Objectives {7}
toxicity
PULMONARY TUBERCULOSIS, RECURRENCE, RECURRENT DISEASE, SECONDARY, REINFECTION
The primary objective of this study is to generate data for a pharmacokinetic–pharmacodynamic modelling approach, and to establish the exposure–response and exposure–toxicity curve for DZD.The aim is to identify the optimal dose of DZD to be used in subsequent studies that will provide the best efficacy and acceptable safety profile for the drug when given daily over 16 weeks in participants with newly diagnosed, uncomplicated, smear-positive, drug-sensitive, pulmonary tuberculosis.This will be supported by the development of a population pharmacokinetic (PK) model.Importantly, DECODE will assess the proportion of participants who suffer relapse within 12 months post randomization, out of those participants completing 16 weeks of therapy and achieving sustained sputum culture conversion, defined as two successive negative liquid media (BD BACTEC™ MGIT ) cultures at or before week 8, with no positives to follow until the week 16 visit.Secondary efficacy objectives are other culture-based response metrics, including month-2 culture status in liquid media and on solid media, and time to culture conversion in liquid and on solid media.The secondary PK objective is to describe the PK of BDQ, DLM and MXF including their main metabolites.In addition, this study has mycobacteriological identification and characterization objectives, which are (i) to assess the minimum inhibitory concentrations of BDQ, DLM, MXF, and DZD of the infecting strain (ii) to investigate the frequency of acquired mutations in the infecting strain over treatment and (iii) to compare the initial and recurrence isolates in participants with recurrent disease by whole genome sequencing to discriminate relapse from reinfection.