Broad-spectrum Rapid Antidote: Varespladib IV to Oral Trial for Snakebite (BRAVIO) (BRAVIO)

Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of Intravenous Varespladib Followed by Oral Varespladib in Addition to Standard of Care 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 a continuous rate infusion (CRI) of IV varespladib followed by transition to the oral dosage form, varespladib-methyl, concurrently with SOC, in participants bitten by venomous snakes.

Note: Funding Source - FDA-OOPD

Study Overview

• Status: Completed
• Conditions: Snakebite; Envenoming, Snake
• Intervention / Treatment: Drug: Varespladib intravenous form; Drug: varespladib-methyl- oral form; Drug: Placebo intravenous form; Drug: Placebo - oral form

Detailed Description

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

Approximately 140 male and female eligible participants will be enrolled and randomized to receive active varespladib or placebo (in addition to SOC)

Randomization will be stratified by the presence or absence of neurotoxicity (SSS nervous system subscore of 0-1 or ≥ 2) at Baseline, and by receipt of antivenom prior to screening, resulting in 4 strata in total.

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner University Medical Center - Phoenix
    • Tucson, Arizona, United States, 85721
      • Arizona Poison & Drug Information Center
  • California
    • Palm Springs, California, United States, 92262
      • Desert Regional Medical Center
    • Rosamond, California, United States, 93560
      • Antelope Valley Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • UF Health Shands Hospital
    • Tampa, Florida, United States, 33606
      • University of South Florida/Tampa General Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Emergency Medicine, University of Kentucky
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Texas
    • El Paso, Texas, United States, 79905
      • Texas Tech University Health Sciences Center El Paso
    • San Antonio, Texas, United States, 78229
      • UT Health San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA:

1. Is a male or female ≥ 18 years of age with venomous snakebite.
2. Patients must have known or suspected venomous snakebite. In India, enrollment will be restricted to patients bitten by suspected or confirmed Russell's viper (Daboia russelii) or krait (Bungarus spp.) In the U.S., any snakebite that meets all other criteria may be eligible.

3. Participants must meet one of two categories of inclusion criteria:

   1. Category 1: The participant is enrolled within 5 hours of venomous snakebite or symptom onset with an SSS score of ≥2 in one system and ≥1 in another system (2+1).

      OR

   2. Category 2: The participant has a suspected or confirmed bite from an elapid and is enrolled within 10 hours of bite or symptom onset with moderate to severe cranial nerve or skeletal muscle weakness.
4. Is willing (or legally authorized representative is willing) to provide informed consent prior to initiation of any study procedures.

EXCLUSION CRITERIA:

