Evaluation of Efficacy and Safety of Low-Dose Liposomal Amphotericin B in Prophylaxis of Invasive Fungal Infections Among Children With Prolonged Neutropenia: A Clinical Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Incidence of Proven or Probable Invasive Fungal Disease
研究概览
简要总结
This is a single-center, single-arm, observational clinical study evaluating the efficacy and safety of low-dose liposomal amphotericin B (1 mg/kg/day, intravenous, once daily) for the prevention of invasive fungal infections in children aged 3-17 years with hematological malignancies who develop prolonged neutropenia (absolute neutrophil count ≤ 0.5×10^9/L, expected to last > 7 days) and are at high risk for invasive fungal disease. Participants are those who, per the treating physician's routine clinical decision, have been initiated on liposomal amphotericin B prophylaxis at 1 mg/kg/day due to intolerance or toxicity to other antifungal agents. The primary outcome is the incidence of proven or probable invasive fungal disease. Secondary outcomes include incidence of pneumonia, persistent unexplained fever >4 days, use of additional systemic antifungal therapy, and adverse events. A total of 30 participants will be enrolled. Data will be collected at baseline, during treatment, and within 7 days after treatment completion.
详细描述
Invasive fungal disease (IFD) is a serious and life-threatening infection caused by pathogenic fungi such as Candida, Aspergillus, and Mucorales, commonly affecting immunocompromised patients with hematological malignancies and those undergoing hematopoietic stem cell transplantation. The incidence of IFD has increased significantly in recent years due to the use of intensive chemotherapy and immunosuppressive agents, which result in prolonged and profound neutropenia (absolute neutrophil count < 500/μL for ≥10 days). Effective antifungal prophylaxis is a critical strategy to reduce IFD-related morbidity and mortality in this high-risk population.
Liposomal amphotericin B (L-AmB) is a broad-spectrum antifungal agent with potent activity against most pathogenic fungi, including azole-resistant strains such as certain Aspergillus and Mucorales species. It is recommended by multiple guidelines as a first-line treatment for candidemia, invasive aspergillosis, and mucormycosis. However, its optimal prophylactic dosing regimen remains unclear, with published studies using widely varying regimens ranging from fixed low-dose (e.g., 50 mg every other day) to intermittent high-dose schedules (e.g., 5 mg/kg twice weekly).
This study proposes a novel prophylactic regimen of L-AmB at a fixed low dose of 50 mg/day (approximately 1 mg/kg/day) administered intravenously once daily. This regimen is designed to provide sustained, continuous drug exposure throughout the high-risk neutropenic period, potentially offering superior protection compared to intermittent high-dose schedules while maintaining a favorable safety profile.
This is a single-center, single-arm, observational clinical study. Participants will be children aged 3-17 years with hematological malignancies who meet the NCCN 2025 V1 guideline criteria for high-risk IFD, including allogeneic hematopoietic stem cell transplantation, autologous hematopoietic cell transplantation with mucosal damage, acute leukemia, grade 3/4 graft-versus-host disease, myelodysplastic syndrome, or other conditions with expected neutropenia >7 days. Participants must have been initiated on L-AmB prophylaxis at 1 mg/kg/day by the treating physician in routine clinical practice due to intolerance or toxicity to other antifungal agents. Key exclusion criteria include prior proven/probable IFD, active fungal infection at screening, significant hypokalemia, severe hepatic or renal impairment, and NYHA Class III/IV heart failure.
A total of 30 participants will be enrolled. Data will be collected at three time points: baseline (Day -3 to 0), treatment period (from Day 1 until the end of L-AmB therapy), and follow-up (within 7 days after treatment completion). Assessments include complete blood counts, serum biochemistry, imaging (chest CT), microbiological tests (G/GM tests, blood cultures, bronchoalveolar lavage fluid cultures or NGS), and recording of neutropenia episodes, fever, pneumonia, and adverse events. IFD diagnosis will be classified according to the Sixth Revised Edition of the Diagnostic Criteria and Treatment Principles for Invasive Fungal Disease in Patients with Hematological Malignancies.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 3 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 3 to 17 years (inclusive), both sexes.
