Discordant Clinical and Microbiological Outcomes are Associated with Late Clinical Relapse in Clinical Trials for Complicated Urinary Tract Infections (cUTI)
Abstract
BACKGROUND
Current FDA guidance recommends that the primary endpoint for complicated urinary tract infection (cUTI) clinical trials be a composite of the clinical and microbiological responses, assessed at a fixed timepoint after therapy. It has been noted that while some participants meet the criteria for clinical success, they do not meet the criteria for microbiological eradication and are classified as failures. These discordant outcomes have raised questions about the utility of the microbiological endpoint.
METHODS
We analyzed participant data from 13 phase 3 clinical trials submitted to the FDA (N = 4842). Outcomes were determined at the Test of Cure (TOC) visit, recommended to occur at least 5 days after therapy and at the Late Follow Up (LFU) visit, recommended to occur 21-28 days after randomization. Clinical and microbiological success were defined as the resolution of cUTI symptoms present at study entry, with no new symptoms (clinical cure), and a reduction in density of the original pathogen to <103 CFU/mL on urine culture (microbiological eradication).
RESULTS
Among included participants, 70.7% were concordant successes at the TOC visit, 18.0% were discordant failures (clinical cure/microbiological persistence), and 6.7% were concordant failures (clinical failure/microbiological persistence). Discordant participants were at an increased risk for clinical failure at the LFU visit, and the risk of late clinical failure increased with time.
CONCLUSIONS
Discordant…
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