Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial.

We aimed to evaluate the efficacy and safety of zoliflodacin versus ceftriaxone plus azithromycin in patients with uncomplicated urogenital gonorrhoea.

我们的目标是评估在治疗非复杂性泌尿生殖道淋病患者中，zoliflodacin与头孢曲松加阿奇霉素的疗效和安全性。

Methods

In this phase 3, multinational, randomised, controlled, open-label, non-inferiority clinical trial, participants aged 12 years and older with clinical suspicion of uncomplicated urogenital gonorrhoea were eligible for inclusion.

在这项第三阶段、多国参与、随机、对照、开放标签、非劣效性临床试验中，年龄在12岁及以上的参与者，如果临床怀疑患有非复杂性泌尿生殖道淋病，就有资格被纳入研究。

The trial was done in 17 outpatient clinics in Belgium, the Netherlands, South Africa, Thailand, and the USA.

该试验在比利时、荷兰、南非、泰国和美国的17个门诊诊所进行。

Participating countries with high disease prevalencewere identified for participation in the study.

确定了疾病高发国家参与研究。

Sites selected for participation were led by principal investigators with research experience, who were knowledgeable in HIV or sexually transmitted infections and treatment.

选定参与的地点由具有研究经验的主要研究员领导，他们在HIV或性传播感染及其治疗方面具有知识。

Feasibility questionnaires and prestudy visits assessed sexually transmitted infection case management guidelines, clinical services, and resources (ie, facility, staff, proposed composition of the study team, standard sexually transmitted infection services offered at the site, assessment of laboratory capacity, research experience and ethical review of clinical trials).

可行性问卷和预研究访问评估了性传播感染病例管理指南、临床服务和资源（即设施、员工、研究团队的建议组成、现场提供的标准性传播感染服务、实验室能力评估、临床试验的研究经验和伦理审查）。

Eligible participants were randomly assigned (2:1) to receive a single dose of zoliflodacin 3 g (oral) or ceftriaxone 500 mg (intramuscular) plus azithromycin 1 g (oral).

符合条件的参与者被随机分配（2:1）接受单剂量的佐利氟沙星3克（口服）或头孢曲松500毫克（肌肉注射）加阿奇霉素1克（口服）。

Treatment assignment was known to the participants and their treating clinicians; however, microbiology laboratory staff were masked and the sponsor's central study team were masked until after database lock.

治疗分配对参与者及其治疗医生是已知的；然而，微生物学实验室工作人员被蒙蔽，赞助商的中央研究团队在数据库锁定后才被揭盲。

The primary endpoint was the proportion of patients with microbiological cure (eradication of Neisseria gonorrhoeae, determined by urethral or endocervical culture) at test of cure (TOC; day 6 ± 2) in the microbiological intention-to-treatpopulation.

主要终点是微生物学意向治疗人群中，在治愈测试（TOC；第6±2天）时，通过尿道或子宫颈内膜培养确定的淋球菌根除的患者比例。

The primary efficacy analysis declared non-inferiority if the upper bound of the two-sided 95% CI for the treatment difference (comparator minus zoliflodacin) fell below the 12% non-inferiority margin.

如果治疗差异（对照组减去zoliflodacin）的双侧95%置信区间的上限低于12%的非劣效性边界，则宣布主要疗效分析显示非劣效性。

The trial is registered with ClinicalTrials.gov, NCT03959527, and EudraCT, 2019-000990-22.

该试验已在ClinicalTrials.gov（注册号NCT03959527）和EudraCT（注册号2019-000990-22）上注册。

Results

Between Nov 6, 2019, and March 16, 2023, 1011 patients were screened. 81 patients did not meet screening criteria and 930 participants were randomly assigned to zoliflodacin (n=621) or comparator (n=309).

2019年11月6日至2023年3月16日期间，共筛查了1011名患者。81名患者未满足筛查标准，930名参与者被随机分配至佐利弗定(n=621)组或对照组(n=309)。

The mean participant age was 29·7 years (SD 9·4). 815 (88%) of 930 participants were assigned male at birth and 115 (12%) participants were assigned female at birth. 514 (55%) of 930 participants were Black or African American, 285 (31%) were Asian, and 113 (12%) were White.

参与者的平均年龄为29.7岁（标准差9.4）。930名参与者中，815名（88%）出生时被指定为男性，115名（12%）出生时被指定为女性。930名参与者中，514名（55%）为黑人或非裔美国人，285名（31%）为亚洲人，113名（12%）为白人。

Microbiological cure rates at TOC in the microbiological intention-to-treat(urogenital) population (primary efficacy endpoint) were 460 (90·9%, 95% CI 88·1-93·3) of 506 participants for zoliflodacin and 229 (96·2%, 92·9-98·3) of 238 participants for comparator.

在微生物学意向治疗（泌尿生殖系统）人群中，治疗结束时的微生物学治愈率（主要疗效终点）为506名参与者中有460名（90.9%，95%置信区间88.1-93.3）对zoliflodacin治疗有效，而238名参与者中有229名（96.2%，92.9-98.3）对对照药物有效。

The estimated difference between groups was 5·3% (95% CI 1·4-8·6) and the upper confidence intervallimit was within the prespecified non-inferiority margin of less than 12%.

两组之间的估计差异为5.3%（95%置信区间1.4-8.6），且上限置信区间在预先设定的非劣效性边界12%以内。

Zoliflodacin was generally well tolerated and adverse events were similar between treatment groups.

Zoliflodacin通常耐受性良好，治疗组之间的不良事件相似。

The most frequently reported treatment-emergent adverse events included headache (61 [10%] of 619 patients), neutropenia (42 [7%]), and leukopenia (24 [4%]) in the zoliflodacin group and injection site pain (38 [12%] of 308 patients), neutropenia (24 [8%]), and diarrhoea (22 [7%]) in the comparator group.

最常报告的治疗后不良事件包括Zoliflodacin组的头痛（619名患者中有61例[10%]）、中性粒细胞减少症（42例[7%]）和白细胞减少症（24例[4%]），以及对照组的注射部位疼痛（308名患者中有38例[12%]）、中性粒细胞减少症（24例[8%]）和腹泻（22例[7%]）。

The majority of adverse events were mild or moderate in severity.

大多数不良事件的严重程度为轻度或中度。

No serious adverse events were reported.

未报告任何严重不良事件。

interpretation

Zoliflodacin was non-inferior to ceftriaxone plus azithromycin for the treatment of uncomplicated urogenital gonorrhoea and had a similar safety profile.

Zoliflodacin 在治疗非复杂性泌尿生殖道淋病方面与头孢曲松加阿奇霉素相比具有非劣效性，并且具有相似的安全性特征。

These data suggest a potential role for zoliflodacin as an effective oral treatment option for uncomplicated urogenital gonorrhoea.

这些数据表明，Zoliflodacin 可能作为一种有效的口服治疗选择，用于非复杂性泌尿生殖道淋病。

funding

German Federal Ministry of Research, Technology and Space, UK Department of Health and Social Care as part of the Global Antimicrobial Resistance Innovation Fund, Japan Ministry of Health, Labour and Welfare, Netherlands Ministry of Health, Welfare and Sport and Directorate-General for International Cooperation, Switzerland Federal Office of Public Health, and the Canton of Geneva, Switzerland.

德国联邦研究、技术和空间部，英国卫生和社会保健部作为全球抗菌素耐药性创新基金的一部分，日本厚生劳动省，荷兰卫生、福利和体育部以及国际合作总司，瑞士联邦公共卫生办公室，以及瑞士日内瓦州。