Outcomes {12}
anaemia, TB, leukopenia, neuropathy, toxicities
ANAEMIA, LEUKOPENIA, NEUROPATHY, THROMBOCYTOPENIA, RECURRENT DISEASE, EVENT, SECONDARY
The primary safety outcome is the occurrence of oxazolidinone class toxicities defined as peripheral or optical neuropathy, incident leukopenia, anaemia or thrombocytopenia, or AEs in line with tyramine pressor response, all of grade 2 or higher, possibly, probably or definitely related to DZD. Participants will be evaluated for AEs on a regular basis during treatment and follow-up phase.The efficacy of DZD will be evaluated by measuring the change in mycobacterial load over time on treatment as quantified by time to positivity in BD BACTEC™ MGIT liquid culture described by non-linear mixed-effects methodology.A secondary endpoint is the proportion of participants who suffer relapse, defined as recurrent disease caused by a strain identical to the baseline isolate, within 12 months post randomization, out of participants completing 16 weeks of therapy and achieving sustained sputum culture conversion defined as two successive negative liquid media cultures at or before WK08, with no positives to follow by the week 16 visit. We will analyze this also by a time-to event analysis (time to recurrent TB, and to relapse). Pharmacokinetic endpoints are chosen to support the development of a population PK model for DZD. In addition, we will use non-compartmental analysis for DZD, BDQ, DLM and their main metabolites, and for MXF, to determine the area under the plasma concentration curve from 0 to 24 h on day 14, the observed maximum concentration, the time of maximum concentration and the minimum observed plasma concentration. Furthermore, the apparent oral clearance, apparent volume of distribution and terminal half-life will be determined for MOX only.Mycobacteriological Identification and Characterization Endpoint: • Isolates will be assessed for minimum inhibitory concentrations of BDQ, DLM, MXF, and DZD of the infecting strain, at baseline and on representative isolate(s) grown at or after WK08, if any.• In the case of recurrent disease, a comparison between bacterial strain causing recurrent disease, and the strain at baseline will be performed by whole genome sequencing, to discriminate relapse from re-infection.