Varespladib for Snake Bites (BRAVIO Trial)
Recruiting in Palo Alto (17 mi)
+9 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Waitlist Available
Sponsor: Ophirex, Inc.
No Placebo Group
Prior Safety Data
Approved in 2 jurisdictions
Trial Summary
What is the purpose of this trial?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
Do I have to stop taking my current medications for the trial?
The trial protocol does not specify if you must stop taking all current medications. However, you cannot participate if you are using certain anticoagulants or antiarrhythmic drugs within 14 days before treatment.
What data supports the idea that Varespladib for Snake Bites is an effective drug?
The available research shows that Varespladib is effective in treating snake bites by inhibiting a key venom component called phospholipase A2 (PLA2). In one study, 80% of mice treated with Varespladib and venom survived, while all mice given venom alone died. Another study found that Varespladib significantly reduced muscle damage and other toxic effects in animal models. These results suggest that Varespladib could be a promising alternative or addition to traditional antivenom treatments.
12345What safety data exists for Varespladib as a treatment?
Varespladib has been evaluated in 29 clinical studies involving over 4600 human subjects for non-snakebite conditions, where it was generally well-tolerated and considered safe. It is currently in Phase 2 clinical trials for snakebite treatment. Preclinical studies and animal models have shown promising results in inhibiting snake venom toxicity.
12345Is the drug Varespladib a promising treatment for snake bites?
Yes, Varespladib is a promising drug for treating snake bites. It works by blocking a key component in snake venom called phospholipase A2 (PLA2), which is responsible for many of the harmful effects of the venom. Studies have shown that Varespladib can effectively reduce the toxic effects of snake venom, improve survival rates in animal models, and potentially serve as a first-line treatment for snakebite envenomation.
12346Eligibility Criteria
Adults (18+) with a venomous snakebite within the last 10 hours can join this trial. They must have certain symptoms measured by an inclusion score and agree to informed consent. People with severe heart, bleeding, or liver conditions, kidney disease, allergies to varespladib, on certain anticoagulants or antiarrhythmics recently, pregnant or breastfeeding women cannot participate.Participant Groups
The BRAVIO study is testing IV varespladib followed by oral varespladib-methyl against placebos in addition to standard care for snakebites. It's a phase 2 trial where participants are randomly assigned treatments in a double-blind manner so neither they nor the researchers know who gets what.
2Treatment groups
Experimental Treatment
Active Control
Group I: Varespladib Intravenous Form (IV) + Varespladib Oral tablet (LY315920) + SOCExperimental Treatment2 Interventions
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.
Group II: Placebo Intravenous (IV) + Placebo Oral + SOCActive Control2 Interventions
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.
Varespladib is already approved in United States, India for the following indications:
🇺🇸 Approved in United States as Varespladib for:
- Snakebite envenoming
🇮🇳 Approved in India as Varespladib for:
- Snakebite envenoming
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Arizona Poison & Drug Information CenterTucson, AZ
Antelope Valley Medical CenterRosamond, CA
Duke University Medical CenterDurham, NC
Emergency Medicine, University of KentuckyLexington, KY
More Trial Locations
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Who is running the clinical trial?
Ophirex, Inc.Lead Sponsor
References
Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation. [2022]Phospholipase A₂s (PLA₂) is a major component of snake venom with diverse pathologic toxicities and, therefore, a potential target for antivenom therapy. Varespladib was initially designed as an inhibitor of mammal PLA₂s, and was recently repurposed to a broad-spectrum inhibitor of PLA₂ in snake venom. To evaluate the protective abilities of varespladib to hemorrhage, myonecrosis, and systemic toxicities that are inflicted by different crude snake venoms, subcutaneous ecchymosis, muscle damage, and biochemical variation in serum enzymes derived from the envenomed mice were determined, respectively. Varespladib treatment showed a significant inhibitory effect to snake venom PLA₂, which was estimated by IC50 in vitro and ED50 in vivo. In animal models, the severely hemorrhagic toxicity of D. acutus and A. halys venom was almost fully inhibited after administration of varespladib. Moreover, signs of edema in gastrocnemius muscle were remarkably attenuated by administration of varespladib, with a reduced loss of myonecrosis and desmin. Serum levels of creatine kinase, lactate dehydrogenase isoenzyme 1, aspartate transaminase, and alanine transaminase were down-regulated after treatment with varespladib, which indicated the protection to viscera injury. In conclusion, varespladib may be a potential first-line drug candidate in snakebite envenomation first aid or clinical therapy.
The synthetic varespladib molecule is a multi-functional inhibitor for PLA2 and PLA2-like ophidic toxins. [2021]Label="BACKGROUND">The treatment for snakebites is early administration of antivenom, which can be highly effective in inhibiting the systemic effects of snake venoms, but is less effective in the treatment of extra-circulatory and local effects. To complement standard-of-care treatments such as antibody-based antivenoms, natural and synthetic small molecules have been proposed for the inhibition of key venom components such as phospholipase A2 (PLA2) and PLA2-like toxins. Varespladib (compound LY315920) is a synthetic molecule developed and clinically tested aiming to block inflammatory cascades of several diseases associated with high PLA2s. Recent studies have demonstrated this molecule is able to potently inhibit snake venom catalytic PLA2 and PLA2-like toxins.
