Amphotericin B for Non-HIV Cryptococcal Meningitis Patients

The primary end point was mortality rate at 4 weeks after randomization. Mortality was treated as a binary variable, and the generalized linear model (GLM) was used for non-inferiority test. Point estimation and one-sided 95% confidence interval (CI) estimation of mortality difference between the two groups will be performed. If the upper limit value of 95% CI is less than 0.10 of the non-inferiority margin, the research result is considered to be in line with the non-inferiority margin. Kaplan-meier was used to draw the four week survival curves of the two groups, and log rank method was used to test the survival curves. Cox proportional hazard regression model was used to analyze the risk of death (HR) and 95% CI of the two groups. Sensitivity analysis: in the above analysis, the patients who lost the follow-up within 4 weeks were excluded for sensitivity analysis; The above non inferiority test GLM analysis and cox model included confounding variables (baseline Log10 fungal load, w

All recorded longitudinal quantitative fungal count measurements up to day 35 (allowing for some delays in the day 28 measurements) will be included in the analysis. EFA will be modeled based on a linear mixed effects model with longitudinal log10-CSF quantitative culture fungal counts as the outcome, interaction terms between the treatment groups and the time since enrolment of the measurement as fixed covariates and random patient-specific intercepts and slopes. The lowest measurable quantitative count is 5 CFU/ml and values below the detection limit (which correspond to recorded values of 0) will be treated as <4.5 CFU/ml, i.e. non-detectable measurements will be treated as left-censored longitudinal observations in the analysis. Based on this model, EFA will be compared between the 3 treatment arms in all patients (intention to treat), in the per-protocol population, and subgroups defined by immune status (immunocompromised; immunocompetent) and baseline fungal burden.

Overall survival will be visualized using Kaplan-Meier curves and modeled using the Cox proportional hazards regression model with stratification by immune status. In addition, survival will be modeled with a multivariable Cox regression model including the following covariates in addition to the treatment group: baseline log10-fungal load, Glasgow coma score less than 15 (yes or no) and immune status.

The disability score at week 10 follow-up is defined as the higher (worse) of " the three simple questions" and the modified Rankin score assessed at that time point, and will be categorized as good outcome, intermediate disability, severe disability, or death (in case the patient died before 10 weeks) as previously described (wellcome-45). The ordinal 10-week score ("good">"intermediate">"severe"> "death") will be compared between the 3 arms with a proportional odds logistic regression model depending on the treatment arm. The result will be summarized as a cumulative odds ratio with corresponding 95% confidence interval and P value. Patients lost to follow up will be analyzed according to their last recorded disability status. If the rate of patients lost to follow-up exceeds 10%, we will also perform an alternative analysis based on multiple imputation of missing values. The three simple questions and the modified Rankin score are listed in Appendix 4.

The frequency of serious and grade 3&4 adverse reactions as well as the frequency of specific adverse events will be summarized (both in terms of the total number of events as well as the number of patients with at least one event). The proportion of patients with at least one such event (overall and for each specific event separately) will be summarized and (informally) compared between the 3 treatment groups based on χ2 test or Fisher's exact test, as appropriate. 6) Visual deficit at 10 weeks and 6 months

The visual acuity at 10 weeks is recorded on a 6 point scale (see Appendix 5) and will be summarized by treatment arm for each eye separately, and overall where "overall" is defined as the worst recorded acuity of either eye. The odds of having "normal acuity" (amongst all surviving patients with a visual assessment) will be informally compared between the treatment arms with a logistic regression model adjusted for immune status.

The time to the first new neurological event or death until 10 weeks will be analyzed in the same way as overall survival. Longitudinal measurements of intracranial pressure during the first 2 weeks will be modeled using a mixed effect model as described for the primary outcome.

The rate of IRIS and the rate of relapse (defined as antifungal treatment intensification or re-treatment) will be modeled with cause-specific proportional hazards models with treatment as the only covariate and stratification by immune status.