Study design and settings
The study is a randomized, placebo-controlled, multicenter trial, which will be conducted at four medical centers, including Huangshi Hospital of Traditional Chinese Medicine, Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, LaoHeKou Tradiational Chinese Medicine Hospital and Leishenshan Hospital of Wuhan, that were selected by the expert committee. A total of 300 patients fulfilling the eligibility criteria will be randomized into two groups (Baidu Jieduan Granule group and control group) in a ratio of 1:1. The study flowchart is illustrated in Fig.1. The Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) checklist is presented in Additional file 1.
Population
Participant with sepsis will be recruited from 4 study sites in China. Patients with eligibility for inclusion criteria and informed consent, will be screened at the clinical trial period. Subjects Patients with meeting any the exclusion criteria, will be excluded before randomization. The recruitment duration will last for 5 months, from February 2020 to June 2020.
Inclusion criteria
Subjects must meet all of the following requirements:
- Be 18-85 years of age.
- Patients with COVID-19 confirmed by SARS-CoV-2 nucleic acid testing of the respiratory specimens showed positive results.
- Provide signed informed consent form.
Exclusion criteria
The exclusion criteria are as follows:
- Diagnosis of sepsis for over 48 h.
- Pregnant and lactating women.
- Severe primary disease influencing the survival, including malignant tumours, hemorrhagic disease and HIV.
- Severe liver and kidney dysfunction.
- Immunosuppressant therapy or an organ transplant within the previous 6 months.
- Participation in other clinical trials in the last 30 days.
- Allergy to one or more component in Chinese herbal medicinal ingredient prescription
Patient withdrawal
- Patients enrollment without meeting inclusion criterion.
- Not suitable for the trail due to deterioration or recovery of patient condition.
- Patients with poor complicance.
- Voluntary withdrawal.
Sample size
A similar clinical trial was conducted, using TCM to decrease the rate of symptom (fever, fatigue, and coughing) in patients with COVID-19 [6]. The rate of recovery of clinical symptoms was 94% in patients received TCM treatment, and 82% in patients received conventional treatments. Considering 90% power with a significance level of 10 %, as well as a rate of withdrawal and loss to follow-up of 10% [7], we plan to recruit at least 150 participants in each group to achieve sufficient precision in a subsequent full trial.
Randomization and blinding
The enrolled participants are randomly assigned to the Baidu Jieduan Granule group or the conventional treatment group, using random numbers. The random sequence of 300 participants from 4 medical centrals will be generated by SPSS 19.0, and stratified according to each center. Two sets of allocation codes are kept opaque envelopes, which should be sent to the lead clinical researcher and each of the centers. Thereafter, the drug administrators arrange the nurse to dispense the study drug, according to a random number. This is an open-label study. The statistical analysis can be carried out by the Professors of Statistics of Shanghai University of Traditional Chinese Medicine, who is blinded to patient allocation.
Interventions
The Baidu Jieduan Granule comprise 15 g of Rheum palmatum L. stem (Dahuang), 30 g of Sargentodoxa cuneata (Oliv.) Rehd. et Wils. (Hongteng), 30 g of Taraxacum mongolicumHand.-Mazz. (Pugongying), 45 g of Raw Gypsum (Sheng Shigao), 9 g of Herba Ephedra (Mahuang),45 g of Talcum (Huashi), 12 g of Amygdalus Communis Vas (Xingren), 9 g of Radix Glycyrrhizae (Gancao), 30 g of Verbena officinalis L.(Mabiancao), 30 g of Polygonum cuspidatum (Huzhang), 30 g of Scutellariae Radix (Huangqin),12 g of Bombyx Batryticatus (Jiangchan), which were packaged in two bags. The Baidu Jieduan Granule will be administered orally, two times a day for 14 days. The Baidu Jieduan Granules are manufactured by Beijing Tcmages Pharmaceutical Co., LTD (Number: Jing 20180032).
The participants will be categorized into two groups receiving either standard Western medicine therapy alone according to the The Protocol for Diagnosis and Treatment of Novel Coronarvirus Pneumonia (7th edition), or the combination of Baidu Jieduan Granule two times a day for 14 days. The routine care includes early fluid resuscitation, antimicrobial anticoagulants, nutritional support and other treatment. Other TCM therapies, including TCM injections and other oral herbal medicine, should be prohibited.
