Clinical trial NCT04145258: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Tuberculous Meningitis
Keywords: Tuberculous Meningitis
Intensified treatment
High dose Rifampicin
Linezolid
Aspirin
Subsaharan Africa
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: European Union
name: European and Developing Countries Clinical Trials Partnership (EDCTP)
First posted: 2019-10-30
Enrollment: 768
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Rate of all-cause death
timeFrame: Up to 40 weeks
Secondary outcomes:
measure: Rate of all-cause death
timeFrame: Up to 8 weeks
measure: Rate of all-cause death or loss to follow-up
timeFrame: Up to 40 weeks
measure: Rate of new central neurological event or aggravation of a central neurological event existing at baseline
timeFrame: Up to 40 weeks
measure: Rate of grade 3-4 adverse events (DAIDS adverse events grading table)
timeFrame: Up to 40 weeks
measure: Rate of serious adverse events
timeFrame: Up to 40 weeks
measure: Rate of solicited treatment related adverse events
timeFrame: Up to 40 weeks
measure: Percentage of patients with disability
timeFrame: 40 weeks
measure: M. tuberculosis culture conversion rate
timeFrame: 1 week and 4 weeks
measure: Time to culture positivity
timeFrame: Up to 40 weeks
measure: Time to first hospital discharge
timeFrame: Up to 40 weeks
measure: Cost-effectiveness incremental ratio of trial interventions
timeFrame: Up to 40 weeks
measure: Prevalence of resistance to anti-TB drugs among patients with positive culture at inclusion
timeFrame: Up to 40 weeks
measure: Subset of patients: In vitro bactericidal activity of anti-TBM treatment
timeFrame: 1 week and 4 weeks
measure: Subset of patients: Maximum Plasma Concentration [Cmax] of rifampicin and linezolid
timeFrame: 1 week and 4 weeks
measure: Subset of patients: Minimum Plasma Concentration [Cmin] of rifampicin and linezolid
timeFrame: 1 week and 4 weeks
measure: Subset of patients: Area Under the Curve [AUC] of rifampicin and linezolid
timeFrame: 1 week and 4 weeks
measure: Subset of patients: Time for maximal concentration [Tmax] of rifampicin and linezolid
timeFrame: 1 week and 4 weeks
measure: Subset of patients: Half-life (t1/2) of rifampicin and linezolid
timeFrame: 1 week and 4 weeks
measure: HIV-infected participants: Rate of new AIDS-defining illnesses
timeFrame: Up to 40 weeks
measure: HIV-infected participants: Percentage of participants with virological success (plasma HIV-1 RNA <50 copies/ml)
timeFrame: 28 weeks and 40 weeks
measure: HIV-infected participants: CD4 count change from baseline
timeFrame: 28 weeks and 40 weeks
measure: HIV-infected participants, subset of patients: Maximum Plasma Concentration [Cmax] of of dolutegravir
timeFrame: 1 week and 4 weeks
measure: HIV-infected participants, subset of patients: Minimum Plasma Concentration [Cmin] of dolutegravir
timeFrame: 1 week and 4 weeks
measure: HIV-infected participants, subset of patients: Area Under the Curve [AUC] of dolutegravir
timeFrame: 1 week and 4 weeks
measure: HIV-infected participants, subset of patients: Time for maximal concentration [Tmax] of dolutegravir
timeFrame: 1 week and 4 weeks
measure: HIV-infected participants, subset of patients: Half-life (t1/2) of dolutegravir
timeFrame: 1 week and 4 weeks
Other outcomes:
Locations:
city: Abidjan
country: Côte D'Ivoire
facility: Cocody University Hospital
city: Abidjan
country: Côte D'Ivoire
facility: Treichville University Hospital
city: Abidjan
country: Côte D'Ivoire
facility: Yopougon University Hospital
city: Antananarivo
country: Madagascar
facility: University Hospital Joseph Raseta Befelatanana
city: Fianarantsoa
country: Madagascar
facility: University Hospital Tambohobe
city: Toamasina
country: Madagascar
facility: Morafeno University Hospital
city: Cape Town
country: South Africa
facility: Kayelitsha District Hospital
city: Cape Town
country: South Africa
facility: Mitchells Plain Hospital
city: Cape Town
country: South Africa
facility: New Somerset Hospital
city: Port Elizabeth
country: South Africa
facility: Dora Nginza Hospital
city: Port Elizabeth
country: South Africa
facility: Livingstone and PE Central Hospitals
city: Mbarara
country: Uganda
facility: Mbarara Regional Reference Hospital
city: Mbarara
country: Uganda
facility: Regional Reference Hospital of Kabale
Study officials:
affiliation: University Hospital, Bordeaux
name: Fabrice Bonnet, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Maitre T, Bonnet M, Calmy A, Raberahona M, Rakotoarivelo RA, Rakotosamimanana N, Ambrosioni J, Miro JM, Debeaudrap P, Muzoora C, Davis A, Meintjes G, Wasserman S, Wilkinson R, Eholie S, Nogbou FE, Calvo-Cortes MC, Chazallon C, Machault V, Anglaret X, Bonnet F. Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis meningitis (INTENSE-TBM): study protocol for a phase III randomized controlled trial. Trials. 2022 Nov 8;23(1):928. doi: 10.1186/s13063-022-06772-1.