A Randomized Trial of Tamoxifen Combined With Amphotericin B and Fluconazole for Cryptococcal Meningitis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 3
- 主要终点
- Early Fungicidal Activity (EFA), i.e. the rate of clearance of yeast from cerebrospinal fluid
研究概览
简要总结
The purpose of this study is to develop initial efficacy, feasibility, and safety data regarding the use of Tamoxifen in combination with amphotericin B and fluconazole in the treatment of cryptococcal meningitis. The results of the study will inform the design and feasibility of a larger study powered to a survival endpoint. The study hypothesis is that adding tamoxifen to standard antifungal therapy increases the rate of clearance of yeast from cerebrospinal fluid. Increased rates of clearance of yeast from cerebrospinal fluid have previously been associated with improved clinical outcomes, including survival and disability.
详细描述
A randomized, open-label trial with 2 parallel arms: standard antifungal therapy versus tamoxifen augmented antifungal therapy during the first 2 weeks (induction phase) of treatment. The study will recruit in two sites in Ho Chi Minh City: the Hospital for Tropical Diseases (HTD), and Cho Ray Hospital (CRH). 25 patients will be enrolled into the two study arms (intervention versus control). All anti-fungal administration will be directly observed by ward staff.
Intervention arm: Induction phase treatment (days 1-14): Tamoxifen will be given orally in a dose of 300mg/day for the first 14 days following randomization. It will be administered by nasogastric tube where patients are unconscious. In addition patients will receive amphotericin 1mg/kg once daily iv and fluconazole 800mg once daily orally. The tamoxifen will be administered in the morning combined with amphotericin and fluconazole dose.
Control arm: Induction phase treatment (days 1-14): Patients will receive amphotericin 1mg/kg/day combined with fluconazole 800mg once daily for the first 2 weeks. Amphotericin and fluconazole will be administered simultaneously.
The primary efficacy endpoint will be the rate of clearance of yeast cells from cerebrospinal fluid (CSF) over the first 2 weeks following randomisation. Patients will be followed for 10 weeks, which is conventional in clinical trials in cryptococcal meningitis. After the first 2 weeks of study treatment, all patients will receive fluconazole 800mg/day for 8 further weeks, until the study end. At this point, HIV infected patients will be switched to long term secondary prophylaxis with fluconazole 200mg/day as per standard practice. For HIV uninfected patients, the decision to continue antifungal treatment, and at which dose, will be made on a case by case basis by the attending physician in consultation with the patient.
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 ≥ 18 years
- •Cryptococcal meningitis (CM) defined as a syndrome consistent with CM and one or more of:
- •positive CSF India ink (budding encapsulated yeasts),
- •C. neoformans cultured from CSF or blood,
- •positive cryptococcal antigen Lateral Flow Antigen Test (LFA) in CSF
- •Informed consent to participate given by patient or acceptable representative
- •Known HIV infection status, or patient agrees to HIV testing on this admission
排除标准
- •Pregnancy or breast-feeding
- •History of thromboembolic disease such as pulmonary embolism or deep venous thrombosis
- •On anti-coagulant medication
- •On medication known to prolong the QT interval other than fluconazole, such as fluoroquinolones or antidepressants.
- •Known cardiac conduction defect including long QT syndromes
- •QTc at baseline > 500ms
- •Currently receiving treatment for cryptococcal meningitis and having received > 4 days of anti-cryptococcal meningitis therapy
- •Known allergy to Tamoxifen
- •Currently or history of receiving treatment with Tamoxifen for breast cancer or other indication
- •Current or history of uterine cancer including endometrial cancer and uterine sarcoma
- •Renal failure (defined as creatinine >3*ULN (upper limit of normal), despite adequate hydration)
- •Failure to consent - the patient, or if they are incapacitated, their responsible relative, declines to enter the study
- •Allergy to amphotericin B or fluconazole
研究组 & 干预措施
Tamoxifen augmented antifungal therapy
Tamoxifen 300mg/day for 2 weeks, combined with standard antifungal therapy (amphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks)
干预措施: Tamoxifen (Drug)
Tamoxifen augmented antifungal therapy
Tamoxifen 300mg/day for 2 weeks, combined with standard antifungal therapy (amphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks)
干预措施: Amphotericin B (Drug)
Tamoxifen augmented antifungal therapy
Tamoxifen 300mg/day for 2 weeks, combined with standard antifungal therapy (amphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks)
干预措施: Fluconazole (Drug)
Standard antifungal therapy
Amphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks.
干预措施: Amphotericin B (Drug)
Standard antifungal therapy
Amphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks.
干预措施: Fluconazole (Drug)
结局指标
主要结局
Early Fungicidal Activity (EFA), i.e. the rate of clearance of yeast from cerebrospinal fluid
时间窗: over the first 2 weeks following randomisation
In the trial, lumbar punctures are scheduled on days 1, 3, 7, 14, and additionally as clinically indicated. Whenever a lumbar puncture is performed, the study team will determine the amount of viable yeast in CSF through culture. Based on the patients' longitudinal quantitative yeast count measurements, EFA will be determined as previously described e.g. see N Engl J Med 2016; 374:542-54
次要结局
- Disability at 10 weeks(at 10 weeks)
- Visual deficit at 10 weeks(at 10 weeks)
- Rate of Cryptococcal meningitis relapse(until 10 weeks)
- QT prolongation(During hospital stay, an average of 10 weeks)
- Time to new neurological event or death until 10 weeks(until 10 weeks)
- Longitudinal measurements of intracranial pressure during the first 2 weeks(during the first 2 weeks)
- CD4 count at 10 weeks(at 10 weeks)
- Survival until 10 weeks after randomization(10 weeks after randomisation)
- Adverse events(During hospital stay, an average of 10 weeks)
- Rate of IRIS until 10 weeks (in HIV infected patients only)(until 10 weeks)
- Blood and CSF concentrations of amphotericin, Tamoxifen and fluconazole(During hospital stay, an average of 10 weeks)