Intensified treatment for tuberculous meningitis to reduce mortality

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)

This study is testing if a stronger treatment for tuberculous meningitis can help people survive better than the standard treatment.

Quick facts

• Phase: PHASE3
• Study type: Interventional
• Enrollment: 768 (estimated)
• Ages: 15 Years and up
• Sex: All
• Sponsor: ANRS, Emerging Infectious Diseases (other gov)
• Locations: 13 sites (Abidjan and 12 other locations)
• Trial ID: NCT04145258 on ClinicalTrials.gov

What this trial studies

This trial evaluates the effectiveness of intensified treatment for tuberculous meningitis (TBM) using high-dose rifampicin and linezolid compared to standard WHO treatment, alongside the use of aspirin versus placebo. It is a randomized controlled, phase III, multicenter trial conducted in sub-Saharan Africa, involving 768 participants aged 15 and older. The study will follow participants for 40 weeks and analyze outcomes using a Cox proportional hazard ratio model, adjusting for various factors such as HIV status and severity of TBM. Sub-studies will also explore pharmacokinetics and multi-omics in selected participants.

Who should consider this trial

Good fit: Ideal candidates include adolescents and adults aged 15 and older diagnosed with definite, probable, or possible tuberculous meningitis.

Not a fit: Patients who have been on TB treatment for more than 5 days or have severe comorbidities such as renal failure or liver dysfunction may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could significantly reduce mortality rates in patients with tuberculous meningitis.

How similar studies have performed: Other studies have shown promise in improving treatment outcomes for TBM, but this specific intensified approach is novel.

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 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.

Where this trial is running

Abidjan and 12 other locations

• Cocody University Hospital — Abidjan, Côte D'Ivoire (NOT_YET_RECRUITING)
• Treichville University Hospital — Abidjan, Côte D'Ivoire (RECRUITING)
• Yopougon University Hospital — Abidjan, Côte D'Ivoire (NOT_YET_RECRUITING)
• University Hospital Joseph Raseta Befelatanana — Antananarivo, Madagascar (RECRUITING)
• University Hospital Tambohobe — Fianarantsoa, Madagascar (RECRUITING)
• Morafeno University Hospital — Toamasina, Madagascar (NOT_YET_RECRUITING)
• Kayelitsha District Hospital — Cape Town, South Africa (RECRUITING)
• Mitchells Plain Hospital — Cape Town, South Africa (RECRUITING)
• New Somerset Hospital — Cape Town, South Africa (RECRUITING)
• Dora Nginza Hospital — Port Elizabeth, South Africa (RECRUITING)
• Livingstone and PE Central Hospitals — Port Elizabeth, South Africa (RECRUITING)
• Mbarara Regional Reference Hospital — Mbarara, Uganda (RECRUITING)
• Regional Reference Hospital of Kabale — Mbarara, Uganda (RECRUITING)

Study contacts

• Principal investigator: Fabrice Bonnet, M.D., Ph.D. — University Hospital, Bordeaux
• Study coordinator: Fabrice Bonnet, M.D., Ph.D.

Conditions: Tuberculous Meningitis, Intensified treatment, High dose Rifampicin, Linezolid, Aspirin, Subsaharan Africa