Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial

Cevik, Muge; Thompson, Lindsay C.; Upton, Caryn; Rolla, Valeria Cavalcanti; Malahleha, Mookho; Mmbaga, Blandina; Ngubane, Nosipho; Bakar, Zamzurina Abu; Rassool, Mohammed; Variava, Ebrahim; Dawson, Rodney; Staples, Suzanne; Lalloo, Umesh; Louw, Cheryl; Conradie, Francesca; Eristavi, Marika; Samoilova, Anastasia; Skornyakov, Sergey N.; Ntinginya, Niyanda Elias; Haraka, Frederick; Praygod, George; Mayanja-Kizza, Harriett; Caoili, Janice; Balanag, Vincent; Dalcolmo, Margareth Pretti; Mchugh, Timothy; Hunt, Robert; Solanki, Priya; Bateson, Anna; Crook, Angela M.; Fabiane, Stella; Timm, Juliano; Sun, Eugene; Spigelman, Melvin; Sloan, Derek J.; Gillespie, Stephen H.

Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial

Bibliographic Details
Main Author:	Cevik, Muge
Publication Date:	2024
Other Authors:	Thompson, Lindsay C., Upton, Caryn, Rolla, Valeria Cavalcanti, Malahleha, Mookho, Mmbaga, Blandina, Ngubane, Nosipho, Bakar, Zamzurina Abu, Rassool, Mohammed, Variava, Ebrahim, Dawson, Rodney, Staples, Suzanne, Lalloo, Umesh, Louw, Cheryl, Conradie, Francesca, Eristavi, Marika, Samoilova, Anastasia, Skornyakov, Sergey N., Ntinginya, Niyanda Elias, Haraka, Frederick, Praygod, George, Mayanja-Kizza, Harriett, Caoili, Janice, Balanag, Vincent, Dalcolmo, Margareth Pretti, Mchugh, Timothy, Hunt, Robert, Solanki, Priya, Bateson, Anna, Crook, Angela M., Fabiane, Stella, Timm, Juliano, Sun, Eugene, Spigelman, Melvin, Sloan, Derek J., Gillespie, Stephen H.
Format:	Article
Language:	eng
Source:	Repositório Institucional da FIOCRUZ (ARCA)
DOI:	10.1016/S1473-3099(24)00223-8
Download full:	https://arca.fiocruz.br/handle/icict/68137
Summary:	Collaborators: SimpliciTB Consortium: Paul Bruinenberg, Maria Beumont, Jerry Nedelman, Mengchun Li, Ntokozo Zuma-Gwala, Shakira Rajaram, Louise Choo, Genevive Wills, Matt Betteridge, Leandra Leandra, Morounfolu Olugbosi, Sergey Borisov.

Item metadata

id	CRUZ_567e8ca01c9e88f77889300a111f20cd
oai_identifier_str	oai:arca.fiocruz.br:icict/68137
network_acronym_str	CRUZ
network_name_str	Repositório Institucional da FIOCRUZ (ARCA)
repository_id_str	2135
spelling	Cevik, MugeThompson, Lindsay C.Upton, CarynRolla, Valeria CavalcantiMalahleha, MookhoMmbaga, BlandinaNgubane, NosiphoBakar, Zamzurina AbuRassool, MohammedVariava, EbrahimDawson, RodneyStaples, SuzanneLalloo, UmeshLouw, CherylConradie, FrancescaEristavi, MarikaSamoilova, AnastasiaSkornyakov, Sergey N.Ntinginya, Niyanda EliasHaraka, FrederickPraygod, GeorgeMayanja-Kizza, HarriettCaoili, JaniceBalanag, VincentDalcolmo, Margareth PrettiMchugh, TimothyHunt, RobertSolanki, PriyaBateson, AnnaCrook, Angela M.Fabiane, StellaTimm, JulianoSun, EugeneSpigelman, MelvinSloan, Derek J.Gillespie, Stephen H.2025-01-20T01:50:45Z2025-01-20T01:50:45Z2024CEVIK, Muge et al. Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial. The Lancet. Infectious Diseases, v. 24, n. 9, p. 1003-1014, Sep. 2024.1473-3099https://arca.fiocruz.br/handle/icict/6813710.1016/S1473-3099(24)00223-81474-4457Collaborators: SimpliciTB Consortium: Paul Bruinenberg, Maria Beumont, Jerry Nedelman, Mengchun Li, Ntokozo Zuma-Gwala, Shakira Rajaram, Louise Choo, Genevive Wills, Matt Betteridge, Leandra Leandra, Morounfolu Olugbosi, Sergey Borisov.TB Alliance.University of St Andrews. School of Medicine. Division of Infection and Global Health Research. St Andrews, UK.University College London. MRC Clinical Trials Unit. London, UK.TASK. Cape Town, South Africa.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em Micobacterioses. Rio de Janeiro, RJ, Brasil.Setshaba Research Centre. Soshanguve, South Africa.Kilimanjaro Clinical Research Institute. Moshi, Tanzania.CHRU. King Dinuzulu. Durban, South Africa.Institut Perubatan Respiratori. Kuala Lumpur, Malaysia.CHRU. Helen Joseph Hospital. Johannesburg, South Africa.PHRU. Tshepong Hospital. Klerksdorp, South Africa.University of Cape Town Lung Institute. Cape Town, South Africa.THINK, Durban. South Africa.Enhancing Care Foundation. Durban, South Africa.Madibeng Centre for Research. Brits, South Africa.University of the Witwatersrand. Reproductive Health and HIV Research Unit. Johannesburg, South Africa.National Center for Tuberculosis and Lung Diseases. Tbilisi, Georgia.Research Institute of Phthisiopulmonology of IM Sechenov First Moscow State Medical University. Moscow, Russia.Ural Research Institute for Phthisiopulmonology. National Medical Research Center of Tuberculosis and Infectious Diseases of Ministry of Health of the Russian Federation. Yekaterinburg, Russia.NIMR-Mbeya. Mbeya, Tanzania.Ifakara Health Institute. Ifakara, Tanzania.Mwanza Intervention Trials Unit. Mwanza, Tanzania.Case Western Reserve University. Kampala, Uganda.Tropical Disease Foundation. Makati City, Manila, Philippines.Lung Center of Philippines. Manila, Philippines.Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sergio Arouca. Rio de Janeiro, RJ, Brasil.University College London. UCL Centre for Clinical Microbiology. London, UK.University College London. UCL Centre for Clinical Microbiology. London, UK.University College London. UCL Centre for Clinical Microbiology. London, UK.University College London. UCL Centre for Clinical Microbiology. London, UK.University College London. MRC Clinical Trials Unit. London, UK.University College London. MRC Clinical Trials Unit. London, UK.TB Alliance. New York, NY, USA.TB Alliance. New York, NY, USA.TB Alliance. New York, NY, USA.University of St Andrews. School of Medicine. Division of Infection and Global Health Research. St Andrews, UK.University of St Andrews. School of Medicine. Division of Infection and Global Health Research. St Andrews, UK.Background: The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB. Methods: SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov (NCT03338621) and is completed. Findings: Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17-3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4-8) on 4 months of BPaMZ and 11 weeks (6-12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3-7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]). Interpretation: For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments.engElsevierBedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trialinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleBedaquilinePretomanidMoxifloxacinPyrazinamidePulmonary tuberculosisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://arca.fiocruz.br/bitstreams/b3a10ef7-d54a-4c00-b8d5-f45299e3fdda/download5a560609d32a3863062d77ff32785d58MD51falseAnonymousREADORIGINALve_Muge Cevik_etal_INI_ENSP_2024.pdfve_Muge Cevik_etal_INI_ENSP_2024.pdfapplication/pdf544772https://arca.fiocruz.br/bitstreams/ebb31c5a-70a4-4fa0-8f07-714030b522a2/download9bbf0b44291db7c62759257a78634c2aMD53trueAnonymousREADmmc1.pdfmmc1.pdfSupplementary