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

Learn more about:
Related Clinical Trial
Trial of a Six-Month Regimen of High-Dose Rifampicin, High-Dose Isoniazid, Linezolid, and Pyrazinamide Versus a Standard Nine-Month Regimen for the Treatment of Adults and Adolescents With Tuberculous Meningitis Cyclophosphamide in the Treatment of Refractory Proliferative Arachnoiditis in CNS Tuberculosis Evaluation of New Biomarker-based Approaches for Improving the Diagnosis of Childhood Tuberculous Meningitis Retrospective Real-word Study of Linezolid for the Treatment of Tuberculous Meningitis Study Of The Long Term Outcome Of Tuberculous Meningitis In Vietnamese Adults Treated With Adjunctive Dexamethasone Adjunctive Corticosteroids for Tuberculous Meningitis in HIV-infected Adults (The ACT HIV Trial) The Relationships Between Gene Polymorphisms of LTA4H and Dexamethasone Treatment for Tuberculous Meningitis Linezolid, Aspirin and Enhanced Dose Rifampicin in HIV-TBM Leukotriene A4 Hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-uninfected Adults With Tuberculous Meningitis Diagnosis of Tuberculous Meningitis by ESAT-6 in CSF Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis Optimizing Antituberculosis Therapy in Adults With Tuberculous Meningitis A Pilot Study of Adjunctive Aspirin for the Treatment of HIV Negative Adults With Tuberculous Meningitis Rifampicin Explorative PK Study for Tuberculous Meningitis Comparing Oral and Intravenous Preparation Immediate Versus Deferred Antiretroviral Therapy for HIV-Associated Tuberculous Meningitis

Brief Title

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

Official Title

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)

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.


        -  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.

Study Phase

Phase 3

Study Type


Primary Outcome

Rate of all-cause death

Secondary Outcome

 Rate of all-cause death


Tuberculous Meningitis



Study Arms / Comparison Groups

 WHO TBM treatment + placebo
Description:  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.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

February 7, 2021

Completion Date

December 2024

Primary Completion Date

March 2024

Eligibility 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.

          -  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

          -  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.




15 Years - N/A

Accepts Healthy Volunteers



Fabrice Bonnet, M.D., Ph.D., +33 (0)5 56 79 58 26, [email protected]

Location Countries

Côte D'Ivoire

Location Countries

Côte D'Ivoire

Administrative Informations



Organization ID


Secondary IDs

EDCTP RIA2017T-2019

Responsible Party


Study Sponsor

ANRS, Emerging Infectious Diseases


 European Union

Study Sponsor

Fabrice Bonnet, M.D., Ph.D., Principal Investigator, University Hospital, Bordeaux

Verification Date

July 2022