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

The randomisation system will be implemented and managed by the Chinese Evidenced-based to terminate the experiment. The cost will be provided by the research team. 280 The investigator will instruct the participants to record the actual dose in their patient's diary. 281 Based on this diary, the investigator will evaluate the subject's adherence to the interventions to the 282 following four levels, and record the results on the case report form at each follow-up: 1) Take 283 prescribed medications; 2) Basically prescribed medication (80% to 120% of the dose of the program); Data entry and management is the responsibility of the assigned data manager who will establish 294 the database and the verification procedure. Then, two specialised trained keyboard operators will input 295 and confirm the data. After checking the CRF, identified entry errors will be corrected until the input 296 data is exactly as the same as the CRF. Any queries on the CRF will be communicated to the 297 researchers through the data query form. These data query forms must be processed, signed and dated 298 timely by the researcher. Resolved data questions must be returned to the data manager, who revises 299 and verifies the data according to the feedback, and correspondingly updates the database, then the 300 necessary data question form can be queried again. The database will be locked after confirming the accuracy of the established database by blind 303 review. Locked data cannot be changed. If any data revision is needed after locking, an official 304 statement jointly signed by the sponsor, main researcher, experimental project managers, statisticians 305 and data manager must be provided. Additionally, revisions will be performed in the statistical 306 analysis. Primary outcome 318 The primary outcome is the time to alleviate influenza-like symptoms: fever; stuffy nose; running 319 nose; sore throat; cough; myalgia; fatigue; headaches; chills and sweating, which will be measured in 320 hours. Alleviation means that the influenza-like symptoms score is ≤1 (mild) and the state is stable 321 for more than 24h 32 . 322 323 Secondary outcomes 324 The secondary endpoints consist of seven aspects: superior to the placebo group and the test group was not inferior to the positive control group. 374 The main index of treatment effectiveness is the period of time until subsidence of symptoms 375 (hours). It has been reported that the average period of time for remission of these symptoms in the 376 placebo group was about 5 days (120 hours) 32 . This trial requires that the average time for 377 symptomatic remission of the test group should be at least 12 hours shorter than the placebo group, it 378 means the Permissible Error () of the superiority trial is 12 hours. In order to be considered clinically 379 significant, the mean time for symptomatic remission in the positive group must less than 12 hours 380 compared with the placebo group, which means the Permissible Error () of the superiority trial is 381 within 12 hours. (Table 6) 382 Based on the above data, the SAS Software was used to estimate the sample size required for 383 "One-way ANOVA". The calculation result is designed for 3 parallel groups. (Table 7) 384 For achieving adequate participant enrolment, atients are recruited for clinical trials mainly through 385 local advertising. And each participant will receive financial compensation after they finishing the 386 entire treatment. For patients who