Coagulation parameters abnormal: PT 20–50 secs, PTT 50–75 secs, platelets 50–100K/mL, or fibrinogen 50–100 mcg/mL 
  Coagulation parameters abnormal: PT 50–100 secs, PTT 75–100 secs, platelets 20–50K/mL, or fibrinogen < 50 mcg/mL 
  Coagulation parameters markedly abnormal, with serious bleeding or the threat of spontaneous bleeding; unmeasurable  PT or     
    PTT, platelets < 20 K/mL, undetectable fibrinogen, severe abnormalities of other laboratory values also fall into this category 
 
0 
1 
2 
3 
4 
Nervous system 
  No signs/symptoms 
  Minimal apprehension, headache, weakness, dizziness, chills, or paresthesia 
  Moderate apprehension, headache, weakness, dizziness, chills, paresthesia, confusion, fasciculation in area of bite site, ptosis, or dysphagia 
  Severe confusion, lethargy, weakness, paralysis, seizures, coma, psychosis, or generalized fasciculation 
 
0 
1 
2 
3 
TOTAL 


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APPENDIX B 
COMPOSITE SNAKEBITE SEVERITY SCORE FOR EFFICACY ENDPOINTS 
Local wound 
  No signs/symptoms 
  Pain, swelling, or ecchymosis within 5–7.5 cm of bite site 
  Pain, swelling, or ecchymosis involving less than half the extremity (7.5–50 cm from bite site) 
  Pain, swelling, or ecchymosis involving half to all of extremity (50–100 cm from bite site) 
  Pain, swelling, or ecchymosis extending beyond affected extremity (more than 100 cm of bite site) 
 
0 
1 
2 
3 
4 
Pulmonary symptoms 
  No signs/symptoms 
  Dyspnea, minimal chest tightness, mild/vague discomfort, respirations of 20–25 breaths per minute 
  Moderate respiratory distress, 26–40 bpm 
  Cyanosis, air hunger, extreme tachypnea, or respiratory insufficiency /failure 
 
0 
1 
2 
3 
Cardiovascular system 
  No signs/symptoms 
  HR 100–125 BPM, palpitations, generalized weakness, benign dysrhythmia, or hypotension 
  HR 126–175 BPM, or hypotension with SBP > 100 mmHg 
  HR > 175 BPM, or hypotension with SBP < l00 mmHg, malignant dysrhythmia, or cardiac arrest 
 
0 
1 
2 
3 
Gastrointestinal system 
  No signs/symptoms 
  Pain, tenesmus, or nausea 
  Vomiting or diarrhea 
  Repeated vomiting, diarrhea, hematemesis, or hematochezia 
 
0 
1 
2 
3 
Hematologic symptoms* 
  No signs/symptoms 
  Coagulation parameters slightly abnormal: PT ULN–20 secs, PTT ULN–50 secs, platelets 100–150K/mL, or fibrinogen 100–150 mcg/mL 
  Coagulation parameters abnormal: PT 20–50 secs, PTT 50–75 secs, platelets 50–100K/mL, or fibrinogen 50–100 mcg/mL 
  Coagulation parameters abnormal: PT 50–100 secs, PTT 75–100 secs, platelets 20–50K/mL, or fibrinogen < 50 mcg/mL 
  Coagulation parameters markedly abnormal, with serious bleeding or the threat of spontaneous bleeding; unmeasurable  PT or     
      PTT, platelets < 20 K/mL, undetectable fibrinogen, severe abnormalities of other laboratory values also fall into this category 
 
0 
1 
2 
3 
4 
Nervous system 
  No signs/symptoms 
  Minimal apprehension, headache, weakness, dizziness, chills, or paresthesia 
  Moderate apprehension, headache, weakness, dizziness, chills, paresthesia, confusion, fasciculation in area of bite site, ptosis, or dysphagia 
  Severe  confusion, lethargy, weakness, paralysis, seizures, coma, psychosis, or generalized fasciculation 
 
0 
1 
2 
3 
Renal system* 
Normal creatinine and urine output 
 
Creatinine 1.5 to 1.9 times baseline, increase in creatinine ≥0.3mg/dl (≥26.5 µmol/L) from baseline, or urine output <0.5 ml/kg/h for >6 h 
Creatinine 2 to 2.9 times baseline or urine output <0.5 ml/kg/h for >12 h  
Creatinine ≥3.0 times baseline, increase in creatinine to ≥4.0 mg/dl (≥353.6 µmol/L), urine output <0.3 ml/kg/h for ≥24 h or anuria ≥12 h, or  
initiation of renal replacement therapy   
 
0 
1 
2 
3 
TOTAL 
 
*Where applicable, confirmatory laboratory test results will be used to score the SSS for efficacy endpoints. 


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APPENDIX C 
STUDY-SPECIFIC REQUIREMENTS 
 
 
Protocol Appendix 
 Assessment Tool 
C1 
 Clinical Global Impression – Improvement (CGI-I) 
C2 
 Patient Global Impression of Change (PGIC) 
C3 
 Patient-Specific Functional Scale (PSFS) 
C4 
 Numeric Pain Rating Scale (NPRS) 
C5 
 Columbia-Suicide Severity Rating Scales 
C6 
 Neurological evaluation (Grip Strength) 
C7 
 Modes of Mechanical Ventilation 
C8 
 Head-Lift Assessment 
C9 
 Analgesic Use 


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Appendix C1: Clinical Global Impression-Improvement (CGI-I) Form 
Baseline CGI-I rating should be in comparison to previous clinical assessments. Additional CGI-
I should be performed on Day 1 at 1, 2, and 3-4 hours post initial dose, then follow normal 
assessment schedule as provided in the Schedule of Events. All post-baseline CGI-I assessments 
should be compared to baseline CGI-I.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 


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Appendix C2: Patient Global Impression of Change Scale 
 
 
 
  
 
 
 
 
  
 
  
 
  
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
    
  
 
 
  
  


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Appendix C3: Patient-Specific Functional Scale 
The PSFS is a 3-item instrument that is administered verbally. Completion takes approximately 
2 minutes.  
On the initial assessment, the question is: “I am going to ask you to identify 3 important 
activities that you are unable to do or are having difficulty with as a result of your snake bite. 
Today, are there any activities that you are unable to do or having difficulty with because of your 
snake bite?” 
The patient then provides 3 activities. The patient then provides a rating for each item on an 
11-item ordinal scale, where 0 is “unable to perform activity” and 10 is “able to perform activity 
at the same level as before injury or problem.” The range of possible single activity scores is 
0 to 10 and the range of possible total score is 0 to 10. 
For all follow-up assessments, the question is: “When I assessed you on [state previous 
assessment date], you told me that you had difficulty with [read all activities from the list]. 
Today, do you still have difficulty with [read and have patient score each item on the list]?” 
References: 
Westaway MD, Stratford PW, Binkley JM. The patient-specific functional scale: validation of its 
use in persons with neck dysfunction. J Orthop Sports Phys Ther 1998; 27(5): 331-338. 
Stratford P, Gill C, Westaway M, Binkley J. Assessing disability and change on individual 
patients: a report of a patient specific measure. Physiotherap Canada 1995; 47(4): 258-63. 
Horn KK, Jennings S. Richardson G, van Vliet D, Hefford C, Abbott JH. The Patient-Specific 
Functional Scale: psychometrics, clinimetrics, and applications as a clinical outcome measure. J 
Orthop Sports Phys Ther 2012; 42(1):30-42. 
Instrument: None 
A sample PSFS assessment form is attached below. 


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Appendix C4: NPRS Form 
The numeric pain rating scale (NPRS) is an 11-point scale for patient self-reporting of pain. This 
scale is administered verbally by the clinical site staff and recorded by the administrator. An 
example NPRS is provided below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix C5: Columbia-Suicide Severity Rating Scale Forms 
1. C-SSRS Baseline/Screening Form 
2. C-SSRS Since Last Visit Form 
 
 


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1. C-SSRS Baseline/Screening Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. C-SSRS Since Last Visit Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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Appendix C6: Grip Strength 
Grip strength will be evaluated using a dynamometer, as a measure of the severity of the 
neurological effects of snakebite. Grip strength should be measured in affected hand if the bite 
occurred in upper extremity or in the patient’s dominant hand if the bite occurred elsewhere 
(i.e. not in an upper extremity). 
The grip strength assessment is an objective measurement of hand function. The subject is asked 
to grip a dynamometer and squeeze with maximal force. The measurement is repeated for a total 
of 3 trials and the greatest value is recorded. Completion takes approximate 1 minute.  
References: 
Jones LA. The assessment of hand function: a critical review of techniques. J Hand Surg 1989; 
14A:221-8. 
Peters MJH, van Nes SI, Vanhoutte EK Bakkers M, van Doorn PA, Merkies ISJ, Faber CG, 
PeriNomS Study group. Revised normative values for grip strength with the Jamar 
dynamometer. J Periph Nervous Sys 2011; 16(1): 47-50. 
 
Instrument: A standard dynamometer, such as the Jamar Hand Dynamometer, will be used 
according to the manufacturer’s instructions. 
 
 


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Appendix C7: Modes of Mechanical Ventilation 
Record the following in all endotracheally intubated patients. Modes of Ventilation will be 
collected in the CRF.  
• Mechanical ventilation modes and ventilator settings  
- 
Control mode ventilation 
◦ 
Volume control 
◦ 
Pressure control 
◦ 
Assist control 
◦ 
Pressure-regulated volume control 
- 
Weaning mode ventilation 
◦ 
Synchronized intermittent mandatory ventilation 
◦ 
Pressure support 
◦ 
Adaptive support ventilation 
◦ 
Airway pressure release ventilation 
◦ 
T piece 
- 
Other 
(Since novel modes such as adaptive support ventilation and airway pressure release 
ventilation can be used during initiation, maintenance, or weaning phases of mechanical 
ventilation, clear documentation is warranted) 
• Record NIF if collected per institutional practice 
 


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Appendix C8: Head-Lift Duration 
The subject is asked to raise their head approximately 8 cm off the bed (enough to see clear 
separation from the head and the mattress). The duration of time that the patient can keep their 
head off the bed is measured for a maximum duration of 5 seconds (e.g. 1, 2, 3, 4, 5 seconds or if 
using timing device e.g. 4.25 seconds). Please note the duration of Head-Lift in seconds. Record 
up to 2 decimal places if using an electronic timing device (e.g. stop-watch). 
References: 
Heier T, Caldwell JE, Feiner JR, Liu L, Ward T, Wright PM. Relationship between normalized 
adductor pollicis train-of-four ratio and manifestations of residual neuromuscular block: a study 
using acceleromyography during near steady-state concentrations of 
mivacurium. Anesthesiology. 2010;113:825–832. 
Lewin MR, Bickler P, Heier T, Feiner J, Montauk L, Mensh B. Reversal of experimental 
paralysis in a human by intranasal neostigmine aerosol suggests a novel approach to the early 
treatment of neurotoxic envenomation. Clin Case Rep. 2013;1(1):7-15. doi:10.1002/ccr3.3 
 
 


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Appendix C9: Analgesic Use 
This analgesic use assessment is derived from data in the patient’s medication history as 
collected through recording of concomitant medication usage, supplemented by focused 
questions if needed. 
For each assessment time point, the patient’s current analgesic use will be characterized by the 
clinical research team based on the strongest category of analgesic taken to treat 
snakebite-related pain, as follows: 
 
The result is a 4-point ordinal scale with a range of possible values  –4. Collection of these data 
should require less than 1 minute in addition to the time for overall medication use. 
Reference: None 
Instrument: None 
Analgesic use category 
Ordinal scale value 
No analgesic 
1 
Nonprescription analgesic only 
2 
Prescription analgesic, non-opioid 
3 
Opioid analgesic (including tramadol, and opioid combination products) 
4 


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APPENDIX D 
COVID-19 PROTOCOL DEVIATIONS 
The impact of COVID-19 on this clinical study and study subjects will be extensively described 
in the SAP and in the CSR. The following aspects will be summarized when protocol deviations 
are due to COVID-19 infection or restriction:  
• Changes to treatment dispensation  
• Changes to treatment administration  
• Changes to visit windows to accommodate delays for some assessments  
• Missing efficacy endpoints  
• Missing visits 
 


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APPENDIX E 
REGULATIONS AND GOOD CLINICAL PRACTICE 
GUIDELINES 
1. Regulations 
Refer to the following United States 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: 








Statistical Analysis Plan 
Sponsor Ophirex, Inc. 
Protocol Number OPX-PR-01 
 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version Final 4.0 
|  Date 26-May-2023 
| 
 Effective date: 17-Aug-2020 Page 5 of 62 
Table of Contents 
Approvals ......................................................................................................................................... 1 
Document History ............................................................................................................................ 4 
Table of Contents ............................................................................................................................. 5 
List of Tables .................................................................................................................................... 9 
List of Abbreviations ...................................................................................................................... 10 
1. 
Overview ............................................................................................................................ 13 
2. 
Study Objective and Endpoints .......................................................................................... 13 
2.1. 
Study Objective ............................................................................................................ 13 
2.2. 
Study Endpoints ........................................................................................................... 14 
2.2.1. Efficacy Endpoints ....................................................................................................... 14 
2.2.2. Safety and Tolerability Endpoints ................................................................................ 15 
2.2.3. Pharmacokinetics .......................................................................................................... 16 
2.2.4. Exploratory Endpoints .................................................................................................. 16 
3. 
Overall Study Design and Plan ........................................................................................... 17 
3.1. 
Overall Design .............................................................................................................. 17 
3.2. 
Sample Size and Power ................................................................................................ 17 
3.3. 
Study Population .......................................................................................................... 17 
3.4. 
Treatments Administered ............................................................................................. 18 
3.5. 
Method of Assigning Subjects to Treatment Groups ................................................... 18 
3.6. 
Blinding and Unblinding .............................................................................................. 19 
3.7. 
Schedule of Events ....................................................................................................... 19 
4. 
Statistical Analysis and Reporting ...................................................................................... 19 
4.1. 
Introduction .................................................................................................................. 19 
4.2. 
Selection of Key Secondary Efficacy Endpoints. ......................................................... 20 
4.3. 
Interim Analysis and Data Monitoring ......................................................................... 21 
5. 
Analysis Populations .......................................................................................................... 21 
6. 
General Issues for Statistical Analysis ............................................................................... 21 
6.1. 
Statistical Definitions and Algorithms .......................................................................... 21 
6.1.1. Baseline ........................................................................................................................ 22 
6.1.2. Adjustments for Covariates .......................................................................................... 22 
6.1.3. Multiple Comparisons .................................................................................................. 22 
6.1.4. Handling of Dropouts or Missing Data ........................................................................ 22 
6.1.5. Analysis Visit Windows ............................................................................................... 25 


