A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB

C. D. Tweed; G. H. Wills; A. M. Crook; E. Amukoye; V. Balanag; A. Y.L. Ban; A. L.C. Bateson; M. C. Betteridge; W. Brumskine; J. Caoili; R. E. Chaisson; M. Cevik; F. Conradie; R. Dawson; A. del Parigi; A. Diacon; D. E. Everitt; S.M. Fabiane; R. Hunt; A. I. Ismail; U. Lalloo; L. Lombard; C. Louw; M. Malahleha; T. D. McHugh; C. M. Mendel; F. Mhimbira; R. N. Moodliar; V. Nduba; A. J. Nunn; I. Sabi; M. A. Sebe; R. A. P. Selepe; S. Staples; S. Swindells; C. H. van Niekerk; E. Variava; M. Spigelman; S. H. Gillespie

doi:10.5588/ijtld.20.0513

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB

C. D. Tweed^*, G. H. Wills, A. M. Crook, E. Amukoye, V. Balanag, A. Y.L. Ban, A. L.C. Bateson, M. C. Betteridge, W. Brumskine, J. Caoili, R. E. Chaisson, M. Cevik, F. Conradie, R. Dawson, A. del Parigi, A. Diacon, D. E. Everitt, S.M. Fabiane, R. Hunt, A. I. IsmailU. Lalloo, L. Lombard, C. Louw, M. Malahleha, T. D. McHugh, C. M. Mendel, F. Mhimbira, R. N. Moodliar, V. Nduba, A. J. Nunn, I. Sabi, M. A. Sebe, R. A. P. Selepe, S. Staples, S. Swindells, C. H. van Niekerk, E. Variava, M. Spigelman, S. H. Gillespie

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.
METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa₂₀₀MZ) or 4 months (4Pa₂₀₀MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa₁₀₀MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.
RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa₂₀₀MZ, 4Pa₂₀₀MZ, 4Pa₁₀₀MZ and controls. There was a 6.6% (95% CI –2.2% to 15.4%) difference per protocol and 9.9% (95%CI –4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa₂₀₀MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.
CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Original language	English
Pages (from-to)	305-314
Number of pages	10
Journal	International Journal of Tuberculosis and Lung Disease
Volume	25
Issue number	4
DOIs	https://doi.org/10.5588/ijtld.20.0513
Publication status	Published - 1 Apr 2021

Keywords

Pulmonary and Respiratory Medicine
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Tweed_2021_IJTLD_partially-randomised-trial_CC
Copyright 2021 The Union. This article is Open Access under the terms of the Creative Commons CC BY licence.
Final published version, 774 KBLicence: CC BY

SimpliciTB - S Gillespie: EDCTP SimpliciTB 2018
Gillespie, S. H. (PI)
European and Developing Countries
1/01/19 → 31/12/22
Project: Standard

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Tweed, C. D., Wills, G. H., Crook, A. M., Amukoye, E., Balanag, V., Ban, A. Y. L., Bateson, A. L. C., Betteridge, M. C., Brumskine, W., Caoili, J., Chaisson, R. E., Cevik, M., Conradie, F., Dawson, R., del Parigi, A., Diacon, A., Everitt, D. E., Fabiane, S. M., Hunt, R., ... Gillespie, S. H. (2021). A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB. International Journal of Tuberculosis and Lung Disease, 25(4), 305-314. https://doi.org/10.5588/ijtld.20.0513

@article{a7167a1020d644a2a1558bdcab4c84d6,

title = "A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB",

abstract = "BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI –2.2% to 15.4%) difference per protocol and 9.9% (95%CI –4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.",

keywords = "Pulmonary and Respiratory Medicine, Infectious Diseases",

author = "Tweed, {C. D.} and Wills, {G. H.} and Crook, {A. M.} and E. Amukoye and V. Balanag and Ban, {A. Y.L.} and Bateson, {A. L.C.} and Betteridge, {M. C.} and W. Brumskine and J. Caoili and Chaisson, {R. E.} and M. Cevik and F. Conradie and R. Dawson and {del Parigi}, A. and A. Diacon and Everitt, {D. E.} and S.M. Fabiane and R. Hunt and Ismail, {A. I.} and U. Lalloo and L. Lombard and C. Louw and M. Malahleha and McHugh, {T. D.} and Mendel, {C. M.} and F. Mhimbira and Moodliar, {R. N.} and V. Nduba and Nunn, {A. J.} and I. Sabi and Sebe, {M. A.} and Selepe, {R. A. P.} and S. Staples and S. Swindells and {van Niekerk}, {C. H.} and E. Variava and M. Spigelman and Gillespie, {S. H.}",

