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High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)

Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pha...

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Autores principales: Marais, Suzaan, Cresswell, Fiona V, Hamers, Raph L., te Brake, Lindsey H.M., Ganiem, Ahmad R., Imran, Darma, Bangdiwala, Ananta, Martyn, Emily, Kasibante, John, Kagimu, Enock, Musubire, Abdu, Maharani, Kartika, Estiasari, Riwanti, Kusumaningrum, Ardiana, Kusumadjayanti, Nadytia, Yunivita, Vycke, Naidoo, Kogieleum, Lessells, Richard, Moosa, Yunus, Svensson, Elin M., Huppler Hullsiek, Katherine, Aarnoutse, Rob E., Boulware, David R., van Crevel, Reinout, Ruslami, Rovina, Meya, David B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: F1000 Research Limited 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542255/
https://www.ncbi.nlm.nih.gov/pubmed/33083560
http://dx.doi.org/10.12688/wellcomeopenres.15565.2
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author Marais, Suzaan
Cresswell, Fiona V
Hamers, Raph L.
te Brake, Lindsey H.M.
Ganiem, Ahmad R.
Imran, Darma
Bangdiwala, Ananta
Martyn, Emily
Kasibante, John
Kagimu, Enock
Musubire, Abdu
Maharani, Kartika
Estiasari, Riwanti
Kusumaningrum, Ardiana
Kusumadjayanti, Nadytia
Yunivita, Vycke
Naidoo, Kogieleum
Lessells, Richard
Moosa, Yunus
Svensson, Elin M.
Huppler Hullsiek, Katherine
Aarnoutse, Rob E.
Boulware, David R.
van Crevel, Reinout
Ruslami, Rovina
Meya, David B.
author_facet Marais, Suzaan
Cresswell, Fiona V
Hamers, Raph L.
te Brake, Lindsey H.M.
Ganiem, Ahmad R.
Imran, Darma
Bangdiwala, Ananta
Martyn, Emily
Kasibante, John
Kagimu, Enock
Musubire, Abdu
Maharani, Kartika
Estiasari, Riwanti
Kusumaningrum, Ardiana
Kusumadjayanti, Nadytia
Yunivita, Vycke
Naidoo, Kogieleum
Lessells, Richard
Moosa, Yunus
Svensson, Elin M.
Huppler Hullsiek, Katherine
Aarnoutse, Rob E.
Boulware, David R.
van Crevel, Reinout
Ruslami, Rovina
Meya, David B.
author_sort Marais, Suzaan
collection PubMed
description Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. Trial registration: ISRCTN15668391 (17/06/2019)
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spelling pubmed-75422552020-10-19 High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study) Marais, Suzaan Cresswell, Fiona V Hamers, Raph L. te Brake, Lindsey H.M. Ganiem, Ahmad R. Imran, Darma Bangdiwala, Ananta Martyn, Emily Kasibante, John Kagimu, Enock Musubire, Abdu Maharani, Kartika Estiasari, Riwanti Kusumaningrum, Ardiana Kusumadjayanti, Nadytia Yunivita, Vycke Naidoo, Kogieleum Lessells, Richard Moosa, Yunus Svensson, Elin M. Huppler Hullsiek, Katherine Aarnoutse, Rob E. Boulware, David R. van Crevel, Reinout Ruslami, Rovina Meya, David B. Wellcome Open Res Study Protocol Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. Trial registration: ISRCTN15668391 (17/06/2019) F1000 Research Limited 2020-08-25 /pmc/articles/PMC7542255/ /pubmed/33083560 http://dx.doi.org/10.12688/wellcomeopenres.15565.2 Text en Copyright: © 2020 Marais S et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Study Protocol
Marais, Suzaan
Cresswell, Fiona V
Hamers, Raph L.
te Brake, Lindsey H.M.
Ganiem, Ahmad R.
Imran, Darma
Bangdiwala, Ananta
Martyn, Emily
Kasibante, John
Kagimu, Enock
Musubire, Abdu
Maharani, Kartika
Estiasari, Riwanti
Kusumaningrum, Ardiana
Kusumadjayanti, Nadytia
Yunivita, Vycke
Naidoo, Kogieleum
Lessells, Richard
Moosa, Yunus
Svensson, Elin M.
Huppler Hullsiek, Katherine
Aarnoutse, Rob E.
Boulware, David R.
van Crevel, Reinout
Ruslami, Rovina
Meya, David B.
High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)
title High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)
title_full High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)
title_fullStr High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)
title_full_unstemmed High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)
title_short High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)
title_sort high dose oral rifampicin to improve survival from adult tuberculous meningitis: a randomised placebo-controlled double-blinded phase iii trial (the harvest study)
topic Study Protocol
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542255/
https://www.ncbi.nlm.nih.gov/pubmed/33083560
http://dx.doi.org/10.12688/wellcomeopenres.15565.2
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