The time‐dependent “cure‐death” model investigating two equally important endpoints simultaneously in trials treating high‐risk patients with resistant pathogens |
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| Authors: | Harriet Sommer Martin Wolkewitz Martin Schumacher |
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| Affiliation: | Institute for Medical Biometry and Statistics, Faculty of Medicine and Medical Center—University of Freiburg, Freiburg, Germany |
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| Abstract: | A variety of primary endpoints are used in clinical trials treating patients with severe infectious diseases, and existing guidelines do not provide a consistent recommendation. We propose to study simultaneously two primary endpoints, cure and death, in a comprehensive multistate cure‐death model as starting point for a treatment comparison. This technique enables us to study the temporal dynamic of the patient‐relevant probability to be cured and alive. We describe and compare traditional and innovative methods suitable for a treatment comparison based on this model. Traditional analyses using risk differences focus on one prespecified timepoint only. A restricted logrank‐based test of treatment effect is sensitive to ordered categories of responses and integrates information on duration of response. The pseudo‐value regression provides a direct regression model for examination of treatment effect via difference in transition probabilities. Applied to a topical real data example and simulation scenarios, we demonstrate advantages and limitations and provide an insight into how these methods can handle different kinds of treatment imbalances. The cure‐death model provides a suitable framework to gain a better understanding of how a new treatment influences the time‐dynamic cure and death process. This might help the future planning of randomised clinical trials, sample size calculations, and data analyses. |
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| Keywords: | antimicrobial resistance competing risks endpoint choice multistate models pseudo‐value regression RCT design |
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