Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis
NCT ID: NCT04145258
Last Updated: 2024-01-22
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE3
768 participants
INTERVENTIONAL
2021-02-07
2026-04-30
Brief Summary
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* 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.
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
FACTORIAL
TREATMENT
QUADRUPLE
Study Groups
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WHO TBM treatment + placebo
* 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.
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)
WHO TBM treatment
2 months of (R-H-Z-E) + 7 months of (R-H)
WHO TBM treatment + aspirin
* 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.
Aspirin
Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)
WHO TBM treatment
2 months of (R-H-Z-E) + 7 months of (R-H)
Intensified TBM treatment + placebo
* 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.
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)
Intensified TBM treatment
2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid
Intensified TBM treatment + aspirin
* 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.
Aspirin
Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)
Intensified TBM treatment
2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid
Interventions
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Aspirin
Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)
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)
WHO TBM treatment
2 months of (R-H-Z-E) + 7 months of (R-H)
Intensified TBM treatment
2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
* 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.
15 Years
ALL
No
Sponsors
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European Union
OTHER
European and Developing Countries Clinical Trials Partnership (EDCTP)
OTHER_GOV
ANRS, Emerging Infectious Diseases
OTHER_GOV
Responsible Party
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Principal Investigators
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Fabrice Bonnet, M.D., Ph.D.
Role: PRINCIPAL_INVESTIGATOR
University Hospital, Bordeaux
Locations
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Cocody University Hospital
Abidjan, , Côte d’Ivoire
Treichville University Hospital
Abidjan, , Côte d’Ivoire
Yopougon University Hospital
Abidjan, , Côte d’Ivoire
University Hospital Joseph Raseta Befelatanana
Antananarivo, , Madagascar
University Hospital Tambohobe
Fianarantsoa, , Madagascar
Morafeno University Hospital
Toamasina, , Madagascar
Kayelitsha District Hospital
Cape Town, , South Africa
Mitchells Plain Hospital
Cape Town, , South Africa
New Somerset Hospital
Cape Town, , South Africa
Dora Nginza Hospital
Port Elizabeth, , South Africa
Livingstone and PE Central Hospitals
Port Elizabeth, , South Africa
Mbarara Regional Reference Hospital
Mbarara, , Uganda
Regional Reference Hospital of Kabale
Mbarara, , Uganda
Countries
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Central Contacts
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Facility Contacts
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Horo Kigninlman, Prof
Role: primary
Gisèle Kouakou, Prof.
Role: primary
Thierry Odehoury-Koudou, Prof
Role: primary
Mamy Jean de Dieu Randria, Prof.
Role: primary
Rivonirina Andry Rakotoarivelo, Prof.
Role: primary
Stéphane Dimby Ralandison, Prof
Role: primary
Graeme Meintjes, Prof.
Role: primary
Graeme Meintjes, Prof.
Role: primary
Sean Wassermann, Dr
Role: primary
Nowshad Alam, Dr
Role: primary
John Black, Dr.
Role: primary
Conrad Muzoora, Dr.
Role: primary
Marion Namutebi, Dr.
Role: primary
References
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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.
Related Links
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INTENSE-TBM project website
Other Identifiers
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EDCTP RIA2017T-2019
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
ANRS 12398 INTENSE-TBM
Identifier Type: -
Identifier Source: org_study_id
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