SnakebitesPhase 2BRAVONCT04996264
Broad-spectrum Rapid Antidote: Varespladib Oral for Snakebite
A Phase 2 study testing Varespladib Methyl in people with Snakebites and Envenoming, run by Ophirex, Inc. at 16 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 5 years and older
- Conditions the study is for
- Snakebites, Envenoming, Envenoming, Snake
- What is being tested?
- Varespladib Methyl
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 95 participants
- Where
- 16 sitesin 2 countries
- Study dates
- 15 Aug 2021to 8 Jun 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Is a male or female subject ≥ 5 years of age with venomous snakebite and must present with an initial SSS of
- 2 points in any SSS category other than gastrointestinal and 1 or more additional points in any other SSS category other than gastrointestinal or
- ≥ 3 in any SSS category other than gastrointestinal.
- SSS scoring should be performed for inclusion assessment without waiting for receipt of Baseline hematological laboratory results. Gastrointestinal scores should not be used for inclusion.
- Index event (snakebite) must be symptomatic and must have occurred within 10 hours of eligibility assessment.
- Must meet one of two categories of inclusion criteria:
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- 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).
- Is willing (or legally authorized representative is willing) to provide informed consent prior to initiation of any study procedures.
Who cannot join
- Has received antivenom treatment for envenoming prior to enrollment in this study.
- 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.
- Has history of cerebrovascular accident or intracranial bleeding of any kind, acute coronary syndrome, myocardial infarction, or severe pulmonary hypertension.
- Has known history of inherited bleeding or coagulation disorder.
- Is, at Screening Visit, using the following anticoagulants: warfarin/coumadin, argatroban, bivalirudin, lepirudin, apixaban, dabigatran, clopidogrel, prasugrel, ticlopidine 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.
- 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, or autoimmune hepatitis.
Show all 10Show fewer
- Reports or has known pre-existing renal impairment or chronic kidney disease (defined as Stage 4 or receiving dialysis or hemofiltration).
- Has a known allergy or significant adverse reaction to varespladib-methyl or related compounds.
- Is considered by the Investigator to be unable to comply with protocol requirements due to geographic considerations, psychiatric disorders, or other compliance concerns.
- 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.
Trial locations and contacts
16 sites in 2 countries.
16 sites in 2 countries
United States8 sites
Agusta University Medical Center
Augusta, Georgia, 30912
Duke University Hospital Durham, NC
Durham, North Carolina, 27710
University of Mississippi Medical Center - Jackson
Jackson, Mississippi, 39216
University of Florida Health
Jacksonville, Florida, 32209
University of Kentucky Chandler Medical Center
Lexington, Kentucky, 40536
Loma Linda University Medical Center
Loma Linda, California, 92354
LSU LA Poison Control Center
Shreveport, Louisiana, 71103
University of Arizona
Tucson, Arizona, 85724
India8 sites
S.P. Medical College Snakebite Research Cell
Bikaner, Rajasthan
Postgraduate Institute of Medical Education and Research
Chandigarh
Calcutta National Medical College
Kolkata, West Bengal
Government medical College
Kozhikode, Calicut
Father Muller medical College Hospital
Mangalore, Karnataka, 575002
K R Hospital Mysore medical College and Research Institute
Mysore, Karnataka
Jawaharlal Institute of Postgraduate Medical Education & Research
Puducherry, Puducherry
Jubilee Mission Medical College and Research Institute
Thrissur, Kerala
About this study
Official 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
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.
Read the 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).
- Conditions
- Snakebites, Envenoming, Envenoming, Snake, Envenomation, Snake
- Being tested
- Varespladib Methyl, Placebo, Standard of care (SOC)
- Keywords
- envenoming, venom, snakebite, snakebite severity score, varespladib, snake, antidote, LY333013, sPLA2
- Medical subject headings
- Snake Bites
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Varespladib MethylDrug
Also called LY333013
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.
PlaceboDrug
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.
Standard of care (SOC)Drug
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.
| Study group | Role | What they receive |
|---|---|---|
| Varespladib-methyl | Experimental | 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. Receives: Drug: Varespladib Methyl; Drug: Standard of care (SOC) |
| Placebo | Placebo comparator | 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. Receives: Drug: Placebo; Drug: Standard of care (SOC) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in the Combined Pulmonary, Cardiovascular, Hematologic, Nervous System, and Renal Subscores of the Snakebite Severity Score (SSS)
Change from baseline (pre-dosing) to 6 and 9 hours after the first dose, in the combined pulmonary, cardiovascular, hematologic symptoms, nervous system, and renal subscores of the SSS. The values from each of these subscores will be totaled. The average of the 6- and 9-hour scores will be used as the post-treatment value.
The Snakebite Severity Scale (SSS) is a tool used to measure the severity of envenoming based on up to 7 body categories: pulmonary, cardiovascular, gastrointestinal, nervous, and renal system (graded at levels from Grade 0 to Grade 3), local wound, and hematological, (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms. The minimum score for the five item SSS is 0 and the maximum score is 16, with the higher score indicating worse symptoms. For the primary outcome we are focusing only on 5 subscores, that does not include the local wound nor the gastrointestinal subscores.
Measured: Baseline to 6 and 9 hours after first dose
Secondary outcomes (6)
Area Under the Curve (AUC) of the Local Wound, Pulmonary, Cardiovascular, Hematologic Symptoms, Renal, and Nervous System Sections of the SSS
Baseline (pre-dosing) through Day 7 in the AUC of the local wound, pulmonary, cardiovascular, hematologic symptoms, nervous, and renal system sections of the SSS.
The Snakebite Severity Scale (SSS) is a tool used to measure the severity of envenoming based on 7 body categories: pulmonary, cardiovascular, gastrointestinal, nervous, and renal effects (graded at levels from Grade 0 to Grade 3), local wound and hematological, (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms. The maximum score for the SSS is 23.
For this outcome, the maximum score is 20 and if this score was present for the entire first week (168 hours) the maximum AUC is 3,370. The minimum AUC is a score of 3 at baseline and a score of 0 at three hours, which gives an AUC of 5.25.
Measured: Baseline through Day 7
Area Under the Curve (AUC) of the Numeric Pain Rating Scale (NPRS)
Numeric Pain Rating Scale is a scale that goes from 0 to 10 with 10 being the worst possible pain. This measure is an AUC measure that is calculated from 0 to 48 hours using trapezoidal function in which the mean score for any given 2 periods of time is multiplied by the elapsed duration of time between those two periods. Each of these mean scores are summed to calculate the AUC. The minimum score is 0 and the maximum is 480.
Measured: From Baseline through Day 3
Clinician Global Impression - Improvement
Clinician Global Impression - Improvement focus on improvement for Day 2. The scale is a 1 to 7 score with 1 indicating very much improved and 7 indicating very much worse.
Measured: Day 2
All-cause Mortality
The number of patients experiencing the event (death). The all-cause mortality will be censored at Day 60.
Measured: Baseline through Day 28
Patient-Specific Functional Scale (PSFS) Score
PSFS total score on Day 7. The PSFS is a 3-item instrument which assesses functional abilities. The total score ranges from 0 to 10 with a lower score indicating greater functional difficulties.
Measured: Day 7
Numeric Pain Rating Scale (NPRS) Score
Change from baseline (pre-dosing) through Day 28 in NPRS score in patients able to respond pre-dosing through Day 28.
The Numeric Pain Rating Scale is an 11-point scale for patient self-reporting of pain with scores ranging from 0 (no pain) to 10 (worst possible pain).
Measured: Baseline through Day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Aug 2021
- Study start15 Aug 2021
- Primary completion7 Jun 2023
- Study completion8 Jun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (37)Papers the sponsor has linked to this study.