Statistical Analysis Plan 
Sponsor Ophirex, Inc. 
Protocol Number OPX-PR-01 
 
 
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Version Final 4.0 
|  Date 26-May-2023 
| 
 Effective date: 17-Aug-2020 Page 6 of 62 
6.1.6. Pooling of Sites ............................................................................................................ 25 
6.1.7. Derived Variables ......................................................................................................... 26 
6.1.8. COVID-19 .................................................................................................................... 30 
7. 
Study Subjects and Demographics ..................................................................................... 31 
7.1. 
Disposition of Subjects and Withdrawals ..................................................................... 31 
7.2. 
Protocol Violations and Deviations .............................................................................. 31 
7.3. 
Demographics and Other Baseline Characteristics ...................................................... 31 
7.4. 
Exposure and Compliance ............................................................................................ 31 
8. 
Efficacy Analysis ............................................................................................................... 32 
8.1. 
Primary Efficacy Analysis............................................................................................ 32 
8.1.1. Primary Efficacy Endpoint ........................................................................................... 32 
8.1.2. Key Secondary Efficacy Endpoints .............................................................................. 33 
8.1.3. SAS Code for Primary and Key Secondary Efficacy Endpoints .................................. 36 
8.2. 
Other Secondary Efficacy Analyses ............................................................................. 38 
8.2.1. Complete SSS from Baseline through Day 7 ............................................................... 38 
8.2.2. SSS Neurologic System Subscore from Baseline through Day 3 ................................. 38 
8.2.3. Coagulation Abnormalities from Baseline through Day 7 ........................................... 39 
8.2.4. Hemolysis Markers at Baseline through Day 3 ............................................................ 40 
8.2.5. Levels of the Myonecrosis Marker (CK) from Baseline Through Day 3 ..................... 40 
8.2.6. NPRS Score in Subjects Able to Respond from Baseline through Day 28 .................. 40 
8.2.7. Kidney Function Markers from Baseline through Day 28 ........................................... 41 
8.2.8. Head-Lift Duration through Day 7 ............................................................................... 41 
8.2.9. Total Duration of Ventilatory Support from Baseline through Day 28 ........................ 41 
8.2.10. Total Duration of ICU Stay from Baseline through Day 28......................................... 42 
8.2.11. Total Duration of Hospitalization from Baseline through Day 28 ............................... 42 
8.2.12. All-Cause Mortality from Baseline through Day 28 .................................................... 42 
8.2.13. Clinical Global Impression–Improvement (CGI-I) from Baseline through Day 7 ....... 43 
8.2.14. Patient Global Impression of Change (PGI-C) from Baseline through Day 7 ............. 43 
8.2.15. Patient-Specific Functional Scale (PSFS) Total Score through Day 28 ....................... 43 
8.3. 
Exploratory Efficacy Analysis ..................................................................................... 43 
8.3.1. Change in the SSS from Baseline through Day 7 Using Compressed SSS Scale ........ 44 
8.3.2. SSS from Baseline through Day 28 After First Dose ................................................... 44 
8.3.3. Grip Strength Pre-Dosing through Day 28 ................................................................... 44 
8.3.4. SSS Neurologic System Subscore from Baseline through Day 7 ................................. 44 
8.3.5. Analgesic Use through Day 28 ..................................................................................... 44 


Statistical Analysis Plan 
Sponsor Ophirex, Inc. 
Protocol Number OPX-PR-01 
 
 
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Version Final 4.0 
|  Date 26-May-2023 
| 
 Effective date: 17-Aug-2020 Page 7 of 62 
8.3.6. Clinical Global Impression – Improvement (CGI-I) from Baseline through Day 
28 ................................................................................................................................. 44 
8.3.7. Patient Global Impression of Change (PGIC) from Baseline through Day 28 ............ 45 
8.3.8. Complete Blood Count (CBC) Laboratory Tests through All SSS Evaluation 
Days ............................................................................................................................. 45 
8.3.9. Transfusion Requirement from Baseline through Day 28 .......................................... 45 
8.3.10. C-reactive Protein (CRP) from Baseline through Day 14 ........................................... 45 
8.3.11. D-dimer Levels from Baseline through Day 14 .......................................................... 45 
8.3.12. Levels of Myonecrosis Marker (CK) from Baseline through Day 3 in Subjects 
Presenting with and without Tourniquets at Enrollment ............................................ 46 
8.3.13. Secretory Phospholipase A2 (sPLA2) in Serum at Specified Timepoints on Days 
1 to 7 in All Subjects ................................................................................................... 46 
8.4. 
Subgroup Analyses of Efficacy Variables ................................................................... 46 
9. 
Safety and Tolerability Analysis ....................................................................................... 46 
9.1. 
Adverse Events ............................................................................................................ 47 
9.1.1. Adverse Events Leading to Withdrawal ...................................................................... 47 
9.1.2. Deaths and Serious Adverse Events ............................................................................ 48 
9.1.3. FDA Medical Queries ................................................................................................. 48 
9.2. 
Vital Signs ................................................................................................................... 48 
9.3. 
Clinical Laboratory Evaluations .................................................................................. 48 
9.4. 
Vital Signs ................................................................................................................... 48 
9.5. 
Electrocardiograms ...................................................................................................... 49 
9.6. 
Physical Examination .................................................................................................. 49 
9.7. 
Concomitant Medication ............................................................................................. 49 
9.8. 
Columbia-Suicide Severity Rating Scale .................................................................... 49 
10. 
Changes from Planned Analysis ....................................................................................... 49 
11. 
Other Planned Analysis ..................................................................................................... 49 
11.1. 
Pharmacokinetic Analysis ........................................................................................... 50 
11.2. 
11.2 Pharmacoeconomic Analysis ............................................................................. 50 
12. 
References ......................................................................................................................... 51 
13. 
Tables, Listings, and Figures ............................................................................................. 51 
13.1. 
Demographic Data Summary Tables and Figures ....................................................... 53 
13.2. 
Efficacy Data ............................................................................................................... 53 
13.3. 
Safety Data .................................................................................................................. 57 
13.4. 
Pharmacokinetic/Pharmacodynamic Data ................................................................... 59 
13.5. 
Other Data Summary Tables ....................................................................................... 59 


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13.6. 
Planned Listing Descriptions ........................................................................................ 59 
13.7. 
Planned Figure Descriptions ........................................................................................ 61 
14. 
Table, Figure, and Listing Shells ....................................................................................... 62 


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List of Tables 
Table 1: Demographic Data Summary Tables and Figures .......................................................... 53 
Table 2: Efficacy Data ................................................................................................................... 53 
Table 3: Safety Data ...................................................................................................................... 57 
Table 4: Other Data Summary Tables ........................................................................................... 59 
Table 5: Planned Listings .............................................................................................................. 59 
Table 6: Planned Figures ............................................................................................................... 61 








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1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Ophirex, Inc. 
protocol number OPX-PR-01 (Randomized, Double-Blinded, Placebo-Controlled Study to 
Evaluate the Safety, Tolerability, and Efficacy of a Multi-Dose Regimen of Oral Varespladib- 
Methyl in Subjects Bitten by Venomous Snakes), dated 03 May 2022 version 3.0 (US) and 
version 3.1 (India). Operational aspects related to collection and timing of planned clinical 
assessments are not repeated in this SAP unless relevant to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials (ICH, 1998). All work planned and reported for this SAP will follow internationally 
accepted guidelines, published by the American Statistical Association (ASA, 2018) and the 
Royal Statistical Society (RSS, 2014), for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be approved before unblinding 
of any data pertaining to Ophirex, Inc.’s study OPX-PR-01. 
2. 
Study Objective and Endpoints 
2.1. 
Study Objective 
The primary objective of the study is to evaluate the efficacy of a multi-dose regimen of oral 
varespladib-methyl alongside standard of care (SOC) compared to SOC alone in subjects after 
venomous snakebite. 
The secondary objective is to evaluate efficacy of varespladib-methyl as treatment for sPLA2- 
induced venom toxicities. 
The exploratory objectives of the study are: 
 To assess the efficacy of varespladib-methyl as evaluated by a compressed snakebite severity 
score (SSS) scale 
 To assess the efficacy of varespladib-methyl as evaluated by SSS 
 To assess the effect of varespladib-methyl on neurological function as evaluated by grip 
strength 
 To assess the effect of varespladib-methyl on neurotoxicity 
 To assess the effect of varespladib-methyl on analgesic use 


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 To evaluate the effect of varespladib-methyl on Clinical Global Impression-Improvement 
(CGI-I) 
 To evaluate the effect of varespladib-methyl on the Patient Global Impression of Change 
(PGIC) 
 To assess the effect of varespladib-methyl on complete blood count (CBC) 
 To assess the effect of varespladib-methyl on transfusion requirement in subjects with 
hemolysis 
 To evaluate the effect of varespladib-methyl on the levels of C-reactive protein (CRP) 
 To assess the safety biomarker D-dimer 
 To assess the effect of varespladib-methyl on myonecrosis markers in subjects with and 
without tourniquets at enrollment 
 To evaluate the levels of secretory phospholipase A2 (sPLA2) in serum 
The pharmacokinetics (PK) of varespladib-methyl in subjects with snakebite envenoming will 
also be assessed. 
2.2. 
Study Endpoints 
2.2.1. Efficacy Endpoints 
2.2.1.1. 
Primary Efficacy Endpoint 
Change in the composite outcome of pulmonary, cardiovascular, hematologic symptoms, renal, 
and nervous system sections of the SSS from Baseline (pre-dosing) to the average of the scores 
from 6 and 9 hours after first dose. 
The estimand for the primary efficacy endpoint of this study is defined here in accordance with 
the ICH E9 Addendum: 
1) Population: The population targeted for the scientific questions is defined via the 
inclusion and exclusion criteria. 
2) Variable (or endpoint): Change from Baseline to the average of 6 and 9 hours of the 
Double-blind Treatment Period in the composite outcome of pulmonary, cardiovascular, 
hematologic, renal, and nervous system sections of the SSS. 
3) Intercurrent Events: The primary estimand will be based on a treatment policy 
analysis. All observed values will be used regardless of occurrence of an intercurrent 
event with the exception of mortality for which the worst possible SSS score will be 
assigned as described in Section 6.1.7.1. 
4) Population level summary: The mean change of the composite outcome of pulmonary, 
cardiovascular, hematologic, renal, and nervous system sections of the SSS from Baseline 
to the average of hours 6 and 9 of the Double-blind Treatment Period will be analyzed 
using an analysis of covariance (ANCOVA) model. Additional details can be found in 
Section 8.1. 


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2.2.1.2. 
Key Secondary Efficacy Endpoints 
Four key (alpha-protected) secondary outcomes have been selected for which formal hypothesis 
testing will be conducted. A fixed-sequence approach to controlling the type I error rate will be 
used. First, the primary endpoint above will be tested, followed by the four key secondary 
endpoints in the sequence with which they are presented below. 
The efficacy of varespladib plus SOC vs. SOC alone will be assessed for these four outcomes. 
Details of this approach are described in section 8.1.2. 
 Area under the curve (AUC) of the pulmonary, cardiovascular, local wound, hematologic 
symptoms, renal, and nervous system sections of the SSS from baseline through Day 7 
 Total antivenom administration in vials from Baseline through Day 28 
 AUC of the Numeric Pain Rating Score (NPRS) from baseline through Day 3 
 
Clinical Global Impression-Improvement (CGI-I) scale at Day 2 
 
2.2.1.3. 
Other Secondary Endpoints 
The study has the following other secondary efficacy endpoints: 
 
Complete SSS from baseline (pre-dosing) through Day 7 
 
SSS neurologic system subscore from Baseline through Day 3 
 
Coagulation abnormalities from Baseline through Day 7 
 
Hemolysis markers from baseline through Day 3 
 
Levels of the myonecrosis marker, creatinine kinase (CK), from Baseline through Day 3 
 Numeric Pain Rating Scale (NPRS) score in subjects able to respond from Baseline 
through Day 28 
 Kidney function markers from baseline through Day 28 
 
Head-Lift duration from Baseline through Day 7 
 Total duration of ventilatory support from Baseline through Day 28 
 Total duration of Intensive Care Unit (ICU) stay from Baseline through Day 28 
 Total duration of hospitalization from Baseline through Day 28 
 All-cause mortality from Baseline through Day 28 
 
CGI-I scale from Baseline through Day 7 
 
PGIC from Baseline through Day 7 
 Patient-Specific Functional Scale (PSFS) total score from Baseline through Day 28 
2.2.2. Safety and Tolerability Endpoints 
The study has the following safety and tolerability endpoints: 
 Incidence and severity of adverse events (AEs), serious AEs (SAEs), and AEs leading to 
discontinuation of Investigational Product (IP) 
 Safety of varespladib-methyl as assessed by the number and rates of reported treatment- 


