Work

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

Year: 2025

Type: article

Abstract: To understand the impact of current regulatory guidance for non-inferiority, randomized controlled trials (RCTs) in uncomplicated urinary tract infection (uUTI) on efficacy outcomes. 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 (≥10 5 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. 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). Differences in primary endpoint success criteria need to be considered when comparing contemporary and historic uUTI RCTs. The trials are registered at Clinicaltrials.gov (EAGLE-2, NCT04020341; EAGLE-3, NCT04187144). • Rates of nitrofurantoin clinical success differed in EAGLE-2/-3 vs historic studies • Composite primary endpoints in uUTI trials contribute to lower success rates • The method of determining clinical success impacts outcome assessment • There is a need for validated measures of clinical success in uUTI clinical trials

Source: Contemporary Clinical Trials Communications

DOI: 10.1016/j.conctc.2025.101572