PROJECT ABSTRACT There is an urgent need for new treatments capable of curing all forms of tuberculosis (TB) more rapidly. Limitations of the methods currently used to assess treatment effectiveness in human TB drug trials impede development of new shorter, more potent antibiotic regimens. The legacy pharmacodynamic (PD) marker (sputum culture) predicts clinical outcomes poorly, fails to detect residual M. tuberculosis (Mtb) that causes relapse, and requires 6-8 weeks to result. Because of the uncertain predictive value of existing culture-based outcomes, there is risk that PD signal in Phase 2 trials may not accurately translate to improved relapse outcomes in Phase 3 trials. Evidence from recent clinical trials suggest that several new non-culture assays performed at the time of treatment completion may predict subsequent microbiologic relapse. If validated, these assays could be developed as novel molecular end-of-treatment outcomes for Phase 2b/c TB trials, thereby assuring that the best new combination antibiotic regimens are advanced to Phase 3 testing. Embedded in the Rapid Research in Diagnostics Development for TB (R2D2) Network, the Candidate Clinical Condition as Prognostic Outcome for TB Study (C3PO) tests pathogen and host biomarkers at the end of treatment as predictors of microbiologic relapse among Vietnamese and Ugandan adolescents and adults completing the global standard 4-drug regimen for drug-susceptible pulmonary TB. C3PO will ascertain recurrent TB via intensive post-treatment microbiologic monitoring. The assays evaluated at the end of TB treatment include the RS ratio®, a novel non-culture sputum assay of bacterial ribosomal RNA synthesis developed by the Consortium for Applied Microbial Metrics (CAMM) and two human blood transcriptional signatures. C3PO hypothesizes that measurable residual disease detected by the RS ratio and a continuing TB-specific blood inflammatory signature at end of treatment will be associated with increased risk for microbiological recurrence. C3PO is designed to establish new molecular outcomes for use in TB clinical trials, thereby accelerating development of shorter, more effective TB treatments.