- •Meets NCCN 2025 V1 guideline criteria for high-risk invasive fungal disease, including allogeneic hematopoietic stem cell transplantation, autologous hematopoietic cell transplantation with mucosal damage, acute leukemia, grade 3/4 graft-versus-host disease, myelodysplastic syndrome, lymphoma(a), multiple myeloma(a), chronic lymphocytic leukemia(a), treatment with purine analogues (fludarabine, clofarabine, nelarabine), chimeric antigen receptor (CAR) T-cell therapy, alemtuzumab therapy, with expected neutropenia >7 days(b) and accompanied by agranulocytosis.
- •Note (a): For these heterogeneous diseases, myeloablative therapy must be met; if neutropenia >7 days is not met, the patient should be excluded.
- •Note (b): Agranulocytosis is defined as absolute neutrophil count ≤0.5×10^9/L, or absolute neutrophil count ≤1×10^9/L with expected decline to ≤0.5×10^9/L within 48 hours.
- •Assessed by the study physician as having high-risk for invasive fungal infection, intolerant or unable to use other antifungal agents due to toxicity or other reasons, and the treating physician has independently decided in routine clinical practice to initiate liposomal amphotericin B for antifungal prophylaxis for 3-5 days, with the selected dosage regimen of 1 mg/kg/day, intravenous, once daily.
- •Patient or legally authorized representative has voluntarily signed the informed consent form.
排除标准
- •Allergy to any component of liposomal amphotericin B, or development of serious adverse events during the initial 3-5 days of prophylactic use.
- •Prior history of proven or probable invasive fungal disease (IFD).
- •Presence of pneumonia, unexplained fever, or clinical/imaging evidence suggestive of or diagnosed as fungal infection during screening.
- •Clinically significant hypokalemia (defined as serum potassium <3.2 mmol/L, or below the lower limit of normal while receiving digitalis therapy) that cannot be corrected before starting trial treatment.
- •Hepatic dysfunction with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥5× upper limit of normal (ULN), or total bilirubin ≥3× ULN.
- •Renal impairment requiring or currently undergoing hemodialysis or peritoneal dialysis.
- •New York Heart Association (NYHA) Class III/IV heart failure.
- •Positive for human immunodeficiency virus (HIV) antibody or Treponema pallidum hemagglutination assay (TPHA).
- •Expected survival <3 months.
- •Pregnant or breastfeeding women, or women of childbearing potential who are not using contraception and planning pregnancy.
- •Any other condition that the investigator considers inappropriate for participation in the clinical trial.
结局指标
主要结局
Incidence of Proven or Probable Invasive Fungal Disease
时间窗: From baseline to 7 days after the end of antifungal prophylaxis treatment
Proven or probable invasive fungal disease (IFD) diagnosed according to the Sixth Revised Edition of the Diagnostic Criteria and Treatment Principles for Invasive Fungal Disease in Patients with Hematological Malignancies. Proven IFD requires histopathological evidence or positive culture from a sterile site. Probable IFD requires the presence of host factors, clinical features, and mycological evidence.
次要结局
- Incidence of Pneumonia With No Identified Pathogen(From baseline to 7 days after the end of antifungal prophylaxis treatment)
- Proportion of Participants With Persistent Unexplained Fever >4 Days(From baseline to 7 days after the end of antifungal prophylaxis treatment)
- Proportion of Participants Requiring Additional Systemic Antifungal Therapy(From baseline to 7 days after the end of antifungal prophylaxis treatment)
- Discontinuation Rate of Liposomal Amphotericin B Due to Adverse Effects or Intolerance(Throughout the treatment period (from Day 1 to the end of liposomal amphotericin B therapy))
- Incidence of Adverse Events(From baseline to 7 days after the end of antifungal prophylaxis treatment)