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Effectiveness and safety of Danmu extract syrup for acute upper respiratory tract infection in children: A real‐world, prospective cohort study

Abstract Aim To evaluate the effectiveness and safety of Danmu Extract Syrup for the treatment of acute upper respiratory tract infection (AURI) in children. Methods In this prospective cohort study, we enrolled children with AURI in the pediatric outpatient department and emergency department of West China Second Hospital. According to the treatment, they were divided into two groups: Danmu Extract Syrup Group (Danmu Group) and Xiaoer Chiqiao Granule Group (Chiqiao Group). The primary outcome was time to symptom remission, and the secondary outcomes were defervescence time, relief time, admission rate, and adherence. We used restricted mean survival time (RMST) to quantify the treatment effects and test noninferiority for primary outcome. Propensity score matching (PSM) was used to adjust confounding. Subgroup analysis and sensitivity analysis were used to verify the robustness of results. Results We enrolled 1036 children with AURI, including 516 in Danmu Group and 520 in Chiqiao Group. After PSM, no significant difference was observed in the baseline characteristics of the two groups. The primary results showed that the RMST difference was –3 h (95% CI: –15.1 to 9.1) and the upper limit of the 95% CI was less than the noninferiority margin of 11 h. There was no statistical difference in the secondary outcomes except for defervescence between the two groups. The results of safety analysis showed that the incidence of adverse events occurred is 4.1% in Danmu Group, which was lower than the incidence of Chiqiao Group (6.9%). Conclusion This study indicated that Danmu extract syrup is noninferiority to Chiqiao Granule for AURI in children.


INTRODUCTION
The World Health Organization (WHO) reports that 36% of the total global disease and injury burden involves children under 15 years of age. 1 In particular, acute upper respiratory tract infection (AURI) is a common disease in children. The global burden of disease survey showed that AURI ranked first among all diseases. 2 If not treated promptly and effectively, AURI can develop into serious diseases, such as lower respiratory tract infections. [3][4][5] Medicine is the most important intervention for diseases; however, there are serious challenges associated with medications, such as off-label drug use and poor drug accessibility. [6][7][8] The current treatments for upper respiratory tract infections are primarily drugs that decrease symptoms but do not shorten the course of the disease and carry the risk of adverse effects due to repeated dosing in children. 3 Traditional Chinese Medicine (TCM) has been used to treat AURI (wind-cold or wind-heat) for more than 1800 years in China and has played a significant role in the control and prevention of infectious diseases, including influenza, SARS, and COVID-19. [9][10][11][12][13][14] However, many TCMs have weak evidence of efficacy.
In turn, they fail to meet the criteria for addition to the list of essential medicines and the policy formulation-related TCM, which has become a bottleneck hindering the development of TCM. 11 Danmu extract syrup is one of the TCMs used for AURI and its main ingredient is Danmu extract. 15 Danmu is produced from Nauclea officinalis (Pierre ex Pitard) belonging to the Rubiaceae family, which is also known as Wutan, Xiongdan tree, etc., and is a characteristic Li medicine in the Hainan Province of China. This plant is only grown in China.
Danmu extract syrup is a new preparation of Danmu and has been used to treat children for 16 years since it was marketed in 2007. Its attending functions include fever reduction, detoxification, reducing swelling, and relieving pain. Therefore, it is suitable for children with acute tonsillitis, acute pharyngitis, acute conjunctivitis, and upper respiratory infection. Clinical studies showed that the effectiveness and safety of Danmu in the treatment of children with AURI might be superior to that of ribavirin granules; however, the quality of these original studies are poor, and the dosage of Danmu for children was not stated. 16 In brief, Danmu extract syrup lacks high-quality evidence of its effectiveness and safety in the treatment of AURI in children. Therefore, we conducted a real-world, prospective cohort study, using Xiaoer Chiqiao Qingre granules as a control to evaluate the effectiveness and safety of Danmu extract syrup for children with AURI.

Study design
From July 2018 to June 2020, we conducted a real-world, prospective cohort study at the pediatric outpatient and emergency department of West China Second Hospital of Sichuan University.

Study patients
The inclusion criteria 22

Grouping situation
According to doctors' prescriptions, patients were divided into treat- The treatment course for the two groups was 3-5 days.

Effectiveness outcome measures
The primary outcome was the time to symptom remission, which is the time required for all symptoms to disappear (symptom score is 0). The symptom scoring standards were formulated following the Guideline We used one-sided α = 0.025, β = 0.2 for noninferiority hypothesis.
The number of cases in each group was calculated as 116 cases, and the number of cases in each group was 145 cases considering 20% of lost visits, and the actual implementation was based on 150 cases in each group, with a total of 300 cases in both groups, and the total sample size was about 1200 cases by multiplying the number of cases by 4 times considering the propensity score matching.

