背景:Gepotidacin是一种新颖的,杀菌,一类三氮杂萘抗生素,通过独特的作用机制和独特的结合位点抑制细菌DNA复制,提供两种II型拓扑异构酶的良好平衡抑制。正在研究口服gepotidacin以治疗简单的尿路感染。我们旨在比较口服gepotidacin与呋喃妥因在无并发症尿路感染的青少年和成年女性个体中的疗效和安全性。
方法:EAGLE-2和EAGLE-3为3期,随机,多中心,双盲,双假人,非劣效性(10%边缘)试验,在全球219个中心招募患者.患者出生时被分配为女性,没有怀孕,12岁或以上,体重40公斤或以上,有两种或多种排尿困难的症状,频率,紧迫性,或下腹部疼痛,有了尿中亚硝酸盐的证据,脓尿,或者两者都有资格入选。通过交互式反应技术将患者随机分配(1:1),以接受口服吉普他星(1500mg,每天两次,共5天)或口服呋喃妥因(100mg,每天两次,共5天)。根据年龄类别和复发性单纯性尿路感染的病史进行随机分层。患者,调查员,和申办研究小组被掩盖治疗分配.主端点,治疗反应(成功或失败)在治愈测试(即,第10-13天),在随机分配的对呋喃妥因敏感的符合泌尿病原体(≥105个菌落形成单位[CFU]/mL)且接受至少一剂研究治疗的患者中进行了评估.符合监管指导,治疗成功被定义为综合临床成功(即,完整的症状解决)和微生物成功(即,将合格的尿路病原体减少至<103CFU/mL),而无需其他全身性抗菌药物使用。安全性分析包括随机分配和接受至少一个剂量的研究治疗的患者。试验在ClinicalTrials.gov注册,NCT04020341(EAGLE-2)和NCT04187144(EAGLE-3),并完成。
结果:研究于2019年10月17日至2022年11月30日(EAGLE-2)进行,2020年4月23日至2022年12月1日(EAGLE-3)。对1680例EAGLE-2患者和1731例EAGLE-3患者进行了筛选,其中1531和1605被随机分配,分别为(EAGLE-2的吉泊地星组767和呋喃妥因组764,以及EAGLE-3的吉泊地星组805和呋喃妥因组800)。经过中期分析,作为一项议定书修正案,两项研究均因疗效而停止。因此,主要分析人群仅包括患者,在中期分析数据截止时,有机会达到治愈测试访问或已知在治愈测试访问之前未获得治疗成功。在EAGLE-2中,320名接受吉泊地星治疗的患者中的162名(50·6%)和287名接受呋喃妥因治疗的患者中的135名(47·0%)具有治疗成功(调整后的差异为4·3%,95%CI-3·6至12·1)。在EAGLE-3中,在277名患者中,有162名(58·5%)接受了吉泊妥因治疗,在264名患者中,有115名(43·6%)接受了呋喃妥因治疗成功(调整后的差异为14·6%,95%CI6·4至22·8)。在两项研究中,Gepoidacin均不劣于呋喃妥因,而在EAGLE-3中优于呋喃妥因。吉泊地星最常见的不良事件是腹泻(在EAGLE-2的766例患者中观察到111例[14%],在EAGLE-3的804例患者中观察到147例[18%])。而呋喃妥因最常见的不良事件是恶心(EAGLE-2的760例患者中有29例[4%],EAGLE-3的798例患者中有35例[4%]).病例多为轻度或中度。没有发生危及生命或致命的事件。
结论:Gepotidacin是一种有效的口服抗生素,具有可接受的安全性和耐受性。作为一流的研究口服抗生素,具有抗常见尿路病原体的活性,包括临床上重要的耐药表型,gepotidacin有可能为患者带来实质性的益处.
