Pharmacokinetics and Tolerability of Adjunctive Linezolid for the Treatment of Tuberculous Meningitis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Drug Clearance (CL/F)
研究概览
简要总结
This is a phase II randomized open-label trial of high versus standard dose rifampin (RIF) with or without linezolid (LZD) for the first 4 weeks of treatment for Tuberculosis Meningitis (TBM) at Masaka Regional Referral Hospital in Uganda. Initial randomization will be to high (35 mg/kg/day) versus standard (10 mg/kg/day) dose oral rifampin for the first 4 weeks of intensive therapy. Participants will then undergo a second randomization to linezolid 1200 mg daily versus no linezolid for the first 4 weeks of therapy. The primary aims are (1) to determine the cerebrospinal fluid and plasma pharmacokinetics of adjunctive LZD 1200 mg daily in TBM patients receiving high or standard dose RIF and (2) to evaluate the tolerability of a 4-week course of LZD in TBM patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
High Dose RIF with LZD
Arm 1 participants will receive high dose oral RIF (35mg/kg/day) and LZD 1200 mg daily for the first 4 weeks of therapy, along with standard doses of Isoniazid (INH), Pyrazinamide (PZA), and Ethambutol (EMB). After 4 weeks, LZD will be discontinued and high dose RIF will return to standard dose for the remainder of treatment.
干预措施: LZD (Drug)
High Dose RIF with LZD
Arm 1 participants will receive high dose oral RIF (35mg/kg/day) and LZD 1200 mg daily for the first 4 weeks of therapy, along with standard doses of Isoniazid (INH), Pyrazinamide (PZA), and Ethambutol (EMB). After 4 weeks, LZD will be discontinued and high dose RIF will return to standard dose for the remainder of treatment.
干预措施: High dose RIF (Drug)
Standard dose RIF with LZD
Arm 2 participants will receive standard dose RIF, INH, PZA, and EMB along with LZD 1200 mg daily. After 4 weeks, LZD will be discontinued.
干预措施: LZD (Drug)
Standard dose RIF with LZD
Arm 2 participants will receive standard dose RIF, INH, PZA, and EMB along with LZD 1200 mg daily. After 4 weeks, LZD will be discontinued.
干预措施: Standard dose RIF (Drug)
High Dose RIF
Arm 3 participants will receive high dose oral RIF (35mg/kg/day) for the first 4 weeks of therapy, along with standard doses of INH, PZA, and EMB. After 4 weeks, high dose RIF will return to standard dose for the remainder of treatment.
干预措施: High dose RIF (Drug)
Standard Dose RIF
Arm 4 participants will receive standard doses of RIF, INH, PZA, and EMB.
干预措施: Standard dose RIF (Drug)
结局指标
主要结局
Drug Clearance (CL/F)
时间窗: 4 weeks
Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability).
Volume of Distribution (Vd)
时间窗: 4 weeks
Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability).
Plasma Absorption Rate Constant (ka)
时间窗: 4 weeks
Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability).
Rate of CSF Uptake (kPC)
时间窗: 4 weeks
Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability).
CSF to Plasma Ratio (PC)
时间窗: 4 weeks
Once plasma parameter estimates were finalized, these were fixed and then linked to CSF concentrations via a hypothetical effect compartment with a unidirectional rate of the entry whose rate was described by KPC and an amount, expressed as PC, or a ratio between plasma concentrations and CSF concentrations. Higher values of KPC indicate faster rates of entry, and higher values of PC indicate greater proportions of linezolid entering from the blood into the CSF. Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability).
次要结局
- Proportion of Participants With Grade 3 or Higher Adverse Events (AE).(4 weeks)
- Proportion of Participants Who Complete LZD Treatment.(4 weeks)
- Modified Rankin Scale (MRS) Performance.(4, 12 and 24 weeks)
- Neurocognitive Battery Performance: Wechsler Adult Intelligence Scale-III Digit Symbol (WAIS-III).(12 and 24 weeks)
- Neurocognitive Battery Performance: Color Trails, Part 1(12 and 24 weeks)
- Neurocognitive Battery Performance: Color Trails, Part 2(12 and 24 weeks)
- Neurocognitive Battery Performance: Category Fluency(12 and 24 weeks)
- Neurocognitive Battery Performance: Hopkins Verbal Learning Test-Revised (HVLT-R)(12 and 24 weeks)
- Neurocognitive Battery Performance: World Health Organization-University of California-Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT).(12 and 24 weeks)
- Neurocognitive Battery Performance: Grooved Pegboard Bilateral(12 and 24 weeks)
- Neurocognitive Battery Performance: Finger Tapping Bilateral(12 and 24 weeks)
- Montreal Cognitive Assessment Performance (Conditional).(12 and 24 weeks)