Study Design
This study presents a randomized, double-blinded, and placebo-controlled clinical trial performed in accordance with the Declaration of Helsinki, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement [18], and the Standard Protocol Items for Clinical Trials with Traditional Chinese Medicine: Recommendations, Explanation and Elaboration (SPIRIT-TCM) Extension 2018 Statement [19] from June 2021 to June 2023. In this study, a total of 80 eligible patients will be enrolled and randomly classified into the JLJ granules group or the placebo control group. All the patients voluntarily signed an informed consent before being included. Each included patient will be numbered in sequence and randomly classified into two groups using a ratio of 1:1. Participants in the JLJ granules group will be instructed to take JLJ granules (110g per day) for 3 consecutive months, while participants in the placebo control group will be given placebo granules with the same appearance and smell as JLJ granules but no therapeutic effect (110g per day) for 3 consecutive months. All of the researchers and patients will be blinded right from the beginning of the trial. All the clinical data, including the results of electronic colonoscopy, will be recorded before the intervention (0 week) and after the intervention (At 3 months, 6 months and 12 months). The proposed project schedule is illustrated as a flowchart in Figure1 and Figure 2.
Objective and Hypothesis
This study’s principal objective was to conduct an evaluation of the clinical efficacy of JLJ granules in the treatment of postoperative patients with CRA, assess the recurrence of CRA, and explore the safety profile of JLJ granules in the treatment of postoperative patients with CRA. In this study protocol, it will be assumed that, compared with the placebo, JLJ granules have better effects in terms of major symptom alleviation, the remission rate of minor symptoms, the Bristol stool scale, the efficacy, and the recurrence rate of CRA for patients with CRA after surgery, with no significant adverse effects despite an adequate safety profile.
Participants
In this study, patients will be recruited in the outpatient department, Department of Gastroenterology and gastrointestinal endoscopy center of Nanjing Integrated Traditional Chinese And Western Medicine Hospital, and diagnosed according to the results of electronic colonoscopy and histopathology. All of the 80 patients included must voluntarily sign an informed consent. Data collection will be performed by two professionally trained researchers to ensure that the data is relatively objective and accurate.
Inclusion Criteria
1. Patients diagnosed with colorectal polyps through colonoscopy and adenoma through histopathological examination, and received resection of the adenoma with biopsy clips or endoscopic resection within 4 weeks, including snare polypectomy (SS), endoscopic mucosal resection (EMR), piecemeal EMR (pEMR), endoscopic submucosal dissection (ESD), etc.;
2. Patients with TCM syndromes of spleen-asthenia with excessive damp [20]; Refer to Table 1 for the clinical symptoms of spleen-asthenia with excessive damp. The cardinal symptoms in line with 2 items and the minor symptoms in line with 1 item shall be diagnosed as spleen-asthenia with excessive damp;
Patients with age ranging from 18 to 65 years old, regardless of gender;
3. Patients that voluntarily accepted observation, and signed the informed consent and ethical principles;
Exclusion Criteria
1. Patients not falling under the diagnostic criteria for colorectal polyps or with pathologies not considered within the diagnostic criteria for adenoma or TCM syndromes of spleen-asthenia with excessive damp;
2. Pregnant or lactating women or those preparing to have children;
3. Patients with an allergic constitution or an allergy to multiple drugs, drug addicts and alcoholics;
4. Patients with comorbidities such as serious cardiovascular, pulmonary, hepatic, renal and hematologic diseases;
5. Patients suspected of canceration or in whom canceration has been confirmed by biopsy;
6. Patients taking drugs or undergoing other clinical trials within one month;
7. Patients with severe physical disabilities (Such as deafness, blindness, intellectual disability, mental disability, etc.) who are unable to cooperate or unwilling to cooperate;
Withdrawal Criteria/Dropout Criteria/ Termination Criteria
1. Patients not in line with the aforementioned inclusion criteria;
2. Patients with incomplete clinical data, lost during medical follow-up, or requested to be withdrawn from the trial;
3. Patients who requested to be withdrawn from the trial, patients with poor compliance or not following the drug administration protocol or with a change in the test drugs or administration of banned drugs;
4. Patients with serious changes in the disease course or complications during the trial;
5. Patients with serious adverse events during the trial, resulting in the inability to continue the trial.
Randomization
In this clinical trial, 80 postoperative patients with CRA will be randomly distributed into a JLJ granules (Treatment) group or the placebo control group in a ratio of 1:1, according to the randomized sequence table generated by SAS 9.4 (SAS Institute Inc, Cary, NC, USA), with each patient attributed a number ranging from 01 to 80; Each of these codes is unique to a specific patient. JLJ granules and placebo granules will be numbered and labeled with the same serial numbers as described above.