Outcomes and measurements
The primary outcome will be the rate of symptom (fever, fatigue, and coughing) recovery. Symptoms recovery was defined as the complete disappearance of fever, fatigue and coughing symptoms.
Secondary outcomes will be duration of symptom recovery, the proportion of cases with reverting on chest CT, the time of negative of SARS-CoV-2 nucleic acid, and the proportion of cases with clinical cure.
Safety outcomes
All safety-related indexes, including the vital signs, a complete blood count and a general urine analysis, biochemical test, fecal occult blood testing, and electrocardiogram results, will be checked and recorded in CRF at every visit. The biochemical test contains C-reactive protein, hepatic function (alanine transaminase, aspartate transaminase, alkaline phosphatase, total bilirubin, and gamma-glutamyltransferase) and renal function (blood urea nitrogen and serum creatinine). Any adverse events will be evaluated by a professional researcher at each visit and recorded on the CRF.
Adverse event reporting
An adverse event (AE) is any undesirable syndrome that connected with the administration of Baidu Jieduan Granule in a patient [14]. Any AEs need be recorded in form immediately, and then evaluated by the physician and the corresponding coordinator. All related information, including occurrence time, severity, duration, the measures adopted and the outcome, can be reported to the sponsors, ethics committees, and drug regulatory authorities in accordance with the provisions. We will follow all subjects with AEs.
Statistical analysis
We will not conduct interim analysis or subgroup analyses for the trial. The independent statistical analysts will be responsible for the data analysis, following the principle of intent-to-treat (ITT) analysis, which contain all subjects with eliminating casas in a minimum and reasonable manner. And then, the statistician timely submits statistical reports to the study director. The statistical analysis is performed in a blinded manner using the SPSS 20.0 software. Continuous variables characterizing each study group will be expressed as means with standard deviations or medians with interquartile ranges. Categorical variables will be reported as frequencies and proportions. The continuous outcomes will be analyzed by unpaired Student’s t-test or Wilcoxon nonparametric statistic, while the count data are compared using a chi-square test or Fisher’s exact test. Two-sided tests will be performed for all the other statistical analyses. P <0.05 will be considered statistically significant.
Trial oversight
Coordination Center: The membership of Coordination Center consists of clinical experts, statisticians and quality control experts from each center. The center is responsible for the management of clinical research trials, cooperative hospitals, pre-clinical trial training courses, and resolving key issues in whole process of study.
Quality control: All centers and researchers are regular monitored and inspected by Clinical Research Organizations (CRO), following the standard protocol throughout the process.
Data management
Trained research staff collect trial data carefully according to a standard protocol and complete paper case report forms (CRFs) accurately, completely, timely and reliably. The data will be entered into Electronical Data Capture (EDC) system and regularly reviewed by a clinical research associate (CRA). If any changes are conducted by researchers, the feedback will be provided to the researchers and CRA. All modifications and paper CRF transfer between investigators, inspectors, and data managers should be documented and maintained appropriately. The data administrators will lock the data on completion of the study. The medical information on all the study participants will be kept strictly confidential. The SPIRIT flowchart of the study has been shown in Fig. 2. Data and research findings will be announced via publication.
Quality control
All investigators of the trial should be trained strictly and comprehensively by the State Food and Drug Administration, following Good Clinical Practice (GCP), to profoundly comprehend the detailed contents of the trial and strengthen compliance, and then, improve the quality of the clinical trial. All qualified researchers will collect data and finish the CRF in an accuracy and complete way. After discharge, the subjects will be followed by phone. Regular monitoring and inspecting will be conducted to confirm whether the related research data are correct, and whether the process of the trial complies with the protocol by CRO once a month. They will check details on informed consent, inclusion and exclusion criteria, the original data, management of AEs, the process of storage and distribution of the research drugs, and CRF.
Ethics
This trial will comply with the principles of Declaration of Helsinki and the regulations on quality management of clinical trials in China. The research protocol has been approved by the Ethics Committee of Huangshi Hospital of Traditional Chinese Medicine (approval number HSZY-PJ-2020-002-01) and registered with the Chinese Clinical Trial Registry (ChiCTR2000029869). All the changes in the trial protocol should be maintained as a program addendum and the revised protocol should be submitted to the Ethics Committee for re-review. Study participants or legal representative will receive sufficient explanation and time to sign the informed consent form prior to the study. Any modification on study protocol or AEs attributable to this study will be reported to the research ethics committees.