Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials

呋喃妥因 双盲 泌尿系统 医学 胃肠病学 外科 内科学 安慰剂 生物 抗生素 病理 替代医学 环丙沙星 微生物学 古生物学
作者
Florian Wagenlehner,Caroline Perry,Thomas M. Hooton,Nicole E. Scangarella-Oman,Helen Millns,Marcy Powell,Emily Jarvis,Jeremy Dennison,Amanda Sheets,Deborah Butler,John Breton,Salim Janmohamed
出处
期刊:The Lancet [Elsevier BV]
卷期号:403 (10428): 741-755 被引量:30
标识
DOI:10.1016/s0140-6736(23)02196-7
摘要

Summary

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.

Findings

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.

Interpretation

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.

Funding

GSK and the US Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
ding应助HHEHK采纳,获得10
刚刚
Zzx完成签到,获得积分10
1秒前
Fin2046发布了新的文献求助30
2秒前
炒鸡小将完成签到,获得积分10
2秒前
机智灵薇发布了新的文献求助10
3秒前
3秒前
橙子完成签到 ,获得积分10
4秒前
刻苦的晓蕾完成签到,获得积分10
4秒前
崔志海完成签到,获得积分10
5秒前
5秒前
6秒前
胡须应助祁乐安采纳,获得20
9秒前
刘钱美子完成签到,获得积分10
9秒前
qian完成签到 ,获得积分10
9秒前
李治海发布了新的文献求助10
10秒前
醉眠完成签到 ,获得积分10
10秒前
Fin2046完成签到,获得积分10
10秒前
学不懂数学完成签到,获得积分10
11秒前
莓烦恼完成签到 ,获得积分10
12秒前
13秒前
白江虎完成签到,获得积分10
14秒前
15秒前
阳光的凌雪完成签到 ,获得积分10
16秒前
文艺小馒头完成签到,获得积分10
16秒前
赵赵发布了新的文献求助20
17秒前
橙子发布了新的文献求助10
19秒前
20秒前
Wsyyy完成签到 ,获得积分10
22秒前
22秒前
ganjqly完成签到,获得积分10
22秒前
董惠玲66发布了新的文献求助10
23秒前
g7001完成签到,获得积分10
25秒前
blue发布了新的文献求助10
25秒前
刘铭晨完成签到,获得积分10
25秒前
XYZ完成签到 ,获得积分10
26秒前
wmszhd完成签到,获得积分10
26秒前
付艳完成签到,获得积分10
26秒前
CAOHOU应助论文顺利采纳,获得10
27秒前
nancy93228完成签到 ,获得积分10
28秒前
高分求助中
【提示信息,请勿应助】关于scihub 10000
Les Mantodea de Guyane: Insecta, Polyneoptera [The Mantids of French Guiana] 3000
徐淮辽南地区新元古代叠层石及生物地层 3000
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
Handbook of Industrial Diamonds.Vol2 1100
Global Eyelash Assessment scale (GEA) 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 550
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4038303
求助须知:如何正确求助?哪些是违规求助? 3576013
关于积分的说明 11374210
捐赠科研通 3305780
什么是DOI,文献DOI怎么找? 1819322
邀请新用户注册赠送积分活动 892672
科研通“疑难数据库(出版商)”最低求助积分说明 815029