Psychometric Evaluation of the Snakebite Severity Score (SSS) in a Multinational Randomized Clinical Trial

Background: Snakebite envenomation (SBE) is a World Health Organization recognized neglected tropical disease (NTD) affecting 1.8 million annually. Currently SBE research lacks standardized, patient-centered outcome measures, hindering comparability and clinical relevance. The Snakebite Severity Score (SSS) is a composite endpoint developed to assess symptom severity across multiple body systems. The present study evaluates the psychometric properties of the SSS using data from the BRAVO Phase 2b clinical trial of varespladib-methyl. Methods: A secondary analysis was conducted using data from the BRAVO clinical trial (NCT04996264), a randomized, double-blind, placebo-controlled Phase 2b study evaluating varespladib-methyl. Patients aged [≥]5 years with symptomatic SBE were enrolled from emergency departments in India and the US. The SSS and modified versions (6-item and 3-item) were administered at baseline and at multiple follow-up time points: 3, 6, and 9 hours post-envenomation, and on days 2, 3, 7, 14, and 28. Psychometric analyses included descriptive statistics, intraclass correlation coefficients (ICC) for reliability, principal component analysis (PCA) for internal structure, and correlations with patient-reported outcomes (PSFS, PGIC, NPRS) and clinician-rated CGI-I for external validity. Results: Ninety-five participants were analyzed (varespladib: n=45; placebo: n=50). The 6-item SSS demonstrated strong reliability (ICC = 0.8 at Days 7-14) and consistent internal structure across subscores. PCA confirmed multidimensionality, with distinct contributions from local wound, nervous system, hematological, and other subscales. External validity was supported through moderate to strong correlations with PGIC, NPRS, and CGI-I, particularly for applications capturing symptom variation over time (AUC, mean scores). The 6-item SSS captured symptom severity more robustly than the 3-item version. Conclusion: The SSS is a reliable and valid multidimensional composite endpoint for assessing clinical severity in SBE. Applications that integrate symptom change over time demonstrate better external validity and are preferable. Findings support SSS use in clinical research to standardize and improve outcome assessment in SBE.