The BRAVO Clinical Study Protocol: Oral Varespladib for Inhibition of Secretory Phospholipase A2 in the Treatment of Snakebite Envenoming. [2023]Label="INTRODUCTION">Snakebite is an urgent, unmet global medical need causing significant morbidity and mortality worldwide. Varespladib is a potent inhibitor of venom secretory phospholipase A2 (sPLA2) that can be administered orally via its prodrug, varespladib-methyl. Extensive preclinical data support clinical evaluation of varespladib as a treatment for snakebite envenoming (SBE). The protocol reported here was designed to evaluate varespladib-methyl for SBE from any snake species in multiple geographies.
PLA2 Inhibitor Varespladib as an Alternative to the Antivenom Treatment for Bites from Nikolsky's Viper Vipera berus nikolskii. [2021]Although envenoming by a small East European species of viper is rarely severe, and only exceptionally fatal, lack of specific antivenom stocks in a few areas within this region and possible severe side effects of antivenom application leave most bites to be treated only with antihistamines and supportive therapy. Varespladib is an effective inhibitor of snake phospholipase, and, as such, it could be considered as first-line therapy. The Nikolsky's viper venom contains an extremely high concentration of phospholipase A2 (PLA2), responsible for the toxic effects of the venom, as well as minor amounts of other toxins. If Varespladib can successfully inhibit PLA2 activity, the Nikolsky's viper could be one of the first venomous snakes having an antitoxin-specific treatment regimen. To assess that, Varespladib was administered alone subcutaneously to adult male CD-1 mice (8 mg/kg) and compared to mice exposed to Vipera berus nikolskii crude venom (8 mg/kg = 10 LD50) or a combination of Varespladib and the same amount of the venom. Experimental animals were monitored for the presence of envenoming symptoms and mortality for 48 h after injection. Eighty percent of mice receiving both Varespladib and venom survived, while 100% of the control group receiving venom alone died within 4 h. Experimental results are consistent with Varespladib acting as an effective antitoxin in the mouse model against Nikolsky's viper venom. Further studies are needed under experimental conditions that more closely resemble natural envenoming (i.e., delayed administration).
Varespladib in the Treatment of Snakebite Envenoming: Development History and Preclinical Evidence Supporting Advancement to Clinical Trials in Patients Bitten by Venomous Snakes. [2023]The availability of effective, reliably accessible, and affordable treatments for snakebite envenoming is a critical and long unmet medical need. Recently, small, synthetic toxin-specific inhibitors with oral bioavailability used in conjunction with antivenom have been identified as having the potential to greatly improve outcomes after snakebite. Varespladib, a small, synthetic molecule that broadly and potently inhibits secreted phospholipase A2 (sPLA2s) venom toxins has renewed interest in this class of inhibitors due to its potential utility in the treatment of snakebite envenoming. The development of varespladib and its oral dosage form, varespladib-methyl, has been accelerated by previous clinical development campaigns to treat non-envenoming conditions related to ulcerative colitis, rheumatoid arthritis, asthma, sepsis, and acute coronary syndrome. To date, twenty-nine clinical studies evaluating the safety, pharmacokinetics (PK), and efficacy of varespladib for non-snakebite envenoming conditions have been completed in more than 4600 human subjects, and the drugs were generally well-tolerated and considered safe for use in humans. Since 2016, more than 30 publications describing the structure, function, and efficacy of varespladib have directly addressed its potential for the treatment of snakebite. This review summarizes preclinical findings and outlines the scientific support, the potential limitations, and the next steps in the development of varespladib's use as a snakebite treatment, which is now in Phase 2 human clinical trials in the United States and India.
Varespladib (LY315920) and Methyl Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting Neurotoxic Snake Venoms. [2021]The phospholipase A2 (PLA2) inhibitor Varespladib (LY315920) and its orally bioavailable prodrug, methyl-Varespladib (LY333013) inhibit PLA2 activity of a wide variety of snake venoms. In this study, the ability of these two forms of Varespladib to halt or delay lethality of potent neurotoxic snake venoms was tested in a mouse model. The venoms of Notechis scutatus, Crotalus durissus terrificus, Bungarus multicinctus, and Oxyuranus scutellatus, all of which have potent presynaptically acting neurotoxic PLA2s of variable quaternary structure, were used to evaluate simple dosing regimens. A supralethal dose of each venom was injected subcutaneously in mice, followed by the bolus intravenous (LY315920) or oral (LY333013) administration of the inhibitors, immediately and at various time intervals after envenoming. Control mice receiving venom alone died within 3 h of envenoming. Mice injected with O. scutellatus venom and treated with LY315920 or LY333013 survived the 24 h observation period, whereas those receiving C. d. terrificus and B. multicinctus venoms survived at 3 h or 6 h with a single dose of either form of Varespladib, but not at 24 h. In contrast, mice receiving N. scutatus venom and then the inhibitors died within 3 h, similarly to the control animals injected with venom alone. LY315920 was able to reverse the severe paralytic manifestations in mice injected with venoms of O. scutellatus, B. multicinctus, and C. d. terrificus. Overall, results suggest that the two forms of Varespladib are effective in abrogating, or delaying, neurotoxic manifestations induced by some venoms whose neurotoxicity is mainly dependent on presynaptically acting PLA2s. LY315920 is able to reverse paralytic manifestations in severely envenomed mice, but further work is needed to understand the significance of species-specific differences in animal models as they compare to clinical syndromes in human and for potential use in veterinary medicine.