Short Intervention and Measurement of Pharmacokinetics of Linezolid in Tuberculosis Meningitis: a Pharmacokinetics and Safety/Tolerability Study
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Linezolid exposure in blood and CSF
研究概览
简要总结
Tuberculosis meningitis (TBM) is the most severe manifestation of TB, resulting in death or neurological disability in up to 50% of affected patients, despite antibacterial treatment. This TBM treatment follows the model for pulmonary TB by using the same first-line TB drugs (a combination of rifampicin, isoniazid, pyrazinamide and ethambutol) and the same dosing guidelines, although it is known that penetration of two of these drugs (rifampicin and ethambutol) into cerebrospinal fluid (CSF) is limited. Improvement of treatment of TBM is urgently needed.
To do so, a combination of two interventions will be investigated in this study. A series of phase II clinical trials on higher doses of the pivotal TB drug rifampicin in Indonesian patients with TBM have shown that the dose of rifampicin can be increased from 10 mg/kg orally (standard dose) up to 30 mg/kg orally, resulting in a strong increase in exposure to this drug in plasma and CSF, no increase in grade III or IV adverse effects, and a reduction in mortality. Similarly, higher doses of rifampicin up to 35 mg/kg resulted in strong increases in plasma concentrations; the doses were well tolerated and reduced time to sputum conversion in African pulmonary TB patients.
Next to a higher dose of rifampicin, the approved antibacterial drug linezolid seems a good candidate for a new TBM regimen. The drug penetrates well into the CSF and is applied successfully against other central nervous system (CNS) infections (e.g. caused by penicillin-nonsusceptible Streptococcus pneumoniae, vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus). In a study in China, linezolid in a dose of 600 mg BID orally strongly increased recovery of patients with TBM response. Linezolid is also being investigated as a new drug for (drug-resistant) pulmonary TB in numerous studies, in a dose of 1200 mg once daily. More severe adverse effects to this drug typically occur only after prolonged treatment during several months, not during short-term treatment.
Overall, linezolid is expected to be a promising and tolerable candidate for a new intensified TBM treatment regimen consisting of a backbone of high dose rifampicin plus linezolid.
详细描述
Overall aim is to determine the most appropriate dose of linezolid in the treatment of TB meningitis, when combined with high-dose rifampicin (35 mg/kg orally), to be tested in larger clinical follow-up studies.
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 old or older
- •Clinically diagnosed as TB meningitis patient
- •CSF/blood glucose ratio < 0.5
- •Willing to participate in the study by signing informed consent
排除标准
- •Patients who have one of the following criteria will be excluded:
- •Failure to diagnostic lumbar puncture
- •Confirmed cryptococcus meningitis (LFA) in HIV-positive patients; or diagnosed as bacterial meningitis based on clinical assessment and routine CSF examination.
- •Treatment for tuberculosis for more than 3 days before admission
- •History of TBM
- •Current treatment with: MAO inhibitors, direct and indirect acting sympathomimetic drugs, vasopressive drugs, dopaminergic compounds, buspiron, serotonin reuptake inhibitors, tricyclic antidepressants, triptans, tramadol and meperidine
- •History (< 2 weeks before start of linezolid) of taking any MAO inhibitors
- •Pregnant or lactating females
- •Hepatic insufficiency (ALT>5x upper normal limit)
- •Kidney dysfunction (eGFR <50ml/min)
- •Known hypersensitivity to rifampicin and/or linezolid
- •Rapid clinical deterioration at time of presentation (sepsis, decreasing consciousness, or signs of cerebral oedema or herniation)
研究组 & 干预措施
Linezolid 600
Subjects in this arm will receive 600 mg linezolid QD along with high-dose rifampicin (~35 mg/kg, based on weight), isoniazid (H) 300 mg, pyrazinamide (Z) 1500 mg and ethambutol (E) 750 mg once daily administered orally for 14 days.
干预措施: Linezolid (Drug)
Linezolid 1200
Subjects in this arm will receive 1200 mg linezolid QD along with rifampicin 1350 mg (~35 mg/kg, based on weight), isoniazid (H) 300 mg, pyrazinamide (Z) 1500 mg and ethambutol (E) 750 mg once daily administered orally for 14 days.
干预措施: Linezolid (Drug)
结局指标
主要结局
Linezolid exposure in blood and CSF
时间窗: day 2 and day 11
Linezolid exposure in blood (full plasma concentration-versus-time profiles (0-24h)) will be measured in 2 days, i.e. day 2 (+/- 1) and at day 11 (+/- 1) of TB treatment. In each sampling day, there will be 6 sampling points i.e. at 0 (pre-dose), 1, 2, 4, 8, and 12 h after study medication intake One CSF sample per patient will be taken at the same day as PK sampling i.e. at 2, 4 or 8 hours post dose.
次要结局
- Blood inflammatory response(at PK days (day 2 and 11), and day 7 and 14)
- Serious adverse event(Day 3, 7, 10 and 14)
- Clinical response(Day 3, 7 and 14.)
- Mortality(Within 14 days and 1 month after starting treatment)
- Neurological response(Day 3, 7 and 14.)
- CSF inflammatory response(at PK sampling days (day 2 and 11))
研究者
Ahmad Rizal Ganiem
MD, PhD
Universitas Padjadjaran