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

  • STATUS
    Recruiting
  • End date
    Dec 24, 2023
  • participants needed
    768
  • sponsor
    French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
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Updated on 24 February 2021
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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.

Description

Settings: Cte 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.

Details
Condition Tuberculous meningitis
Treatment Aspirin, Placebo of aspirin, WHO TBM treatment, Intensified TBM treatment
Clinical Study IdentifierNCT04145258
SponsorFrench National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
Last Modified on24 February 2021

Eligibility

 Yes No Not Sure

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
Platelet count < 50 x 109/L
Total bilirubin > 2.6 times the Upper Limit of Normal
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
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