Supplementary file 1_Efficacy and safety of Xiao’er Fengre Qing oral liquid versus Oseltamivir in treating pediatric influenza (wind-heat invading the defense syndrome): a multicenter, randomized, non-inferiority trial.docx

BackgroundXiao’er Fengre Qing Oral Liquid (XFQOL) is developed based on the classical traditional Chinese medicinal formula Yinqiao Powder. Compared to the original formulation, XFQOL exhibits enhanced heat-clearing, detoxification, and fever reduction, which can effectively address the common complications associated with influenza in children and is well-suited for pediatric use. However, there is currently a lack of high-quality evidence from clinical trials to support its efficacy and safety in clinical applications.
ObjectiveThis study aimed to investigate the efficacy and safety of XFQOL compared with Oseltamivir in pediatric influenza.
MethodsA multicenter, block-randomized, double-blind, double-dummy, positive-drug-controlled, non-Inferiority clinical trial design was conducted. The study plans to enroll 420 pediatric participants, with 210 in each group. The experimental group will receive XFQOL with an Oseltamivir granules placebo, and the control group will receive Oseltamivir granules with a XFQOL placebo for 5 days, followed by a 2-day post-treatment observation. The primary endpoint was clinical recovery time, while secondary endpoints included complete fever resolution time, the area under the curve (AUC) of Canadian Acute Respiratory Illness and Flu Scale (CARIFS) symptom dimension Score over time, Traditional Chinese Medicine (TCM) syndrome efficacy, disappearance rates for individual symptoms, incidences of complications and severe and critical influenza, the usage of acetaminophen, and viral negative conversion rate. Safety evaluation focused on adverse events (AE) and adverse drug reactions (ADR).
ResultsA total of 418 participants were included in the Full Analysis Set, with 208 in the experimental group and 210 in the control group. Baseline characteristics were comparable between the groups. The median time to clinical recovery was 3 days for both groups, with a hazard ratio and its 95% confidence interval (experimental group/control group) of 1.115 (95% CI: 0.912–1.363). Non-inferiority testing demonstrated that the experimental group was not inferior to the control group. Subgroup analyses (positive for RT-PCR influenza, positive for RT-PCR influenza A, positive for RT-PCR influenza B) yielded results consistent with the primary endpoint. The median time to complete fever resolution was 32 h in both groups, with no statistically significant difference (P = 0.407). There were no statistically significant differences in the AUC of CARIFS symptom scores over time between the groups (P = 0.211). No significant differences were observed between the groups in the efficacy rates of TCM syndromes of Wind-Heat Invading the Defense Syndrome (P = 0.076) and Fright-complicated Syndrome (P = 0.168); however, significant differences were found in Phlegm-complicated Syndrome (P = 0.008) and Food-stagnation-complicated Syndrome (P = 0.024). The disappearance rates for individual symptoms, such as red and swollen pharynx, cough, copious sputum or audible phlegm sounds in the throat, and lack of appetite, showed statistically significant differences between the groups (P < 0.05), while no significant differences were observed for other symptoms. No statistically significant differences were observed between the experimental and control groups in the incidence of complications and severe and critical influenza, the usage of acetaminophen, and viral negative conversion rate (P > 0.05). The incidence rates of AE (P = 0.885) and ADR (P = 0.685) were comparable between the two groups, with no statistically significant differences observed.
ConclusionThe efficacy of XFQOL in treating pediatric influenza (Wind-Heat Invading the Defense Syndrome) is non-inferior to Oseltamivir with respect to clinical recovery time. Additionally, its effectiveness in terms of fever reduction, symptom alleviation, incidences of complications and severe and critical influenza, the usage of acetaminophen, and viral negative conversion rate is comparable to that of Oseltamivir. Furthermore, it demonstrates good safety, suggesting its potential for clinical application.
Clinical Trial Registration:clinicaltrials.gov, identifier ChiCTR2300076191.

背景：小儿风热清口服液（Xiao’er Fengre Qing Oral Liquid，XFQOL）是基于经典中药方剂银翘散（Yinqiao Powder）开发而成。相较于原方，XFQOL在清热、解毒、退热方面疗效更优，可有效应对儿童流感常见并发症，适配儿科临床使用需求。但目前仍缺乏高质量临床试验证据支撑其临床应用的有效性与安全性。
目的：本研究旨在对比XFQOL与奥司他韦（Oseltamivir）治疗儿童流感的有效性与安全性。
方法：本研究采用多中心、区组随机、双盲双模拟、阳性药对照的非劣效性临床试验设计。计划纳入420名儿科受试者，每组各210例。试验组给予XFQOL联合奥司他韦颗粒安慰剂，对照组给予奥司他韦颗粒联合XFQOL安慰剂，疗程为5天，随后进行2天的治疗后观察。本研究的主要终点为临床恢复时间，次要终点包括完全退热时间、加拿大急性呼吸道疾病与流感量表（Canadian Acute Respiratory Illness and Flu Scale, CARIFS）症状维度评分随时间变化的曲线下面积（AUC）、中医证候疗效、各症状消失率、并发症及重症/危重症流感发生率、对乙酰氨基酚使用情况以及病毒转阴率。安全性评价重点关注不良事件（AE）与药品不良反应（ADR）。
结果：最终共有418名受试者纳入全分析集（Full Analysis Set），其中试验组208例，对照组210例。两组受试者基线特征均衡可比。两组的临床恢复中位时间均为3天，试验组相较于对照组的风险比及其95%置信区间为1.115（95% CI：0.912~1.363）。非劣效性检验结果显示，试验组疗效非劣于对照组。亚组分析（流感RT-PCR阳性、甲型流感RT-PCR阳性、乙型流感RT-PCR阳性）结果与主要终点一致。两组完全退热中位时间均为32小时，差异无统计学意义（P=0.407）。两组CARIFS症状评分随时间变化的曲线下面积差异无统计学意义（P=0.211）。两组在风热犯卫证中医证候疗效（P=0.076）及夹惊证疗效（P=0.168）上无显著差异，但在夹痰证（P=0.008）与夹食滞证（P=0.024）疗效上存在显著差异。两组在个别症状的消失率上存在统计学差异，包括咽喉红肿、咳嗽、痰多或喉间痰鸣、食欲不振（P<0.05），其余症状则无显著差异。两组在并发症及重症/危重症流感发生率、对乙酰氨基酚使用情况、病毒转阴率方面均无统计学差异（P>0.05）。两组的不良事件发生率（P=0.885）与药品不良反应发生率（P=0.685）相当，差异无统计学意义。
结论：XFQOL治疗儿童流感（风热犯卫证）在临床恢复时间方面的疗效非劣于奥司他韦。此外，其在退热、症状缓解、并发症及重症/危重症流感发生率、对乙酰氨基酚使用情况以及病毒转阴率方面的疗效与奥司他韦相当。同时，本品安全性良好，具备临床应用潜力。
临床试验注册：clinicaltrials.gov，注册号ChiCTR2300076191。