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emergent adverse events (TEAEs) from beginning of treatment until last Follow-Up 
Visit/Phone call at Day 28 
 Treatment-related SAE from beginning of treatment until last Follow-up Visit/Phone call 
at Day 28 
 Safety as assessed by 
o Vital signs 
o Clinical laboratory evaluations: complete blood count (CBC), urinalysis, 
liver function tests (LFTs), renal function tests (albumin, creatinine, blood 
urea nitrogen [BUN], estimated glomerular filtration rate [eGFR]) 
o 12-lead electrocardiogram (ECG) 
 Concomitant medications and therapies 
 Columbia-Suicide Severity Rating Scale (C-SSRS) evaluated at Baseline or at the earliest 
time point clinically allowable (ideally Day 1) and then at every study visit through Day 
28 
Safety endpoints will be analyzed according to the following FDA Medical Queries (FMQs): 
 Hepatic Injury (Narrow and Broad) 
 Acute Kidney Injury (Narrow and Broad) 
 Stroke and Transient Ischemic Attack [TIA] (Narrow and Broad) 
 Myocardial Ischemia (Narrow) 
 Arrythmia (Narrow) 
 Cardiac Conduction Disturbance (Narrow) 
 Hypersensitivity (Standard Narrow and Broad) 
2.2.3. Pharmacokinetics 
PK parameters of varespladib-methyl in plasma from a subset of adult and pediatric subjects at 
specified timepoints on Days 1 and 3 and from all subjects pre-dose on Day 7. 
2.2.4. Exploratory Endpoints 
The exploratory efficacy endpoints of this study include the following: 
 Change in the SSS from Baseline through Day 7 using a compressed SSS scale. 
 SSS from Baseline through Day 28 
 Grip strength pre-dosing through Day 28 
 
SSS neurologic system subscore from Baseline through Day 7 
 Analgesic use from Baseline through Day 28 
 CGI-I from Baseline through Day 28 
 PGIC from Baseline through Day 28 
 CBC through all SSS evaluation days 
 Transfusion requirement from Baseline through Day 28 


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 CRP from Baseline through Day 14 
 D-dimer levels from Baseline through Day 14 
 Levels of myonecrosis marker (CK) from Baseline through Day 3 in subjects presenting 
with and without tourniquets at enrollment 
 Secretory phospholipase A2 (sPLA2) in serum at specified timepoints on Days 1 to 7 in 
all subjects 
3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
This is a multi-center, randomized, double-blind, placebo-controlled, phase 2 study designed to 
evaluate the safety, tolerability, and efficacy of varespladib-methyl, concurrently with SOC, in 
subjects bitten by venomous snakes. Subjects who have experienced a venomous snakebite with 
evidence of snakebite venom toxicity (see Study Population, Section 3.3, below) and who meet 
other inclusion criteria will be eligible for participation in the study. Consenting participants will 
be enrolled and randomized to receive study drug (active varespladib-methyl or placebo) in a 1:1 
ratio. Study drug will be taken twice a day for a period of 7 days. Subjects in both arms of the 
trial will receive SOC. Outcomes will be assessed over a follow-up period of 28 days. 
3.2. 
Sample Size and Power 
The sample size for this phase 2 study was determined by a formal power calculation based 
on the primary efficacy endpoint. This study was powered at 85% to detect a statistically 
significant (2-sided alpha = 0.05) treatment effect. The assumptions are the following: 
 2-sided alpha level 5% 
 Power 85% 
 Randomization ratio 1:1 
 A minimum difference in the change from Baseline to the average at 6- and 9-hour 
pulmonary, cardiovascular, hematologic, renal, and nervous system subscores of the 
SSS of 1.1 points and a standard deviation 1.75 
A sample size of 94 patients will provide 85% power to identify a difference of 1.1 in the 
primary outcome (two-sided alpha = 0.05). The sample size has been calculated using nQuery 8. 
The randomization scheme will be 1:1 stratified by age group (5 to < 11, 11 to < 18, and ≥ 18 
years old) and by the presence or absence of neurotoxicity (SSS nervous system subscore of 0–1 
or ≥ 2) at Baseline, resulting in 6 strata in total. 
Because we anticipate up to 15% withdrawal through the end of the study, we requested 
permission to enroll up to 110 patients to ensure adequate power for secondary outcomes. 
3.3. 
Study Population 
The study population comprises subjects of both genders, aged ≥5 years, with venomous 
snakebite. The index event (snakebite) must be symptomatic and symptom onset must have 


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occurred within 10 hours of eligibility assessment and the subject must be willing (or legally 
authorized representative is willing) to provide informed consent prior to initiation of any study 
procedures. 
Subjects must meet one of two categories of inclusion criteria: 
1. Subjects who have not yet completed their initial dose of antivenom may be 
eligible if they have an SSS inclusion criteria score (excludes GI and renal 
subscores) of ≥3 points in any singe SSS category or a score of 2 in one category 
and at least 1 in any other category. 
2. Subjects who have completed their initial dose of antivenom may be eligible if 
they have an SSS inclusion criteria score (excludes GI and renal subscores) of ≥2 
points. 
3.4. 
Treatments Administered 
Varespladib-methyl or placebo will be administered, concurrently with institutional SOC, to 
subjects with suspected or confirmed snakebite envenoming: 
 Adult subjects will receive an initial loading dose of 500 mg (2 × 250 mg oral tablet) 
varespladib-methyl upon randomization, followed by dosing with 250 mg varespladib- 
methyl (1 x 250 mg oral tablet) approximately 12 hours later, and subsequent BID dosing 
with 1 x 250 mg varespladib-methyl oral tablets for the remainder of the 7-day treatment 
period. Tablets may be administered via feeding tube (e.g., naso- or orogastric tubes) in 
subjects requiring mechanical ventilation. 
 Pediatric subjects (ages 5 to < 18) will be administered doses of varespladib-methyl 
determined by allometric scaling, provided as 50 mg capsules. Age-appropriate capsules, 
as described in Section 7.3 of the protocol, may be administered via feeding tube (e.g., 
naso- or orogastric tubes) in subjects requiring mechanical ventilation. 
 The timing of initial snakebite envenoming, and administration of SOC will be 
considered when determining study subject eligibility. 
3.5. 
Method of Assigning Subjects to Treatment Groups 
In this parallel-group randomized study, subjects who meet study entry criteria will be randomly 
assigned in a 1:1 ratio to varespladib-methyl or placebo. The randomization schedule, which will 
be computer generated using a permuted block algorithm, will randomly allocate IP to 
randomization numbers. The randomization numbers will be assigned sequentially through a 
central interactive web response system (IWRS) as subjects are entered into the study. The 
randomization schedule will be stratified by age group (5 to < 11 years, 11 to < 18 years, and ≥ 
18 years) and by the presence or absence of moderate to severe neurotoxicity (SSS nervous 
system subscore of 0−1 or ≥ 2) at Baseline, resulting in 6 strata in total. Study center will not be a 
blocking factor in the randomization schedule. The block sizes will not be divulged to the 
Sponsor or the investigative team. No one involved in the study performance will have access to 
the randomization schedule before official unblinding of treatment assignment. The 


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randomization schedule will be prepared by the clinical research organization (CRO) before the 
start of the study. No subject will be randomized into this study more than once. 
A subject will be considered randomized when the IWRS has given the treatment number to be 
allocated. 
3.6. 
Blinding and Unblinding 
All subjects, investigators, and study personnel involved in the conduct of the study, including 
data management, will be blinded to treatment assignment except for a specified unblinded 
statistician and programmer from the study CRO who will have access to the randomization 
code. 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. If an 
interim analysis is conducted, then unblinded personnel who are not otherwise involved in the 
study will prepare the data for review. 
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 subject’s treatment assignment. 
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 subject’s treatment assignment. 
Unblinding for an individual subject will not result in unblinding the treatment assignments for 
the remaining subjects in the study. Thus, the overall study blind will not be compromised. 
3.7. 
Schedule of Events 
Please see Table 1 of the protocol 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 will primarily use SAS (release 9.4 or higher). If the use of other 
software is warranted, the final statistical methodology report will detail what software was used 
for what purposes. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
non-missing values, mean, standard deviation, median, 25th percentile, 75th percentile, minimum, 
and maximum. 
Categorical (qualitative) variable summaries will include the frequency and percentage of 


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subjects who are in the particular category or each possible value. In general, the denominator 
for the percentage calculation will be based upon the total number of subjects in the study 
population for the treatment groups, unless otherwise specified. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Means will be reported to 1 degree of precision 
more than the observed data and measures of spread will be reported to 2 degrees of precision 
more than the observed data. Medians will be reported to the degree of precision measured. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and P values will be reported. Corresponding 95% confidence intervals (CIs) 
will be presented for statistical tests. 
This study is considered a confirmatory study. Statistical tests will be regarded as formal tests of 
specific hypotheses. 
4.2. 
Selection of Key Secondary Efficacy Endpoints. 
The AUC of the pulmonary, cardiovascular, local wound, hematologic symptoms, renal, and 
nervous system sections of the SSS from baseline through Day 7 will provide a comprehensive 
measure of snakebite envenoming pathology through the first week. This outcome differs from 
the primary outcome because it includes the local wound score, which is an important 
component of snakebite envenoming pathology in both the U.S. and India. Also, by covering the 
7-day period following randomization, it will enable the assessment of benefits of varespladib on 
the resolution of toxicity in different organ systems occurring at different time points within the 
first week. 
Total antivenom administration from Baseline through Day 28 is an important secondary 
outcome. Administration of antivenom by clinicians is based on illness severity and clinical 
status over time: Patients who continue to manifest toxicity will typically receive additional 
doses. Antivenom has medical risks, including both hypersensitivity reactions and serum 
sickness. Moreover, antivenom is expensive and in many settings in both the U.S and India there 
is limited availability of antivenom (e.g., many small emergency departments in the U.S. do not 
stock antivenom). If sPLA2 inhibition with varespladib reduces the need for antivenom, that 
would indicate a more rapid improvement in the patient’s clinical condition, and be important to 
both patients and healthcare systems. 
Pain is an important clinical manifestation of snakebite envenoming. While snakes use venom 
primarily for predation and defense, venom sPLA2 toxins directly affect or potentiate the action 
of other venom toxins to activate mammalian sensory neurons and cause enhanced pain 
(Kazandjian et al., 2021). In the U.S., bites from the common venomous snake species 
(Agkistrokon spp. and Crotalus spp.) often result in severe pain. Pain is not only a cause of 
immediate suffering, pain also correlates with tissue injury and short-term disability and 
predisposes patients to persistent symptoms and delays in return to work. Evidence that 
varespladib reduces pain symptoms in humans following snakebite envenoming would provide 
important evidence of efficacy that is distinct from the primary and other key secondary 


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endpoints. 
The CGI-I provides a global summary of a patient’s improvement from the clinician’s perspective. 
This global summary has the potential to integrate information about improvements in multiple 
organ systems, which is valuable because of the complex and heterogenous pathology of snakebite 
envenoming. The investigators who are participating in the trial have extensive experience caring for 
patients bitten by venomous snakes and will be able to evaluate accurately what constitutes a 
meaningful improvement. 
4.3. 
Interim Analysis and Data Monitoring 
No interim efficacy analyses are planned. 
The data safety monitoring board (DSMB) operates under a charter that was finalized prior to the 
start of the study. The DSMB evaluates the safety data 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 stopping recruitment. If toxicity is observed, the treatment assignment for the 
subject(s) involved may be unblinded by the DSMB at its discretion. 
5. 
Analysis Populations 
The following analysis populations are planned for this study: 
 Safety Population (SAF): The Safety Population includes all subjects who receive any 
amount of IP. Subjects who are members of the SAF population will be analyzed 
according to the treatment received. This population will be used for analysis of 
demographics, baseline characteristics, and all safety analyses. 
 Intent-To-Treat Population (ITT): The ITT population includes all subjects who have 
been randomized. Subjects included in the ITT population will be analyzed as 
randomized. The ITT population will be used for analysis of demographics, baseline 
characteristics, and all efficacy analyses.* 
 Per-Protocol Population (PP): The PP population includes all subjects in the ITT 
without any significant protocol deviation. Subjects who are members of the PP 
population will be analyzed as randomized. This will be a secondary supporting 
population for the primary efficacy analyses.* 
 Pharmacokinetic Population (PK): The PK Population includes all subjects in the SAF 
Population who provide at least 1 evaluable post-dose PK measurement. Subjects who 
are members of the PK population will be analyzed according to the treatment received.* 
*Assignment of subjects to populations will be confirmed at a blinded data review meeting to be 
held before the study database is locked. 
6. 
General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 


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Prior to analyses, lab values will be standardized to consistent units. 
6.1.1. Baseline 
Observations recorded before or immediately after the first dose of treatment will be used as the 
baseline observation for all calculations of change from baseline. 
6.1.2. Adjustments for Covariates 
The comparison of the primary and secondary efficacy endpoints between the varespladib- 
methyl and placebo groups for the primary efficacy analysis will be adjusted for four variables: 
(1) baseline SSS composed of the pulmonary, cardiovascular, hematologic, renal, and nervous 
system sections treated as a continuous variable; (2) age group treated as a dichotomous variable 
(age 5-17 vs. age ≥18 years); (3) baseline neurotoxicity (SSS neurological system subscore) 
treated as a dichotomous variable (0-1 vs. ≥2); and (4) Country (U.S. vs. India). Because we 
anticipate low numbers of patients in the two pediatric age group strata, we have collapsed these 
two strata into a single group (age 5-17) for the purpose of data analysis. A sensitivity analysis 
for the primary and key secondary endpoints will include a fourth covariate: completion of the 
initial dose of antivenom prior to initiation of study drug (Yes or No). 
The mixed model for repeated measurements (MMRM) will be adjusted for baseline SSS, 
baseline neurotoxicity, age group, completion of the initial dose of antivenom prior to initiation 
of study drug, and scheduled timepoint of assessment. It will also include terms for treatment-by- 
time interaction and baseline score-by-time interaction. 
The Cox model to estimate the hazard ratios for all-cause mortality will be adjusted for baseline 
SSS, baseline neurotoxicity, age group, and completion of the initial dose of antivenom prior to 
initiation of study drug. 
6.1.3. Multiple Comparisons 
A gatekeeping or fixed-sequence procedure will be used for testing the key secondary endpoints. 
See details in Section 8.1.2. 
6.1.4. Handling of Dropouts or Missing Data 
For the primary efficacy analysis, subjects with a missing SSS at either 6- or 9- hours will be 
given an “average” SSS at 6 and 9 hours equal to the single score that is available from this time 
period. For subjects with missing SSS’s at both 6 and 9 hours, the site investigator will be asked 
to use all available contemporaneous clinical and laboratory data to determine the SSS at these 
time points. These scores will be obtained and finalized prior to database lock to ensure that 
investigators are blinded during this process. Finally, if missing data persists after the prior 
methods, then multiple imputation will be performed based on country, gender, baseline age, 
baseline SSS scores, treatment assignment, and available post-baseline SSS scores. Subscores 


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will be imputed and then the SSS score will be derived. More details on the multiple imputation 
process are provided in Section 6.1.4.1 below. 
For the first key secondary endpoint, AUC of the SSS through Day 7, for any missing data, the 
site investigators will again be asked to use all available contemporaneous clinical and laboratory 
data to determine the SSS at these time points. If data are still missing, multiple imputation will 
be used to determine missing scores and subscores based on country, baseline age, gender, 
baseline SSS scores, treatment assignment, and available post-baseline SSS scores. More details 
on the multiple imputation process are provided in Section 6.1.4.1 below. 
For the second key secondary endpoint, total antivenom administration, if the patient has 
complete data on antivenom administration through Day 3, then no change will be made to the 
total antivenom administered. This decision reflects the fact that in clinical practice in the U.S. 
and India, antivenom administration after 48 hours is uncommon. If the patient is missing data 
prior to Day 3, then the treatment of missing data will depend on the reason for missingness. If 
the patient has been discharged from the hospital, then no changes will be made to the available 
total amount of antivenom administered. If the patient has missing data prior to Day 3 and has 
not been discharged from the hospital or is transferred to another hospital, we will review each 
case and based on the patient’s SSS will determine if the patient met criteria of additional 
antivenom. If the patient did meet criteria for additional antivenom, then we will assume a single 
additional dose was given to the patient, with the number of vials in this dose corresponding to 
the standard treatment dose in the region where the patient is receiving care. 
For the third key secondary endpoint, AUC of the NPRS through Day 3, multiple imputation will 
be used to replace missing scores based on country, baseline age, gender, baseline NPRS scores, 
treatment assignment, and available post-baseline NPRS scores. More details on the multiple 
imputation process are provided in Section 6.1.4.1 below. 
 
