Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis
- Conditions
- Tuberculous Meningitis
- Interventions
- Registration Number
- NCT04145258
- Lead Sponsor
- ANRS, Emerging Infectious Diseases
- Brief Summary
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.
- Detailed Description
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:
* The PK-PD sub-study will take place in the 4 participating countries, and involve 40 participants in total.
* The Multi-Omics sub-study will only take place in South-Africa. It will involve 160 participants in this country.
Participants in each sub-study will sign a specific informed consent.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 768
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description WHO TBM treatment + placebo WHO TBM treatment * 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. WHO TBM treatment + aspirin WHO TBM treatment * 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. Intensified TBM treatment + placebo Intensified TBM treatment * 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. Intensified TBM treatment + aspirin Intensified TBM treatment * 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. WHO TBM treatment + placebo Placebo of aspirin * 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. Intensified TBM treatment + placebo Placebo of aspirin * 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. WHO TBM treatment + aspirin Aspirin * 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. Intensified TBM treatment + aspirin Aspirin * 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.
- Primary Outcome Measures
Name Time Method Rate of all-cause death Up to 40 weeks
- Secondary Outcome Measures
Name Time Method 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 Plasma Cmax, cerebrospinal fluid \[CSF\] Cmax, and plasma/CSF Cmax ratio
Subset of patients: Minimum Plasma Concentration [Cmin] of rifampicin and linezolid 1 week and 4 weeks Plasma Cmin, cerebrospinal fluid \[CSF\] Cmin, and plasma/CSF Cmin ratio
Subset of patients: Area Under the Curve [AUC] of rifampicin and linezolid 1 week and 4 weeks Plasma AUC, cerebrospinal fluid \[CSF\] AUC, and plasma/CSF AUC ratio
Subset of patients: Time for maximal concentration [Tmax] of rifampicin and linezolid 1 week and 4 weeks Plasma Tmax, cerebrospinal fluid \[CSF\] Tmax, and plasma/CSF Tmax ratio
Subset of patients: Half-life (t1/2) of rifampicin and linezolid 1 week and 4 weeks Plasma t1/2, cerebrospinal fluid \[CSF\] t1/2, and plasma/CSF t1/2 ratio
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 Plasma Cmax, cerebrospinal fluid \[CSF\] Cmax, and plasma/CSF Cmax ratio
HIV-infected participants, subset of patients: Minimum Plasma Concentration [Cmin] of dolutegravir 1 week and 4 weeks Plasma Cmin, cerebrospinal fluid \[CSF\] Cmin, and plasma/CSF Cmin ratio
HIV-infected participants, subset of patients: Area Under the Curve [AUC] of dolutegravir 1 week and 4 weeks Plasma AUC, cerebrospinal fluid \[CSF\] AUC, and plasma /CSF AUC ratio
HIV-infected participants, subset of patients: Time for maximal concentration [Tmax] of dolutegravir 1 week and 4 weeks Plasma Tmax, cerebrospinal fluid \[CSF\] Tmax, and plasma /CSF Tmax ratio
HIV-infected participants, subset of patients: Half-life (t1/2) of dolutegravir 1 week and 4 weeks Plasma t1/2, cerebrospinal fluid \[CSF\] t1/2, and plasma/CSF t1/2 ratio
Trial Locations
- Locations (13)
Mbarara Regional Reference Hospital
🇺🇬Mbarara, Uganda
Regional Reference Hospital of Kabale
🇺🇬Mbarara, Uganda
Treichville University Hospital
🇨🇮Abidjan, Côte D'Ivoire
Yopougon University Hospital
🇨🇮Abidjan, Côte D'Ivoire
Cocody University Hospital
🇨🇮Abidjan, Côte D'Ivoire
Morafeno University Hospital
🇲🇬Toamasina, Madagascar
Dora Nginza Hospital
🇿🇦Port Elizabeth, South Africa
New Somerset Hospital
🇿🇦Cape Town, South Africa
Livingstone and PE Central Hospitals
🇿🇦Port Elizabeth, South Africa
University Hospital Joseph Raseta Befelatanana
🇲🇬Antananarivo, Madagascar
University Hospital Tambohobe
🇲🇬Fianarantsoa, Madagascar
Kayelitsha District Hospital
🇿🇦Cape Town, South Africa
Mitchells Plain Hospital
🇿🇦Cape Town, South Africa