Blinding
Before the trial completion, all the patients, clinicians, nurses, data managers, statisticians and other personnel will be blinded, and the random sequence table and number must be kept strictly confidential. The blinding can only be uncovered with the consent of the main researcher after completion of the trial and data analysis or in case an emergently severe adverse event occurs. Placebo and JLJ granules will be both packed in opaque packages, which will be exactly the same in appearance, color, smell, taste, dosage and packaging.
Intervention
JLJ Granules Group
Patients randomly classified into the JLJ granules group will be provided with Jianpi Lishi Jiedu granules. Administration method: A pack of granules (110g/pack) is dissolved into 150 ml of warm water every day, and divided into 2 equal doses for administration at 2 separate times. The JLJ granules are produced by Tiangjiang Pharmaceutical Co., Ltd. (Jiangyin), with a herbal formula comprising 15g of pilose asiabell roots, 10g of fried atractylodes macrocephala, 30g of glabrous greenbrier rhizome, 15g of orsythia suspensa, 30g of honeysuckle stem, and 10g of cynanchum roseum.
Placebo Control Group
Patients in the control group will be provided with placebo-control granules. The administration method will be the same as with the JLJ granules. The dosage of each pack of placebo-control granules must also be 110g. The main components of the placebo-control granules includes starch, maltodextrin, caramel pigment, etc., free from any therapeutic effect.
Study period
The course of intervention is set as 3 months. Follow-ups were conducted at month 3, 6 and 12, clinical data will be recorded again, and a follow-up colonoscopy undergone. A safety evaluation will be carried out for all the patients after treatment initiation (Comprising blood routine, urine routine, stool routine, liver and kidney function and electrocardiography).
Outcomes
Primary Outcome
1. Cardinal TCM symptom scores: The scores and details regarding TCM syndrome are given in Table 1;
2. Bristol Stool Scale [21] Type 1: The stool forms separate hard lumps and is difficult to pass; Type 2: The stool is sausage-shaped, with a lumpy surface; Type 3: The stool is strip-shaped, with cracks on the surface; Type 4: The stool is strip-shaped, soft and smooth; Type 5: The stool forms soft lumps; Type 6: The stool is mushy; Type 7: The stool is watery.
3. The recurrence rate of CRA: Refer to the Diagnostic Criteria and Therapeutic Effect for Diseases and Syndromes in Traditional Chinese Medicine (Chinese Medicine Industry Standards of the People's Republic of China; ZY/T001.1–94); Recurrence refers to the formation of new adenomatous lesions after complete resection of the initial lesions, appearing at the original affected site or at other sites. The recurrence rate of adenomas = the number of patients with recurrence/the number of intra-group patients * 100%.
Secondary Outcome
1. Minor TCM symptom scores: The scores and details of TCM syndrome are provided in Table 1;
2. Safety indicators: Including blood routine, urinalysis, stool routine, liver and kidney functions and electrocardiography;
3. The efficacy of TCM symptoms: Refer to the Diagnostic Criteria and Therapeutic Effect for Diseases and Syndromes in Traditional Chinese Medicine (Chinese Medicine Industry Standards of the People’s Republic of China; ZY/T001.1–94);
1). Clinical control: After treatment, symptoms and signs almost disappeared and patients returned to normal activities and work. The efficacy rate for syndromes is ≥90%.
2). Excellent efficacy: After treatment, the signs and symptoms, and the results of examinations improved significantly. The efficacy rate for syndromes is ≥60% but < 90%.
3). Efficacy: After treatment, improvement of the symptoms and signs, and examination results was observed. The efficacy rate for syndromes is ≥ 30%, but < 60%.
