NCT04145258招募中3 期
Intensified Tuberculosis Treatment to Reduce the Mortality of HIV-infected and Uninfected Patients With Tuberculosis Meningitis: a Phase III Randomized Controlled Trial (Acronym: INTENSE-TBM)
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 768
- 试验地点
- 16
- 主要终点
- Rate of all-cause death
研究概览
简要总结
INTENSE-TBM is randomized controlled, phase III, multicenter, 2 x 2 factorial plan superiority trial assessing the efficacity of two interventions to reduce mortality from tuberculous meningitis (TBM) in adolescents and adults with or without HIV-infection in sub-Saharan Africa:
- Intensified TBM treatment with high-dose rifampicin and linezolid, compared to WHO standard TBM treatment.
- Aspirin, compared to not receiving aspirin. The trial will be open-label for anti-TB treatment and placebo-controlled for aspirin treatment.
详细描述
Settings: Côte d'Ivoire, Madagascar, Uganda, South Africa.
Follow-up: Participants will be followed up for 40 weeks.
Sample size: 768 patients (192 in each arm).
Primary analysis: We will use a Cox proportional hazard ratio model to compare intensified TB treatment with WHO standard TB treatment, and aspirin with placebo, adjusting for the initial stratification variables (trial country, HIV status, British Medical Research Council |BMRC] severity grade). The primary analysis will be conducted in the intention to treat population.
Sub-studies:
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The trial will be open-label for anti-TB treatment and placebo-controlled for aspirin treatment
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
- •Age ≥ 15 years
- •TBM defined as "definite", "probable" or "possible"
- •Signed Informed Consent
- •Definite TBM = at least one of the following criteria: acid-fast bacilli seen in CSF microscopy, positive CSF M. tuberculosis culture, or positive CSF M. tuberculosis commercial nucleic acid amplification test.
- •Probable TBM = total modified Marais score ≥12 when neuroimaging is available, or ≥10 when neuroimaging is not available (at least 2 points should come from CSF or cerebral imaging criteria).
- •Possible TBM = total modified Marais 6-11 when neuroimaging is available, or 6-9 when neuroimaging is not available.
排除标准
- •> 5 days of TB treatment
- •Renal failure (eGFR<30 ml/min, CKD-EPI formula).
- •Neutrophil count < 0.6 x 109/L.
- •Hemoglobin concentration < 8 g/dL.
- •Total bilirubin > 2.6 times the Upper Limit of Normal
- •Platelet count < 50 x 109/L.
- •ALT > 5 times the Upper Limit of Normal.
- •Clinical evidence of liver failure or decompensated cirrhosis.
- •For women: more than 17 weeks pregnancy or breastfeeding.
- •For patients without decrease level of consciousness (Glasgow Coma Scale = 15): Peripheral neuropathy scoring Grade 3 or above on the Brief Peripheral Neuropathy Score (BPNS).
- •Documented M. tuberculosis resistance to rifampicin.
- •Positive gram-stain, bacterial culture or cryptococcal antigen in the Cerebral Spinal Fluid.
- •Evidence of active bleeding (hemoptysis, gastrointestinal bleeding, hematuria, intracranial bleeding).
- •Inability to collect Cerebral Spinal Fluid, except for patients with confirmed tuberculosis (by rapid molecular test or culture) from another biological sample and clinical and/or CT scan evidence of meningitis.
- •Major surgery within the last two weeks prior to inclusion.
- •Ongoing chronic aspirin treatment (eg for cardiovascular risk).
- •Current use of drugs contraindicated with study drugs and that cannot be safely stopped (see Appendix 1: Drugs contra-indicated with study drugs).
- •In available history from patients:
- •Evidence of past intracranial bleeding.
- •Evidence of past of peptic ulceration.
- •Evidence of recent (< 3 month) gastrointestinal bleeding.
- •Known hypersensitivity contraindicating the use of study drugs .
- •Evidence of porphyria.
- •Evidence of hyperuricemia or gout.
- •Any reason which at the discretion of the investigator would compromise safety and cooperation in the trial.
研究组 & 干预措施
WHO TBM treatment + placebo
Other
- Inclusion (D-0) to end of Week-8 (W-8): isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + placebo of aspirin
- W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.
干预措施: Placebo of aspirin (Drug)
WHO TBM treatment + aspirin
Other
- Inclusion (D-0) to end of Week-8 (W-8): isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + aspirin 200 mg/d
- W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.
