Amphotericin B for Non-HIV Cryptococcal Meningitis Patients

Study Overview
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Brief Summary
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Cryptococcus neoformans and C. gatti are important causes of central nervous system (CNS) infections with significant mortality, remaining a great public health challenge worldwide. Commonly seen as an opportunistic infection in adults with HIV/AIDS, cryptococcal meningitis (CM) accounts for 15% of HIV-related mortality globally [1]. In addition, a growing number of non-HIV CM patients have been observed in recent years with fatality approaching 30% in some areas [2,3]. It occurs in both those with natural or iatrogenic immunosuppression, as well as the apparently immunocompetent individuals. Approximately 65-70% of non-HIV CM patients were without any predisposing factors, particularly in the East Asia [4,5]. With the increasing number of hematopoietic stem cell transplantation, solid organ transplantation recipients and administration of immunosuppressive and corticosteroids agents, this illness will assume even greater public health significance. Current Infectious Disease Society of America (IDSA) guideline suggest the use of combination antifungal therapy: normal dose amphotericin (0.7-1mg/kg/day) combined with flucytosine for a minimum of 4 weeks, followed by fluconazole (600-800 mg/day) for a minimum of 10 weeks in total for HIV patients [6]. However, for non-HIV and immunocompetent patients, the treatment remains controversial. IDSA guideline recommended that the treatment of non-HIV patients could refer to the treatment of HIV patients. That is, amphotericin B combined with flucytosine is still administered in the induction period. However, as amphotericin B have nonspecific effect on ergosterol, it has strong side effects (hepatorenal toxicity, electrolyte disorder, anemia, ventricular fibrillation, etc.). Therefore, the dose of amphotericin B may not be appropriate for Asian patients due to the different drug metabolism and pharmacokinetic. In the prospective studies of Bennett[7] and Dismuke[8], low dose amphotericin B (0.3 mg/kg/d) combined with flucytosine achieved response rates of 66% and 85% at 6 weeks, respectively. A similar conclusion was also extracted from a large multicenter retrospective study that low dose amphotericin B (&lt;0.7 mg/kg/d) combined with flucytosine for a minimum of 2 weeks, followed by fluconazole could achieve a response rate of 84%, indicating that the efficacy of low dose amphotericin B (&lt; 0.7 mg/kg/d) may be equivalent with normal dose in non-HIV patients. Therefore, we plan to conduct a prospective, multicenter, open-label randomized controlled study to compare the efficacy and safety of normal dose amphotericin B (0.7 mg/kg/ d) and low dose amphotericin B (0.5 mg/kg/d) in the initial antifungal treatment for non-HIV cryptococcal meningitis patients.

Official Title
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A Multi-center, Prospective, Randomized Trial of Amphotericin B in the Initial Antifungal Therapy for Non-HIV Cryptococcal Meningitis Patients

Conditions
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Cryptococcal Meningitis, Antifungal Agents

Intervention / Treatment
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* Drug: Amphotericin B 0.5 mg/kg/day i.v. combined with flucytosine four times per day orally for the first 4 weeks.
* Drug: Amphotericin B 0.7 mg/kg/day i.v. combined with flucytosine four times per day orally for the first 4 weeks.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age more than 18 years HIV antibody negative Cryptococcal meningitis defined as a syndrome consistent with CM and one or more of: 1) positive CSF India ink (budding encapsulated yeasts), 2) C.neoformans cultured from CSF or blood, 3) positive cryptococcal antigen Lateral Flow Antigen Test (LFA) in CSF, 4) positive brain tissue representing Cryptococcus Having no severe immunocompromised conditions Informed consent to participate given by patient or acceptable representative Exclusion Criteria: Previously cryptococcal disease Currently receiving treatment for cryptococcal meningitis and having received ≥72 hours of anti-cryptococcal meningitis therapy in 96 hours Creatinine clearance lower than 80 ml/min Liver dysfunction (defined as ALT or AST &gt; 2×ULN and bilirubin &gt; 1.5×ULN, or ALT or AST &gt; 3×ULN, or bilirubin &gt; 2×ULN) Liver cirrhosis or chronic liver failure Pregnancy or breast-feeding Known allergy to study drugs Failure to consent - the patient, or if they are incapacitated, their responsible relative, declines to enter the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Normal dose amphotericin B (0.7 mg/kg/d)<br>Study regimen 1: amphotericin B 0.7 mg/kg/day i.v. plus flucytosine for 4 weeks | Drug: Amphotericin B 0.7 mg/kg/day i.v. combined with flucytosine four times per day orally for the first 4 weeks.<br>* Different amphotericin B dosage<br>|
| Experimental: Low dose amphotericin B (0.5 mg/kg/d)<br>Amphotericin B 0.5 mg/kg/day i.v. plus flucytosine for 4 weeks | Drug: Amphotericin B 0.5 mg/kg/day i.v. combined with flucytosine four times per day orally for the first 4 weeks.<br>* Different amphotericin B dosage<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality rate at 4 weeks after randomization. | 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 | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFA rate at 2 weeks after randomization | 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. | 2 weeks | 
| urvival until 2 weeks, 10 weeks and 6 months after randomization | 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. | up to 6 months | 
| Disability at 10 weeks and 6 months | 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. | up to 6 months | 
| Adverse events | 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 | 4 weeks | 
| 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. | up to 6 months | 
| Time to new neurological event or death until 10 weeks | 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. | up to 10 weeks | 
| Rate of IRIS at 10 weeks and 6 months | 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. | up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cryptococcal Meningitis, Antifungal agents, amphotericin B, non-HIV