Supplementary file 5_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）基于经典中药方剂银翘散（Yinqiao Powder）开发。相较于原方剂，本品可增强清热、解毒与退热功效，能有效应对儿童流感常见并发症，且适配儿科用药需求。但目前尚缺乏高质量临床试验证据支持其临床应用的有效性与安全性。
目的 本研究旨在对比小儿风热清口服液与奥司他韦（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。试验组给予小儿风热清口服液联合奥司他韦颗粒安慰剂，对照组给予奥司他韦颗粒联合小儿风热清口服液安慰剂，疗程均为5天，随后进行2天的治疗后观察。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）症状维度得分随时间变化的曲线下面积（area under the curve, AUC）、中医证候（Traditional Chinese Medicine, TCM）疗效、各单项症状消失率、并发症及重症/危重症流感发生率、对乙酰氨基酚（acetaminophen）使用情况以及病毒转阴率。安全性评价重点关注不良事件（adverse event, AE）与药品不良反应（adverse drug reaction, ADR）。
结果 全分析集共纳入418名受试者，试验组208例，对照组210例。两组基线特征具有可比性。两组临床恢复中位时间均为3天，试验组/对照组的风险比及其95%置信区间（confidence interval, CI）为1.115（95%CI：0.912~1.363）。非劣效性检验结果显示试验组非劣于对照组。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症状得分随时间变化的曲线下面积差异无统计学意义（P=0.211）。两组风热犯卫证与夹惊证的证候有效率差异无统计学意义（P=0.076、P=0.168）；但夹痰证与夹食滞证的证候有效率差异有统计学意义（P=0.008、P=0.024）。咽红肿、咳嗽、痰多或喉间痰鸣、食欲不振等单项症状消失率组间差异有统计学意义（P<0.05），其余症状差异无统计学意义。两组并发症及重症/危重症流感发生率、对乙酰氨基酚使用情况、病毒转阴率差异无统计学意义（P>0.05）。两组不良事件发生率（P=0.885）与药品不良反应发生率（P=0.685）均具有可比性，差异无统计学意义。
结论 针对儿童流感（风热犯卫证），小儿风热清口服液在临床恢复时间方面的疗效非劣于奥司他韦。此外，本品在退热、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，提示其具有临床应用潜力。
临床试验注册：clinicaltrials.gov，注册号ChiCTR2300076191。