背景:GSK和美国负责准备和响应的助理部长办公室,生物医学高级研究与发展局。
BACKGROUND: Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and a unique binding site, providing well balanced inhibition of two type II topoisomerase enzymes. Oral gepotidacin is under investigation to treat uncomplicated urinary tract infections. We aimed to compare the efficacy and safety of oral gepotidacin with that of nitrofurantoin in adolescent and adult female individuals with uncomplicated urinary tract infections.
METHODS: EAGLE-2 and EAGLE-3 were phase 3, randomised, multicentre, double-blind, double-dummy, non-inferiority (10% margin) trials, in which patients were enrolled at 219 centres worldwide. Patients assigned female at birth, non-pregnant, aged 12 years or older, weighing 40 kg or more, with two or more symptoms of dysuria, frequency, urgency, or lower abdominal pain, and with evidence of urinary nitrite, pyuria, or both were eligible for inclusion. Patients were randomly assigned (1:1) centrally by interactive response technology to receive oral gepotidacin (1500 mg twice daily for 5 days) or oral nitrofurantoin (100 mg twice daily for 5 days), with randomisation stratified by age category and history of recurrent uncomplicated urinary tract infections. Patients, investigators, and the sponsor study team were masked to treatment assignment. The primary endpoint, therapeutic response (success or failure) at test-of-cure (ie, day 10-13), was evaluated in randomly assigned patients with nitrofurantoin-susceptible qualifying uropathogens (≥105 colony-forming units [CFU] per mL) and who received at least one dose of study treatment. Conforming to regulatory guidance, therapeutic success was defined as combined clinical success (ie, complete symptom resolution) and microbiological success (ie, reduction of qualifying uropathogens to <103 CFU/mL) without other systemic antimicrobial use. Safety analyses included patients who were randomly assigned and who received at least one dose of study treatment. The trials are registered with ClinicalTrials.gov, NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3), and are completed.
RESULTS: Studies were undertaken from Oct 17, 2019, to Nov 30, 2022 (EAGLE-2), and from April 23, 2020, to Dec 1, 2022 (EAGLE-3). 1680 patients in EAGLE-2 and 1731 patients in EAGLE-3 were screened for eligibility, of whom 1531 and 1605 were randomly assigned, respectively (767 in the gepotidacin group and 764 in the nitrofurantoin group in EAGLE-2, and 805 in the gepotidacin group and 800 in the nitrofurantoin group in EAGLE-3). After an interim analysis, which was prospectively agreed as a protocol amendment, both studies were stopped for efficacy. Thus, the primary analysis population included only patients who, at the time of the interim analysis data cutoff, had the opportunity to reach the test-of-cure visit or were known to not have attained therapeutic success before the test-of-cure visit. In EAGLE-2, 162 (50·6%) of 320 patients assigned gepotidacin and 135 (47·0%) of 287 patients assigned nitrofurantoin had therapeutic success (adjusted difference 4·3%, 95% CI -3·6 to 12·1). In EAGLE-3, 162 (58·5%) of 277 patients assigned gepotidacin and 115 (43·6%) of 264 patients assigned nitrofurantoin had therapeutic success (adjusted difference 14·6%, 95% CI 6·4 to 22·8). Gepotidacin was non-inferior to nitrofurantoin in both studies and superior to nitrofurantoin in EAGLE-3. The most common adverse event with gepotidacin was diarrhoea (observed in 111 [14%] of 766 patients in EAGLE-2 and in 147 [18%] of 804 patients in EAGLE-3), whereas the most common adverse event with nitrofurantoin was nausea (in 29 [4%] of 760 patients in EAGLE-2 and in 35 [4%] of 798 patients in EAGLE-3). Cases were mostly mild or moderate. No life-threatening or fatal events occurred.
CONCLUSIONS: Gepotidacin is an efficacious oral antibiotic with acceptable safety and tolerability profiles. As a first-in-class investigational oral antibiotic with activity against common uropathogens, including clinically important drug-resistant phenotypes, gepotidacin has the potential to offer substantial benefit to patients.
BACKGROUND: GSK and the US Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority.