Amphotericin B for Non-HIV Cryptococcal Meningitis Patients (ABNCM)

December 11, 2023 updated by: Li-Ping Zhu, Huashan Hospital

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

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 (<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 (< 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.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

250

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
      • Nanning, China, 530000
        • The Fourth People's Hospital of Nanning
    • Shanghai
      • Shanghai, Shanghai, China, 200040
        • Huashan Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age more than 18 years
  2. HIV antibody negative
  3. 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
  4. Having no severe immunocompromised conditions
  5. Informed consent to participate given by patient or acceptable representative

Exclusion Criteria:

  1. Previously cryptococcal disease
  2. Currently receiving treatment for cryptococcal meningitis and having received ≥72 hours of anti-cryptococcal meningitis therapy in 96 hours
  3. Creatinine clearance lower than 80 ml/min
  4. Liver dysfunction (defined as ALT or AST > 2×ULN and bilirubin > 1.5×ULN, or ALT or AST > 3×ULN, or bilirubin > 2×ULN)
  5. Liver cirrhosis or chronic liver failure
  6. Pregnancy or breast-feeding
  7. Known allergy to study drugs
  8. Failure to consent - the patient, or if they are incapacitated, their responsible relative, declines to enter the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional 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)
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.
Different amphotericin B dosage
Experimental: Low dose amphotericin B (0.5 mg/kg/d)
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.
Different amphotericin B dosage

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality rate at 4 weeks after randomization.
Time Frame: 4 weeks
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
Time Frame: 2 weeks
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
Time Frame: up to 6 months
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
Time Frame: up to 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
Time Frame: 4 weeks
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
Time Frame: up to 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
Time Frame: up to 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
Time Frame: up to 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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Huashan Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 13, 2023

Primary Completion (Estimated)

August 31, 2025

Study Completion (Estimated)

August 31, 2026

Study Registration Dates

First Submitted

December 4, 2023

First Submitted That Met QC Criteria

December 11, 2023

First Posted (Estimated)

December 21, 2023

Study Record Updates

Last Update Posted (Estimated)

December 21, 2023

Last Update Submitted That Met QC Criteria

December 11, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Huashan Hospital ID

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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