Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial

CITATION: Tweed, C. D., et al. 2019. Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial. Lancet Respiratory Medicine, 7(12):1048-1058, doi:10.1016/ S2213-2600(19)30366-2The original publication is available at https://www.thelancet.comBackground: New anti-tuberculosis regimens that are shorter, simpler, and less toxic than those that are currently available are needed as part of the global effort to address the tuberculosis epidemic. We aimed to investigate the bactericidal activity and safety profile of combinations of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in the first 8 weeks of treatment of pulmonary tuberculosis. Methods: In this multicentre, open-label, partially randomised, phase 2b trial, we prospectively recruited patients with drug-susceptible or rifampicin-resistant pulmonary tuberculosis from seven sites in South Africa, two in Tanzania, and one in Uganda. Patients aged 18 years or older with sputum smear grade 1+ or higher were eligible for enrolment, and a molecular assay (GeneXpert or MTBDR plus ) was used to confirm the diagnosis of tuberculosis and to distinguish between drug-susceptible and rifampicin-resistant tuberculosis. Patients who were HIV positive with a baseline CD4 cell count of less than 100 cells per uL were excluded. Patients with drug-susceptible tuberculosis were randomly assigned (1:1:1) using numbered treatment packs with sequential allocation by the pharmacist to receive 56 days of treatment with standard tuberculosis therapy (oral isoniazid, rifampicin, pyrazinamide, and ethambutol; HRZE), or pretomanid (oral 200 mg daily) and pyrazinamide (oral 1500 mg daily) with either oral bedaquiline 400 mg daily on days 1–14 then 200 mg three times per week (B load PaZ) or oral bedaquiline 200 mg daily (B 200 PaZ). Patients with rifampicin-resistant tuberculosis received 56 days of the B 200 PaZ regimen plus moxifloxacin 400 mg daily (BPaMZ). All treatment groups were open label, and randomisation was not stratified. Patients, trial investigators and staff, pharmacists or dispensers, laboratory staff (with the exception of the mycobacteriology laboratory staff), sponsor staff, and applicable contract research organisations were not masked. The primary efficacy outcome was daily percentage change in time to sputum culture positivity (TTP) in liquid medium over days 0–56 in the drug-susceptible tuberculosis population, based on non-linear mixed-effects regression modelling of log 10 (TTP) over time. 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 , NCT02193776 , and all patients have completed follow-up. Findings: Between Oct 24, 2014, and Dec 15, 2015, we enrolled 180 patients with drug-susceptible tuberculosis (59 were randomly assigned to B load PaZ, 60 to B 200 PaZ, and 61 to HRZE) and 60 patients with rifampicin-resistant tuberculosis. 57 patients in the B load PaZ group, 56 in the B 200 PaZ group, and 59 in the HRZE group were included in the primary analysis. B 200 PaZ produced the highest daily percentage change in TTP (5·17% [95% Bayesian credibility interval 4·61–5·77]), followed by B load PaZ (4·87% [4·31–5·47]) and HRZE group (4·04% [3·67–4·42]). The bactericidal activity in B 200 PaZ and B load PaZ groups versus that in the HRZE group was significantly different. Higher proportions of patients in the B load PaZ (six [10%] of 59) and B 200 PaZ (five [8%] of 60) groups discontinued the study drug than in the HRZE group (two [3%] of 61) because of adverse events. Liver enzyme elevations were the most common grade 3 or 4 adverse events and resulted in the withdrawal of ten patients (five [8%] in the B load PaZ group, three [5%] in the B 200 PaZ group, and two [3%] in the HRZE group). Serious treatment-related adverse events affected two (3%) patients in the B load PaZ group and one (2%) patient in the HRZE group. Seven (4%) patients with drug-susceptible tuberculosis died and four (7%) patients with rifampicin-resistant tuberculosis died. None of the deaths were considered to be related to treatment. Interpretation: B 200 PaZ is a promising regimen to treat patients with drug-susceptible tuberculosis. The bactericidal activity of both these regimens suggests that they have the potential to shorten treatment, and the simplified dosing schedule of B 200 PaZ could improve treatment adherence in the field. However, these findings must be investigated further in a phase 3 trial assessing treatment outcomes. Funding: TB Alliance, UK Department for International Development, Bill & Melinda Gates Foundation, US Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and the Federal Ministry for Education and Research of Germany.https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(19)30366-2/fulltextPublisher's versio

Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment : a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis

New antituberculosis regimens are urgently needed to shorten tuberculosis treatment. Following on from favourable assessment in a 2 week study, we investigated a novel regimen for efficacy and safety in drug-susceptible and multidrug-resistant (MDR) tuberculosis during the first 8 weeks of treatment.; We did this phase 2b study of bactericidal activity--defined as the decrease in colony forming units (CFUs) of Mycobacterium tuberculosis in the sputum of patients with microscopy smear-positive pulmonary tuberculosis-at eight sites in South Africa and Tanzania. We enrolled treatment-naive patients with drug-susceptible, pulmonary tuberculosis, who were randomly assigned by computer-generated sequences to receive either 8 weeks of moxifloxacin, 100 mg pretomanid (formerly known as PA-824), and pyrazinamide (MPa100Z regimen); moxifloxacin, 200 mg pretomanid, and pyrazinamide (MPa200Z regimen); or the current standard care for drug-susceptible pulmonary tuberculosis, isoniazid, rifampicin, PZA, and ethambutol (HRZE regimen). A group of patients with MDR tuberculosis received MPa200Z (DRMPa200Z group). The primary outcome was bactericidal activity measured by the mean daily rate of reduction in M tuberculosis CFUs per mL overnight sputum collected once a week, with joint Bayesian non-linear mixed-effects regression modelling. We also assessed safety and tolerability by monitoring adverse events. This study is registered with ClinicalTrials.gov, number NCT01498419.; Between March 24, 2012, and July 26, 2013 we enrolled 207 patients and randomly assigned them to treatment groups; we assigned 60 patients to the MPa100Z regimen, 62 to the MPa200Z regimen, and 59 to the HRZE regimen. We non-randomly assigned 26 patients with drug-resistant tuberculosis to the DRMPa200Z regimen. In patients with drug-susceptible tuberculosis, the bactericidal activity of MPa200Z (n=54) on days 0-56 (0·155, 95% Bayesian credibility interval 0·133-0·178) was significantly greater than for HRZE (n=54, 0·112, 0·093-0·131). DRMPa200Z (n=9) had bactericidal activity of 0·117 (0·070-0·174). The bactericidal activity on days 7-14 was strongly associated with bactericidal activity on days 7-56. Frequencies of adverse events were similar to standard treatment in all groups. The most common adverse event was hyperuricaemia in 59 (29%) patients (17 [28%] patients in MPa100Z group, 17 [27%] patients in MPa200Z group, 17 [29%] patients. in HRZE group, and 8 [31%] patients in DRMPa200Z group). Other common adverse events were nausea in (14 [23%] patients in MPa100Z group, 8 [13%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 8 [31%] patients in DRMPa200Z group) and vomiting (7 [12%] patients in MPa100Z group, 7 [11%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 4 [15%] patients in DRMPa200Z group). No on-treatment electrocardiogram occurrences of corrected QT interval more than 500 ms (an indicator of potential of ventricular tachyarrhythmia) were reported. No phenotypic resistance developed to any of the drugs in the regimen.; The combination of moxifloxacin, pretomanid, and pyrazinamide, was safe, well tolerated, and showed superior bactericidal activity in drug-susceptible tuberculosis during 8 weeks of treatment. Results were consistent between drug-susceptible and MDR tuberculosis. This new regimen is ready to enter phase 3 trials in patients with drug-susceptible tuberculosis and MDR-tuberculosis, with the goal of shortening and simplifying treatment.; Global Alliance for TB Drug Development

Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL

Summary: Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union’s Horizon 2020 research and innovation programme and EFPIA