Intravenous Followed by Oral Varespladib as Late Adjunctive Therapy for Snakebite: a Phase II Randomized Clinical Trial

Background: Snakebite envenoming causes an estimated 138,000 deaths and more than 400,000 cases of permanent disability each year, disproportionately affecting low-resource regions. Antivenom is the only treatment but requires intravenous administration. We evaluated intravenous followed by oral varespladib as adjunctive therapy to antivenom in hospitalized patients with snakebite envenoming. Methods and findings: In this multicenter, randomized, double-blind, placebo-controlled phase II trial in India (CTRI/2023/10/058782) and the USA (NCT05717062), patients with snakebite envenoming were randomly assigned (1:1) to receive varespladib or placebo in addition to standard of care. For elapid envenoming, the primary endpoint was time to recovery of 5-second head-lift. For viper envenoming, the primary endpoint was area under the curve (AUC) from baseline to Day 14 of a 3-item Snakebite Severity Score (SSS). Between June 3rd, 2023 and October 19th, 2024, 140 patients were randomized and 139 were analyzed (73 varespladib; 66 placebo). Study drug was initiated a mean of 7.3 hours after the bite and 3.3 hours after antivenom. Among elapid-bite patients, mean time to head-lift recovery was 27.6 hours with varespladib vs. 36.2 hours with placebo (p = 0.6). Among viper-bite patients, SSS AUC to Day 14 was 660 vs. 629 in varespladib vs. placebo (p = 0.7). No serious adverse event occurred with varespladib. Conclusions: In this trial in which varespladib was initiated on average 7 hours after snakebite and several hours after antivenom, adjunctive varespladib did not improve the primary endpoints. Other study designs and settings will be needed to assess the effect of varespladib when initiated prior to antivenom.