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

Abstract

Background 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 MTBDRplus) 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 credibil...

Deploying a novel tuberculosis molecular bacterial load assay to assess the elimination rate ofMycobacterium tuberculosisin patients with multidrug-resistant tuberculosis in Tanzania

“…These findings may contradict those from a phase 2b trial where the bactericidal activity of a bedaquiline containing regimen as was measured by culture media at day 56 proved an unreliable indicator of a regimen's ability to predict long term treatment outcomes or shorten treatment duration, and rather raise the question of whether TB-MBLA may in fact be a superior predictor to culture. [20] Another important finding from this study of TB-MBLA is that M. tuberculosis elimination kinetics were regimen-dependent. Overall, more rapid elimination occurred during the first 28 days for all regimens, yet that earlier rapid elimination was more prominent at day 14 for patients who received kanamycin regardless of receipt of bedaquiline, followed by those who received an all-oral bedaquiline containing regimen, which did not achieve these rates of elimination until 1 month or more of treatment.…”

“…Nevertheless, modelling M. tuberculosis elimination for 4 months as we accomplished here has been used as marker for treatment failure and relapse in several observational studies [18,30] , and exceeds the duration of monitoring used in other trials of R/MDR-TB regimens that have employed conventional culture based techniques. [20] Additionally, this study had no control over the treatment regimens prescribed. However, given the feasibility of TB-MBLA and the comparability of this study's findings to those prior with TB-MBLA in drug-susceptible TB [8] , we plan to apply TB-MBLA systematically within an ongoing operational research protocol for injectable-free RR/MDR-TB treatment in Tanzania, that employs standardized regimens over varying treatment durations.…”

“…Together, these findings provide insight into formulating optimal all-oral bedaquiline containing regimens with the best potential to shorten MDR-TB treatment duration [20,26,31] . Given the ease of use of TB-MBLA and the fact that it does not require laboratory procedures associated with culture or the prolonged time to receive a culture-based result, we envision that TB-MBLA can be used to make regimen adjustments, and enhance infection control practices for patients with RR/MDR-TB and health workers in hospital and community settings…”

Mycobacterial Cell Wall: A Source of Successful Targets for Old and New Drugs

“…The combination PMD/PZA/MXF was more bactericidal than PMD/BDQ or PMD/PZA and as potent as the standard regimen (INH/RIF/EMB/PZA) [201]. In a phase 2b clinical trial (NCT02193776), the efficacy, safety and tolerability of the combination PMD/BDQ/PZA were assessed in newly diagnosed drug-susceptible, smear-positive pulmonary TB patients treated for 8 weeks [202]. TB patients converted more rapidly to sputum negativity with PMD/BDQ/PZA than the standard regimen.…”

Multidrug-resistant Mycobacterium tuberculosis: a report of cosmopolitan microbial migration and an analysis of best management practices

“…Almost 50 years after the introduction of rifampicin, three new TB-antibiotics (bedaquiline, delamanid, pretonamid) were lanced and a number of older and repurposed drugs became increasingly important for the treatment of MDR-TB [2,[20][21][22][23][24][25]. As drug-susceptibility testing is complemented by genotypic methods offering rapid information on drug resistance patterns, individualized MDR-TB regimens can be designed more rapidly -an approach we also used.…”