Assessing non-inferiority in treatment trials regarding severe infectious diseases: An extension to the entire follow-up period using a cure-death multistate model [PublishAheadOfPrint]

Background: In current and former clinical trials for the development of antibacterial drugs, various primary endpoints have been used and treatment effects are mostly evaluated in non-inferiority analyses at the end of follow-up which varies between studies. A more convincing and highly patient-relevant statement would be a non-inferiority assessment over the entire follow-up period with cure and death as co-primary endpoints, while preserving the desired alpha level for statistical testing.

Materials and Methods: To account for the time-dynamic pattern of cure and death, we apply a cure-death multistate model. The endpoint of interest is "get cured and stay alive over time". Non-inferiority between treatments over the entire follow-up period is studied by means of one-sided confidence bands provided by a flexible resampling technique.

Results: We illustrate the technique on a recently published study and establish non-inferiority in being cured and alive over a time frame of interest for the entire population, patients with hospital-acquired pneumonia, but not for the subset of patients with ventilator-associated pneumonia. Our analysis improves the original results in the sense that our endpoint is more patient-benefiting, a stronger non-inferiority statement is demonstrated, and the time-dependency of cure and death, competing events, and different follow-up times is captured.

Summary: Multistate methodology combined with confidence bands add a valuable statistical tool for clinical trials in the context of infection control. The framework is not restricted to the cure-death model, but can be adapted to more complex multistate endpoints and equivalence or superiority analyses.

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