Clinical trial NCT06178627: Amphotericin B for Non-HIV Cryptococcal Meningitis Patients
Official title: A Multi-center, Prospective, Randomized Trial of Amphotericin B in the Initial Antifungal Therapy for Non-HIV Cryptococcal Meningitis Patients
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE4
Conditions: Cryptococcal Meningitis
Antifungal Agents
Keywords: Cryptococcal Meningitis
Antifungal agents
amphotericin B
non-HIV
Lead sponsor: Huashan Hospital
Sponsor class: OTHER
First posted: 2023-12-21
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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 \&gt; 2×ULN and bilirubin \&gt; 1.5×ULN, or ALT or AST \&gt; 3×ULN, or bilirubin \&gt; 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

Primary outcomes:
measure: Mortality rate at 4 weeks after randomization.
timeFrame: 4 weeks
Secondary outcomes:
measure: EFA rate at 2 weeks after randomization
timeFrame: 2 weeks
measure: urvival until 2 weeks, 10 weeks and 6 months after randomization
timeFrame: up to 6 months
measure: Disability at 10 weeks and 6 months
timeFrame: up to 6 months
measure: Adverse events
timeFrame: 4 weeks
measure: Visual deficit at 10 weeks and 6 months
timeFrame: up to 6 months
measure: Time to new neurological event or death until 10 weeks
timeFrame: up to 10 weeks
measure: Rate of IRIS at 10 weeks and 6 months
timeFrame: up to 6 months
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Huashan Hospital
state: Shanghai
city: Nanning
country: China
facility: The Fourth People's Hospital of Nanning
Study officials:
References:
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