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 centers in the trial until local ethical approval has been obtained. This study is registered at https://upload.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000031377 (UMIN000027381), on April 27th, 2017. We have to change our registration from UMIN to https://jrct.niph.go.jp/en-latest-detail/jRCTs041180063 (jRCTs041180063) on July 30th, 2019 as a result of the revision of the domestic law in 2018 in Japan. 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:
- 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.
- Age of at least 20 years and less than 75 years
- Ability to communicate with the investigators
- Abdominal pain and/or fever > 37.5°C
- 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
Randomization, allocation concealment, and blinding
The baseline measures will be taken before randomization. The web-based online randomization system used in this trial was provided by an independent academic research organization at Kyoto Prefectural University of Medicine. In this registration method, the principal investigator or research coordinator accesses the URL of the Web registration system and registers himself, and obtains the allocation result. For registered case information, fax the information entered on the CRF form to the data center. Allocation of subjects to each treatment group is performed using the central registration system using minimization method. Whether a patient has a history of diverticulitis (initial or recurrence) and the severity ( with abscess formation on CT and / or CRP ≧ 10 or without abscess formation and CRP < 10) are used as adjustment factor in minimization . 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. Only the number of allocation is written on the test drug box, and nobody except data center knows whether it is real DBT or placebo. So all participants and treatment providers, those measuring the outcomes, and those who will analyse the data 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 placebo does not contain extract of DBT but was made in almost the same process, so the shape is almost the same as the real DBT. In addition, in order to make the scent and taste closer to the actual drug, some fragrance that does not affect the effect was used. 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 all randomized 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.
- In a patient with a fever of 37.5°C and abdominal pain requiring treatment at baseline, both fever relief within 3 days and elimination of abdominal pain within 4 days are confirmed.
- In a patient with abdominal pain requiring treatment, without fever of ≥ 37.5°C at baseline, disappearance of abdominal pain is observed within 4 days.
The definition of symptom change is as follows.
① Fever relief
Fever relief is defined as the absence of fever of 37.5 degrees or more without the use of antipyretic analgesics. Even when an antipyretic analgesic is used, if the fever of 37.5 ° C or more does not occur even after 6 hours from the administration of the antipyretic analgesic, it is determined that the patient has fever relief.
② Elimination of abdominal pain
Elimination of abdominal pain means that there is no abdominal pain without using antipyretic analgesics. Even when the antipyretic analgesic is used, it is determined that the abdominal pain has disappeared if no abdominal pain develops after 6 hours from the administration of the antipyretic analgesic. Obtain VAS three times daily during the course of the abdominal pain.
- Number of hospital days: Number of days until discharge, including the registration date, after trial registration.
- 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.
- Thermal type: Differences between the values at the time of registration (baseline value) of body temperature and the values on each measurement day.
- Number of days until oral ingestion: Number of days until the beginning of oral intake, including the registration date, after trial registration.
- Recurrence rate (1-year follow-up observation): Rate of recurrence at 1 year after randomizaition. After discharge, recurrence is regarded as diagnosis of colonic diverticulitis.
- 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. The values for treatment success found in the previous study (79% and 50%) have been analyzed and calculated separately from the results of the author's retrospective study, and the treatment success rate based on the elimination of abdominal pain within 4 days is 75% in the patients treated with DBT and 50% in without DBT. The target differences between the groups are large, but there has been no standard acute-phase treatment of diverticulitis, except for surgery, which has a very different invasiveness. Although the enrollment of patients in the acute phase is required and study enrollment is technically difficult, the authors considered it clinically important to prospectively evaluate the efficacy of DPT, which can be expected to have the large therapeutic effect observed in previous retrospective study, and planned RCT. 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. In our previous study the dropout was 2% therefore in our study we will assume that we will have a 2% dropout. We use the method by Fleiss et al . Based on these consideration, a sample size of 170 patients (85 per arm) is required to provide the trial with 90% power to detect the superiority of experimental treatment over control, at a two-sided alpha level of 5%. The sample sizes is also identical to the tables in Fleiss: Statistical Methods for Rates and Proportions.
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 interim safety data and study operation periodically. Additionally, all data will be monitored every month by central monitoring method. In this study, interim analysis for efficacy is not planned. Final analysis is performed by data center and our statistician. 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.