Impact of updated regulatory guidelines on study results in contemporary uncomplicated urinary tract infection clinical trials and implications for trial conduct and drug development: a comparative analysis with EAGLE-2 and EAGLE-3
Abstract
Aim To understand the impact of current regulatory guidance for non-inferiority, randomized controlled trials (RCTs) in uncomplicated urinary tract infection (uUTI) on efficacy outcomes. Methods EAGLE-2 and EAGLE-3 were phase 3, non-inferiority RCTs of oral gepotidacin (1500 mg twice daily for 5 days) vs nitrofurantoin (100 mg BID for 5 days) in females with uUTI. The composite (clinical and microbiological) primary endpoint, therapeutic response (success or failure), was assessed at test-of-cure (day 10–13) in participants with nitrofurantoin-susceptible uropathogens (≥105 colony forming units/mL). Success required symptom resolution plus microbiological eradication; missing data or additional antibacterial use were considered failure. EAGLE-2/-3 results were compared with historic nitrofurantoin RCTs and exploratory endpoints – symptom “resolution or near resolution” (one mild symptom remaining) and investigator-assessed clinical response (IACR) – were used as alternative measures of clinical success. Results Nitrofurantoin therapeutic success was substantially lower in EAGLE-2/-3 (47 %/44 %) than historic studies (61–94 %) using different endpoints. Clinical success rates based on “resolution or near resolution” of symptoms were: 78.3 %/77.2 % (EAGLE-2) and 75.7 %/75.3 % (EAGLE-3) for gepotidacin/nitrofurantoin, respectively. IACR rates were: 84.5 %/82.6 % (EAGLE-2) and 75.5 %/76.4 % (EAGLE-3) (post hoc analysis). Conclusion Differences in primary endpoint success…
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