Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis (INTENSE-TBM)

ANRS, Emerging Infectious Diseases

Status and phase: Enrolling; Phase 3

Conditions: Tuberculous Meningitis

Treatments: Drug: Intensified TBM treatment; Drug: WHO TBM treatment; Drug: Aspirin; Drug: Placebo of aspirin

Study type: Interventional

Funder types: Other

Identifiers

NCT04145258

ANRS 12398 INTENSE-TBM

EDCTP RIA2017T-2019 (Other Grant/Funding Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 768 estimated patients

Sex: All

Ages: 15+ years old

Volunteers: No Healthy Volunteers

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 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Quadruple Blind

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768 participants in 4 patient groups

WHO TBM treatment + placebo

Other group

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.

Treatment:

Drug: Placebo of aspirin

Drug: WHO TBM treatment

WHO TBM treatment + aspirin

Other group

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 + aspirin 200 mg/d * W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.

Treatment:

Drug: Aspirin

Drug: WHO TBM treatment

Intensified TBM treatment + placebo

Other group

Description:

* Inclusion (D-0) to end of Week-8 (W-8): high dose rifampicin (35 mg/kg/d) + high dose linezolid (1200 mg/d from D-0 to end of W-4, then 600 mg/d from W-5 to W-8) + isoniazid 5 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.

Treatment:

Drug: Placebo of aspirin

Drug: Intensified TBM treatment

Intensified TBM treatment + aspirin

Other group

Description:

* Inclusion (D-0) to end of Week-8 (W-8): high dose rifampicin (35 mg/kg/d) + high dose linezolid (1200 mg/d from D-0 to end of W-4, then 600 mg/d from W-5 to W-8) + isoniazid 5 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + aspirin 200 mg/d * W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.

Treatment:

Drug: Aspirin

Drug: Intensified TBM treatment