Design of Two Phase III, Randomized, Multicenter Studies Comparing Gepotidacin with Nitrofurantoin for the Treatment of Uncomplicated Urinary Tract Infection in Female Participants

Abstract

Background: Uncomplicated urinary tract infections (uUTIs) are among the most common community-acquired infections for women worldwide. Treatment options are increasingly limited by antibiotic resistance; novel oral antibiotics are urgently needed. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial deoxyribonucleic acid (DNA) replication by a distinct mechanism of action, which confers activity against most strains of target pathogens, such as Escherichia coli and Staphylococcus saprophyticus, including those resistant to current antibiotics. Here, we describe the designs of two near-identical phase III clinical trials (EAGLE-2 and EAGLE-3) evaluating gepotidacin for the treatment of uUTI.

Methods: These are phase III, randomized, multicenter, parallel-group, double-blind, double-dummy, comparator-controlled, noninferiority studies, comparing the efficacy and safety of gepotidacin to nitrofurantoin in the treatment of uUTI. Eligible participants are women aged ≥ 12 years with ≥ 2 uUTI symptoms, randomized (1:1) to receive oral gepotidacin (1500 mg) plus placebo or nitrofurantoin (100 mg) plus placebo, twice daily for 5 days. The primary therapeutic endpoint is composite clinical and microbiological efficacy, with noninferiority comparisons made in individuals with a qualifying (≥ 10⁵ colony-forming units/mL urine) nitrofurantoin-susceptible uropathogen.

Results: These trials were designed in accordance with US Food and Drug Administration (2019) and European Medicines Agency (2018) guidance, particularly the composite endpoint and microbiological evaluability requirements. Across the trials ~ 5000 participants are planned to be enrolled from > 200 centers globally.

Conclusions: Gepotidacin represents an important potential treatment option being evaluated to address the need for novel oral antibiotics to treat uUTI. These trials are registered at ClinicalTrials.gov ( https://clinicaltrials.gov/ ) where the full protocols can be accessed under trial IDs: NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3).

Keywords: Acute cystitis; Antibiotic; Antimicrobial; Gepotidacin; Nitrofurantoin; Phase III clinical trial; Uncomplicated urinary tract infection.

Fig. 1

EAGLE-2 and EAGLE-3 study design. ^aThere will be central randomization with stratification by age category (< 18 years, ≥ 18 to 50 years, or > 50 years) and uUTI recurrence [nonrecurrent infection or recurrent infection, defined as a confirmed infection (not including the current infection in the calculation) with at least one prior episode within the past 3 months, at least two prior episodes within the past 6 months, or at least three prior episodes within the past 12 months before study entry]. ^bStudy treatment will be administered under double-blind, double-dummy conditions. Each dose should be taken after food consumption and with water. BID twice daily, HPF high-power field, TOC test-of-cure, uUTI uncomplicated urinary tract infection, WBC white blood cell