Primary Outcome
Coronavirus nucleic acid test
The coronavirus nucleic acid test by reverse transcription polymerase chain reaction ( RT-PCR ) will be conducted at the baseline and day 3, day 7, day 10 and day 14 of the study intervention. The time ( in days ) of the respiratory tract sample and blood specimens SARS-CoV2 RT-PCR to be negative for two consecutive times based on the first testing time will be defined as primary outcome.
Secondary outcomes
Murray lung injury score
Murray lung injury score (Murray LIS) will also be taken at the baseline and day 3, day 7, day 10 and day 14 of the study intervention. Murray LIS is the average of four variables proposed for an expanded definition of the acute respiratory distress syndrome (ARDS) to facilitate the study and treatment of acute lung injury[24], and is considered very useful in defining the severity of ARDS in clinical and research studies. Derived empirically by expert consensus, the score is composed of four components[25]: 1) chest radiograph; 2) hypoxemia score (PaO2/FiO2 ratio); 3) positive end-expiratory pressure level (PEEP); and 4) static compliance of respiratory system. For LIS, each of the four components is categorized from 0 to 4, where a higher number is worse (Table 1). The total LIS is obtained by dividing the aggregate sum by the number of components used. For example, if one component is unavailable then the LIS would be the sum of the three other components divided by three. Lastly, Murray LIS are categorized as no significant lung damage(0-.25), mild/moderate (0.25-2.5), or severe (2.5 or more).
MuLBSTA score
MuLBSTA score system is composed of six parameters which are easy to get clinically: 1) Multilobular infiltration on chest imaging; 2) Lymphopenia(peripheral blood lymphocyte count≦0.8*109/L); 3) Bacterial co-infection; 4) Smoking history; 5) Hypertension; 6) Age ≧ 60 years[26]. The MuLBSTA score shows promise for the risk stratification and prediction of overall mortality of patients hospitalized with viral pneumonia. The sum value of MuLBSTA is 22 ( Table 2 ). Patients will be divided in to high-risk( 12-22 ) and low-risk( 0-11 ) groups considering the cut-off value of 12. This will be taken at the baseline and day 3, day 7, day 10 and day 14 of the study intervention, too.
TCM Syndrome Scoring System
TCM Syndrome Scoring System will be used at the baseline and day 3, day 7, day 10 and day 14 of the drug intervention. It is a checklist covering 4 main, 7 secondary and 13 accompanying items. These items are the symptoms and signs summarized by experts according to the clinical manifestations of COVID-2019[27]. The main items consisting of fever, cough, debilitationand short breath use a four-point scale (0, 2, 4 and 6) depending on the severity; the 7 secondary items including dysphoria, diarrhea, pharyngalgia, expectoration, muscular soreness, nasal obstruction and rhinorrhoea use 0-3-point scale; the 13 accompanying items contain chest pain, headache, aversion to cold, dizziness, nausea and vomiting, anorexia, abdominal distension, dry mouth, anxiety, spontaneous sweating, insomnia, wheezing and blood tinged sputum, and each item is rated on 0-1 scale ( 0 stands for asymptomatic, 1 stands for symptomatic ). The total scores sum up to a range from 0 to 58, with higher scores indicating more severe levels of disease.
Safety outcomes
Test safety will be monitored during this trial. Participants will accept a routine physical examination, including breath rate, heart rate, temperature, blood pressure, weight, routine urine test, routine blood test, liver, kidney function tests, and an electrocardiogram.
Adverse event reporting and treating
Adverse events (AEs) will be defined as unpredictable, undesirable symptoms, signs or diseases related to the treatment and will be recorded and managed by the researchers during the treatment period. The researchers will scrupulously evaluate the relationship between these adverse events and the experimental drugs, then manage them quickly and properly. Furthermore, patients will be continuously followed up until their condition returns to normal. Participants who might be injured during the study will get a financial compensation.
Quality control, data collection and management
All Traditional Chinese physicians will receive a series of training sessions before the start of this study, to ensure that they could make the most appropriate and accurate prescription of Chinese medicine. And every prescription will be checked and perfected by the expert group in order to achieve better therapeutic effect .
To keep the information confidential, the experimental data will be carefully recorded in CRFs which will be identified by IDs rather than identifiable information and will be stored separately and securely in the linking document. To guarantee the data quality, the completed CRFs will be input in Microsoft Access by two researchers. For some emergent reasons, investigators were bound to
During the study, the First Affiliated Hospital of Wenzhou Medical University is responsible for making regular visits (once a week) to review trial conduct, and the Ethics Committee will monitor for protocol violations weekly, there was no conflict of interest with the sponsors or researchers.
STATISTICAL ANALYSIS
We will use log-rank test for the primary outcome, if the influence of confounding factors needs to be considered, Cox proportional hazard model can be used. For all secondary outcomes, Wilcoxon rank sum test will be used. For safety evaluation of TCM, two-sided t-test will be applied to each safety measurement after data normalization.
To better understand the nature the missing mechanisms, we will characterize the type of subjects who have missing data, then statistical models to impute missing values if the assumption of missing at random is met will be used.