A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis.

BACKGROUND: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. METHODS: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. DISCUSSION: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. TRIAL REGISTRATION: DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

Outcomes from patients with presumed drug resistant tuberculosis in five reference centers in Brazil

Background: The implementation of rapid drug susceptibility testing (DST) is a current global priority for TBcontrol. However, data are scarce on patient-relevant outcomes for presumptive diagnosis of drug-resistanttuberculosis (pDR-TB) evaluated under field conditions in high burden countries.Methods: Observational study of pDR-TB patients referred by primary and secondary health units. TB referencecenters addressing DR-TB in five cities in Brazil. Patients age 18 years and older were eligible if pDR-TB, culturepositive results for Mycobacterium tuberculosis and, if no prior DST results from another laboratory were used by aphysician to start anti-TB treatment. The outcome measures were median time from triage to initiating appropriateanti-TB treatment, empirical treatment and, the treatment outcomes.Results: Between February,16th, 2011 and February, 15th, 2012, among 175 pDR TB cases, 110 (63.0%) confirmed TBcases with DST results were enrolled. Among study participants, 72 (65.5%) were male and 62 (56.4%) aged 26 to45 years. At triage, empirical treatment was given to 106 (96.0%) subjects. Among those, 85 were treated with firstline drugs and 21 with second line. Median time for DST results was 69.5 [interquartile - IQR: 35.7–111.0] days and,for initiating appropriate anti-TB treatment, the median time was 1.0 (IQR: 0–41.2) days. Among 95 patients thatwere followed-up during the first 6 month period, 24 (25.3%; IC: 17.5%–34.9%) changed or initiated the treatmentafter DST results: 16/29 MDRTB, 5/21 DR-TB and 3/45 DS-TB cases. Comparing the treatment outcome to DS-TBcases, MDRTB had higher proportions changing or initiating treatment after DST results (p = 0.01) and favorableoutcomes (p = 0.07).Conclusions: This study shows a high rate of empirical treatment and long delay for DST results. Strategies tospeed up the detection and early treatment of drug resistant TB should be prioritized.