Dataset Information

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.

SUBMITTER: Tweed CD

PROVIDER: S-EPMC8009598 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Tweed C D CD Wills G H GH Crook A M AM Amukoye E E Balanag V V Ban A Y L AYL Bateson A L C ALC Betteridge M C MC Brumskine W W Caoili J J Chaisson R E RE Cevik M M Conradie F F Dawson R R Del Parigi A A Diacon A A Everitt D E DE Fabiane S M SM Hunt R R Ismail A I AI Lalloo U U Lombard L L Louw C C Malahleha M M McHugh T D TD Mendel C M CM Mhimbira F F Moodliar R N RN Nduba V V Nunn A J AJ Sabi I I Sebe M A MA Selepe R A P RAP Staples S S Swindells S S van Niekerk C H CH Variava E E Spigelman M M Gillespie S H SH

The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 20210401 4

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 treatm ...[more]

PMID: 33762075

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Project description:BackgroundGlobally rifampicin-resistant tuberculosis disease affects around 460,000 people each year. Currently recommended regimens are 9-24 months duration, have poor efficacy and carry significant toxicity. A shorter, less toxic and more efficacious regimen would improve outcomes for people with rifampicin-resistant tuberculosis.MethodsTB-PRACTECAL is an open-label, randomised, controlled, phase II/III non-inferiority trial evaluating the safety and efficacy of 24-week regimens containing bedaquiline and pretomanid to treat rifampicin-resistant tuberculosis. Conducted in Uzbekistan, South Africa and Belarus, patients aged 15 and above with rifampicin-resistant pulmonary tuberculosis and requiring a new course of therapy were eligible for inclusion irrespective of HIV status. In the first stage, equivalent to a phase IIB trial, patients were randomly assigned one of four regimens, stratified by site. Investigational regimens include oral bedaquiline, pretomanid and linezolid. Additionally, two of the regimens also included moxifloxacin (arm 1) and clofazimine (arm 2) respectively. Treatment was administered under direct observation for 24 weeks in investigational arms and 36 to 96 weeks in the standard of care arm. The second stage of the study was equivalent to a phase III trial, investigating the safety and efficacy of the most promising regimen/s. The primary outcome was the percentage of unfavourable outcomes at 72 weeks post-randomisation. This was a composite of early treatment discontinuation, treatment failure, recurrence, lost-to-follow-up and death. The study is being conducted in accordance with ICH-GCP and full ethical approval was obtained from Médecins sans Frontières ethical review board, London School of Hygiene and Tropical Medicine ethical review board as well as ERBs and regulatory authorities at each site.DiscussionTB-PRACTECAL is an ambitious trial using adaptive design to accelerate regimen assessment and bring novel treatments that are effective and safe to patients quicker. The trial took a patient-centred approach, adapting to best practice guidelines throughout recruitment. The implementation faced significant challenges from the COVID-19 pandemic. The trial was terminated early for efficacy on the advice of the DSMB and will report on data collected up to the end of recruitment and, additionally, the planned final analysis at 72 weeks after the end of recruitment.Trial registrationClinicaltrials.gov NCT02589782. Registered on 28 October 2015.

Dataset Information

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

Publications

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

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