1. Has history of or is suspected to have CVA or intracranial bleeding of any kind, acute coronary syndrome, MI, or severe pulmonary hypertension.
2. Has known history of inherited bleeding or coagulation disorder.
3. 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 any antiarrhythmic drugs within 14 days prior to treatment.
4. 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.
5. Reports or has known pre-existing renal impairment or chronic kidney disease.
6. Has a known allergy or significant adverse reaction to varespladib or varespladib-methyl.
7. Is considered by the Investigator to be unable to comply with protocol requirements due to geographic considerations, psychiatric disorders, or other compliance concerns.
8. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Varespladib Intravenous Form (IV) + Varespladib Oral tablet (LY315920) + SOC; Participants will receive intravenous (IV) infusion of varespladib at dose of 0.45 milligrams per kilogram per hour (mg/kg/hr) for six hours. This infusion will continue until when the participant meets clinical criteria for transition to oral drug, -If criteria are met, they will be transitioned to varespladib-methyl (initial dose of 500 mg) then continued oral dosing q12 (once every 12 hours) of 250 mg for the remainder of the study period. Participants that do not meet the criteria for transitioning to the oral drug will remain on the IV infusion at 0.45 mg/kg/hr (along with SOC) and assessed twice a day until they meet criteria for transition to oral drug.	Drug: Varespladib intravenous form; This is a lyophilized drug contained in 100 mg vials to be reconstituted in Water for Injection (WFI), followed by dilution into 0.9% Sodium Chloride Injection.; Other Names: LY315920; Drug: varespladib-methyl- oral form; Varespladib-methyl (LY333013) is an immediate-release, oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration.; Other Names: LY333013
Active Comparator: Placebo Intravenous (IV) + Placebo Oral + SOC; Participants will receive intravenous (IV) infusion of placebo matched to varespladib for six hours. This infusion will continue until the participant meets clinical criteria for transition to oral drug. If criteria are met, they will be transitioned to the oral placebo then continued oral dosing for the remainder of the study period. Participants that do not meet the criteria for transitioning to the oral drug will remain on the IV infusion (along with SOC) and assessed twice a day until they meet criteria for transition to oral drug.	Drug: Placebo intravenous form; The intravenous placebo will be saline (0.9%). Blinding will be ensured by covering the bag containing the investigational product with opaque covers.; Drug: Placebo - oral form; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
For subjects bitten by vipers: Area Under the Curve (AUC) of an abbreviated Snakebite Severity Score	For subjects bitten by vipers: Area Under the Curve (AUC) of an abbreviated Snakebite Severity Score (SSS) composed of local wound, hematologic, and neurologic subscores from Baseline (pre-dosing) to Day 14. The independent p-values from subjects bitten by elapids and subjects bitten by vipers will be analyzed using Fisher's combined probability test to obtain a single global p-value for testing the primary endpoint. The Snakebite Severity Scale is a tool used to measure the severity of envenoming, a higher score indicates worse symptoms.	Baseline to Day 14
For subjects bitten by elapids: Time to complete head-lift recovery defined by a 5-second head-lift of 5 seconds.	The independent p-values from subjects bitten by elapids and subjects bitten by vipers will be analyzed using Fisher's combined probability test to obtain a single global p-value for testing the primary endpoint.	Baseline to Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Antivenom Requirement, measured in number of vials of antivenom administered to the subject, from baseline (pre-dosing) through Day 28		Baseline through Day 28
Area under the curve of the composite outcome of pulmonary, cardiovascular, local wound, hematologic, renal, and nervous system sections of the SSS from Baseline to Day 7, among patients randomized within 5 hours from bite.	The SSS is a tool developed to measure the severity of snakebite envenoming. Each category is graded from 0 to 3 or 4 (depending on the body category) and a higher score indicates worse signs or symptoms.	Baseline to Day 7
Complete Snakebite Severity Scale Score (SSS) recovery, from baseline to Day 28.	Complete snakebite severity score (SSS) recovery, defined as a composite score of 0 for the pulmonary, cardiovascular, local wound, hematologic, renal, and nervous system sections of the SSS at Day 28. The SSS is a tool developed to measure the severity of snakebite envenoming. Each category is graded from 0 to 3 or 4 (depending on the body category) and a higher score indicates worse signs or symptoms.	Baseline through Day 28
Duration of Hospitalization from baseline (pre-dosing) through Day 28		Baseline through Day 28
Patient Specific Functional Scale (PSFS) score at Day 3 and Day 7.	Patient Specific Functional Scale (PSFS) is a brief, interview-format questionnaire that is used to assess functional disability and any changes in performance of activities. The patient 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 (0 is unable to perform and 10 is perform as before injury/illness).	Day 3 and Day 7

Collaborators and Investigators

• Sponsor: Ophirex, Inc.
• Investigators: Principal Investigator: Timothy Platts-Mills, MD, MSc, Ophirex, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2023
• Primary Completion (Actual): November 28, 2024
• Study Completion (Actual): February 24, 2025

Study Registration Dates

• First Submitted: January 20, 2023
• First Submitted That Met QC Criteria: January 30, 2023
• First Posted (Actual): February 8, 2023

Study Record Updates

• Last Update Posted (Actual): June 27, 2025
• Last Update Submitted That Met QC Criteria: June 25, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: snake; antidote; Envenoming, Snakebite, varespladib
• Additional Relevant MeSH Terms: Wounds and Injuries; Chemically-Induced Disorders; Poisoning; Bites and Stings; Snake Bites; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Phospholipase A2 Inhibitors; Varespladib methyl
• Other Study ID Numbers: OPX-PR-03; FD-R-7839 (Other Grant/Funding Number: FDA-OOPD)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No