Efficacy and safety of Chou-Ling-Dan granules in the treatment of seasonal influenza via combining Western and traditional Chinese medicine: protocol for a multicentre, randomised controlled clinical trial

He, Jiayang; Li, Zhengtu; Huang, Wanyi; Guan, Wenda; Ma, Hongxia; Yang, Zi feng; Wang, Xinhua

forms must be processed, signed and dated timely by the researcher. Resolved data questions must be returned to 275 the data manager, who revises and verifies the data according to the feedback, and correspondingly 276 updates the database, then the necessary data question form can be queried again. The database will be locked after confirming the accuracy of the established database by blind 279 review. Locked data cannot be changed. If any data revision is needed after locking, an official 280 statement jointly signed by the sponsor, main researcher, experimental project managers, 281 statisticians and data manager must be provided. Additionally, revisions will be performed in the 282 statistical analysis. After data have been reviewed, all cases will be assessed to confirm the intent-to-treat 285 population (ITTP), modified intent-to-treatment population (MITTP), per-protocol population (PPP) 286 and the safety analysis population (SAP). The decision will be approved by the data manager, study 287 promoter, and researchers, and will end with unblinding after locking the database. Primary outcome 295 The primary outcome is the time to alleviate influenza-like symptoms: fever; stuffy nose; 296 running nose; sore throat; cough; myalgia; fatigue; headaches; chills and sweating, which will be 297 measured in hours. Alleviation means that the influenza-like symptoms score is ≤1 (mild) and the 298 state is stable for more than 24h 26 . 299 300 Secondary outcomes 301 The secondary endpoints consist of seven aspects: ii. The area under the curve (AUC) analysis of nine influenza-like symptom scores, provide 306 indications of disease severity. The AUC is calculated as the product of the daily symptom scores 307 multiplied by the duration of the illness. 308 iii. The treatment efficacy for different TCM syndromes is assessed by the TCM syndrome scores. The indices of vital signs, cardiopulmonary signs, electrocardiography and clinical laboratory 322 tests (biochemistry, haematology and urine examination) will be compared before and after the 323 treatment to assess for safety. Additionally, research interviewers will keep in touch with each 324 participant to monitor safety. 325 Any adverse events in the vital signs, symptoms and disease or laboratory parameters of the 326 patients that occur after entering clinical trials will be recorded. The occurrence of adverse events is 327 not necessarily related to the study drugs. Adverse events are divided into three levels: mild; Committee. Any cause-and-effect relationship between adverse events and the study drugs will be 333 determined by the classifications shown in Table 5 . If the patient has a serious adverse event, it is necessary to know the specific situation of the 335 medication，unblinding is permissible only after obtaining the consent of the main investigator. 336 Once the emergency letter is read, the case is treated as shedding. Organization for influenza-like illnesses (ILIs) were used as the basis for influenza surveillance. If a 343 patient presents with an acute cough and fever, clinicians must be highly vigilant to test for 344 infections caused by the influenza virus. In general, the rate of ILI cases that lead to a clinical 345 diagnosis of influenza infection is approximately 18 to 80%, which is higher than other clinical 346 diagnoses, for example, acute infections of the upper respiratory tract 20,27 . We selected adult ILI 347 patients for inclusion into the study. 348 Furt