appendixapplication/pdf4905025https://arca.fiocruz.br/bitstreams/67cfc4a7-9255-4a8a-a3b8-7be25ed0e6e5/download4f299d2bb8ed32581fc3b485e43a34b5MD55falseAnonymousREADTHUMBNAILcapa_page-0001.jpgcapa_page-0001.jpgimage/jpeg1356898https://arca.fiocruz.br/bitstreams/9955b26e-dc4e-47cf-b6c7-ccaf865bf046/downloade2144e63369aa42c241031d2b83ce49dMD54falseAnonymousREADve_Muge Cevik_etal_INI_ENSP_2024.pdf.jpgve_Muge Cevik_etal_INI_ENSP_2024.pdf.jpgGenerated Thumbnailimage/jpeg6751https://arca.fiocruz.br/bitstreams/95a30909-c7b0-4883-a85b-5c0e4492cc85/downloadbd52f3b456d13d9e0e47195156bc7c03MD519falseAnonymousREADmmc1.pdf.jpgmmc1.pdf.jpgGenerated Thumbnailimage/jpeg3083https://arca.fiocruz.br/bitstreams/3b8dd469-e6df-4b6b-ad2f-3639b1bb4fe9/downloadd0650445d85fa2ab60c0673128f284f2MD521falseAnonymousREADTEXTve_Muge Cevik_etal_INI_ENSP_2024.pdf.txtve_Muge Cevik_etal_INI_ENSP_2024.pdf.txtExtracted texttext/plain66113https://arca.fiocruz.br/bitstreams/96e3db70-6352-451c-a89b-612435a590f2/download9e9a0b746ac761808182cab8d45aa76eMD518falseAnonymousREADmmc1.pdf.txtmmc1.pdf.txtExtracted texttext/plain100582https://arca.fiocruz.br/bitstreams/27fc8893-8978-432b-98f0-66abdf27d59e/downloadac9b5c0355c4502739f67e9e20aed2c4MD520falseAnonymousREADicict/681372025-07-30 01:31:36.541open.accessoai:arca.fiocruz.br:icict/68137https://arca.fiocruz.brRepositório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352025-07-30T04:31:36Repositório Institucional da FIOCRUZ (ARCA) - 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dc.title.none.fl_str_mv	Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial
title	Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial
spellingShingle	Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial Cevik, Muge Bedaquiline Pretomanid Moxifloxacin Pyrazinamide Pulmonary tuberculosis
title_short	Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial
title_full	Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial
title_fullStr	Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial
title_full_unstemmed	Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial
title_sort	Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial
author	Cevik, Muge
author_facet	Cevik, Muge Thompson, Lindsay C. Upton, Caryn Rolla, Valeria Cavalcanti Malahleha, Mookho Mmbaga, Blandina Ngubane, Nosipho Bakar, Zamzurina Abu Rassool, Mohammed Variava, Ebrahim Dawson, Rodney Staples, Suzanne Lalloo, Umesh Louw, Cheryl Conradie, Francesca Eristavi, Marika Samoilova, Anastasia Skornyakov, Sergey N. Ntinginya, Niyanda Elias Haraka, Frederick Praygod, George Mayanja-Kizza, Harriett Caoili, Janice Balanag, Vincent Dalcolmo, Margareth Pretti Mchugh, Timothy Hunt, Robert Solanki, Priya Bateson, Anna Crook, Angela M. Fabiane, Stella Timm, Juliano Sun, Eugene Spigelman, Melvin Sloan, Derek J. Gillespie, Stephen H.
author_role	author
author2	Thompson, Lindsay C. Upton, Caryn Rolla, Valeria Cavalcanti Malahleha, Mookho Mmbaga, Blandina Ngubane, Nosipho Bakar, Zamzurina Abu Rassool, Mohammed Variava, Ebrahim Dawson, Rodney Staples, Suzanne Lalloo, Umesh Louw, Cheryl Conradie, Francesca Eristavi, Marika Samoilova, Anastasia Skornyakov, Sergey N. Ntinginya, Niyanda Elias Haraka, Frederick Praygod, George Mayanja-Kizza, Harriett Caoili, Janice Balanag, Vincent Dalcolmo, Margareth Pretti Mchugh, Timothy Hunt, Robert Solanki, Priya Bateson, Anna Crook, Angela M. Fabiane, Stella Timm, Juliano Sun, Eugene Spigelman, Melvin Sloan, Derek J. Gillespie, Stephen H.