- Other trials for SnakebitesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 95 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ophirex, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Premier Research
- Responsible party
- Sponsor
- Investigators
- Matthew Lewin, MD, PhD, Principal investigator, Ophirex, Inc.Timothy F Platts-Mills, MD, MSc, Principal investigator, Ophirex, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04996264
- Sponsor's protocol ID
- OPX-PR-01
- Acronym
- BRAVO
- Status last verified
- Jun 2025
- First submitted
- 30 Jul 2021
- Last updated
- 1 Jul 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Varespladib. Am J Cardiovasc Drugs. 2011;11(2):137-43. doi: 10.2165/11533650-000000000-00000.
PubMed 21446779Alangode A, Rajan K, Nair BG. Snake antivenom: Challenges and alternate approaches. Biochem Pharmacol. 2020 Nov;181:114135. doi: 10.1016/j.bcp.2020.114135. Epub 2020 Jul 3.
PubMed 32628928Albulescu LO, Xie C, Ainsworth S, Alsolaiss J, Crittenden E, Dawson CA, Softley R, Bartlett KE, Harrison RA, Kool J, Casewell NR. A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite. Nat Commun. 2020 Dec 15;11(1):6094. doi: 10.1038/s41467-020-19981-6.
PubMed 33323937Anderson BO, Moore EE, Banerjee A. Phospholipase A2 regulates critical inflammatory mediators of multiple organ failure. J Surg Res. 1994 Feb;56(2):199-205. doi: 10.1006/jsre.1994.1032.
PubMed 8121178Arce-Bejarano R, Lomonte B, Gutierrez JM. Intravascular hemolysis induced by the venom of the Eastern coral snake, Micrurus fulvius, in a mouse model: identification of directly hemolytic phospholipases A2. Toxicon. 2014 Nov;90:26-35. doi: 10.1016/j.toxicon.2014.07.010. Epub 2014 Aug 1.
PubMed 25088177Bittenbinder MA, Zdenek CN, Op den Brouw B, Youngman NJ, Dobson JS, Naude A, Vonk FJ, Fry BG. Coagulotoxic Cobras: Clinical Implications of Strong Anticoagulant Actions of African Spitting Naja Venoms That Are Not Neutralised by Antivenom but Are by LY315920 (Varespladib). Toxins (Basel). 2018 Dec 4;10(12):516. doi: 10.3390/toxins10120516.
PubMed 30518149Bryan-Quiros W, Fernandez J, Gutierrez JM, Lewin MR, Lomonte B. Neutralizing properties of LY315920 toward snake venom group I and II myotoxic phospholipases A2. Toxicon. 2019 Jan;157:1-7. doi: 10.1016/j.toxicon.2018.11.292. Epub 2018 Nov 14.
PubMed 30447275Bulfone TC, Samuel SP, Bickler PE, Lewin MR. Developing Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite. J Trop Med. 2018 Jul 30;2018:4320175. doi: 10.1155/2018/4320175. eCollection 2018.
PubMed 30154870Chippaux JP. Estimate of the burden of snakebites in sub-Saharan Africa: a meta-analytic approach. Toxicon. 2011 Mar 15;57(4):586-99. doi: 10.1016/j.toxicon.2010.12.022. Epub 2011 Jan 9.
PubMed 21223975Fernandez ML, Quartino PY, Arce-Bejarano R, Fernandez J, Camacho LF, Gutierrez JM, Kuemmel D, Fidelio G, Lomonte B. Intravascular hemolysis induced by phospholipases A2 from the venom of the Eastern coral snake, Micrurus fulvius: Functional profiles of hemolytic and non-hemolytic isoforms. Toxicol Lett. 2018 Apr;286:39-47. doi: 10.1016/j.toxlet.2017.11.037. Epub 2017 Nov 29.
PubMed 29197624Fontana Oliveira IC, Gutierrez JM, Lewin MR, Oshima-Franco Y. Varespladib (LY315920) inhibits neuromuscular blockade induced by Oxyuranus scutellatus venom in a nerve-muscle preparation. Toxicon. 2020 Nov;187:101-104. doi: 10.1016/j.toxicon.2020.08.023. Epub 2020 Sep 2.
PubMed 32889027Gerardo 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. 2019 Apr 1;154(4):346-354. doi: 10.1001/jamasurg.2018.5069.
