Discordant outcomes at cUTI test-of-cure visit associated with risk of clinical failure
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An analysis of phase 3 trials of patients with complicated UTIs found that having discordant outcomes at a test-of-cure visit — clinical success but microbiological failure — was associated with an increased risk for late clinical failure.
“When evaluating clinical trials for antibacterial drugs for complicated urinary tract infections (cUTIs), the FDA currently recommends a composite endpoint [composed of] the clinical and microbiological responses,” Nadia Kadry, PhD, and Mukil Natarajan, MD, both of the FDA’s Center for Drug Evaluation and Research, told Healio.
“In recent clinical trials for antibacterial drugs for cUTI, it has been noted that some participants achieve clinical success at the primary endpoint but are microbiological failures due to positive urine cultures,” they said.
Kadry and Natarajan said that as a result, these participants with microbiological persistence are considered failures on the composite endpoint, raising questions about the utility of the microbiological component of the endpoint.
“Moreover, because patients are typically not screened for microbiological persistence following antibacterial drug therapy in the clinic, there has been growing interest in focusing endpoints on clinical success,” they said.
To provide data on this, Kadry, Natarajan and colleagues analyzed participant data from 13 phase 3 clinical trials submitted to the FDA. Outcomes were determined at the test-of-cure (TOC) visit — typically occurring at least 5 days after therapy — and at the late follow-up (LFU) visit — recommended to occur 21 to 28 days after randomization.
According to the study, clinical and microbiological success were defined as the resolution of cUTI symptoms present at study entry, with no new symptoms referred to as clinical cure, and a reduction in concentration of the original pathogen to less than103 CFU/mL on urine culture referred to as microbiological eradication.
Among included participants, 70.7% were “concordant successes” at the TOC visit, whereas 18% were considered “discordant failures” with clinical cure and microbiological persistence and 6.7% were “concordant failures” with clinical failure and microbiological persistence.
Compared with patients with concordant success, patients with discordant outcomes were at an increased risk of symptom relapse or clinical failure at the LFU visit, suggesting that “bacteriuria at the TOC visit increases the risk of clinical relapse at later visits.” The researchers added, however, that this did not appear to be influenced by relative bacterial density.
“Microbiological outcomes appear to be an important component of the composite endpoint, as bacterial persistence may predict later clinical failure,” Kadry and Natarajan said. “Although monitoring bacterial persistence in the urine following antibacterial drug therapy may not reflect clinical practice, our findings suggest it remains an important consideration when evaluating antibacterial drugs for efficacy in clinical trials.”
They added that participant factors contributing to discordant outcomes, as well as additional determinants of clinical failure at later visits, “remain future areas of investigation.”
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