For the fourth key secondary endpoint, CGI-I at Day 2, multiple imputation will be used to model 
missing values; with more details in Section 6.1.4.1 below. 
Individuals who cannot respond to patient-reported assessments due to severity of snakebite 
envenoming will be given a score corresponding to the worst score available in the assessment. 
Specific assessments and unable to respond scores are: 
 PSFS = 0 (Unable to perform activity) 
 PGIC =10 (Feel much worse) 
 
Grip Strength = 0 
A tipping point analysis will be conducted as a sensitivity analysis to handle missing data for the 
primary efficacy endpoint. More details are provided in Section 6.1.4.3 below. 
For the key secondary efficacy endpoints, a sensitivity analysis to handle missing data will be 
conducted only if results cannot be calculated for more than 10 study participants. In this case, 
the nature of the sensitivity analysis will be determined on review of the data. 


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6.1.4.1. 
Multiple Imputation 
The multiple imputation (MI) procedures for the primary and key secondary endpoints are 
described below. 
For the primary analysis, missing data not due to mortality, and not addressed by the averaging 
rules above, will be imputed using the following regression-based multiple imputation model. 
The following imputation algorithm will be applied to each SSS subscore separately, then the 
primary outcome SSS score will be derived. 
1. The first step is to understand the pattern of missingness. In order to perform the multiple 
imputation, a monotone missing pattern must be achieved. For example, if there exist 
values for baseline and Day 2 visits, but missing values for the Day 1 (8-10h) visit, 
Markov-Chain Monte-Carlo (MCMC) method will be used to impute the small amount of 
missing data that may be missing at the intermediate visits that is required to make the 
missing data pattern monotone before applying the multiple imputation algorithm. This 
method uses a non-informative Jeffreys prior to derive the posterior mode from the 
expectation-maximization (EM) algorithm as the starting values for the MCMC method. 
This MCMC method will use seed of 432832. To avoid values that could not be observed 
in practice, imputed values will be constrained to be integers in the range of 0 to 3 or 0 to 
4 by convention to align with the scale of the questionnaire. A total of 10 imputations 
will be done in the MCMC step. 
2. Once the monotone pattern is achieved, the next step is to implement the imputation 
algorithm. For this, the Predictive Mean Matching method (PMM) will be used. This 
method is particularly helpful if the normality assumption is violated. For subjects with 
complete data up to a particular visit, a PMM model will be fit that includes the outcome 
at that visit as the dependent variable; and as independent variables gender, treatment 
assignment, study site, and non-missing scores using a seed of 931428. This process will 
be repeated 15 times, resulting in a total of 150 complete analysis datasets. 
3. For each completed dataset, any necessary derived variables will be computed. Then the 
ANCOVA model will be performed for the 6 and 9 hour average SSS score. The results 
will be combined into one MI inference (LS mean, associated 95% CI, and p-value) using 
PROC MIANALZE as illustrated (Ratitch et al., 2013). 
The first key secondary analysis on AUC will use the same process above, except in step 3 the 
AUC will be derived for each subject in each imputed dataset, then analyzed and aggregated as 
above using PROC MIANALZE (Ratitch et al., 2013). 
The secondary key secondary analysis on antivenom amounts will not use multiple imputation. 
The third key secondary analysis on NPRS AUC will use the same process above, except in step 
3 the NPRS-AUC will be derived for each subject in each imputed dataset, then analyzed and 
aggregated as above using PROC MIANALZE (Ratitch et al., 2013). 


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The fourth key secondary analysis on CGI-I will use the same MI method described above, except 
using baseline and post-baseline CGI-I scores. 
6.1.4.2. 
SAS Code for Multiple Imputation 
See below for SAS code describing the multiple imputation approach. 
Step 1: 
proc mi data=&base._tr out=&base._mcmc seed=432832 nimpute=10 
minimum=0 maximum=&maxval. round=1; 
mcmc impute=monotone prior=jeffreys; 
em maxiter = 300; 
var visit1-visitN; 
run; 
Step 2: 
proc mi data=&base._mcmc seed=931428 nimpute=15 out=&base._pmm 
minimum=0 maximum=&maxval. round=1; 
by _imputation1_; 
class sexn trt01pn countryn; 
monotone regpmm(visit1-visitN) ; 
var sexn age trt01pn countryn visit1-visitN; 
run; 
6.1.4.3. 
Tipping Point Analysis 
A sensitivity analysis for the primary endpoint will be performed by creating a table in which each 
patient who is missing primary outcome data is represented. For each of these patients, all possible 
values for the primary outcome that go towards the null hypothesis (i.e., decreasing SSS score for 
Placebo subjects and increasing SSS scores for Varespladib-Methyl subjects) will be examined 
and the p-value for the primary efficacy endpoint will be recalculated. This analysis will show the 
range of outcomes for which the results of the primary analysis shift from significant (i.e., α ≤ 
0.05) to non-significant (i.e., α > 0.05). 
6.1.5. Analysis Visit Windows 
Statistical analyses will be based on the assessment schedule described in the protocol. 
6.1.6. Pooling of Sites 
The question of pooling of sites does not arise since study sites will not be taken into account in 
the analyses. 


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6.1.7. Derived Variables 
6.1.7.1. 
Primary Endpoint: Change in SSS from Baseline to Average at 6 and 9 hours 
The primary endpoint SSS will be calculated from responses to the pulmonary, cardiovascular, 
hematologic, renal, and nervous system sections of the SSS. The sum of the values of the 5 
subsections will be the total SSS used to calculate the primary endpoint. The primary endpoint 
will be the change from baseline to the average of the 6 hr and 9 hr scores: Change = (Baseline - 
[6hr + 9hr]/2). As such, a negative score will indicate an increase in severity from baseline 
(subject has gotten worse), and a positive score will indicate a decrease in severity from baseline 
(subject has gotten better). A subject who dies before 6 hours will receive the worst possible 
score (score = 16) to represent the SSS at 6 and 9 hrs. A subject who dies between the 6 and 9- 
hour period will receive the worst possible score (score = 16) at 9 hours, and this value will be 
averaged with the score at 6 hours for calculating the primary endpoint. 
6.1.7.2. 
SSS-AUC7d 
The AUC calculation includes the pulmonary, cardiovascular, local wound, hematologic, renal, 
and nervous system sections of the SSS assessment up to 7±1 days. The calculation will include 
the baseline assessment. All assessments within baseline and baseline + 8 days will be included 
in the calculation. This endpoint will be analyzed according to the missing data procedures 
described in Section 6.1.4 above. 
In order to standardize the duration of time for each SSS-AUC7d calculation, the “Day 7” SSS 
will be set at exactly 168 hours regardless of when it was actually assessed for this endpoint, 
with two exceptions: 
1) For patients whose “Day 7” score was assessed prior to Day 7 (prior to 144 hours) and whose 
score is higher at the “Day 14” assessment than at the “Day 7” assessment, we will linearly 
interpolate between the “Day 7” and “Day 14” scores to impute the score at 168 hours. 
2) For patients whose “Day 7” occurs on Day 10 or later (240 hours), we will linearly interpolate 
between “Day 3” and “Day 7” to impute the score at 168 hours. 
The AUC will be calculated using the trapezoidal rule: average the SSS scores between two 
adjacent timepoints, multiply by the difference in time points in hours, repeating this across all 
time points and summing the results to obtain the total AUC across a fixed range of time. Thus 
the AUC at a particular timepoint j is calculated as follows. 
 
AUC𝑗= 1
2 (𝑆𝑆𝑆𝑗+ 𝑆𝑆𝑆𝑗−1)(𝑡𝑗−𝑡𝑗−1) 
where 𝑡 is measured in hours; 𝑗 = 1, … , 𝐽; and 𝐽 is the total number of timepoints at which SSS is 
measured. 𝐽 = 6 if all planned SSS assessments are performed. Thus the total AUC for subject 𝑖 
from baseline to Day 7 is as follows. 


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AUC𝑖,BL to Day 7 = 1
2 ∑(SSS𝑖,𝑗+ SSS𝑖,𝑗−1)
𝐽
𝑗=1
(𝑡𝑖,𝑗−𝑡𝑖,𝑗−1) 
Thus AUC is calculated for each subject with baseline and post-baseline SSS scores, subject to 
the constraints on missingness described above. An example of this applied in SAS is provided at 
lexjansen.com/wuss/2004/posters/c_post_the_sas_calcuations_.pdf 
• where:The SSS assessments SSS0, SSS1, … , SSSJ are made at times 𝑡0, … , 𝑡𝐽 
• 𝑡0 is the time of the initiation of the IV infusion 
• SSS0 is the SSS assessment at baseline 
• 𝑡𝑗 is the 𝑗th timepoint at which SSS is assessed such that 𝑡𝐽 − 𝑡0 ≤ 7 day 
6.1.7.3. 
NPRS-AUC3d  
The calculation will include all assessments from baseline to Day 3. The procedures for dealing 
with missing data are described in Section 6.1.4. See section 6.1.7.14 for definitions of Day 1, 
Day 2, and Day 3. 
In order to standardize the duration of time for each NPRS-AUC3d calculation, the “Day 3” 
NPRS will be set at exactly 48 hours regardless of when it was actually assessed for this 
endpoint, with two exceptions: 
1) For patients whose “Day 3” score was assessed prior to Day 3 (prior to 36 hours) and whose 
score is higher at the “Day 7” assessment than at the “Day 3” assessment, we will linearly 
interpolate between the “Day 3” and “Day 7” scores to impute the score at 48 hours. 
2) For patients whose “Day 3” occurs more than 12 hours after 48 hours (60 hours), we will 
linearly interpolate between “Day 2” and “Day 3” to impute the score at 48 hours. 
The AUC will be calculated using the trapezoidal rule: average the NPRS scores between two 
adjacent timepoints, multiply by the difference in time points in hours, repeating this across all 
time points and summing the results to obtain the total AUC across a fixed range of time. Thus 
the AUC at a particular timepoint j is calculated as follows. 
 
AUC𝑗= 1
2 (NPRS𝑗+ NPRS𝑗−1)(𝑡𝑗−𝑡𝑗−1 ) 
where 𝑡 is measured in hours; 𝑗 = 1, … , 𝐽; and 𝐽 is the total number of timepoints at which NPRS 
is measured. 𝐽 = 5 if all planned NPRS assessments are performed. Thus the total AUC for 
subject 𝑖 from baseline to Day 3 is as follows. 
 