PubMed 30758508Gutierrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA. Snakebite envenoming. Nat Rev Dis Primers. 2017 Sep 14;3:17063. doi: 10.1038/nrdp.2017.63.
PubMed 28905944Gutierrez 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 Feb 20;12(2):131. doi: 10.3390/toxins12020131.
PubMed 32093386Halilu S, Iliyasu G, Hamza M, Chippaux JP, Kuznik A, Habib AG. Snakebite burden in Sub-Saharan Africa: estimates from 41 countries. Toxicon. 2019 Mar 1;159:1-4. doi: 10.1016/j.toxicon.2018.12.002. Epub 2018 Dec 27.
PubMed 30594637
Study at a glance
From the registry record, last updated by the sponsor on 1 Jul 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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
- ClinicalTrials.gov ID
- NCT04996264
- Acronym / sponsor ID
- BRAVO / OPX-PR-01
- Conditions
- Snakebites, Envenoming, Envenoming, Snake, Envenomation, Snake
- Keywords
- envenoming, venom, snakebite, snakebite severity score, varespladib, snake, antidote, LY333013
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 95 participants (actual)
- Lead sponsor
- Ophirex, Inc.Industry (pharma, biotech, devices)
- Collaborators
- Premier Research
- Study start
- 15 Aug 2021 (actual)
- Primary completion
- 7 Jun 2023 (actual)
- Study completion
- 8 Jun 2023 (actual)
- First posted
- 9 Aug 2021 (actual)
- Results
- Posted 1 Jul 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Varespladib-methyl | Experimental | Drug: Varespladib Methyl, Drug: Standard of care (SOC)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. |
| Placebo | Placebo comparator | Drug: Placebo, Drug: Standard of care (SOC)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. |
Who may qualify
- Ages
- 5 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (12 listed)
- Is a male or female subject ≥ 5 years of age with venomous snakebite and must present with an initial SSS of
- SSS scoring should be performed for inclusion assessment without waiting for receipt of Baseline hematological laboratory results. Gastrointestinal scores should not be used for inclusion.
- Index event (snakebite) must be symptomatic and must have occurred within 10 hours of eligibility assessment.
- Must meet one of two categories of inclusion criteria:
- SSS inclusion score of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at least one system.
Key exclusion criteria (10 listed)
- Has received antivenom treatment for envenoming prior to enrollment in this study.
- 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.
- Has history of cerebrovascular accident or intracranial bleeding of any kind, acute coronary syndrome, myocardial infarction, or severe pulmonary hypertension.
- Has known history of inherited bleeding or coagulation disorder.
- Is, at Screening Visit, using the following anticoagulants: warfarin/coumadin, argatroban, bivalirudin, lepirudin, apixaban, dabigatran, clopidogrel, prasugrel, ticlopidine 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Varespladib MethylAlso: LY333013Varespladib-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. | Drug | Varespladib-methyl |
| PlaceboThe 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. | Drug | Placebo |
| Standard of care (SOC)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. | Drug | Placebo, Varespladib-methyl |
Primary outcome
Change in the Combined Pulmonary, Cardiovascular, Hematologic, Nervous System, and Renal Subscores of the Snakebite Severity Score (SSS)
Time frame: Baseline to 6 and 9 hours after first dose
Change from baseline (pre-dosing) to 6 and 9 hours after the first dose, in the combined pulmonary, cardiovascular, hematologic symptoms, nervous system, and renal subscores of the SSS. The values from each of these subscores will be totaled. The average of the 6- and 9-hour scores will be used as the post-treatment value. The Snakebite Severity Scale (SSS) is a tool used to measure the severity of envenoming based on up to 7 body categories: pulmonary, cardiovascular, gastrointestinal, nervous, and renal system (graded at levels from Grade 0 to Grade 3), local wound, and hematological, (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms. The minimum score for the five item SSS is 0 and the maximum score is 16, with the higher score indicating worse symptoms. For the primary outcome we are focusing only on 5 subscores, that does not include the local wound nor the gastrointestinal subscores.
