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Early Fungicidal Activity as a Candidate Surrogate Endpoint for All-Cause Mortality in Cryptococcal Meningitis: A
Jairo M Montezuma-Rusca1, John H Powers2, Dean Follmann3
1Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
Background:
Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality. In clinical trials evaluating treatments for CM, biomarkers of early fungicidal activity (EFA) in cerebrospinal fluid (CSF) have been proposed as candidate surrogate endpoints for all- cause mortality (ACM). However, there has been no systematic evaluation of the group-level or trial-level evidence for EFA as a candidate surrogate endpoint for ACM.
Methods:
We conducted a systematic review of randomized trials in treatment of CM to evaluate available evidence for EFA measured as culture negativity at 2 weeks/10 weeks and slope of EFA as candidate surrogate endpoints for ACM. We performed sensitivity analysis on superiority trials and high quality trials as determined by Cochrane measures of trial bias.
Results:
Twenty-seven trials including 2854 patients met inclusion criteria. Mean ACM was 15.8% at 2 weeks and 27.0% at 10 weeks with no overall significant difference between test and control groups. There was a statistically significant group-level correlation between average EFA and ACM at 10 weeks but not at 2 weeks. There was also no statistically significant group-level correlation between CFU culture negativity at 2weeks/10weeks or average EFA slope at 10 weeks. A statistically significant trial-level correlation was identified between EFA slope and ACM at 2 weeks, but is likely misleading, as there was no treatment effect on ACM.
Conclusions:
Mortality remains high in short time periods in CM clinical trials. Using published data and Institute of Medicine criteria, evidence for use of EFA as a surrogate endpoint for ACM is insufficient and could provide misleading results from clinical trials. ACM should be used as a primary endpoint evaluating treatments for cryptococcal meningitis.
Insights
Early fungicidal activity (EFA) is not a reliable surrogate for cryptococcal meningitis (CM) mortality. All-cause mortality (ACM) should remain the primary endpoint in CM clinical trials to avoid misleading results.
Area of Science:
- Infectious Diseases
- Clinical Trials
- Biomarkers
Background:
- Cryptococcal meningitis (CM) is a major cause of death in HIV patients.
- Early fungicidal activity (EFA) in cerebrospinal fluid (CSF) is proposed as a surrogate endpoint for all-cause mortality (ACM) in CM clinical trials.
- Previous systematic evaluations of EFA as a surrogate endpoint for ACM are lacking.
Purpose of the Study:
- To systematically review evidence for EFA as a surrogate endpoint for ACM in CM treatment trials.
- To evaluate EFA measured by culture negativity and slope as candidate surrogate endpoints.
- To assess group-level and trial-level evidence for EFA's surrogate endpoint validity.
Main Methods:
- Systematic review of randomized controlled trials (RCTs) for CM treatment.
- Inclusion of 27 trials with 2854 patients.
- Sensitivity analysis on superiority and high-quality trials using Cochrane measures.
Main Results:
- No significant overall difference in ACM between treatment groups.
- A significant group-level correlation between average EFA and ACM at 10 weeks, but not at 2 weeks.
- No significant group-level correlation for culture negativity or EFA slope; a misleading trial-level correlation for EFA slope was observed.
Conclusions:
- Mortality rates in short-term CM trials remain high.
- Evidence for EFA as a surrogate endpoint for ACM is insufficient and potentially misleading.
- All-cause mortality (ACM) should be the primary endpoint for evaluating CM treatments.
