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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

BACKGROUND: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB), particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40% in HIV-negative patients and up to 70% in HIV-co-infected patients. To reduce TBM-ind...

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Autores principales: Maitre, Thomas, Bonnet, Maryline, Calmy, Alexandra, Raberahona, Mihaja, Rakotoarivelo, Rivonirina Andry, Rakotosamimanana, Niaina, Ambrosioni, Juan, Miró, José M., Debeaudrap, Pierre, Muzoora, Conrad, Davis, Angharad, Meintjes, Graeme, Wasserman, Sean, Wilkinson, Robert, Eholié, Serge, Nogbou, Frédéric Ello, Calvo-Cortes, Maria-Camilla, Chazallon, Corine, Machault, Vanessa, Anglaret, Xavier, Bonnet, Fabrice
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9640846/
https://www.ncbi.nlm.nih.gov/pubmed/36348453
http://dx.doi.org/10.1186/s13063-022-06772-1
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author Maitre, Thomas
Bonnet, Maryline
Calmy, Alexandra
Raberahona, Mihaja
Rakotoarivelo, Rivonirina Andry
Rakotosamimanana, Niaina
Ambrosioni, Juan
Miró, José M.
Debeaudrap, Pierre
Muzoora, Conrad
Davis, Angharad
Meintjes, Graeme
Wasserman, Sean
Wilkinson, Robert
Eholié, Serge
Nogbou, Frédéric Ello
Calvo-Cortes, Maria-Camilla
Chazallon, Corine
Machault, Vanessa
Anglaret, Xavier
Bonnet, Fabrice
author_facet Maitre, Thomas
Bonnet, Maryline
Calmy, Alexandra
Raberahona, Mihaja
Rakotoarivelo, Rivonirina Andry
Rakotosamimanana, Niaina
Ambrosioni, Juan
Miró, José M.
Debeaudrap, Pierre
Muzoora, Conrad
Davis, Angharad
Meintjes, Graeme
Wasserman, Sean
Wilkinson, Robert
Eholié, Serge
Nogbou, Frédéric Ello
Calvo-Cortes, Maria-Camilla
Chazallon, Corine
Machault, Vanessa
Anglaret, Xavier
Bonnet, Fabrice
author_sort Maitre, Thomas
collection PubMed
description BACKGROUND: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB), particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40% in HIV-negative patients and up to 70% in HIV-co-infected patients. To reduce TBM-induced morbidity and mortality, the INTENSE-TBM trial evaluates two interventions in both HIV-infected and uninfected patients: an anti-TB treatment intensification using oral high-dose rifampicin (35 mg/kg daily) and linezolid (1200 mg daily and then 600 mg daily) during the first 8 weeks of the anti-TB treatment and the use of adjunctive aspirin (200 mg daily). METHODS: This is a randomized controlled, phase III, multicenter, 2 × 2 factorial plan superiority trial. The trial has four arms, combining the two experimental treatments (intensified TBM regimen and aspirin) with the two reference treatments (WHO standard TB treatment and placebo), and is open-label for anti-TB treatment and double-blind placebo-controlled for aspirin treatment. This trial is conducted in adults or adolescents of age ≥15 years with TBM defined as “definite,” “probable,” or “possible” using Tuberculosis Meningitis International Research Consortium criteria, in four African countries: Ivory Coast, Madagascar, Uganda, and South Africa. The primary outcome is all-cause death between inclusion and week 40. DISCUSSION: The INTENSE-TBM trial represents a key opportunity to enhance TBM treatment with widely available existing drugs notably in high-incidence settings of both TB and HIV. The trial design is pragmatic and the results will permit early and effective applications in TBM patient care, in both HIV and TB high-incidence countries. TRIAL REGISTRATION: ClinicalTrials.gov NCT04145258. Registered on October 30, 2019. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-022-06772-1.
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spelling pubmed-96408462022-11-14 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 Maitre, Thomas Bonnet, Maryline Calmy, Alexandra Raberahona, Mihaja Rakotoarivelo, Rivonirina Andry Rakotosamimanana, Niaina Ambrosioni, Juan Miró, José M. Debeaudrap, Pierre Muzoora, Conrad Davis, Angharad Meintjes, Graeme Wasserman, Sean Wilkinson, Robert Eholié, Serge Nogbou, Frédéric Ello Calvo-Cortes, Maria-Camilla Chazallon, Corine Machault, Vanessa Anglaret, Xavier Bonnet, Fabrice Trials Study Protocol BACKGROUND: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB), particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40% in HIV-negative patients and up to 70% in HIV-co-infected patients. To reduce TBM-induced morbidity and mortality, the INTENSE-TBM trial evaluates two interventions in both HIV-infected and uninfected patients: an anti-TB treatment intensification using oral high-dose rifampicin (35 mg/kg daily) and linezolid (1200 mg daily and then 600 mg daily) during the first 8 weeks of the anti-TB treatment and the use of adjunctive aspirin (200 mg daily). METHODS: This is a randomized controlled, phase III, multicenter, 2 × 2 factorial plan superiority trial. The trial has four arms, combining the two experimental treatments (intensified TBM regimen and aspirin) with the two reference treatments (WHO standard TB treatment and placebo), and is open-label for anti-TB treatment and double-blind placebo-controlled for aspirin treatment. This trial is conducted in adults or adolescents of age ≥15 years with TBM defined as “definite,” “probable,” or “possible” using Tuberculosis Meningitis International Research Consortium criteria, in four African countries: Ivory Coast, Madagascar, Uganda, and South Africa. The primary outcome is all-cause death between inclusion and week 40. DISCUSSION: The INTENSE-TBM trial represents a key opportunity to enhance TBM treatment with widely available existing drugs notably in high-incidence settings of both TB and HIV. The trial design is pragmatic and the results will permit early and effective applications in TBM patient care, in both HIV and TB high-incidence countries. TRIAL REGISTRATION: ClinicalTrials.gov NCT04145258. Registered on October 30, 2019. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-022-06772-1. BioMed Central 2022-11-08 /pmc/articles/PMC9640846/ /pubmed/36348453 http://dx.doi.org/10.1186/s13063-022-06772-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Study Protocol
Maitre, Thomas
Bonnet, Maryline
Calmy, Alexandra
Raberahona, Mihaja
Rakotoarivelo, Rivonirina Andry
Rakotosamimanana, Niaina
Ambrosioni, Juan
Miró, José M.
Debeaudrap, Pierre
Muzoora, Conrad
Davis, Angharad
Meintjes, Graeme
Wasserman, Sean
Wilkinson, Robert
Eholié, Serge
Nogbou, Frédéric Ello
Calvo-Cortes, Maria-Camilla
Chazallon, Corine
Machault, Vanessa
Anglaret, Xavier
Bonnet, Fabrice
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Study Protocol
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9640846/
https://www.ncbi.nlm.nih.gov/pubmed/36348453
http://dx.doi.org/10.1186/s13063-022-06772-1
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