干预措施: Aspirin (Drug)
Intensified TBM treatment + placebo
Other
- Inclusion (D-0) to end of Week-8 (W-8): high dose rifampicin (35 mg/kg/d) + high dose linezolid (1200 mg/d from D-0 to end of W-4, then 600 mg/d from W-5 to W-8) + isoniazid 5 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + placebo of aspirin
- W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.
干预措施: Placebo of aspirin (Drug)
Intensified TBM treatment + aspirin
Other
- Inclusion (D-0) to end of Week-8 (W-8): high dose rifampicin (35 mg/kg/d) + high dose linezolid (1200 mg/d from D-0 to end of W-4, then 600 mg/d from W-5 to W-8) + isoniazid 5 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + aspirin 200 mg/d
- W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.
干预措施: Aspirin (Drug)
WHO TBM treatment + placebo
Other
- Inclusion (D-0) to end of Week-8 (W-8): isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + placebo of aspirin
- W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.
干预措施: WHO TBM treatment (Drug)
WHO TBM treatment + aspirin
Other
- Inclusion (D-0) to end of Week-8 (W-8): isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + aspirin 200 mg/d
- W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.
干预措施: WHO TBM treatment (Drug)
Intensified TBM treatment + placebo
Other
- Inclusion (D-0) to end of Week-8 (W-8): high dose rifampicin (35 mg/kg/d) + high dose linezolid (1200 mg/d from D-0 to end of W-4, then 600 mg/d from W-5 to W-8) + isoniazid 5 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + placebo of aspirin
- W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.
干预措施: Intensified TBM treatment (Drug)
Intensified TBM treatment + aspirin
Other
- Inclusion (D-0) to end of Week-8 (W-8): high dose rifampicin (35 mg/kg/d) + high dose linezolid (1200 mg/d from D-0 to end of W-4, then 600 mg/d from W-5 to W-8) + isoniazid 5 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + aspirin 200 mg/d
- W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.
干预措施: Intensified TBM treatment (Drug)
结局指标
主要结局
Rate of all-cause death
时间窗: Up to 40 weeks
次要结局
- M. tuberculosis culture conversion rate(1 week and 4 weeks)
- Rate of new central neurological event or aggravation of a central neurological event existing at baseline(Up to 40 weeks)
- Rate of grade 3-4 adverse events (DAIDS adverse events grading table)(Up to 40 weeks)
- Rate of serious adverse events(Up to 40 weeks)
- Rate of solicited treatment related adverse events(Up to 40 weeks)
- Percentage of patients with disability(40 weeks)
- Rate of all-cause death(Up to 8 weeks)
- Rate of all-cause death or loss to follow-up(Up to 40 weeks)
- Time to culture positivity(Up to 40 weeks)
- Time to first hospital discharge(Up to 40 weeks)
- Cost-effectiveness incremental ratio of trial interventions(Up to 40 weeks)
- Prevalence of resistance to anti-TB drugs among patients with positive culture at inclusion(Up to 40 weeks)
- Subset of patients: In vitro bactericidal activity of anti-TBM treatment(1 week and 4 weeks)
- Subset of patients: Maximum Plasma Concentration [Cmax] of rifampicin and linezolid(1 week and 4 weeks)
- Subset of patients: Minimum Plasma Concentration [Cmin] of rifampicin and linezolid(1 week and 4 weeks)
- Subset of patients: Area Under the Curve [AUC] of rifampicin and linezolid(1 week and 4 weeks)
- Subset of patients: Time for maximal concentration [Tmax] of rifampicin and linezolid(1 week and 4 weeks)
- Subset of patients: Half-life (t1/2) of rifampicin and linezolid(1 week and 4 weeks)
- HIV-infected participants: Rate of new AIDS-defining illnesses(Up to 40 weeks)
- HIV-infected participants: Percentage of participants with virological success (plasma HIV-1 RNA <50 copies/ml)(28 weeks and 40 weeks)
- HIV-infected participants: CD4 count change from baseline(28 weeks and 40 weeks)
- HIV-infected participants, subset of patients: Maximum Plasma Concentration [Cmax] of of dolutegravir(1 week and 4 weeks)
- HIV-infected participants, subset of patients: Minimum Plasma Concentration [Cmin] of dolutegravir(1 week and 4 weeks)
- HIV-infected participants, subset of patients: Area Under the Curve [AUC] of dolutegravir(1 week and 4 weeks)
- HIV-infected participants, subset of patients: Time for maximal concentration [Tmax] of dolutegravir(1 week and 4 weeks)
- HIV-infected participants, subset of patients: Half-life (t1/2) of dolutegravir(1 week and 4 weeks)
研究者
研究点 (16)
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