A comparison of clinical development pathways to advance tuberculosis regimen development

BMC Infectious Diseases

Research

M. Z. Imperial¹  R. M. Savic¹  V. Chang¹  P. P. J. Phillips²  P. Nahid² 

[1] Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA;UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA;UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA;

关键词: Adaptive Clinical Trials;    Tuberculosis;    Clinical Trial Design;   

DOI  :  10.1186/s12879-022-07846-w

 received in 2022-04-21, accepted in 2022-11-04,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundCurrent 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.MethodsClinical 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.ResultsBoth 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).ConclusionsIn 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.

【 授权许可】

CC BY   
© The Author(s) 2022

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