Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With 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.

      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.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Rate of all-cause death

Secondary Outcome

 Rate of all-cause death

Condition

Tuberculous Meningitis

Intervention

Aspirin

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.

Publications

* 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

Drug

Estimated Enrollment

768

Start Date

February 9, 2020

Completion Date

December 2023

Primary Completion Date

March 30, 2023

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.

          -  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.
      

Gender

All

Ages

15 Years - N/A

Accepts Healthy Volunteers

No

Contacts

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


NCT ID

NCT04145258

Organization ID

ANRS 12398 INTENSE-TBM

Secondary IDs

EDCTP RIA2017T-2019

Responsible Party

Sponsor

Study Sponsor

ANRS, Emerging Infectious Diseases

Collaborators

 European Union

Study Sponsor

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


Verification Date

February 2021