Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis
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)
ANRS, Emerging Infectious Diseases
768 participants
Feb 7, 2021
INTERVENTIONAL
Conditions
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.
Eligibility
Inclusion Criteria6
- 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 Criteria25
- \> 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.
Interventions
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)
2 months of (R-H-Z-E) + 7 months of (R-H)
2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid
Locations(13)
View Full Details on ClinicalTrials.gov
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NCT04145258