Trial design
This will be a two-arm, randomised, single-blind, placebo-controlled clinical trial. The trial will be coordinated at the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangzhou, China) and all participants will be recruited from this hospital. This trial will be funded through the Guangdong Provincial Bureau of Traditional Chinese Medicine (grant number, 20181117). Ethical approval has been obtained from the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (BF–2018–178–01). This trial has been registered prospectively with the Chinese Clinical Trail Registry (registration number, ChiCTR1900024072). The protocol of our intended trial has been prepared according to the Standard Protocol Items: Recommendations for Interventional Trials checklist statement (see Online Supplementary Appendix 1).[19]
Participants
Ninety patients who conform to the diagnostic criteria of pneumonia-derived sepsis [1] and admitted to an intensive care unit within the Second Affiliated Hospital of Guangzhou University of Chinese Medicine from August 2019 to August 2021 will be enrolled (Table 1).. All patients must provide written informed consent before participating in our trial.
Disease severity will be evaluated according to two criteria: Acute Physiology And Chronic Health Evaluation (APACHE) II, and Sequential Organ Failure/Sepsis Related Organ Failure Assessment (SOFA). Patients will be randomised into two groups: primary disease in the treatment group (45 cases) and primary disease in the control group (45 cases). Comparisons on age, sex, APACHE II scores, SOFA scores, oxygenation index, and positive end-expiratory pressure between patients in the two groups will be collected.
Inclusion criteria
Participants will be recruited from the King Fahd Hospital of Guangzhou University of Chinese Medicine. Individuals will be included in the trial if they fulfil specific criteria: (i) patients who meet the diagnosis of sepsis based on TCM theory, and patients who meet the diagnostic criteria of sepsis in western medicine; (ii) the infection site is the lung; (iii) the baseline APACHE II score is >8; (iv) patients of either sex are aged 18–80 years.
Exclusion criteria
The exclusion criteria are patients: (i) with a malignant tumor and advanced cachexia; (ii) with a severe bleeding tendency or coagulation disorder; (iii) who are pregnant or lactating; (iv) have a mental disability which makes them unable to understand or cooperate with trial investigators; (v) who are currently participating in or participated in other clinical trials within 1 month of our trial starting; (vi) with contraindications to use of enemas or fiberoptic bronchoscopy; (vii) Yin deficiency and Yang deficiency in traditional Chinese medicine.
Criteria for exiting the trial
Participants will be withdrawn from the study if they suffer: (i) septic shock; (ii) severe stenosis/obstruction of the upper respiratory tract or hemoptysis; (iii) active bleeding of the digestive tract, faecal incontinence, intestinal perforation, or mechanical intestinal obstruction.
Sample size
In this trial, α will be 0.05, and β will be 0.10. The formula used for calculation of the trial size will be:
nc = (μ1α/2 + μ1β)2s2(11/k)/(μtμc)2
The mean ± standard deviation of the HMGB1 level in the control group and test group obtained from the literature is (7.12±1.86) and (4.05±1.89), and nc = 45. The total sample size according to this calculation has been determined to be 90 cases.
Randomisation
Eligible participants will be randomised at a 1:1 ratio to receive an XCD enema (experimental arm) or saline therapy of XCD (control arm). Both types of treatment will be conventional (see below). A randomisation list will be generated centrally, in a stratified fashion, using a random permuted-block design of size four and six. A researcher who is not part of the screening, evaluation or treatment in our trial will allocate participants to one of the groups using a sealed, opaque, tamperproof and numbered envelope before recruitment.
Blinding
The trial product will be provided in a blinded manner. All enema fluid will be covered by a cloth. When the enema is prepared, the enema liquids for both groups will be at 37°C. During the trial, patients will be blinded strictly to randomised interventions. The treating physician will know the type of treatment the participant will be given: participants will not have access to such information. The treating physician will be asked not to talk about the treatment groups to other people. Upon completion of the trial, each participant will be interviewed, and asked about the group which they think they were in.
Treatment methods
With regard to primary disease, conventional treatment (e.g., infection prevention; organ-function support; resuscitation after shock; correction of disturbances in water and electrolyte balance; maintenance of acid–base balance) and a lung-protective ventilation strategy (if necessary) will be conducted for patients in both groups. Meanwhile, on that basis, enema therapy using XCD will be added in the treatment group.