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.contributor.author.fl_str_mv	Cevik, Muge Thompson, Lindsay C. Upton, Caryn Rolla, Valeria Cavalcanti Malahleha, Mookho Mmbaga, Blandina Ngubane, Nosipho Bakar, Zamzurina Abu Rassool, Mohammed Variava, Ebrahim Dawson, Rodney Staples, Suzanne Lalloo, Umesh Louw, Cheryl Conradie, Francesca Eristavi, Marika Samoilova, Anastasia Skornyakov, Sergey N. Ntinginya, Niyanda Elias Haraka, Frederick Praygod, George Mayanja-Kizza, Harriett Caoili, Janice Balanag, Vincent Dalcolmo, Margareth Pretti Mchugh, Timothy Hunt, Robert Solanki, Priya Bateson, Anna Crook, Angela M. Fabiane, Stella Timm, Juliano Sun, Eugene Spigelman, Melvin Sloan, Derek J. Gillespie, Stephen H.
dc.subject.en.none.fl_str_mv	Bedaquiline Pretomanid Moxifloxacin Pyrazinamide Pulmonary tuberculosis
topic	Bedaquiline Pretomanid Moxifloxacin Pyrazinamide Pulmonary tuberculosis
description	Collaborators: SimpliciTB Consortium: Paul Bruinenberg, Maria Beumont, Jerry Nedelman, Mengchun Li, Ntokozo Zuma-Gwala, Shakira Rajaram, Louise Choo, Genevive Wills, Matt Betteridge, Leandra Leandra, Morounfolu Olugbosi, Sergey Borisov.
publishDate	2024
dc.date.issued.fl_str_mv	2024
dc.date.accessioned.fl_str_mv	2025-01-20T01:50:45Z
dc.date.available.fl_str_mv	2025-01-20T01:50:45Z
dc.type.status.fl_str_mv	info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv	info:eu-repo/semantics/article
format	article
status_str	publishedVersion
dc.identifier.citation.fl_str_mv	CEVIK, Muge et al. Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial. The Lancet. Infectious Diseases, v. 24, n. 9, p. 1003-1014, Sep. 2024.
dc.identifier.uri.fl_str_mv	https://arca.fiocruz.br/handle/icict/68137
dc.identifier.issn.none.fl_str_mv	1473-3099
dc.identifier.doi.none.fl_str_mv	10.1016/S1473-3099(24)00223-8
dc.identifier.eissn.none.fl_str_mv	1474-4457
identifier_str_mv	CEVIK, Muge et al. Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial. The Lancet. Infectious Diseases, v. 24, n. 9, p. 1003-1014, Sep. 2024. 1473-3099 10.1016/S1473-3099(24)00223-8 1474-4457
url	https://arca.fiocruz.br/handle/icict/68137
dc.language.iso.fl_str_mv	eng
language	eng
dc.rights.driver.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.publisher.none.fl_str_mv	Elsevier
publisher.none.fl_str_mv	Elsevier
dc.source.none.fl_str_mv	reponame:Repositório Institucional da FIOCRUZ (ARCA) instname:Fundação Oswaldo Cruz (FIOCRUZ) instacron:FIOCRUZ
instname_str	Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str	FIOCRUZ
institution	FIOCRUZ
reponame_str	Repositório Institucional da FIOCRUZ (ARCA)
collection	Repositório Institucional da FIOCRUZ (ARCA)
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repository.name.fl_str_mv	Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)
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Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial

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