Efficacy and safety of onradivir in adults with acute uncomplicated influenza A infection in China: a multicentre, double-blind, randomised, placebo-controlled and oseltamivir-controlled, phase 3 trial.

Our previous, phase 2 clinical trial showed that a 600 mg regimen of onradivir initiated within 48 h of symptom onset can expedite the recovery of adult patients from acute, uncomplicated influenza.

我们之前进行的2期临床试验表明，如果在症状出现后48小时内开始使用600毫克的onradivir治疗方案，可以加快成年患者从急性、非复杂性流感中的恢复。

Here, we aimed to evaluate the safety and therapeutic efficacy of onradivir in a larger group with acute, uncomplicated influenza.

在这里，我们的目标是评估奥司他韦在较大群体中治疗急性、非复杂性流感的安全性和疗效。

Methods

This randomised, double-blind, multicentre, placebo-controlledand oseltamivir-controlled, phase 3 trial was conducted at 68 clinical sites in China.

这是一项随机、双盲、多中心、安慰剂对照和奥司他韦对照的III期临床试验，在中国的68个临床试验点进行。

Eligible participants were adults (aged 18-64 years) with an influenza-like illness who screened positive by rapid IAV antigen testing at the first clinical visit, and had a fever (axillary temperature ≥38·0°C) with at least one moderate systemic and one moderate respiratory symptom within 48 h of symptom onset.

符合条件的参与者是成年人（18-64岁），他们在首次临床就诊时通过快速IAV抗原检测呈阳性，并在症状发作后48小时内出现发热（腋温≥38.0°C）以及至少一种中度全身症状和一种中度呼吸系统症状的流感样疾病患者。

Patients were randomly assigned into three treatment groups, stratified by influenza symptom scores (≤11 or ≥12), in a 2:1:1 ratio by an interactive web response system, with each treatment lasting 5 days: 600 mg oral onradivir tablets once daily, 75 mg oral oseltamivir phosphate capsules twice daily, or oral placebo.

患者被随机分配到三个治疗组，根据流感症状评分（≤11或≥12）进行分层，通过交互式网络响应系统以2:1:1的比例分配，每种治疗持续5天：每日一次口服600毫克的onradivir片剂，每日两次口服75毫克的磷酸奥司他韦胶囊，或口服安慰剂。

The primary outcome was the efficacy of onradivir versus placebo in the time to alleviation of symptoms (TTAS), from treatment initiation to the remission of influenza symptoms, in the intention-to-treatinfection (ITTI) population (ie, all participants who were randomly assigned and tested positive for IAV).

主要结果是onradivir与安慰剂在症状缓解时间（TTAS）上的疗效，从治疗开始到流感症状缓解，针对的是意向治疗感染（ITTI）人群（即所有被随机分配并检测出IAV阳性的参与者）。

The safety endpoints were the frequency and severity of adverse events in all participants who received treatment at least once.

安全性终点是所有至少接受一次治疗的参与者中不良事件的频率和严重程度。

This trial is registered with ClinicalTrials.gov (NCT04683406) and is completed.

该试验已在ClinicalTrials.gov注册（NCT04683406），并已完成。

This clinical trial was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (EC-2020-080[YW]-02).

这项临床试验已获得中国广州医科大学附属第一医院伦理委员会的批准（EC-2020-080[YW]-02）。

Results

Between May 12, 2022, and May 16, 2023, 943 patients were screened, of whom 750 met the inclusion criteria and were randomly assigned to a group. 48 had negative IAV tests, resulting in an ITTI population of 702 participants (413 [59%] men and 289 [41%] women; mean age 28·1 years [SD 9·7]): 349 in the onradivir group, 177 in the oseltamivir group, and 176 in the placebo group.

在2022年5月12日至2023年5月16日期间，共筛查了943名患者，其中750名符合纳入标准并被随机分配到各组。48人IAV检测结果为阴性，因此ITTI人群共有702名参与者（413名[59%]男性和289名[41%]女性；平均年龄28.1岁[标准差9.7]）：349名在onradivir组，177名在oseltamivir组，176名在安慰剂组。

The baseline viral load (mean 5·15 log10 copies per mL [SD 1·02]) and the total score of seven influenza symptoms at enrolment were similarly distributed among the groups.

基线病毒载量（平均5.15 log10拷贝/毫升[标准差1.02]）和入组时七种流感症状的总分在各组间分布相似。

The median TTAS in the onradivir group was significantly shorter than that of placebo (38·83 h [95% CI 35·32-41·18] vs 63·35 h [55·48-68·48], difference -24·52 h, p<0·0001, HR 1·53 [95% CI 1·27-1·85]) and similar to that of the oseltamivir group (42·17 h [38·27-52·83], p=0·092, HR 1·12 [0·93-1·35].

在 onradivir 组中，TTAS 的中位数显著短于安慰剂组（38.83小时 [95% 置信区间 35.32-41.18] 对比 63.35小时 [55.48-68.48]，差异 -24.52小时，p<0.0001，风险比 HR 1.53 [95% 置信区间 1.27-1.85]）并且与奥司他韦组相似（42.17小时 [38.27-52.83]，p=0.092，HR 1.12 [0.93-1.35]）

Adverse events occurred in 250 (67%) of 373 in the onradivir group, 104 (55%) of 189 in the placebo group, and 89 (47%) of 188 in the oseltamivir group.

在 onradivir 组中，有250例（67%）的373例患者出现不良事件，在安慰剂组中有104例（55%）的189例患者出现不良事件，在奥司他韦组中有89例（47%）的188例患者出现不良事件。

Although the incidenceof diarrhoea was higher in the onradivir group (184 [49%]) than in the placebo (44 [23%]) or oseltamivir (28 [15%]) groups, most incidences were grade 1 or 2, lasted a median of 2 days (IQR 1-3), and resolved without medication.

尽管在奥那替韦组中腹泻的发生率（184 [49%]）高于安慰剂（44 [23%]）或奥司他韦（28 [15%]）组，但大多数病例为1级或2级，中位持续时间为2天（四分位数间距1-3天），且无需用药即可自行缓解。

interpretation

Onradivir has similar curative efficacy to oseltamivir for acute, uncomplicated influenza infections in adult patients, with an acceptable safety profile.

对于成人急性、非复杂性流感感染患者，奥那替韦与奥司他韦的治疗效果相似，具有可接受的安全性。

At a time when reduced susceptibility to antiviral drugs is a growing concern, this study indicates that onradivir could be an alternative antiviral option or a candidate for use in combination with other antiviral agents for uncomplicated IAV infection.

在抗病毒药物耐药性日益成为关注焦点的当下，本研究指出，Onradivir 可能成为治疗非复杂性流感病毒（IAV）感染的另一种抗病毒选择，或与其他抗病毒药物联合使用的候选药物。

funding

National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine; National Natural Science Foundation of China; Guangdong Science and Technology Foundation; Major Project of Guangzhou National Laboratory; Guangdong Raynovent Biotechnology.

国家中医药多学科创新团队项目；国家自然科学基金；广东省科技基金；广州国家实验室重大项目；广东锐诺文生物科技。