For XCD, gypsum, radix et rhizoma rhei, almond powder, and Trichosanthis pericarpium will be the basic prescription, with addition or subtraction of components as needed. Then, 200 ml of XCD will be used for strong frying at 37°C. The enema will be given once a day over 1 week of treatment.
Outcomes
The primary outcomes will be: (i) 28-day mortality; (ii) levels of TNF-, IL–6, HMGB–1 and IL–10 in bronchoalveolar lavage fluid and serum 1, 3 and 7 days after treatment completion with respect to baseline levels; (iii) static lung compliance, dynamic lung compliance, plateau pressure, and peak airway pressure 1, 3 and 7 days after treatment completion with respect to baseline levels.
Secondary outcomes will be the: (i) symptom score of TCM; (ii) duration of parenteral nutrition; (iii) prevalence of complications (e.g., abdominal distension and ventilator-associated pneumonia) after treatment completion.
Measurements will be taken at baseline, 1, 3 and 7 days during the intervention, and 28 days after completing the intervention.
Statistical methods
All randomised patients will be assessed on an intent-to-treat basis. Safety analyses will be undertaken for all patients who received at least one treatment session.
Data will be entered into SPSS v24 (IBM, Armonk, NY, USA) for analyses. Baseline characteristics will be presented according to the treatment group. Binary and categorical variables will be summarised by frequencies and percentages. Percentages will be calculated according to the number of patients for whom data are available. If values are missing, the denominator (which will be minus the number of patients assigned to the treatment group) will be reported in the body or as a footnote to the summary table. Continuous variables will be summarised by the mean ± SD as well as by quartiles. Before summarising continuous outcomes, a test of normality will be carried out. If the outcome has a normal distribution, it will be summarised by mean ± SD in each arm, and the difference between arms will be tested using the Student’s t-test. However, if evidence of a normal distribution is absent, data will be summarised using the median (interquartile range). In such cases, the Wilcoxon rank sum test will be used to test the difference between arms.
The treatment effect for the primary outcome and continuous secondary outcomes will be assessed through analysis of covariance adjusted for the baseline measurement score. The overall treatment effect over time for all continuous outcomes (which will be collected repeatedly over the course of the trial) will be estimated using mixed linear models to take into account the correlation within each individual. The mixed linear model will include a random intercept adjusted with the baseline score, using time as a categorical and the interaction between treatment and time. P-values will not be adjusted for multiplicity. However, the outcomes will be categorised clearly according to the degree of importance (primary, main secondary, and other secondary) and a limited number of subgroup analyses will be pre-specified.
Categorical binary efficacy measurements will be assessed primarily using logistic regression. All tests will be two-sided, with P < 0.05 considered significant.
Safety measures
XCD has no known side-effects. If side-effects develop or the symptoms of any participants worsen during the trial or follow-up period, appropriate medical care will be given until the situation is resolved. Such participants will be withdrawn from the trial and take the corresponding treatment measures, if necessary. Observed side-effects will be recorded and reported to the Ethics Committee of Guangdong Provinical Hospital of Chinese Medicine.
Privacy and confidentiality
Screening, assessment and treatment will be done in a private area within the Department of Critical Care Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine. Data will be coded, and only one of the researchers will have the key for the codes. All data will be saved in a secured computer protected with a password. Only researchers will have access to data. Upon report writing and publication, data will be presented collectively; the identity of any participant will not be disclosed.
Involvement by participants and the public
Patients or the public were not involved in the development of our trial protocol. The findings of the trial will be disseminated to participants and the community in general through newsletters and presentations in the community.
Ethics and dissemination
The protocol of our trial was approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (BF–2018–178–01). Any amendment to the protocol which may impact the conduct of the trial will be approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine before implementation. The trial was registered in the Chinese Clinical Trail Registry (registration number, ChiCTR1900024072) on 24 June 2019. While the trial is being conducted, the Monitoring Office for Research and Research Ethics at the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (where the trial will be conducted) will monitor the various milestones of the trial. The trial will be explained to all participants by one of the researchers. All participants will sign a consent form before beginning any procedures of our trial. The results of our trial will be presented in international conferences and will be published in a peer-reviewed journal.
