Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2021 Apr 1;25(4):305-314.
doi: 10.5588/ijtld.20.0513.

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

C D Tweed  1 , G H Wills  1 , A M Crook  1 , E Amukoye  2 , V Balanag  3 , A Y L Ban  4 , A L C Bateson  5 , M C Betteridge  6 , W Brumskine  7 , J Caoili  8 , R E Chaisson  9 , M Cevik  10 , F Conradie  11 , R Dawson  12 , A Del Parigi  6 , A Diacon  13 , D E Everitt  6 , S M Fabiane  1 , R Hunt  5 , A I Ismail  14 , U Lalloo  15 , L Lombard  6 , C Louw  16 , M Malahleha  17 , T D McHugh  5 , C M Mendel  6 , F Mhimbira  18 , R N Moodliar  19 , V Nduba  20 , A J Nunn  1 , I Sabi  21 , M A Sebe  22 , R A P Selepe  23 , S Staples  19 , S Swindells  24 , C H van Niekerk  25 , E Variava  26 , M Spigelman  6 , S H Gillespie  10
Affiliations
Randomized Controlled Trial

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

C D Tweed et al. Int J Tuberc Lung Dis. .

Abstract
in English, French

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.

CONTEXTE :: Le traitement de la TB est long et toxique et de nouveaux protocoles sont requis.

MÉTHODES :: Des patients atteints de TB pulmonaire sensible aux médicaments (DS-TB) ont été randomisés pour recevoir : 200 mg de prétomanide (Pa, PMD) quotidien, 400 mg de moxifloxacine (M) et 1500 mg de pyrazinamide (Z) pendant 6 mois (6Pa200MZ) ou pendant 4 mois (4Pa200MZ) ; 100 mg de PMD quotidien pendant 4 mois dans la même combinaison (4Pa100MZ) ; ou un traitement standard de DS-TB pendant 6 mois. Le résultat principal a été l’échec du traitement ou la rechute à 12 mois après la randomisation. La marge de non infériorité pour les différences entre groupes a été de 12,0%. Le recrutement a été mis en pause à la suite de trois décès et n’a pas été repris.

RÉSULTATS :: Quatre sur 47 (8,5%), 11 sur 57 (19,3%), 14 sur 52 (26,9%) et 1 sur 53 (1,9%) des résultats de DS-TB ont été défavorables pour 6Pa200MZ, 4Pa200MZ, 4Pa100MZ, et les témoins. Il y a eu une différence de 6,6% (IC 95% −2,2 à 15,4) par protocole et 9,9% (IC 95% −4,1 à 23,9) en réponse défavorable entre les témoins et 6Pa200MZ. Des effets secondaires de grade 3+ ont affecté 68 patients sur 203 (33,5%) recevant des protocoles expérimentaux et 19 sur 68 (27,9%) on control. Dix sur 203 (4,9%) participants en bras expérimental et 2 sur 68 (2,9%) on control sont décédés.

CONCLUSION :: Les protocoles Pa200MZ n’ont pas atteint la non infériorité dans cet essai sous-puissant. La priorité reste l’évaluation du PMD.

PubMed Disclaimer

Figures

Figure 1
Figure 1
CONSORT diagram, indicating randomisations and exclusions. Patients with RR-TB were not randomised and allocated to receive 6MPa200Z. Pa 200 mg daily, M 400 mg and Z 1500 mg for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); Pa 100 mg daily for 4 months in the same combination (4Pa100MZ). Late identification of drug resistance and withdrawal of consent were the most common reasons for exclusion during follow-up. AFB = acid-fast bacilli; RR-TB = rifampicin-resistant TB; DS-TB = drug-susceptible TB; H = isoniazid; R = rifampicin; Z = pyrazinamide; E = ethambutol; Pa = pretomanid; M = moxifloxacin; ITT= intention-to-treat; MITT = modified ITT; LTFU = lost to follow-up. CONSORT = Consolidated Standards of Reporting Trials.
Figure 2
Figure 2
KM curves: A) time to first culture-negative status by trial treatment arm; and B) time to an unfavourable outcome by treatment arm in the modified intention-to-treat analysis.
See this image and copyright information in PMC

References

    1. World Health Organization. Geneva, Switzerland: WHO; 2019. Global tuberculosis report, 2019. WHO/CDS/TB/2019.15.
    1. Furin J, Cox H, Pai M. Tuberculosis. Lancet. 2019;393:1642–1656. - PubMed
    1. Stover CK, et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature. 2000;405:962–966. - PubMed
    1. Hu Y, Coates ARM, Mitchison DA. Comparison of the sterilising activities of the nitroimidazopyran PA-824 and moxifloxacin against persisting Mycobacterium tuberculosis. Int J Tuberc Lung Dis. 2008;12:69–73. - PubMed
    1. Prideaux B, et al. The association between sterilizing activity and drug distribution into tuberculosis lesions. Nat Med. 2015;21:1223–1227. - PMC - PubMed

Publication types

LinkOut - more resources