note = "STAND was sponsored by TB Alliance with support from the UK Department for International Development, UK Department of Health (London, UK), Bill and Melinda Gates Foundation (Seattle, WA, USA), US Agency for International Development (Washington DC, USA), Directorate General for International Cooperation of the Netherlands (Amsterdam, The Netherlands), Irish Aid (Dublin, Ireland), Australia Department of Foreign Affairs and Trade (Canberra ACT, Australia) and the Federal Ministry for Education and Research of Germany (Berlin, Germany) through KfW (Kreditanstalt fur Wiederaufbau) and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH; Bethesda, MD, USA) under Award Numbers UM1 AI068634 and UM1 AI068636. AMC and AJN are supported by Medical Research Council Grant: MC_UU_12023/27 Tuberculosis Treatment Trials.",

year = "2021",

month = apr,

day = "1",

doi = "10.5588/ijtld.20.0513",

language = "English",

volume = "25",

pages = "305--314",

journal = "International Journal of Tuberculosis and Lung Disease",

issn = "1027-3719",

publisher = "International Union against Tubercul. and Lung Dis.",

number = "4",

}

Tweed, CD, Wills, GH, Crook, AM, Amukoye, E, Balanag, V, Ban, AYL, Bateson, ALC, Betteridge, MC, Brumskine, W, Caoili, J, Chaisson, RE, Cevik, M, Conradie, F, Dawson, R, del Parigi, A, Diacon, A, Everitt, DE, Fabiane, SM, Hunt, R, Ismail, AI, Lalloo, U, Lombard, L, Louw, C, Malahleha, M, McHugh, TD, Mendel, CM, Mhimbira, F, Moodliar, RN, Nduba, V, Nunn, AJ, Sabi, I, Sebe, MA, Selepe, RAP, Staples, S, Swindells, S, van Niekerk, CH, Variava, E, Spigelman, M & Gillespie, SH 2021, 'A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB', International Journal of Tuberculosis and Lung Disease, vol. 25, no. 4, pp. 305-314. https://doi.org/10.5588/ijtld.20.0513

TY - JOUR

T1 - A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB

AU - Tweed, C. D.

AU - Wills, G. H.

AU - Crook, A. M.

AU - Amukoye, E.

AU - Balanag, V.

AU - Ban, A. Y.L.

AU - Bateson, A. L.C.

AU - Betteridge, M. C.

AU - Brumskine, W.

AU - Caoili, J.

AU - Chaisson, R. E.

AU - Cevik, M.

AU - Conradie, F.

AU - Dawson, R.

AU - del Parigi, A.

AU - Diacon, A.

AU - Everitt, D. E.

AU - Fabiane, S.M.

AU - Hunt, R.

AU - Ismail, A. I.

AU - Lalloo, U.

AU - Lombard, L.

AU - Louw, C.

AU - Malahleha, M.

AU - McHugh, T. D.

AU - Mendel, C. M.

AU - Mhimbira, F.

AU - Moodliar, R. N.

AU - Nduba, V.

AU - Nunn, A. J.

AU - Sabi, I.

AU - Sebe, M. A.

AU - Selepe, R. A. P.

AU - Staples, S.

AU - Swindells, S.

AU - van Niekerk, C. H.

AU - Variava, E.

AU - Spigelman, M.

AU - Gillespie, S. H.

N1 - STAND was sponsored by TB Alliance with support from the UK Department for International Development, UK Department of Health (London, UK), Bill and Melinda Gates Foundation (Seattle, WA, USA), US Agency for International Development (Washington DC, USA), Directorate General for International Cooperation of the Netherlands (Amsterdam, The Netherlands), Irish Aid (Dublin, Ireland), Australia Department of Foreign Affairs and Trade (Canberra ACT, Australia) and the Federal Ministry for Education and Research of Germany (Berlin, Germany) through KfW (Kreditanstalt fur Wiederaufbau) and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH; Bethesda, MD, USA) under Award Numbers UM1 AI068634 and UM1 AI068636. AMC and AJN are supported by Medical Research Council Grant: MC_UU_12023/27 Tuberculosis Treatment Trials.

PY - 2021/4/1

Y1 - 2021/4/1

N2 - BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI –2.2% to 15.4%) difference per protocol and 9.9% (95%CI –4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

AB - BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI –2.2% to 15.4%) difference per protocol and 9.9% (95%CI –4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

KW - Pulmonary and Respiratory Medicine

KW - Infectious Diseases

U2 - 10.5588/ijtld.20.0513

DO - 10.5588/ijtld.20.0513

M3 - Article

SN - 1027-3719

VL - 25

SP - 305

EP - 314

JO - International Journal of Tuberculosis and Lung Disease

JF - International Journal of Tuberculosis and Lung Disease

IS - 4

ER -

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB

Abstract

Keywords

UN SDGs

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SimpliciTB - S Gillespie: EDCTP SimpliciTB 2018

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