A comparison of clinical development pathways to advance tuberculosis regimen development.

ABSTRACT

BACKGROUND: Current tuberculosis (TB) regimen development pathways are slow and in urgent need of innovation. We investigated novel phase IIc and seamless phase II/III trials utilizing multi-arm multi-stage and Bayesian response adaptive randomization trial designs to select promising combination regimens in a platform adaptive trial. METHODS: Clinical trial simulation tools were built using predictive and validated parametric survival models of time to culture conversion (intermediate endpoint) and time to TB-related unfavorable outcome (final endpoint). This integrative clinical trial simulation tool was used to explore and optimize design parameters for aforementioned trial designs. RESULTS: Both multi-arm multi-stage and Bayesian response adaptive randomization designs were able to reliably graduate desirable regimens in ≥ 95% of trial simulations and reliably stop suboptimal regimens in ≥ 90% of trial simulations. Overall, adaptive phase IIc designs reduced patient enrollment by 17% and 25% with multi-arm multi-stage and Bayesian response adaptive randomization designs respectively compared to the conventional sequential approach, while seamless designs reduced study duration by 2.6 and 3.5 years respectively (typically ≥ 8.5 years for standard sequential approach). CONCLUSIONS: In this study, we demonstrate that adaptive trial designs are suitable for TB regimen development, and we provide plausible design parameters for a platform adaptive trial. Ultimately trial design and specification of design parameters will depend on clinical trial objectives. To support decision-making for clinical trial designs in contemporary TB regimen development, we provide a flexible clinical trial simulation tool that can be used to explore and optimize design features and parameters.