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AUC𝑖,BL to Day 3 = 1
2 ∑(NPRS𝑖,𝑗+ NPRS𝑖,𝑗−1)
𝐽
𝑗=1
(𝑡𝑖,𝑗−𝑡𝑖,𝑗−1)  
Thus AUC is calculated for each subject with baseline and post-baseline NPRS scores, subject to 
the constraints on missingness described above.  
6.1.7.4. 
Complete SSS 
The complete SSS will be calculated from responses to all system sections of the SSS. The sum 
of the values of the 7 subsections will be the total SSS used to calculate the total complete SSS 
score. 
6.1.7.5. 
Coagulation Abnormalities 
Coagulation laboratory values (PT, PTT, platelets, and fibrinogen) will each be analyzed separately. For 
these analyses, each value at each time point will be categorized following the criteria established in the 
Snakebite Severity Score (Dart et al., 1996). Additional details are provided in Section 8.2.3. 
6.1.7.6. 
Hemolysis 
The assessment of hemolysis will be based on free hemoglobin concentration (mg/dL), which 
will be treated as a continuous variable. 
6.1.7.7. 
Antivenom Administered 
The amount of antivenom administered will be categorized into three groups: low, medium, and 
high. The relevant value for these categorizations will be the total vials of antivenom given to the 
patient for which the treatment was initiated after the receipt of study drug. (Antivenom given to 
patients before the receipt of study drug will not be included in this total.) The categorizations 
are defined below, separately for each of the major types of antivenom: 
India Polyvalent Antivenom (includes all antivenom given to participants in India)  
Low: 0 vials 
Med: >0 to 10 vials 
High: >10 vials 
CroFab 
Low: 0 vials 
Med: >0 to 6 vials 
High: >6 vials 
ANAVIP  
Low: 0 vials 
Med: >0 to 10 vials 


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High: >10 vials 
6.1.7.8. 
Time from Initiation of Ventilatory Support to Initiation of Weaning 
The total time from initiation of ventilatory support to initiation of weaning will be calculated in 
hours. Subsequent re-intubations will not be included in this calculation. 
6.1.7.9. 
Duration of Ventilatory Support 
The duration (hours) of ventilatory support for primary neurotoxic envenoming will be 
calculated as the total duration of mechanical (ventilator) or manual (bag valve mask) methods 
used to assist or replace spontaneous respiration. If a subject is reintubated one or more times, 
these additional periods of ventilatory support (from initiation of ventilatory support to 
extubation or removal or ventilatory support) will be included as part of the total time. 
∑ 
(𝑡𝑖𝑚𝑒 𝑜𝑓 𝑟𝑒𝑚𝑜𝑣𝑎𝑙 𝑜𝑓 𝑠𝑢𝑝𝑝𝑜𝑟𝑡 − 𝑡𝑖𝑚𝑒 𝑜𝑓 𝑖𝑛𝑖𝑡𝑖𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑠𝑢𝑝𝑝𝑜𝑟𝑡) 
𝑓𝑜𝑟 𝑒𝑎𝑐ℎ 𝑣𝑒𝑛𝑡𝑖𝑙𝑎𝑡𝑖𝑜𝑛 
6.1.7.10. 
Duration of ICU Stay 
The length of ICU stay from baseline to Day 28 will be calculated using the following duration 
in hours 
∑ 
(𝐼𝐶𝑈 𝑑𝑖𝑠𝑐ℎ𝑎𝑟𝑔𝑒 𝑑𝑎𝑡𝑒 𝑎𝑛𝑑 𝑡𝑖𝑚𝑒 − 𝐼𝐶𝑈 𝑎𝑑𝑚𝑖𝑠𝑠𝑖𝑜𝑛 𝑑𝑎𝑡𝑒 𝑎𝑛𝑑 𝑡𝑖𝑚𝑒) 
𝑓𝑜𝑟 𝑒𝑎𝑐ℎ 𝑒𝑝𝑖𝑠𝑜𝑑𝑒 
The duration of ICU stay will be truncated at Day 28. If a discharge date and time is after Day 
28, it will be replaced by Day 28. 
6.1.7.11. 
Duration of hospitalization 
The length of hospital stay from baseline to Day 28 will be calculated using the following 
duration in hours 
∑ 
(𝑑𝑖𝑠𝑐ℎ𝑎𝑟𝑔𝑒 𝑑𝑎𝑡𝑒 𝑎𝑛𝑑 𝑡𝑖𝑚𝑒 − 𝑎𝑑𝑚𝑖𝑠𝑠𝑖𝑜𝑛 𝑑𝑎𝑡𝑒 𝑎𝑛𝑑 𝑡𝑖𝑚𝑒) 
𝑓𝑜𝑟 𝑒𝑎𝑐ℎ 𝑎𝑑𝑚𝑖𝑠𝑠𝑖𝑜𝑛 
The duration of hospitalization will be truncated at Day 28. If a discharge date and time is after 
Day 28, it will be replaced by Day 28. 
6.1.7.12. 
Treatment-Emergent Adverse Event 
Treatment-emergent AEs are defined as AEs that first occur or worsen in severity after the first 
dose of IP and prior to 30 days after last administration of IP. 
Where an AE start date/time or end date/time is partially or fully missing, and it is unclear as to 


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whether the AE is a TEAE, it will be assumed that it is TEAE. 
6.1.7.13. 
Percent of Study Medication Compliance 
The percent of study medication compliance will be calculated as follows: 
100 ∗
∑
Number of oral doses dispended at visit (𝑖−1) −Number of oral doses returned at visit 𝑖
Number of oral doses that the subject was instructed to take from visit (𝑖−1) to visit 𝑖
𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡
𝑖=2
 
where the denominator is greater than zero. 
6.1.7.14. 
 SSS Score using Compressed SSS Scale 
The compressed SSS will be calculated by first subtracting 1 from non-zero responses to the 
pulmonary, cardiovascular, hematologic, renal, and nervous system sections of the SSS. The sum of 
the adjusted values of the 5 subsections will be the total SSS used to calculate the compressed score. 
The endpoint will be the change from baseline through Day 7 compressed scores: Change = Baseline – 
Score (at each time).   
6.1.7.15. 
Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
Day 1 will refer to activities that occurred at baseline through the first 12 hours after the patient 
receives the study drug (regardless of whether the calendar day has changed). Day 2 assessments 
will occur at least 12 hours and not more than 18 hours after the 8-10 hour assessment on Day 1. 
Thereafter, Day will refer to calendar day following the initiation of treatment (e.g., Day 28 will 
occur 27 days after the day on which the patient received their first dose of study drug). 
P values will be displayed with two significant figures if the value is greater than or equal to 0.01 
(eg., 0.XX) and with one significant figure is less than 0.01 (eg., 0.00X). If a P value less than 
0.0001 occurs, it will be shown in tables as < 0.0001. 
Adverse events will be coded using the latest MedDRA version thesaurus. 
6.1.8. COVID-19 
The potential impact of COVID-19 on this clinical trial and trial participants will be described in 
listings and in the CSR. 
The following aspects will be summarized when protocol deviations are due to COVID-19 
infection or restriction: 
 Changes to treatment dispensation 
 Changes to treatment administration 
 Changes to visit windows to accommodate delays for some assessments 


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 Missing efficacy endpoints 
 Missing visits 
7. 
Study Subjects and Demographics 
7.1. 
Disposition of Subjects and Withdrawals 
Disposition will include tabulations by treatment group and overall: 
 the number of subjects randomized into each treatment group 
 the number of subjects who received treatment 
 the number of subjects who received the entire course of treatment 
 the number of subjects completing the study 
 tabulated reasons for discontinuation from the study 
 and number of subjects in each analysis population. 
The total number of (1) screening failures and (2) withdrawals prior to receipt of study drug and 
the reasons for screen failure and withdrawals prior to receipt of study drug will be presented in 
separate tables. 
7.2. 
Protocol Violations and Deviations 
A by-subject listing of protocol deviations will be presented. Protocol deviations will also be 
reported by major vs. minor status. Protocol deviations classified as important will be re- 
classified as major; protocol deviations classified as non-important will be re-classified as minor. 
7.3. 
Demographics and Other Baseline Characteristics 
These analyses will be conducted for the ITT and SAF populations. 
Summary statistics for age, gender, race, ethnicity, height, and weight will be presented by 
treatment group. 
The envenoming history, including the anatomic location of envenoming, initial swelling, snake 
identification, key toxicities as measured in Baseline SSS subscores, and tourniquet use will be 
summarized by treatment group. If obtained, results of the 20WBCT will also be summarized by 
treatment group. 
The number and percent of subjects reporting various medical histories, grouped by MedDRA 
system organ class and preferred term, will be tabulated by treatment group. 
7.4. 
Exposure and Compliance 
IP exposure and dosing information including the number of doses per subjects and amount of IP 
received will be tabulated by treatment arm and age group. 
For each treatment, IP compliance will be summarized by compliance category (≤ 80%, 80- 
120%, ≥ 120%) and the number of subjects in each compliance category. Study medication 
compliance will also be summarized as a continuous variable using descriptive statistics. This 


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analysis will be conducted for the SAF population. 
8. 
Efficacy Analysis 
8.1. 
Primary Efficacy Analysis 
8.1.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in the composite outcome of the pulmonary, 
cardiovascular, hematologic, renal, and nervous system sections of the snakebite severity score 
(SSS) from Baseline (pre-dosing) to the average of the scores from 6 and 9 hours after first dose: 
Change = (Baseline – [6hr + 9hr]/2). 
The ITT population will be used to analyze the primary efficacy endpoint. For completeness the 
analyses will be repeated for the PP population. 
Descriptive statistics for the SSS as well as the 6hr and 9hr mean scores will be tabulated by 
treatment group. 
The primary analysis will use ANCOVA. A sensitivity analysis will use rank-regression 
applying the same adjustment covariates as specified in the ANCOVA. To better understand the 
appropriateness of applying a parametric vs. nonparametric approach, the CSR will include 
diagnostics plots of ANCOVA residuals. 
The change from baseline to the average of the 6hr and 9hr scores will be compared between 
treatment groups using an ANCOVA with the baseline SSS score, subject age group, the 
presence or absence of baseline neurotoxic symptoms, and country as covariates. The 
varespladib-methyl to placebo (varespladib-methyl vs. placebo) will be compared at the 5% two- 
sided significance level; corresponding 95% two-sided confidence interval for the difference will 
be presented. 
Six sets of subgroup analyses will be performed: (1) patient age, (2) baseline neurotoxic 
symptoms, (3) prior receipt of antivenom, (4) country, (5) snake type, and (6) timing of receipt of 
study drug. The following paragraphs describe these six sets of subgroup analyses. 
1. Patient age. Summary statistics, including baseline SSS and least square means from the 
ANCOVA, will be presented separately for pediatric (5 to 17 years) and adult (≥18 years) 
subjects. If the study includes too few children to fit an ANCOVA, only summary statistics will 
be presented. 
2. 
Baseline neurotoxic symptoms. The treatment effect will be estimated in subjects with and 
without moderate or severe neurotoxic symptoms at baseline (SSS nervous system score of 0-1 
vs. 2-3). These analyses will be analogous to those described for the pediatric and adult subgroup 
analyses, except that the ANCOVA will include age group, but not neurotoxicity. 
3. 
Prior receipt of antivenom. The treatment effect will be estimated separately in subjects who 
have and have not completed an initial dose of antivenom prior to initiation of study drug. These 
analyses will be analogous to those described for the pediatric and adult subgroup analyses, except 
that the ANCOVA will include age group but not receipt of antivenom prior to initiation of study 


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drug. 
4. 
Country. The treatment effect will be estimated in separately in subjects enrolled in the U.S. 
and those enrolled in India. These analyses will be analogous to those described for the pediatric and 
adult subgroup analyses, except that the ANCOVA will include age group but not country. 
5. 
Snake type. The treatment effect will be estimated separately in subjects bitten by vipers, 
elapids, and unknow snake types. These analyses will be analogous to those described for the 
pediatric and adult subgroup analyses, except that the ANCOVA will include age group. 
6. 
Timing of receipt of study drug. The treatment effect will be estimated separately in subjects 
for whom the time from bite or symptom onset to receipt of study drug was <5 hours and >5 
hours. These analyses will be analogous to those described for the pediatric and adult subgroup 
analyses, except that the ANCOVA will include age group. 
There will be several sensitivity analyses. 
Sensitivity analysis will be conducted for the primary efficacy analysis (1) adding completion of 
the initial dose of antivenom prior to the initiation of study drug as a covariate and (2) using a 
compressed SSS as the outcome and applying the same analytic methods as described above. A 
separate set of analyses will estimate the effect of treatment on individual component subscores 
of the SSS. 
Other sensitivity analyses will estimate the treatment effect on the primary endpoint excluding 
data from one site at a time. For this analysis, data from sites that enrolled 10 patients or fewer 
will be combined and excluded as a single group. The purpose of this sensitivity analysis is to 
assess whether data from any single site has an outsized effect on the estimated treatment effect 
of the primary endpoint. 
Another sensitivity analysis will apply the tipping point approach described in Section 6.1.4.3. 
Sensitivity and subgroups analyses of the primary and key secondary endpoints will not be part 
of the gatekeeping procedure for hierarchical testing of endpoints. 
8.1.2. Key Secondary Efficacy Endpoints 
The ITT population will be used to analyze the secondary efficacy endpoints. All secondary 
endpoints will be analyzed using the prespecified assessment timepoints according to the 
protocol. All statistical models for change from baseline in a particular endpoint will include 
covariates for baseline value of the particular endpoint, baseline SSS, baseline neurotoxicity 
(Yes, No; based on the SSS neurological system subscore), age group (5-17, 18+), and country 
(U.S. vs. India). Key secondary endpoints will be tested sequentially using a fixed-sequence 
gatekeeping procedure for the hierarchical testing of multiple endpoints. The significance of the 
treatment effect for the primary endpoint (i.e., change in SSS from baseline to average at 6 and 9 
hours) will be the first hypothesis tested, using a significance level of 0.05. If the null hypothesis 
for the primary endpoint is rejected, then the first key secondary endpoint (i.e., AUC of SSS 
through Day 7) will be tested, also with a significance level of 0.05. If the null hypothesis for this 
test is rejected, the second key secondary endpoint (total antivenom use) will be tested (α=0.05). 


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If the null hypothesis for this test is rejected, the third key secondary endpoint (AUC of NPRS 
through Day 3) will be tested (α=0.05). If the null hypothesis for this test is rejected, the fourth 
key secondary endpoint (CGI-I at Day 2) will be tested (α=0.05). Sensitivity and subgroups 
analyses of the primary and key secondary endpoints will not be part of the gatekeeping 
procedure for hierarchical testing of endpoints. 
8.1.2.1. 
AUC of the Pulmonary, Cardiovascular, Local Wound, Hematologic Symptoms, 
Renal, and Nervous System Sections of the SSS from Baseline Through Day 7 
The SSS-AUC7d will be compared between treatment groups within an ANCOVA model with 
the baseline SSS score, age group (5 to 17 years, ≥ 18 years), baseline neurotoxicity, and country 
as covariates. The comparison of varespladib-methyl to placebo (varespladib-methyl vs. placebo) 
will be tested at a 5% two-sided significance level; the corresponding 95% two-sided confidence 
intervals will be presented. The AUC will be calculated according to Section 6.1.7.2. Also note 
that this SSS score is calculated only using the pulmonary, cardiovascular, local wound, 
hematologic, renal, and nervous system subscores. A reduction in SSS-AUC (i.e., negative 
parameter estimate) will represent a faster improvement in snake bite symptoms on average. 
Individual subscore AUCs by treatment group will also be summarized using descriptive 
statistics. Subgroup analyses will estimate the treatment effect separately for pediatric and adult 
patients, for patients with and without clinically significant neurotoxicity, for patient who have 
and have not completed an initial dose of antivenom prior to randomization, for the U.S. and for 
India, for each snake type (viper, elapid, and unknown), and for patients for whom the time from 
bite or symptom onset to receipt of study drug was <5 hours and ≥5 hours. 
8.1.2.2. 
Total Differential Antivenom Requirement from Baseline through Day 28 
The total number of vials of antivenom administered will be analyzed using a proportional odds 
logistic regression with three ordered categories. For each type of antivenom administered, the 
number of vials of antivenom from baseline through Day 28 will be categorized as low, medium, 
or high. Cutoffs for these categories are based on recommendations regarding treatment for each 
antivenom type as well as a review of available blinded data. 
 
