A Multi-center, Prospective, Randomized Trial of Amphotericin B in the Initial Antifungal Therapy for Non-HIV Cryptococcal Meningitis Patients
试验速览
- 阶段
- 4 期
- 状态
- Enrolling By Invitation
- 入组人数
- 250
- 试验地点
- 2
- 主要终点
- Mortality rate at 4 weeks after randomization.
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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 > 2×ULN and bilirubin > 1.5×ULN, or ALT or AST > 3×ULN, or bilirubin > 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
研究组 & 干预措施
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
干预措施: Amphotericin B 0.7 mg/kg/day i.v. combined with flucytosine four times per day orally for the first 4 weeks. (Drug)
Low dose amphotericin B (0.5 mg/kg/d)
Amphotericin B 0.5 mg/kg/day i.v. plus flucytosine for 4 weeks
干预措施: Amphotericin B 0.5 mg/kg/day i.v. combined with flucytosine four times per day orally for the first 4 weeks. (Drug)
结局指标
主要结局
Mortality rate at 4 weeks after randomization.
时间窗: 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
次要结局
- Time to new neurological event or death until 10 weeks(up to 10 weeks)
- Disability at 10 weeks and 6 months(up to 6 months)
- Visual deficit at 10 weeks and 6 months(up to 6 months)
- EFA rate at 2 weeks after randomization(2 weeks)
- urvival until 2 weeks, 10 weeks and 6 months after randomization(up to 6 months)
- Adverse events(4 weeks)
- Rate of IRIS at 10 weeks and 6 months(up to 6 months)