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

• Status: Recruiting
• Trial end date: 2023-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: ANRS, Emerging Infectious Diseases; French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
• Collaborators: European and Developing Countries Clinical Trials Partnership (EDCTP); European Union
• Treatments: Aspirin; Linezolid; Rifampin

Criteria

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.

• 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.