Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Tuberculous Meningitis

Intervention / Treatment
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* Drug: Aspirin
* Drug: Placebo of aspirin
* Drug: WHO TBM treatment
* Drug: Intensified TBM treatment


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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. Exclusion criteria: > 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.

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: WHO TBM treatment + placebo<br>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. | Drug: Placebo of aspirin<br>* Two placebo tablets with the same appearance of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)<br>Drug: WHO TBM treatment<br>* 2 months of (R-H-Z-E) + 7 months of (R-H)<br>* Other names: Standard WHO treatment for TB meningitis;|
| Other: WHO TBM treatment + aspirin<br>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. | Drug: Aspirin<br>* Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)<br>Drug: WHO TBM treatment<br>* 2 months of (R-H-Z-E) + 7 months of (R-H)<br>* Other names: Standard WHO treatment for TB meningitis;|
| Other: Intensified TBM treatment + placebo<br>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. | Drug: Placebo of aspirin<br>* Two placebo tablets with the same appearance of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)<br>Drug: Intensified TBM treatment<br>* 2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid<br>|
| Other: Intensified TBM treatment + aspirin<br>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. | Drug: Aspirin<br>* Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)<br>Drug: Intensified TBM treatment<br>* 2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of all-cause death |  | Up to 40 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of all-cause death |  | Up to 8 weeks | 
| Rate of all-cause death or loss to follow-up |  | Up to 40 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 | 
| M. tuberculosis culture conversion rate |  | 1 week and 4 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 | Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio | 1 week and 4 weeks | 
| Subset of patients: Minimum Plasma Concentration [Cmin] of rifampicin and linezolid | Plasma Cmin, cerebrospinal fluid [CSF] Cmin, and plasma/CSF Cmin ratio | 1 week and 4 weeks | 
| Subset of patients: Area Under the Curve [AUC] of rifampicin and linezolid | Plasma AUC, cerebrospinal fluid [CSF] AUC, and plasma/CSF AUC ratio | 1 week and 4 weeks | 
| Subset of patients: Time for maximal concentration [Tmax] of rifampicin and linezolid | Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma/CSF Tmax ratio | 1 week and 4 weeks | 
| Subset of patients: Half-life (t1/2) of rifampicin and linezolid | Plasma t1/2, cerebrospinal fluid [CSF] t1/2, and plasma/CSF t1/2 ratio | 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 | Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio | 1 week and 4 weeks | 
| HIV-infected participants, subset of patients: Minimum Plasma Concentration [Cmin] of dolutegravir | Plasma Cmin, cerebrospinal fluid [CSF] Cmin, and plasma/CSF Cmin ratio | 1 week and 4 weeks | 
| HIV-infected participants, subset of patients: Area Under the Curve [AUC] of dolutegravir | Plasma AUC, cerebrospinal fluid [CSF] AUC, and plasma /CSF AUC ratio | 1 week and 4 weeks | 
| HIV-infected participants, subset of patients: Time for maximal concentration [Tmax] of dolutegravir | Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma /CSF Tmax ratio | 1 week and 4 weeks | 
| HIV-infected participants, subset of patients: Half-life (t1/2) of dolutegravir | Plasma t1/2, cerebrospinal fluid [CSF] t1/2, and plasma/CSF t1/2 ratio | 1 week and 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculous Meningitis, Intensified treatment, High dose Rifampicin, Linezolid, Aspirin, Subsaharan Africa