Gonorrhea, caused by Neisseria gonorrhoeae (NG), is the second most common bacterial sexually transmitted infection (STI). Rates of antimicrobial resistance to standard care are increasing worldwide, with many antibiotic classes now ineffective against NG. Gepotidacin is a first-in-class,bactericidal, triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by inhibition of two enzymes, where a single target-specific mutation does not significantly impact susceptibility. Gepotidacin confers activity against NG, including most strains resistant to marketed antibiotics. Here, we describe the design of a phase 3 clinical trial (EAGLE-1; NCT04010539) evaluating gepotidacin for the treatment of uncomplicated urogenital gonorrhea. This phase 3, randomized, multicenter, sponsor-blinded, noninferiority study across six countries is comparing the efficacy of gepotidacin with ceftriaxone plus azithromycin in 400 patients with uncomplicated urogenital gonorrhea (microbiological intent-to-treat population) and assessing the safety of gepotidacin in approximately 600 patients (intent-to-treat population). Eligible participants 12years of age or older with clinical suspicion of urogenital gonococcal infection and a NG-positive urogenital sample and/or purulent discharge are randomized 1:1 to receive oral gepotidacin (2 × 3000mg 10-12h apart) or ceftriaxone (500mg, intramuscular) plus azithromycin (1g, oral). The primary endpoint is culture-confirmed bacterial eradication of NG from the urogenital site at the test-of-cure (days 4-8) visit. This trial was designed in accordance with US Food and Drug Administration (2015) and European Medicines Agency (2011) guidance, particularly the primary endpoint and microbiological evaluability requirements. This study will help characterize the risk-benefit profile of gepotidacin for treating uncomplicated urogenital gonorrhea. Gepotidacin is an important potential treatment for gonorrhea to help address the urgent unmet need of multidrug resistance and the increasingly limited number of oral treatment options. ClinicalTrials.gov identifier, NCT04010539.