6 secondary outcomes
Area Under the Curve (AUC) of the Local Wound, Pulmonary, Cardiovascular, Hematologic Symptoms, Renal, and Nervous System Sections of the SSS
Time frame: Baseline through Day 7
Area Under the Curve (AUC) of the Numeric Pain Rating Scale (NPRS)
Time frame: From Baseline through Day 3
Clinician Global Impression - Improvement
Time frame: Day 2
All-cause Mortality
Time frame: Baseline through Day 28
Patient-Specific Functional Scale (PSFS) Score
Time frame: Day 7
Numeric Pain Rating Scale (NPRS) Score
Time frame: Baseline through Day 28
Results and safety
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Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Jul 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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- Background: PubMed 25088177Arce-Bejarano R, Lomonte B, Gutierrez JM. Intravascular hemolysis induced by the venom of the Eastern coral snake, Micrurus fulvius, in a mouse model: identification of directly hemolytic phospholipases A2. Toxicon. 2014 Nov;90:26-35. doi: 10.1016/j.toxicon.2014.07.010. Epub 2014 Aug 1.
- Background: PubMed 30518149Bittenbinder MA, Zdenek CN, Op den Brouw B, Youngman NJ, Dobson JS, Naude A, Vonk FJ, Fry BG. Coagulotoxic Cobras: Clinical Implications of Strong Anticoagulant Actions of African Spitting Naja Venoms That Are Not Neutralised by Antivenom but Are by LY315920 (Varespladib). Toxins (Basel). 2018 Dec 4;10(12):516. doi: 10.3390/toxins10120516.
- Background: PubMed 30447275Bryan-Quiros W, Fernandez J, Gutierrez JM, Lewin MR, Lomonte B. Neutralizing properties of LY315920 toward snake venom group I and II myotoxic phospholipases A2. Toxicon. 2019 Jan;157:1-7. doi: 10.1016/j.toxicon.2018.11.292. Epub 2018 Nov 14.
- Background: PubMed 30154870Bulfone TC, Samuel SP, Bickler PE, Lewin MR. Developing Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite. J Trop Med. 2018 Jul 30;2018:4320175. doi: 10.1155/2018/4320175. eCollection 2018.
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- Background: PubMed 29197624Fernandez ML, Quartino PY, Arce-Bejarano R, Fernandez J, Camacho LF, Gutierrez JM, Kuemmel D, Fidelio G, Lomonte B. Intravascular hemolysis induced by phospholipases A2 from the venom of the Eastern coral snake, Micrurus fulvius: Functional profiles of hemolytic and non-hemolytic isoforms. Toxicol Lett. 2018 Apr;286:39-47. doi: 10.1016/j.toxlet.2017.11.037. Epub 2017 Nov 29.
- Background: PubMed 32889027Fontana Oliveira IC, Gutierrez JM, Lewin MR, Oshima-Franco Y. Varespladib (LY315920) inhibits neuromuscular blockade induced by Oxyuranus scutellatus venom in a nerve-muscle preparation. Toxicon. 2020 Nov;187:101-104. doi: 10.1016/j.toxicon.2020.08.023. Epub 2020 Sep 2.
- Background: PubMed 30758508Gerardo 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. 2019 Apr 1;154(4):346-354. doi: 10.1001/jamasurg.2018.5069.
- Drug Development and Drug Interactions \| Table of Substrates, Inhibitors and InducersLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Matthew Lewin, MD, PhD principal investigator
Ophirex, Inc.
Timothy F Platts-Mills, MD, MSc principal investigator
Ophirex, Inc.
16 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Varespladib Methyl in people with Snakebites and Envenoming, run by Ophirex, Inc. at 16 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 16 sites in United States, India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 1 Jul 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in the Combined Pulmonary, Cardiovascular, Hematologic, Nervous System, and Renal Subscores of the Snakebite Severity Score (SSS) (time frame: Baseline to 6 and 9 hours after first dose). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04996264, which also lists 37 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jul 2025.