Tuberculous Meningitis
Conditions
Keywords
Tuberculous Meningitis, Intensified treatment, High dose Rifampicin, Linezolid, Aspirin, Subsaharan Africa
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.
Interventions
DRUGAspirin
Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)
Two placebo tablets with the same appearance of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)
DRUGWHO TBM treatment
2 months of (R-H-Z-E) + 7 months of (R-H)
DRUGIntensified TBM treatment
2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid
Sponsors
European Union
European and Developing Countries Clinical Trials Partnership (EDCTP)
ANRS, Emerging Infectious Diseases
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The trial will be open-label for anti-TB treatment and placebo-controlled for aspirin treatment
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 15 years 2. TBM defined as definite, probable or possible 3. 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Rate of all-cause death | Up to 40 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Rate of all-cause death | Up to 8 weeks | — |
| 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 |
| 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 |
Countries
Côte d’Ivoire, Madagascar, South Africa, Uganda
Contacts
Primary ContactFabrice Bonnet, M.D., Ph.D.
Backup ContactXavier Anglaret, M.D., Ph.D.
Outcome results
None listed