India Polyvalent Antivenom (all antivenom administered in India) 
 
Low: 0 vials 
 
Medium: > 0 to 10 vials 
 
High: > 10 vials 
CroFab 
 
 
Low: 0 vials 
 
Medium: > 0 to 6 vials 
 
High: > 6 vials 


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ANAVIP 
 
Low: 0 vials 
 
Medium: > 0 to 10 vials 
 
High: > 10 vials 
This model will use the following covariates: baseline SSS score, age group (5 to 17 years, ≥ 18 
years), baseline neurotoxicity, receipt of antivenom prior to baseline (Yes, No), and country.  The 
treatment effect will be summarized with an estimated odds ratio. The comparison of varespladib-
methyl to placebo (varespladib-methyl vs. placebo) will be tested at a 5% two-sided significance 
level; the corresponding 95% two-sided confidence intervals will be presented.  Subgroup analyses 
will estimate the treatment effect separately for pediatric and adult patients, for patients with and 
without clinically significant neurotoxicity, for patient who have and have not completed an initial 
dose of antivenom prior to randomization, for the U.S. and for India, for each snake type (viper, 
elapid, and unknown), and for patients for whom the time from bite or symptom onset to receipt of 
study drug was <5 hours and ≥5 hours.  
 
As an analysis of model fit, the assumption of proportional odds will be tested. An exploratory 
analysis will calculate a binomial logistic regression model collapsing the medium and high 
antivenom categories into a single category. The dependent variable will be either “low” or “medium 
or high” antivenom use. The model will use the same set of covariates described above. 
 
8.1.2.3. 
AUC of the NPRS from Baseline Through Day 3 
An ANOCVA will be used to compare the NPRS-AUC3d for the two treatment groups with 
baseline NPRS score, age group (5 to 17 years, ≥ 18 years), baseline neurotoxicity, and country 
as covariates. The comparison of varespladib-methyl to placebo (varespladib-methyl vs. placebo) 
will be tested at a 5% two-sided significance level; the corresponding 95% two-sided confidence 
interval will be presented. The AUC will be calculated according to Section 6.1.7.3. A reduction 
in NPRS-AUC (i.e., negative parameter estimate) will represent a faster average improvement in 
pain symptoms. Subgroup analyses will estimate the treatment effect separately for pediatric and 
adult patients, for patients with and without clinically significant neurotoxicity, for patient who 
have and have not completed an initial dose of antivenom prior to randomization, for the U.S. 
and for India, for each snake type (viper, elapid, and unknown), and for patients for whom the 
time from bite or symptom onset to receipt of study drug was <5 hours and ≥5 hours. 
8.1.2.4. 
Clinical Global Impression – Improvement (CGI-I) at Day 2 
CGI-I (1-7 scale) at Day 2 will be treated as a continuous variable with scores compared using 
ANCOVA, with treatment as the variable of interest, and with baseline SSS, age group, baseline 
CGI-I score, baseline neurotoxicity, and country as covariates. The model will be used to 
estimate the effect of treatment on CGI-I scores at Day 2. The comparison of varespladib-methyl 
to placebo (varespladib-methyl vs. placebo) will be tested at a 5% two-sided significance level; 


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the corresponding p-value and 95% two-sided confidence intervals will be presented. 
A sensitivity analysis will add completion of initial dose of antivenom prior to initiation of study 
drug as a covariate. Subgroup analyses will estimate the treatment effect separately for pediatric 
and adult patients, for patients with and without clinically significant neurotoxicity, for patient 
who have and have not completed an initial dose of antivenom prior to randomization, for the 
U.S. and for India, for each snake type (viper, elapid, and unknown), and for patients for whom 
the time from bite or symptom onset to receipt of study drug was <5 hours and ≥5 hours. 
8.1.3. SAS Code for Primary and Key Secondary Efficacy Endpoints 
Sample SAS code is provided below for these analyses using standard ADaM terminology; 
where TRT01PN is a numeric treatment group variable (0,1), AGEGR2BL is the two-group age 
strata (5 to 11 years, 12 to 17 years), NEUROBL is the indicator variable for baseline 
neurotoxicity (No, Yes), and ANTIVBLG is a three-group categorical variable for type of 
antivenom prior to baseline (Indian Polyvalents, CroFab, and ANAVIP). Note that PROC 
MIXED reduces to ANCOVA when no REPEATED statement is used. The LSMEANS option 
within will provide the treatment effect estimates of interest. 
Primary Efficacy Endpoint 
Proc univariate data=ADEFF; /*visually inspect distribution*/ 
Where PARAM=”Primary Outcome SSS Score”; 
Class AVISIT; 
Var CHG; 
Histogram; 
Run; 
Proc mixed data=ADMI plots=studentpanel alpha=0.05; 
By _imputation_; 
Where PARAM=”Primary Outcome SSS Score” and AVISIT=”Average of 6 and 
9 hours”; 
Class TRT01PN(ref=’0’) AGEGR2BL(ref=’5 to 11 years’) 
NEUROBL(ref=’No’) COUNTRY(ref=’India’); 
model CHG = BASE TRT01PN AGEGR2BL NEUROBL COUNTRY; 
lsmeans TRT01PN / cl pdiff; 
run; 
proc mianalyze data=Estimates alpha=0.05; 
modeleffects estimate; 
stderr StdErr; 
run; 
/*code for sensitivity analyses using initial antivenom dose as a 
covariate, compressed SSS score, and component subscores are similar*/ 
Key Secondary Efficacy Endpoint #1, SSS-AUC 
Proc mixed data=ADMI alpha=0.05; 
By _imputation_; 
Where PARAM=”Primary Outcome SSS-AUC through Day 7” and AVISIT=”Day 
7”; 


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Class TRT01PN(ref=’0’) AGEGR2BL(ref=’5 to 11 
years’) NEUROBL(ref=’No’) COUNTRY(ref=’India’); 
model AVAL = TRT01PN SSSBL AGEGR2BL NEUROBL COUNTRY; 
lsmeans TRT01PN / cl pdiff; 
run; 
proc mianalyze data=Estimates alpha=0.05; 
modeleffects estimate; 
stderr StdErr; 
run; 
 
Key Secondary Efficacy Endpoint #2, Antivenom 
proc logistic data = adeff descending; 
where paramcd = 'ANTIVG'; 
class TRT01PN(ref = '2') AGEGR2BL(ref = '5 to 17 years') 
NEUROBL(ref = 'N') ANTIVBL(ref = 'N') COUNTRY(ref=’India’) 
/param = ref; 
model AVALC = TRT01PN SSSBL AGEGR2BL NEUROBL ANTIVBL COUNTRY / 
link = clogit aggregate scale = none; 
run; 
Key Secondary Efficay Endpoint #3, NPRS-AUC 
Proc mixed data=ADMI alpha=0.05; 
By _imputation_; 
Where PARAM=” NPRS-AUC through Day 3 - MI” and AVISIT=”Day 3”; 
Class TRT01PN(ref=’0’) AGEGR2BL(ref=’5 to 11 
years’) NEUROBL(ref=’No’) COUNTRY(ref=’India’); 
model AVAL = TRT01PN SSSBL AGEGR2BL NEUROBL COUNTRY; 
lsmeans TRT01PN / cl pdiff; 
run; 
proc mianalyze data=Estimates alpha=0.05; 
modeleffects estimate; 
stderr StdErr; 
run; 
Key Secondary Efficay Endpoint #4, CGI-I 
Proc mixed data=ADMI alpha=0.05; 
Where PARAM=”CGI-I Score” and AVISIT=”Day 2”; 
Class TRT01PN(ref=’0’) AGEGR2BL(ref=’5 to 11 years’) 
NEUROBL(ref=’No’) COUNTRY(ref=’India’); 
Model AVAL = TRT01PN SSSBL AGEGR2BL NEUROBL COUNTRY; 
lsmeans TRT01PN / cl pdiff; 
run; 
proc mianalyze data=Estimates alpha=0.05; 
modeleffects estimate; 
stderr StdErr; 
run; 


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8.2. 
Other Secondary Efficacy Analyses 
The other secondary efficacy analyses will be interpreted as exploratory analyses. All secondary 
endpoints will be analyzed according to the prespecified assessment timepoints listed in the 
protocol. Statistical models will include covariates for baseline SSS, baseline neurotoxicity (Yes, 
No; based on the SSS neurological system subscore), age group (5-17, 18+), and, when 
available, the baseline value of the particular endpoint unless otherwise specified below. A 
sensitivity analysis will include as a covariate yes/no completion of an initial dose of antivenom 
prior to randomization. The methods described here are what is currently planned. However, for 
each analysis, we will examine the distribution of the strata pooled over treatment and placebo. If 
the data are unlikely to support the planned analysis or if the model fails to converge, removal of 
covariates and different estimation routines will be attempted and described in the CSR. 
8.2.1. Complete SSS from Baseline through Day 7 
The complete SSS (all sub-sections including pulmonary, cardiovascular, hematologic, renal, 
nervous system, gastrointestinal, and local wound) from baseline through Day 7 after first dose 
will be summarized using descriptive statistics of observed values and changes from baseline. 
The post baseline complete SSS scores at each time point will be analyzed, without replacement 
of missing values, using a restricted maximum likelihood (REML) based repeated measures 
approach (MMRM). Analyses will include a random intercept and the fixed effects of treatment, 
baseline total SSS, age group (5-17 years, ≥ 18 years), baseline neurotoxicity, and visit 
(categorical) as covariates. The model will include a treatment-by-time interaction. An 
unstructured covariance model will be used to model the within-subject errors. The Kenward- 
Roger approximation will be used to estimate denominator degrees of freedom. If this analysis 
fails to converge, simpler structures (e.g., first-order compound symmetry and then 
autoregressive order-1 structures) will be tested in a model without treatment effect; the 
covariance structure and the degree of freedom approximation converging to the best fit, as 
determined by Akaike’s Information Criterion, will be used in the full model. A description of all 
tested models and results from these models will be provided as an appendix in the CSR. Within 
this model, the estimate of interest is the effect of treatment at each time point, performed at 
significance level of 5%. The corresponding 95% two-sided confidence intervals will be 
presented at each time point of assessment. 
8.2.2. SSS Neurologic System Subscore from Baseline through Day 3 
The SSS neurologic system subscore from baseline through Day 3 after first dose will be 
summarized using descriptive statistics of observed values and changes from baseline. The SSS 
neurologic system subscore will be analyzed with a similar MMRM as the one described in 
Section 8.2.1. The MMRM will be used to assess the treatment effect on change in SSS 
neurologic system subscore through Day 3. The MMRM will include treatment as fixed effect as 
the variable of interest, with visit and visit by treatment interaction as covariates. The model will 
be used to estimate the effect of treatment on SSS neurologic subscore at each assessment time 


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point through Day 3. Treatment effect will be summarized via LS means, p-values, and 95% two-
sided confidence intervals.  
This analysis will be conducted in two groups of patients: (1) subjects with a baseline SSS 
neurologic system subscore ≥1; and (2) subjects with a baseline SSS neurologic system subscore 
≥2. 
Note: The effect of varespladib on neurotoxicity is supported by the observation that varespladib 
prevents, reverses, or delays lethality from venom neurotoxicity in animals experimentally 
envenomed with Mojave rattlesnake, coral snake, krait, and taipan venoms even when administered 
at a point when weakness is refractory to antivenom reversal (e.g., Prasarnpun 2005; Anil et al. 2010; 
Lewin et al. 2018a, 2018b; and Gutierrez et al. 2021). Neurologic outcomes were not selected as the 
focus of the primary or key secondary efficacy endpoints because of the unexpectedly small number 
of severely neurotoxic patients enrolled in the trial. 
8.2.3. Coagulation Abnormalities from Baseline through Day 7 
Each of the four coagulation lab values (PT, PTT, platelets, and fibrinogen) will be analyzed 
using a proportional odds logistic regression with five ordered categories. Categories for the lab 
values in each of these analyses will use those defined by the Snakebite Severity Score (Dart et 
al. 1996), with normal lab values receiving a score of 0 and abnormal lab values receiving a 
score of 1 to 4 based on the following published cutoffs.  
Coagulation 
Parameter 
0 
1 
2 
3 
4 
Units 
Prothrombin 
Lab 
Above lab 
>20 to 50 
>50 to 100 
Unmeasureable 
Sec 
Time 
validated 
ref range to 
sec 
sec 
or above 100 sec 
reference 
20 sec 
range 
Partial 
Thromboplastin 
Time 
Lab 
validated 
reference 
range 
Above lab 
ref range to 
50 sec 
>50 to 75 
sec 
>75 to 100 
sec 
Unmeasureable 
or above 100 sec 
Sec 
Platelet count 
Lab 
validated 
reference 
range 
100,000 to 
ref 
50,000 to 
<100,000K 
20,000 to 
<50,000 
Less than 20,000 
/mL 
Fibrinogen 
Lab 
validated 
reference 
range 
100 to ref 
50 to <100 Less than 50 
Undetectable 
mg/dL 