Research registration, ethics review, and informed consent
This trial was registered at the China Clinical Research Registration Center (a first-level registration member of the WHO clinical trial registration platform). The registration number is ChiCTR1800016745.

Ethics approval was obtained from the Ethics Committee of West
China Second Hospital of Sichuan University. Prior to involvement in the trial, subjects, or their legal guardians fully understood the content of the study, agreed to participate, and signed informed consent forms. 25

Data collection and follow-up
We collected data on the basic characteristics of patients, medication usage (both research medicines and other medicines), symptom scores, and occurrence of adverse events. We conducted follow-up by telephone to collect data on medication, symptoms, and adverse events.
The longest follow-up time was 14 days after enrollment. The staff in charge of follow-up were uniformly trained, and the follow-up data were recorded on a paper version of the case report form, which was inputted into the electronic data capture (EDC) system. After input, the data were automatically checked by the EDC system and reviewed by professional researcher.

Statistical analysis methods
Statistical analyses mainly included baseline comparability analysis between groups, analysis of medicine effectiveness, and safety analysis. In statistical descriptive analysis, quantitative data were described by means, standard deviations, medians, and quartiles; nominal data were described by absolute numbers and constituent ratios. In statistical inference analysis, if the quantitative data conformed to normal distribution and homogeneity of variance, the data were analyzed by Data processing and statistical analyses were performed using R software (version: 3.5.1) and SAS version 9.4 (SAS Institute, Cary, NC).

Patient screening
From  there was no significant difference between the two groups (p = 1.000).

Safety evaluation
The results of the safety evaluation showed that the number of adverse events in the Danmu group was 28 (5.4%), which was lower than that in the Chiqiao group (57 (11.0%)). Common adverse events in both groups included diarrhea, vomiting, rash, poor appetite, and nausea. The incidence of serious adverse events was 0.2% (1/516) in the Danmu group and 0.2% (1/520) in the Chiqiao, and none was related to Danmu or Chiqiao (Table 5).

Subgroup analysis and sensitivity analysis
The results of subgroup analysis showed no significant difference in symptom recovery time between the Danmu and Chiqiao groups by gender, age, diagnosis, health status, or year of enrollment, indicating no interaction, as shown in Figure 3. In the sensitivity analysis,

DISCUSSION
In this study, RMST analysis after PSM was selected as the primary analysis, and noninferiority analysis was performed using the 95%

F I G U R E 2
The histograms of the density of propensity scores for cohort before and after matching (1.0, 1.6) the two groups. The shorter recovery times in the Chiqiao group before PSM may be due to the better health status, lower first-day symptom scores, and higher use of antipyretic and analgesic drugs compared with those in the Danmu group (Table 1). After PSM, only cases with matching baseline characteristics in both groups were retained, and the rest were excluded (Table 1 and Figure 2). We used RMST results after PSM as the primary result because the two groups were unbalanced at baseline, before PSM, and there was confounding bias affecting the outcome estimates. 26   and additional medication (including antibiotics, proprietary Chinese medicines, and symptomatic medicine). In the statistical analysis, multifactor analysis was used to control for the above confounding factors and reduce bias arising from them. Subgroup and sensitivity analyses were used to explore interactions and the robustness of the results.
Fourth, in this study, Xiaoer Chiqiao Qingre granules were selected as the positive control, which not only has the indication for use in children on the label but is also one of the commonly used proprietary Chinese medicines for the clinical treatment of children with AURI.
The taste of Danmu extract syrup is better than that of Xiaoer Chiqiao Qingre granule, which is more bitter and discourages children from taking it and may reduce compliance. In addition, the cost of Danmu is lower than that of Chiqiao. Finally, the inclusion and exclusion criteria in this study were less stringent than those in randomized controlled trials, and the treatment regimen and combined medication were more consistent with clinical practice, which better reflected the efficacy and safety of the drug in the actual medical environment.
Although multivariate analysis and propensity score were used to control for confounding bias, the results might still be biased due to unknown confounders. Furthermore, consistent with all single-center studies, there were sample representativeness limitations, and it is recommended to consider the consistency of the population and application conditions when extrapolating conclusions.
In conclusion, in terms of effectiveness of treatment for AURI, Danmu was noninferior to Chiqiao in decreasing the time to symptom remission. The time to defervescence was significantly shorter in the Danmu group, but there was no significant difference in time to symptom relief, adherence, and hospital admission rate. In terms of safety, the incidence of adverse events in the Danmu group was lower than that in the Chiqiao group.