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)

Overview

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.

Interventions

• Drug Aspirin
  Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)
• Drug Placebo of aspirin
  Two placebo tablets with the same appearance of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)
• Drug WHO TBM treatment
  2 months of (R-H-Z-E) + 7 months of (R-H)
• Drug Intensified TBM treatment
  2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid

Primary outcome measures

• Rate of all-cause death [Time frame: Up to 40 weeks]

Secondary outcome measures (12)

• Rate of all-cause death [Time frame: Up to 8 weeks]
• Rate of all-cause death or loss to follow-up [Time frame: Up to 40 weeks]
• Rate of new central neurological event or aggravation of a central neurological event existing at baseline [Time frame: Up to 40 weeks]
• Rate of grade 3-4 adverse events (DAIDS adverse events grading table) [Time frame: Up to 40 weeks]
• Rate of serious adverse events [Time frame: Up to 40 weeks]
• Rate of solicited treatment related adverse events [Time frame: Up to 40 weeks]
• Percentage of patients with disability [Time frame: 40 weeks]
• M. tuberculosis culture conversion rate [Time frame: 1 week and 4 weeks]
• Time to culture positivity [Time frame: Up to 40 weeks]
• Time to first hospital discharge [Time frame: Up to 40 weeks]
• Cost-effectiveness incremental ratio of trial interventions [Time frame: Up to 40 weeks]
• Prevalence of resistance to anti-TB drugs among patients with positive culture at inclusion [Time frame: Up to 40 weeks]

Eligibility criteria

Inclusion criteria

• Age ≥ 15 years
• TBM defined as "definite", "probable" or "possible"
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

South Africa · 5 centers

• Kayelitsha District Hospital — Cape Town
• Mitchells Plain Hospital — Cape Town
• New Somerset Hospital — Cape Town
• Dora Nginza Hospital — Port Elizabeth
• Livingstone and PE Central Hospitals — Port Elizabeth

Côte d’Ivoire · 3 centers

• Cocody University Hospital — Abidjan
• Treichville University Hospital — Abidjan
• Yopougon University Hospital — Abidjan

Madagascar · 3 centers

• University Hospital Joseph Raseta Befelatanana — Antananarivo
• University Hospital Tambohobe — Fianarantsoa
• Morafeno University Hospital — Toamasina

Uganda · 2 centers

• Mbarara Regional Reference Hospital — Mbarara
• Regional Reference Hospital of Kabale — Mbarara

Publications

• 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-TB PMID 36348453
• Ariza-Vioque E, Ello F, Andriamamonjisoa H, Machault V, Gonzalez-Martin J, Calvo-Cortes MC, Eholie S, Tchabert GA, Ouassa T, Raberahona M, Rakotoarivelo R, Razafindrakoto H, Rahajamanana L, Wilkinson RJ, Davis A, Maxebengula M, Abrahams F, Muzoora C, Nakigozi N, Nyehangane D, Nanjebe D, Mbega H, Kaitano R, Bonnet M, Debeaudrap P, Miro JM, Anglaret X, Rakotosamimanana N, Calmy A, Bonnet F, Ambrosio PMID 35767219

Identifiers

NCT: NCT04145258 · ANRS 12398 INTENSE-TBM · EDCTP RIA2017T-2019

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