Assessing Statistical Methods for Estimating the Cerebrospinal Fluid Early Fungicidal Activity as an Endpoint for Cryptococcal Meningitis Clinical Trials: A Systematic Review and Simulation Study.

Background: Cryptococcal meningitis is a life-threatening infection of the central nervous system. Early fungicidal activity (EFA), which measures how quickly Methods: We conducted a systematic literature review to summarize the usage and reporting of both methods in cryptococcal meningitis clinical trials. We then evaluated their performance and operating characteristics under various simulation scenarios and applied both approaches to data from a phase 2 trial. Results: The 2-step approach and mixed model approach yielded discrepant CSF EFA estimates across literature review, simulation experiments, and real data analysis. The 2-step approach using linear regression produced steeper estimates and larger estimated treatment effects. The linear mixed model yielded smaller standard errors but estimates were biased toward the null, especially when early culture sterility was common. Conclusions: The 2-step approach is preferred for estimating EFA in cryptococcal meningitis studies, especially when early culture sterility occurs. EFA estimates should not be interpreted or compared across studies without accounting for the underlying statistical models and data preprocessing.