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Analysis for each of the four coagulation parameters will be run separately for each time point 
from Day 1 3 hours to Day 7. The models will use the following covariates: baseline SSS score, 
age group (5 to 17 years, ≥ 18 years), baseline neurotoxicity, receipt of antivenom prior to 
baseline (Yes, No), and country. The treatment effect will be summarized  with an estimated odds  
ratio and tested at a 5% two-sided significance level; the corresponding 95% two-sided 
confidence intervals will be presented. These analysis will only include subjects with lab value-
specific coagulation abnormalities (hematology subscore ≥1 as derived from the relevant 
coagulation lab value) at baseline. 
8.2.4. Hemolysis Markers at Baseline through Day 3 
Concentrations of free hemoglobin through Day 3 will be presented using graphs and summary 
statistics by treatment arm and time points. 
An MMRM approach as described in Section 8.2.1 will be used to assess the treatment effect on 
change in free hemoglobin (continuous variable) through Day 3. The MMRM will include 
treatment as fixed effect, baseline SSS, age group, baseline free hemoglobin, baseline 
neurotoxicity, visit, and visit by treatment interaction as covariates. The model will be used to 
estimate the effect of treatment on hemolysis at each assessment time point through Day 3. 
Treatment effect will be summarized by LS means, p-values, and 95% two-sided confidence 
intervals. 
Only subjects with hemolysis at baseline (free hemoglobin ≥ 15 mg/dL) will be included in this 
analysis. Additional analyses will examine the effect of treatment on other indicators of 
hemolysis including LDH and haptoglobin. 
8.2.5. Levels of the Myonecrosis Marker (CK) from Baseline Through Day 3 
Absolute value and change from baseline of creatine kinase (U/L) will be presented in graphs 
and summarized descriptively by treatment at baseline through Day 3. 
An MMRM approach as described in Section 8.2.1 will be used to assess the effect of treatment 
on change in CK through Day 3. The MMRM will include treatment as a fixed effect as the 
variable of interest, with baseline CK, baseline neurotoxicity, age group, visit, and visit by 
treatment interaction as covariates. The model will be used to estimate the effect of treatment on 
myonecrosis at each assessment time point through Day 3. Treatment effect will be summarized 
by LS means, p-values, and 95% two-sided confidence intervals. 
Only subjects with CK ≥ 2x institutional reference range at baseline will be included in this 
analysis. 
8.2.6. NPRS Score in Subjects Able to Respond from Baseline through Day 28 


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The absolute values and change of NPRS will be tabulated by treatment arm and visit. An 
MMRM approach as described in Section 8.2.1 will be used to assess the treatment effect on 
NPRS scores through Day 28. The MMRM will include the fixed effect of treatment as the 
variable of interest, with the baseline NPRS, baseline SSS, age group, baseline neurotoxicity, and 
visit, and visit by treatment interaction as covariates. 
8.2.7. Kidney Function Markers from Baseline through Day 28 
Descriptive summaries of absolute value and change from the baseline of kidney function 
markers (i.e., creatine) will be tabulated by treatment group and visit. The mean change from 
baseline through Day 28 will be compared between treatment arm using an MMRM. The 
MMRM will include treatment as fixed effect as the variable of interest, with the baseline SSS, 
baseline kidney function measure, age group, baseline neurotoxicity, and visit, and visit by 
treatment interaction as covariates. The model will be used to estimate the effect of treatment on 
kidney function at each assessment time point through Day 28. Treatment effect will be 
summarized by LS means, p-values, and 95% two-sided confidence intervals. 
Only subjects with a creatinine ≥ 2x the upper limit of normal at baseline will be included in the 
analysis. 
8.2.8. Head-Lift Duration through Day 7 
The number and proportion of subjects who are able to hold their head up for 5 seconds will be 
tabulated by treatment arm and visit. 
A logistic generalized linear mixed model will be used to analyze the change from baseline to 
Day 7. Analyses will include the fixed effect of treatment as the covariate of interest, with 
baseline head-lift duration, age group, baseline neurotoxicity, visit (categorical), and visit by 
treatment interaction as covariates. The model will be used to estimate the effect of treatment on 
head-lift duration at each assessment time point through Day 7. LS means at each assessment 
time point will be calculated and tabulated from the model. 
Only subjects with an SSS nervous system subscore ≥ 2 at baseline will be included in the 
analysis. 
8.2.9. Total Duration of Ventilatory Support from Baseline through Day 28 
The number and percent of subjects who need ventilatory support and the duration of time from 
initiation of ventilatory support to initiation of weaning will be tabulated by treatment arm. The 
time from initiation of ventilatory support to initiation of weaning will be compared using the 
Wilcoxon Rank Sum Test. 
If the number of patients receiving ventilatory support is less than 5, this outcome will be 
reported descriptively. 


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8.2.10. Total Duration of ICU Stay from Baseline through Day 28 
Duration of ICU stay through 28 days post-baseline will be summarized by treatment arm. 
Duration will be measured in days. 
The duration of ICU stay will be compared between treatment groups using the Wilcoxon Rank 
Sum Test. 
If fewer than five patients report ICU stay, this outcome will be reported descriptively. 
8.2.11. Total Duration of Hospitalization from Baseline through Day 28 
Duration of hospitalization through 28 days post-baseline will be summarized by treatment arm 
separately for the United States and India, recognizing the anticipated differences in the typical 
duration of hospital stay for patients experience snakebite envenoming in the two countries. 
Duration will be measured in days. 
For patients enrolled in the United States, the duration of hospitalization will be compared 
between treatment groups using ANCOVA with baseline SSS, age group, and baseline 
neurotoxicity as covariates. 
For patients enrolled in India, the duration of hospitalization will be compared using the 
Wilcoxon Rank Sum Test. A non-parametric test will be used for the data from India because the 
data are anticipated to exhibit rightward skew, with a few patients having a much longer duration 
of hospitalization than most. 
Only hospitalization stays from baseline through Day 28 will be included in this analysis. 
8.2.12. All-Cause Mortality from Baseline through Day 28 
 
All-cause mortality will be analyzed using a time-to-event approach. Summaries will include the 
number of subjects experiencing the event (death) and the number of subjects censored; the 
median, lower quartile and upper quartile estimate of time-to-event; and point estimates for the 
mortality rates. 
A Kaplan-Meier graph of mortality by treatment group will be presented. 
The null hypothesis of no difference between varespladib-methyl and placebo will be tested 
using a Cox proportional hazard regression model with a categorical variable for the treatment 
arm as independent variable and adjusted for baseline SSS, age group, baseline neurotoxicity, 
and completion of initial dose of antivenom prior to initiation of study drug which will be 
presented together with two-sided 95% confidence intervals, as well as the corresponding P 
value. 


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All-cause mortality will be censored at Day 28. 
If fewer than 5 subjects die, this analysis will not be performed. All deaths will be listed. 
8.2.13. Clinical Global Impression–Improvement (CGI-I) from Baseline through Day 7 
CGI-I (1-7 scale) will be treated as a continuous variable and summary statistics will be reported 
at each visit and depicted graphically showing mean scores for each treatment group over time. 
CGI-I scores from baseline through day 7 will be compared using MMRM, with treatment as the 
variable of interest, with baseline SSS, age group, baseline CGI-I score, and baseline 
neurotoxicity as covariates. The model will be used to estimate the effect of treatment on CGI-I 
scores at each assessment time point through Day 7. 
Secondarily, CGI-C will be dichotomized into subjects who are responders (score of either 1 – 
very much improved; 2 – much improved) vs. non-responders (scores of 3-7). The proportion of 
responders within each treatment group will be compared with logistic regression including the 
same covariates described above. 
8.2.14. Patient Global Impression of Change (PGI-C) from Baseline through Day 7 
PGI-C (0-10 scale) will be treated as a continuous variable. Means and standard deviations will 
be tabulated at each visit and graphically for each treatment group over time. PGI-C scores from 
baseline through day 7 will be compared using MMRM, with treatment as the variable of 
interest, and baseline SSS, age group, baseline PGI-C score, baseline neurotoxicity, and visit, 
and treatment by visit interaction as covariates. The MMRM approach will be similar to the 
model described in Section 8.2.1. LS means and changes after baseline will be calculated from 
the model at Day 7. Logistic regression will also be used to compare PGI-C responders by 
treatment group at each visit through Day 7. A responder is defined as a PGI-C score of 3 or 
lower. 
8.2.15. Patient-Specific Functional Scale (PSFS) Total Score through Day 28 
PSFS (0-10 scale) will be treated as a continuous variable. The means and standard deviations 
will be tabulated at each visit and depicted graphically for each treatment group over time. PSFS 
scores through day 28 will be compared using MMRM, with treatment as the variable of interest, 
and baseline SSS, age group, baseline neurotoxicity, and visit, and visit by treatment interaction 
as covariates. The MMRM approach will be similar to the model described in Section 8.2.1. The 
model will be used to estimate the effect of treatment on PSFS scores at each assessment time 
point through Day 28. 
8.3. 
Exploratory Efficacy Analysis 
The ITT population will be used for the exploratory analyses. 


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8.3.1. Change in the SSS from Baseline through Day 7 Using Compressed SSS Scale 
The compressed SSS as well as the 6hr and 9hr mean scores will be calculated by first 
subtracting 1 from non-zero responses to the pulmonary, cardiovascular, hematologic, renal, and 
nervous system sections of the SSS. The sum of the adjusted values of the 5 subsections will be 
the total SSS used to calculate the compressed score. The endpoint will be the change from 
baseline through Day 7 compressed scores: Change = Baseline – Score (at each time). 
Descriptive statistics for the compressed SSS scores will be tabulated by treatment group. 
The change from baseline to the average of the 6hr and 9hr of the compressed SSS will be 
presented by treatment group within an analysis of covariance model (ANCOVA) with the 
baseline SSS score, age group, the presence or absence of baseline neurotoxic symptoms as 
covariates. 
8.3.2. SSS from Baseline through Day 28 After First Dose 
The SSS from baseline through Day 28 post-initial dose will be summarized using descriptive 
statistics of absolute values and change from baseline at each time point and depicted 
graphically. 
When more than one SSS assessment falls within the same time window, then only the SSS 
assessment closest to the middle point of the time window will be assigned to the time point. In 
case of values that are equidistant to the middle point, the latest assessment only will be assigned 
to the time point. 
8.3.3. Grip Strength Pre-Dosing through Day 28 
Descriptive summaries of absolute value and change from the baseline of grip strength will 
tabulated by treatment group and visit and depicted graphically. 
8.3.4. SSS Neurologic System Subscore from Baseline through Day 7 
Descriptive summaries of absolute value and change from the baseline for the SSS neurologic 
system subscore will be tabulated by treatment group and visit from baseline through Day 7 and 
depicted graphically. 
8.3.5. Analgesic Use through Day 28 
The number and proportion of subjects reporting (1) any analgesic and (2) any opioid use will be 
tabulated by treatment group and time point. 
8.3.6. Clinical Global Impression – Improvement (CGI-I) from Baseline through Day 28 


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Descriptive summaries of absolute value and change from baseline of CGI-I will be tabulated by 
treatment group and visit and depicted graphically. 
8.3.7. Patient Global Impression of Change (PGIC) from Baseline through Day 28 
Descriptive summaries of absolute value and change from baseline of PGIC will be tabulated by 
treatment group and visit and depicted graphically. 
8.3.8. Complete Blood Count (CBC) Laboratory Tests through All SSS Evaluation Days 
The number of subjects with CBC laboratory values below, within, or above the normal range by 
visit and in relation to baseline will be tabulated for key clinical CBC laboratory analytes: white 
blood cell count, hemoglobin level, platelet count (shift table). Denominator of the percentages 
will be the number of subjects in the ITT Population. 
8.3.9. Transfusion Requirement from Baseline through Day 28 
The transfusion requirement will be assessed using the following indicators. 
 Time to Hb stabilization 
 Patients having transfusion event 
 Time to first transfusion 
 Total number of transfusions per subject 
 Total blood units administered 
Number and percentage of subject with a transfusion event will be described in summary tables 
by treatment arm and visit. Summary statistics of the total number of transfusions and the total 
blood units required will be presented in tables by treatment arm and visit for subject having a 
transfusion event. 
Time to hemoglobin (Hb) stabilization and time to first transfusion will be analyzed using a 
descriptive time-to-event approach. Summaries will include the number of subjects experiencing 
the event and the number of subjects censored; the median, lower quartile and upper quartile 
estimate of time-to-event. 
8.3.10. C-reactive Protein (CRP) from Baseline through Day 14 
The absolute values and change from baseline of CRP test results will be tabulated by treatment arm 
and visit. 
8.3.11. D-dimer Levels from Baseline through Day 14 
D-dimer test results will be displayed in the data listings. Values outside the normal range will be 


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flagged, along with corresponding normal ranges. 
8.3.12. Levels of Myonecrosis Marker (CK) from Baseline through Day 3 in Subjects 
Presenting with and without Tourniquets at Enrollment 
The analysis described in Section 8.2.5 will be repeated for subjects: 
 with tourniquets at enrollment 
 without tourniquets at enrollment 
Only subjects with CK ≥ 2x institutional reference range at baseline will be included in the 
analysis. 
8.3.13. Secretory Phospholipase A2 (sPLA2) in Serum at Specified Timepoints on Days 1 to 7 in 
All Subjects 
Descriptive summaries of absolute values and change from the baseline of sPLA2 levels will be 
tabulated by treatment group and visit and depicted graphically. 
All sPLA2 from pre-dosing to Day 7 will be presented and used to (1) calculate maximum 
concentrations in both treatment groups, (2) compare concentration-time curves using a 
nonlinear regression to quantify a change in the half-maximal effective concentration (EC50) and 
its confidence interval, and (3) to compute a p-value that tests the null hypothesis that there is no 
difference between curves. 
sPLA2 analysis will be performed by a third-party central lab. The analysis of sPLA2 will focus 
on enzyme activity. If available, another analysis will examine sPLA2 mass. 
8.4. 
Subgroup Analyses of Efficacy Variables 
The primary efficacy endpoint and the three key secondary efficacy endpoints will be analyzed 
by doing separate subgroup analyses for the following subgroups: (1) pediatric (age 5 to 17 
years) and adult (≥18 years) subgroups, (2) among subjects with and without neurotoxic 
symptoms at baseline as described in section 8.1, (3) among subjects who did and did not 
complete an initial dose of antivenom prior to randomization, (4) among subjects enrolled in the 
U.S. and India, (5) among patients bitten by vipers, elapids, and unknown snake types, and (6) 
among patients for whom the time from bite or symptom onset to receipt of study drug was <5 
hours and ≥5 hours. 
9. 
Safety and Tolerability Analysis 
Safety will be evaluated from reported TEAEs, changes in clinical laboratory values, changes in 
vital signs, and electrocardiogram (ECG) results, and concomitant medications and therapies. 


