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

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

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Abstract

B A C K G R O U N D: Treatment for TB is lengthy and toxic, and new regimens are needed. M E T H O D S: 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. R E S U LT S: 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 6Pa₂ 0 ₀MZ, 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 3þ 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. C O N C L U S I O N: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Original language	English (US)
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
State	Published - Apr 1 2021

Keywords

Drug resistance
K E Y W O R D S: tuberculosis
TB treatment
TB-HIV

ASJC Scopus subject areas

General Medicine

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10.5588/IJTLD.20.0513

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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

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

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

abstract = "B A C K G R O U N D: Treatment for TB is lengthy and toxic, and new regimens are needed. M E T H O D S: 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. R E S U LT S: 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 6Pa2 0 0MZ, 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{\th} 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. C O N C L U S I O N: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.",

keywords = "Drug resistance, K E Y W O R D S: tuberculosis, TB treatment, TB-HIV",

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 Fabiane, {S. M.} 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.}",

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doi = "10.5588/IJTLD.20.0513",

language = "English (US)",

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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.

PY - 2021/4/1

Y1 - 2021/4/1

N2 - B A C K G R O U N D: Treatment for TB is lengthy and toxic, and new regimens are needed. M E T H O D S: 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. R E S U LT S: 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 6Pa2 0 0MZ, 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 3þ 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. C O N C L U S I O N: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

AB - B A C K G R O U N D: Treatment for TB is lengthy and toxic, and new regimens are needed. M E T H O D S: 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. R E S U LT S: 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 6Pa2 0 0MZ, 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 3þ 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. C O N C L U S I O N: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

KW - Drug resistance

KW - K E Y W O R D S: tuberculosis

KW - TB treatment

KW - TB-HIV

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

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