1. Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials.
- Author
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Pullen, Matthew F, Hullsiek, Katherine Huppler, Rhein, Joshua, Musubire, Abdu K, Tugume, Lillian, Nuwagira, Edwin, Abassi, Mahsa, Ssebambulidde, Kenneth, Mpoza, Edward, Kiggundu, Ruben, Akampurira, Andrew, Nabeta, Henry W, Schutz, Charlotte, Evans, Emily E, Rajasingham, Radha, Skipper, Caleb P, Pastick, Katelyn A, Williams, Darlisha A, Morawski, Bozena M, and Bangdiwala, Ananta S
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CEREBROSPINAL fluid examination , *AMPHOTERICIN B , *ANTIFUNGAL agents , *CLINICAL trials , *CRYPTOCOCCUS neoformans , *CULTURES (Biology) , *FUNGI , *MENINGITIS , *REGRESSION analysis , *SURVIVAL , *SECONDARY analysis , *PROPORTIONAL hazards models , *DESCRIPTIVE statistics , *FLUCONAZOLE , *COLONY-forming units assay , *PHARMACODYNAMICS - Abstract
Background In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. Methods We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010–2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. Results Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40–0.59 (n = 182), 39% for 0.30–0.39 (n = 112), 35% for 0.20–0.29 (n = 87), and 50% for those with EFA < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P < .01) and lower proportion of patients with CSF pleocytosis (P < .001). Conclusions EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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