Cerebrospinal fluid early fungicidal activity as a surrogate endpoint for cryptococcal meningitis survival in clinical trials. Pullen, M. F., Hullsiek, K. H., Rhein, J., Musubire, A. K., Tugume, L., Nuwagira, E., Abassi, M., Ssebambulidde, K., Mpoza, E., Kiggundu, R., Akampurira, A., Nabeta, H. W., Schutz, C., Evans, E. E., Rajasingham, R., Skipper, C. P., Pastick, K. A., Williams, D. A., Morawski, B. M., Bangdiwala, A. S., Meintjes, G. A, Muzoora, C., Meya, D. B., & Boulware, D. R. Clinical Infectious Diseases, 71(7):e45–e49, jan, 2020. ![Cerebrospinal fluid early fungicidal activity as a surrogate endpoint for cryptococcal meningitis survival in clinical trials [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex 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 \textgreater = 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 \textless 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA \textless 0.20 to those with EFA \textgreater = 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 \textless .01) and lower proportion of patients with CSF pleocytosis (P \textless .001). CONCLUSIONS: EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of \textgreater = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA \textless 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.
@article{Pullen2020,
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 {\textgreater} = 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 {\textless} 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA {\textless} 0.20 to those with EFA {\textgreater} = 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 {\textless} .01) and lower proportion of patients with CSF pleocytosis (P {\textless} .001). CONCLUSIONS: EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of {\textgreater} = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37{\%}) compared to 50{\%} mortality with EFA {\textless} 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.},
author = {Pullen, Matthew F. and Hullsiek, Katherine Huppler and Rhein, Joshua and Musubire, Abdu K. and Tugume, Lillian and Nuwagira, Edwin and Abassi, Mahsa and Ssebambulidde, Kenneth and Mpoza, Edward and Kiggundu, Ruben and Akampurira, Andrew and Nabeta, Henry W. and Schutz, Charlotte and Evans, Emily E. and Rajasingham, Radha and Skipper, Caleb P. and Pastick, Katelyn A. and Williams, Darlisha A. and Morawski, Bozena M. and Bangdiwala, Ananta S. and Meintjes, Graeme A and Muzoora, Conrad and Meya, David B. and Boulware, David R.},
doi = {10.1093/cid/ciaa016},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Pullen et al. - 2020 - Cerebrospinal fluid early fungicidal activity as a surrogate endpoint for cryptococcal meningitis survival in cli.pdf:pdf;:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Pullen et al. - 2020 - Cerebrospinal fluid early fungicidal activity as a surrogate endpoint for cryptococcal meningitis survival in (2).pdf:pdf},
issn = {15376591},
journal = {Clinical Infectious Diseases},
keywords = {cryptococcal meningitis,cryptococcus,early fungicidal activity,fund{\_}ack,meningitis,original,surrogate endpoint},
mendeley-tags = {fund{\_}ack,original},
month = {jan},
number = {7},
pages = {e45--e49},
pmid = {31912875},
title = {{Cerebrospinal fluid early fungicidal activity as a surrogate endpoint for cryptococcal meningitis survival in clinical trials}},
url = {https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa016/5698219},
volume = {71},
year = {2020}
}
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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 \\textgreater = 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 \\textless 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA \\textless 0.20 to those with EFA \\textgreater = 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 \\textless .01) and lower proportion of patients with CSF pleocytosis (P \\textless .001). CONCLUSIONS: EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of \\textgreater = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA \\textless 0.20. This EFA threshold may be considered a target for a surrogate endpoint. 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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 {\\textgreater} = 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 {\\textless} 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA {\\textless} 0.20 to those with EFA {\\textgreater} = 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 {\\textless} .01) and lower proportion of patients with CSF pleocytosis (P {\\textless} .001). CONCLUSIONS: EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of {\\textgreater} = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37{\\%}) compared to 50{\\%} mortality with EFA {\\textless} 0.20. This EFA threshold may be considered a target for a surrogate endpoint. 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