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All safety analyses will be performed on the SAF Population. No inferential statistical tests are 
planned. 
9.1. 
Adverse Events 
All AEs, TEAEs, and SAEs will be coded using the MedDRA thesaurus. 
A summary table will present the number and percentage of subjects for each treatment group 
reporting: 
 AEs 
 TEAEs 
 TEAEs related to IP 
 Moderate TEAEs 
 Severe TEAEs 
 Serious TEAEs 
 Serious TEAEs related to IP 
 TEAEs resulting in death. 
Summaries of the incidence (number and percentage of subjects reporting the TEAE and the 
number of TEAEs) of TEAEs will be displayed for each treatment group by: 
 System organ class, and preferred term 
 Maximum severity by system organ class, and preferred term 
 Strongest relationship to IP by system organ class, and preferred term. 
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. However, all multiple occurrences will be included 
in the number of events. The number of subjects experiencing anaphylaxis or acute 
hypersensitivity reactions will also be summarized by treatment group. This comparison will be 
conducted regardless of the determination of causal relationship to the study drug. 
In the summaries showing severity and relationship to IP, the event with the maximum severity 
or strongest relationship will be reported. If a particular event is missing the severity and/or 
relationship, then the strongest possible severity or relationship will be assumed for analysis. 
By-subject AE data listings with all AEs will be displayed. 
9.1.1. Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
IP, by treatment group, system organ class, and preferred term will be prepared for the SAF 
Population. 
A data listing of AEs leading to withdrawal of IP will also be provided, displaying details of the 
event(s) captured on the eCRF. 


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9.1.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. Moreover, all-cause mortality will be 
analyzed as described in Section 8.2.12. 
Serious adverse events will be listed and tabulated by system organ class and preferred term and 
presented by treatment. 
9.1.3. FDA Medical Queries 
The number and percentage of subjects experiencing the following FMQs will be reported by 
treatment group. Construction of each item will be based on the PTs specified at 
https://www.regulations.gov/docket/FDA-2022-N-1961/document. 
 Hepatic Injury (Narrow and Broad) 
 Acute Kidney Injury (Narrow and Broad) 
 Stroke and TIA (Narrow and Broad 
 Myocardial Ischemia (Narrow) 
 Arrythmia (Narrow) 
 Cardiac Conduction Disturbance (Narrow) 
 Hypersensitivity (Standard Narrow and Broad) 
9.2. 
Vital Signs 
Descriptive summaries of actual values and changes from baseline will be calculated for all vital 
signs including systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, and 
body temperature. 
9.3. 
Clinical Laboratory Evaluations 
The number of subjects with clinical laboratory values (chemistry, hematology, urinalysis) 
below, within, or above the normal range by visit and in relation to baseline will be tabulated for 
each clinical laboratory analyte (shift table). Continuous summaries of observed values and 
changes from baseline will also be reported. Denominators of the percentages will be the number 
of subjects in the SAF Population. 
All laboratory test results, including coagulation and hematological function tests, will be 
displayed in by-subject listings and those that are outside the normal range will be flagged, along 
with corresponding normal ranges. 
By-subject pregnancy test results will be listed. 
9.4. 
Vital Signs 


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Descriptive summaries of actual values and changes from baseline will be calculated for all vital 
signs (systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, and body 
temperature). 
9.5. 
Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG results will be 
summarized for the SAF Population by treatment group. Summaries of observed values and 
change from baseline will also be reported. 
9.6. 
Physical Examination 
The number and percentage of subjects with normal, abnormal clinically significant, and 
abnormal not clinically significant physical examination results by body system will be 
summarized for the SAF Population by treatment group. 
9.7. 
Concomitant Medication 
Prior and concomitant medications by Anatomical Therapeutic Chemical (ATC) level 3 will be 
summarized descriptively by treatment group using counts and percentages. 
Prior medications will be presented separately from concomitant medications. Medications that 
started before the first drug use will be considered prior medications whether or not they were 
stopped before the first IP. Any medications continuing or starting after the first drug use will be 
concomitant. If a medication starts before the first drug use and continues after the first drug use 
it will be considered both prior and concomitant. Where a medication start date or end date is 
partially or fully missing, and it is unclear as to whether the medication is prior or concomitant, it 
will be assumed that it is concomitant. 
Concomitant use of analgesics will also be summarized and presented separately. 
Medications will be coded using the latest WHO-DD version. 
9.8. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS items will be tabulated by treatment group and visit. 
10. 
Changes from Planned Analysis 
Several changes have occurred since version 1.0 of the SAP. For example, multiple 
imputation and fixed-sequence testing were added in SAP v3.0; and the FMQs and additional 
sensitivity analysis on the primary endpoint were added in SAP v4.0. More details are 
provided in the Document History section above. All changes were made while the study 
team was blind to treatment assignment and prior to database lock. 
11. 
Other Planned Analysis 


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11.1. 
Pharmacokinetic Analysis 
Descriptive summaries of the concentration level of varespladib-methyl in plasma and sPLA2 
activity at specified timepoints will be tabulated by treatment group. 
By-subject concentrations of varespladib-methyl in plasma will also be presented. 
The pharmacokinetic characterization of drug concentrations for each dose to be profiled will be 
performed using noncompartmental analysis (NCA). 
The PK parameter estimates will be completed using Phoenix WinNonlin (Pharsight 
Corporation) software using the actual elapsed times from dose administration to sample 
collection. For plasma concentration data, all values below the limit of quantification (BLQ) will 
be set to 0 for summary statistics and graphs. For the PK parameter calculation, BLQ plasma 
concentrations occurring before Tmax will be set to 0, with the exception of a BLQ value 
occurring between two measurable concentrations, in which case it will be set to missing. 
Standard PK parameters assessed will include measures of the extent of absorption using 
estimates of the area under the plasma concentration-time curve from time 0 to the time of the 
last quantifiable plasma concentration (AUC0-t), Area under the plasma concentration-time 
curve from time 0 to infinity (if data permits) (AUC0-inf) and rate of absorption using the 
maximum serum plasma concentration (Cmax), the time of Cmax (Tmax), apparent first order 
terminal elimination half-life (t1/2), apparent terminal phase rate constant (λz) (if data permits). 
Any subject for whom the portion of the AUC extrapolated to infinity exceeds 20% of the total 
AUC0-inf will be excluded from the calculation of the descriptive statistics for AUC0-inf. 
Other PK parameters may be derived, where appropriate, and as data permit. 
For noncompartmental analysis, plasma concentrations will be listed and summarized at each 
time point using descriptive statistics. Descriptive statistics reported will include the arithmetic 
mean, SD, CV%, geometric mean, minimum, maximum, and median. Only the range and the 
median will be reported for Tmax and Tlast, as these are categorical parameters. The PK 
parameters will also be summarized by treatment using descriptive statistics. 
Individual plasma concentration plots and mean data graphs will be produced using both linear 
and semi-logarithmic scales. Mean data graphs will show plasma concentration profiles by 
treatment group. Pharmacokinetic parameter estimates and summaries will be completed for the 
subjects in the PK population. 
Exploratory analysis to correlate PK endpoints with sPLA2 activity may be conducted and 
documented in a separate analysis plan. 
The PK analyses will be performed by a third-party central lab. 
11.2. 
 Pharmacoeconomic Analysis 
Pharmacoeconomic analyses will be conducted to estimate the effect of varespladib treatment on 
the cost of care. These analyses will include, but are not limited to, the amount of antivenom 
given to the patient and the duration of hospital stay. 




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The following are planned summary tables for protocol number OPX-PR-01. The table numbers 
and page numbers are place holders only and will be determined when the tables are produced. 






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Table 14.2.3.9 Sensitivity Analysis of Antivenom Categories: Binomial Logistic Regression ITT Population 
Table 14.2.3.2.1 Statistical Analysis of NPRS-AUC through Day 7: ANCOVA ITT Population 
Table 14.2.3.2.2 Statistical Analysis of NPRS-AUC through Day 7: ANCOVA by Age Group ITT Population 
Table 14.2.3.2.3 Statistical Analysis of NPRS-AUC through Day 7: ANCOVA by Country (US, India) ITT Population 
Table 14.2.3.2.4 Statistical Analysis of NPRS-AUC through Day 7: ANCOVA by Snake Type (Viper, Elapid, and 
Unknown) ITT Population 
Table 14.2.3.2.5 Statistical Analysis of NPRS-AUC through Day 7: ANCOVA by Time from Bite or Symptom Onset 
to Receipt of Study Drug (<5 hours and ≥5 hours) ITT Population 
Table 14.2.3.2.6 Statistical Analysis of NPRS-AUC through Day 7: ANCOVA by Antivenom Status Prior to Baseline 
ITT Population 
Table 14.2.3.2.7 Statistical Analysis of NPRS-AUC through Day 7: ANCOVA by Baseline Neurotoxicity Status ITT 
Population 
Table 14.2.4.0 Key Secondary Outcome: CGI-I Scores at Day 2 Overall and Prespecified Subgroups ITT Population 
Table 14.2.4.1 Statistical Analysis of CGI-I Scores at Day 2: ANCOVA ITT Population 
Table 14.2.4.2 Statistical Analysis of CGI-I Scores at Day 2: ANCOVA by Country (US, India) ITT Population 
Table 14.2.4.3 Statistical Analysis of CGI-I Scores at Day 2: ANCOVA by Snake Type (Viper, Elapid, Unknown) 
ITT Population 
Table 14.2.4.4 Statistical Analysis of CGI-I Scores at Day 2: ANCOVA by Time from Bite or Symptom Onset to 
Receipt of Study Drug (<5 hours and ≥5 hours) ITT Population 
Table 14.2.4.5 Statistical Analysis of CGI-I Scores at Day 2: ANCOVA by Age Group ITT Population 
Table 14.2.4.6 Statistical Analysis of CGI-I Scores at Day 2: ANCOVA by Antivenom Status Prior to Baseline ITT 
Population 
Table 14.2.4.7 Sensitivity Analysis of CGI-I Scores at Day 2: ANCOVA ITT Population 
Table 14.2.5.1 Statistical Analysis of SSS Total Scores through Day 7: MMRM ITT Population 
Table 14.2.5.2 Statistical Analysis of Neurologic Subscore through Day 3 in Patients with Baseline Neurologic 
Subscore ≥1: MMRM ITT Population 
Table 14.2.5.3 Statistical Analysis of Neurologic Subscore through Day 3 in Patients with Baseline Neurologic 
Subscore ≥2: MMRM ITT Population 
Table 14.2.6.1 Summary of Coagulation Abnormalities in Patients with Hematology Score ≥ 1 from Baseline through 
Day 7 ITT Population 
Table 14.2.6.2 Statistical Analysis of Coagulation Abnormalities in Patients with Hematology Score ≥ 1 from Baseline 
through Day 7: Proportional Odds Logistic Regression ITT Population 
Table 14.2.7.1 Statistical Analysis of Hemolysis Markers in Subjects with Hemolysis at Baseline (free hemoglobin 
>=15 mg/dL) through Day 3: MMRM ITT Population 
Table 14.2.8.1 Statistical Analysis of Creatinine Kinase (CK) in Subjects with CK >=2X Reference Range at Baseline 
through Day 3: MMRM ITT Population 
Table 14.2.9.1 Statistical Analysis of Kidney Function Markers from Baseline through Day 28: MMRM ITT 
Population 














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14.6.1.8 
ITT Subset 
Hematological Snakebite Severity Subscore by Treatment Arm and 
Visit, in Subjects with Subscore ≥1 at Baseline, through Day 28 
14.6.1.9 
ITT Subset 
Renal Snakebite Severity Subscore by Treatment Arm and Visit, in 
Subjects with Subscore ≥1 at Baseline, through Day 28 
14.6.1.10 
ITT Subset 
Local Wound Snakebite Severity Subscore by Treatment Arm and 
Visit, in Subjects with Subscore ≥1 at Baseline, through Day 28 
14.6.1.11 
ITT Subset 
Gastrointestinal Snakebite Severity Subscore by Treatment Arm and 
Visit, in Subjects with Subscore ≥1 at Baseline, through Day 28 
14.6.2.1 
ITT 
Primary Outcome Snakebite Severity Score by Treatment Arm 
14.6.3.1 
ITT 
Partial Thromboplastin Time by Treatment Arm and Visit 
14.6.3.2 
ITT 
Prothrombin Time by Treatment Arm and Visit 
14.6.3.3 
ITT 
Thrombin Time by Treatment Arm and Visit 
14.6.3.4 
ITT 
Coagulation Abnormalities by Treatment Arm and Visit 
14.6.4.1 
ITT 
Free Hemoglobin Concentration by Treatment Arm and Visit 
14.6.4.2 
ITT 
Lactate Dehydrogenase by Treatment Arm and Visit 
14.6.4.3 
ITT 
Haptoglobin by Treatment Arm and Visit 
14.6.4.4 
ITT 
Abnormal Lactate Dehydrogenase by Treatment Arm and Visit 
14.6.5 
ITT 
Myonecrosis Marker (CK) by Treatment Arm and Visit 
14.6.6 
ITT 
Kaplan Meier Graph of All-cause Mortality 
14.6.7 
ITT 
PGI-C by Treatment Arm and Visit 
14.6.8 
ITT 
CGI-I by Treatment Arm and Visit 
14.6.9 
ITT 
PSFS by Treatment Arm and Visit 
14.6.10 
PK 
Varespladib Plasma Concentrations 
14. 
Table, Figure, and Listing Shells 
This SAP is intended for submission to regulatory authority and TLF shells have not been 
included.