A Randomized Double Blinded Phase 2b Clinical Trial Comparing Standard Dose With Two Higher Doses of Rifampicin for Treatment of Adults With Tuberculous Meningitis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Rifampicin concentrations in plasma and cerebrospinal fluid (CSF)
研究概览
简要总结
Tuberculous meningitis (TBM) is the most severe form of tuberculosis infection with high mortality. Current treatment regimens are not based on clinical trials. Rifampicin is a key drug for TBM, but its penetration into the brain is limited, suggesting that a higher dose may be more effective.
There are several highly relevant, outstanding questions related to the appropriate dose of rifampicin for TBM, before a multicenter phase 3 trial can be performed. These are:
- Previous phase 2a randomized clinical trial (done in the same setting as this proposed study) suggests that high doses of intravenous rifampicin (600mg, circa 13 mg/mg) for TBM is safe and associated with a survival benefit in adults. Given that i.v. rifampicin is not readily available, this needs to be confirmed using an equivalent higher oral dose of rifampicin.
- Recent pharmacokinetic analysis of a continuation trial comparing 600 mg i.v. rifampicin with 750 mg and 900 mg oral rifampicin suggests that an even higher dose may be needed; but this has not been examined
- Based on those previous data, there is a need to explore a longer duration of high-dose rifampicin for a subsequent phase 3 randomized clinical trial; treatment response in the investigators previous trial suggest that the optimal duration may be > 14 days.
- There is a need to explore relevant treatment endpoints besides mortality including neurological, neuroradiological and inflammatory response.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 15 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or Female, aged 15 years or above.
- •Clinical suspicion of TBM and CSF/blood glucose ratio < 0.
- •None or less than 3 days of anti-tuberculosis chemotherapy taken for the current infection.
- •Patient or representative (if the patient is incapacitated) is willing and able to give informed consent for participation in the study.
- •Willingness to allow storage of specimens.
排除标准
- •Patients may not enter the study if any of the following apply:
- •Liver dysfunction (ALT > 5 times upper limit); kidney dysfunction (eGFR < 50 ml/min)
- •Pregnancy or breastfeeding (negative urine pregnancy test for all females of child-bearing age).
- •Confirmed cryptococcus meningitis (LFA), or confirmed bacterial meningitis (microscopy).
- •Rapid clinical deterioration at time of presentation (e.g. signs of sepsis, decreasing consciousness or signs of cerebral oedema, or herniation)
研究组 & 干预措施
Rifampicin 450 mg (standard dose)
Twenty patients will receive 1 tablet of 450 mg Rifampicin and 2 tablets of placebo once daily for 30 days.
Unconscious subjects will receive oral drugs via nasogastric tubes (NGT).
After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.
Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.
Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)
干预措施: Placebo (Drug)
Rifampicin 450 mg (standard dose)
Twenty patients will receive 1 tablet of 450 mg Rifampicin and 2 tablets of placebo once daily for 30 days.
Unconscious subjects will receive oral drugs via nasogastric tubes (NGT).
After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.
Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.
Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)
干预措施: Other TB drugs (Drug)
Rifampicin 450 mg (standard dose)
Twenty patients will receive 1 tablet of 450 mg Rifampicin and 2 tablets of placebo once daily for 30 days.
Unconscious subjects will receive oral drugs via nasogastric tubes (NGT).
After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.
Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.
Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)
干预措施: Adjuvant dexamethasone (Drug)
Rifampicin 900 mg per oral
Twenty patients will receive 2 tablets of 450 mg Rifampicin and 1 tablet of placebo once daily for 30 days.
Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)
After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.
Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.
Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)
干预措施: Placebo (Drug)
Rifampicin 900 mg per oral
Twenty patients will receive 2 tablets of 450 mg Rifampicin and 1 tablet of placebo once daily for 30 days.
Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)
After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.
Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.
Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)
干预措施: Rifampicin (Drug)
Rifampicin 900 mg per oral
Twenty patients will receive 2 tablets of 450 mg Rifampicin and 1 tablet of placebo once daily for 30 days.
Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)
After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.
Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.
Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)
干预措施: Other TB drugs (Drug)
Rifampicin 900 mg per oral
Twenty patients will receive 2 tablets of 450 mg Rifampicin and 1 tablet of placebo once daily for 30 days.
Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)
After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.
Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.
Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)
干预措施: Adjuvant dexamethasone (Drug)
Rifampicin 1350 mg per oral
Twenty patients will receive 3 tablets of 450 mg Rifampicin and 0 tablet of placebo once daily for 30 days.
Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)
After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.
Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.
Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)
干预措施: Rifampicin (Drug)
Rifampicin 1350 mg per oral
Twenty patients will receive 3 tablets of 450 mg Rifampicin and 0 tablet of placebo once daily for 30 days.
Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)
After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.
Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.
Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)
干预措施: Other TB drugs (Drug)
Rifampicin 1350 mg per oral
Twenty patients will receive 3 tablets of 450 mg Rifampicin and 0 tablet of placebo once daily for 30 days.
Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)
After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.
Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.
Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)
干预措施: Adjuvant dexamethasone (Drug)
结局指标
主要结局
Rifampicin concentrations in plasma and cerebrospinal fluid (CSF)
时间窗: Day 2 (+/- 1) after administration of study drugs
The rifampicin concentrations in plasma are measured from blood samples that are obtained by intensive pharmacokinetic sampling at 6 sampling time points (h0, 1, 2, 4, 8, 12 post dose). CSF rifampicin concentration will be measured using CSF sample taken by means of lumbar puncture at hour 3-6 post dose at the same day of blood sampling.
次要结局
- Sensitivity of GeneXpert for diagnosing TBM(Within 6 weeks)
- Rifampicin concentrations in plasma and CSF at steady-state(Day 10 (+/- 1) after starting treatment with study drugs)
- Grade 3 and 4 and serious adverse events(Within 60 days)
- Mortality(180 days)
- Neurological response(Within 60 days)
- Resolution of blood and CSF inflammatory response(7 days)
- Neuroradiological response(60 days)