Cerebrospinal fluid early fungicidal activity as a surrogate endpoint for cryptococcal meningitis survival in clinical trials


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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.

Original languageEnglish (US)
Pages (from-to)E45-E49
JournalClinical Infectious Diseases
Issue number7
StatePublished - Oct 1 2020

Bibliographical note

Funding Information:
This research was supported by the National Institute of Neurologic Diseases and Stroke and Fogarty International Center ((R01NS086312, K01TW010268, R25TW009345, K43TW010718), the National Institute of Allergy and Infectious Diseases (U01AI089244, T32AI055433), United Kingdom Medical Research Council / DfID / Wellcome Trust Global Clinical Trials (M007413/1), and Grand Challenges Canada (S4-0296-01). G. M. was supported by the Wellcome Trust (098316 and 203135/Z/16/Z), the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (grant 64787), NRF incentive funding (UID: 85858) and the South African Medical Research Council through its Tuberculosis and Human Immunodeficiency Virus Collaborating Centres Programme with funds received from the National Department of Health (RFA SAMRC-RFA-CC: TB/HIV/AIDS-01-2014).

Publisher Copyright:
© 2020 The Author(s).


  • Cryptococcal meningitis
  • Cryptococcus
  • Early fungicidal activity
  • Meningitis
  • Surrogate endpoint


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