Study design and settings
A brief flowchart of the entire study is shown in Fig. 1. This study is a two-group, randomized, double-blind, placebo-controlled, multi-center trial, which will evaluate the efficacy and safety of DBT for acute diverticulitis patients. The study will be conducted throughout Japan. Patients will be recruited from the gastroenterology inpatient departments of 13 hospitals. Informed consent will be obtained from all study participants. The study protocol was designed in accordance with the ethical principles in the Declaration of Helsinki and regional regulations. Central ethical approval of this study has been confirmed from the Central Review Board of Kanazawa University Hospital (ref approval no.6058) and we will not begin recruiting at other centres in the trial until local ethical approval has been obtained. This study is registered at http://www.umin.ac.jp/ctr/index-j.htm (UMIN000027381). The protocol includes elements recommended in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)  checklist (Additional file 1).
Setting and participants
This study will be conducted in Japan. Patients will be recruited from the gastroenterology and surgery inpatient department at each of the hospitals in different districts in Japan.
Participants who meet the following inclusion criteria are eligible:
1. Moderate to severe diverticulitis: diagnosis will be based on computed tomography (CT) images showing diverticula-like structure combined with tenderness or abdominal pain, a thickening of colon wall, signs of inflammation of pericolonic fat, tissue density, and vascular involvement. Pericolonic abscess, free air or extravasation, and accumulation of fluid will also be assessed to predict prognosis.
2. Age of at least 20 years and less than 75 years
3. Ability to communicate with the investigators
4. Abdominal pain and/or fever > 37.5°C
5. Provision of written informed consent for participation after receiving sufficient explanation for participation in this study and achieving sufficient understanding.
Participants who meet the following exclusion criteria will not be enrolled:
1. Severe dysfunction in the following organs, based on blood tests within 4 weeks before treatment starts:
a. Renal function: serum creatinine value 1.5-fold greater than the upper limit of the institutional standard
b. Liver function: serum AST value or serum ALT value 3-fold greater than the upper limit of the institutional standard
c. Central nervous function: encephalopathy or a patient suspected of it
d. Electrolytes: serum sodium < 125 mEq / L, serum potassium < 3.3 mEq / L
2. Highly likely to exhibit abscess perforation due to malnutrition (Alb < 2.5 g / dL)
3. Symptoms of obstructive ileus
4. Chronic anorexia, abdominal pain, and/or diarrhea symptoms before the onset of colorectal diverticulitis
5. Performance status (an indicator of general condition and the degree of restriction of the patient's daily life) of ≥ 3, before the onset of colorectal diverticulitis
6. History of DBT administration
7. Treatment with insulin preparations
8. Immunocompromised status
9. Pregnancy or postpartum status
10. Advanced allergy to Kampo formulas
11. Doctor’s judgement to be inappropriate for inclusion in this study.
Randomization, allocation concealment, and blinding
The web-based online randomization system used in this trial was provided by an independent academic research organization at Kyoto Prefectural University of Medicine. Enrolled patients who provide informed consent will be randomized 1:1 in a blinded manner into either an experimental treatment group receiving a 10-day DBT regimen plus conventional therapy, or a control group receiving a 10-day placebo regimen plus conventional therapy. All participants and investigators will be blinded to treatment allocation.
We will use DBT extract, which consists of five crude drugs in fixed proportions: Rhei Rhizoma (2.0 g), Natrium sulfuricum (1.8 g), Moutan Cortex (4.0 g), Persicae Semen (4.0 g), and Benincasae Semen (6.0 g), in 7.5 g of extract. DBT extract (Tsumura, Tokyo)—or placebo manufactured by Tsumura Co., Ltd., based on good manufacturing practice standards—at 2.5 g will be administered three times per day, 7.5 g per day, for 10 days. The administration of DBT or placebo begins immediately after informed consent and web-based randomization. No restrictions will be imposed on the standard treatments for acute diverticulitis or any other disease while DBT is administered. If the clinical evolution is appropriate, a regular diet will be initiated, and the patient will be discharged; the patient will return as an outpatient 1 week later. We will ask patients whether they have relapsed, 1 year after discharge. When any serious adverse event occurs or patients do not wish to further participate in the trial, they will be excluded from the examination.
The study data collection process is outlined in Table 1.
[Table 1 near here]
Treatment success rate
If criteria below are satisfied, treatment will be defined as successful.
1. In a patient with a fever of 37.5°C and abdominal pain requiring treatment at baseline, both fever reduction and disappearance of abdominal pain are confirmed.
2. In a patient with abdominal pain requiring treatment, without fever of ≥ 37.5°C at baseline, disappearance of abdominal pain is observed.
For patients who use any antipyretic analgesic after randomization, the disappearance of abdominal pain is confirmed if no abdominal pain is present at ≥ 6 hours from the administration of antipyretic analgesic.
1. Number of hospital days: Number of days until discharge, including the registration date, after trial registration.
2. Change in inflammatory response (CRP, WBC, neutrophil count): Differences between the value at the time of registration (baseline value) of each measurement and the value at each measurement day.
3. Thermal type: Differences between the values at the time of registration (baseline value) of body temperature and the values on each measurement day.
4. Number of days until oral ingestion: Number of days until the beginning of oral intake, including the registration date, after trial registration.
5. Recurrence rate (1-year follow-up observation): Rate of recurrence at 1 year after trial registration. After discharge, recurrence is regarded as diagnosis of colonic diverticulitis.
6. Adverse events (types and frequency of side effects): Side effects will be recorded for each observed adverse event, and the type and frequency will be determined.
Calculation of the sample size in this trial was based on treatment success rate. Based on the results of our retrospective study, we expected that the treatment success rate would be 75% in the experimental treatment group and 50% in the control group. Based on this expectation, a sample size of 150 patients (75 per arm) would provide the trial with 90% power to detect the superiority of experimental treatment over control, at a two-sided alpha level of 5%.
Treatment success rate will be compared between groups using the Pearson chi-square test. Time to confirmed treatment-success will be summarized using the Kaplan-Meier method. Continuous variables will be summarized as mean and standard deviations, and comparisons will be made using the unpaired Student’s t-test. Categorical variables will be summarized as frequency and proportions, and comparisons will be made using the chi-square test. Two-sided p-values less than 0.05 will be considered statistically significant.
Quality control and trial management
The management structure comprises the principle investigator (PI), a trial management group, and a data monitoring committee. The trial management group is responsible for conducting the trial and will meet monthly to discuss trial progress. The PI will visit each collaborative hospital for face-to-face meetings and sharing of information to promote patient recruitment. The data monitoring committee will review safety and efficacy data. All data will be monitored every month by central monitoring method. Additional monitoring may be performed at the discretion of the monitoring manager. The data monitoring committee met once, prior to the start of patient recruitment. At least twice per year, participating investigators, research assistants, and research nurses will be required to attend a training workshop for clinical research to ensure strict adherence to the study protocol and familiarity with the trial administration process. The data collected in this trial will comprise information recorded in case report forms and questionnaires. Data quality will be checked regularly by research assistants and overseen by monitors; all modifications will be marked on case report forms, and data managers will recheck the data before they are officially logged. The database will be locked after all data have been cleaned. If participants withdraw from the trial during the study period, the reasons will be documented, and the dropout rate will be statistically analyzed.