4). Lack of efficacy: After treatment, symptoms and signs and the results of examinations did not improve compared to before the treatment. The efficacy rate for syndromes was < 30%.
Table 1 The scores of TCM syndrome
symptoms
|
Scores of TCM symptoms
|
None
|
Mild
|
Moderate
|
Severe
|
0
|
1
|
2
|
3
|
Cardinal TCM symptom
|
|
|
|
|
Diarrhea or mucus
|
None
|
Diarrhea or mucus, defecate 3-4times/d
|
Diarrhea or mucus, defecate 5-10times/d
|
Diarrhea or mucus, defecate>10times/d
|
Constipation
|
None
|
Dry stool, defecate 1time/d
|
Dry stool, defecate once/2-3 days
|
Very dry stool, defecate once/5-7 days
|
abdominal pain
|
None
|
Occasionally, mild abdominal pain
|
Sometimes, moderate abdominal pain
|
Often, severe abdominal pain
|
abdominal distension
|
None
|
Occasionally, mild abdominal distension
|
Sometimes, moderate abdominal distension
|
Often, severe abdominal distension
|
inappetence
|
None
|
Mild, less than 1 / 3 reduction in food intake
|
Moderate, More than 1 / 3 reduction in food intake
|
Severe, No eating all day long
|
Dry or sticky feeling in the mouth
|
None
|
Mild, occasionally
|
Moderate, sometimes
|
Severe, often
|
Minor TCM symptom
|
|
|
|
|
Fatigue
|
None
|
Mild, be able to insist on light physical work
|
Moderate, Barely stick to daily activities
|
Severe, inactive all day
|
bowel sound
|
None
|
Mild, occasionally
|
Moderate, sometimes
|
Severe, often
|
Nausea or vomiting
|
None
|
Mild, occasionally
|
Moderate, sometimes
|
Severe, often
|
Tongue and Pulse:
|
Additional Information
Moreover, general information (Such as gender, age, and BMI) and disease-related information (Such as patient's family history, adenoma location, adenoma morphology, adenoma size, etc.) will be obtained while enrolling the patients and during follow-up.
Adverse events
During the whole study process, a close observation must be conducted on the occurrence of adverse events. Any adverse events shall be recorded in the standard SAE form. Patients experiencing serious adverse events must be subjected to a close follow-up and managed appropriately. Detailed reports of every adverse event will be sent to the Ethics Committee of Nanjing Integrated Traditional Chinese And Western Medicine Hospital.
Oversight and Quality Control
In order to ensure the accuracy and objectivity of this experiment, a third-party testing institution will be employed, and all of the data collection and quality control will be completed and recorded by trained investigators. Additionally, endoscopic resection of the adenomas must be a senior digestive endoscopic physician, and supervised by another senior digestive endoscopic physician to ensure complete removal of the adenoma. Investigators from the third-party testing institution must be on the field to carry out the supervision and record the relevant data.
Quality Control of Herbs
All the Chinese herbal medicine granules and control placebo granules to be used in this study are manufactured by Tiangjiang Pharmaceutical Co., Ltd. (Jiangyin, China), and all the Chinese herbal medicines and auxiliary materials meet the criteria in the Good Agricultural Practice for Chinese Crude Drugs of the National Medical Products Administration.
Ethics and Registration
This study protocol has been approved by the Ethics Committee of Nanjing Integrated Traditional Chinese And Western Medicine Hospital (No.202102, Additional file1 and 2). All the patients voluntarily signed the informed consent (Additional files 3 and 4) before registration. This study has been registered with the Chinese Clinical Trial Registry (ChiCTR). (URL: http://www.chictr.org.cn/, No. ChiCTR2100044297).
Sample size
The sample size is estimated based on the two sample rate tests; test level: α=0.05, test efficacy: 1-β; 1-β=0.9, so β=0.1. Take α=0.05 (bilateral), β=0.1, Zα/2=Z0.05/2=1.96, and Z0.10=1.282, the sample size of the treatment group and the control group each account for 50%, thus Q1=Q2=0.5. As per the previous literature [22], we assumed that the symptom relief rate of the TCM treatment group is about 81.2% (p1≈0.81), and the symptom relief rate of the placebo-control group is roughly 59.4% (p2≈0.59). As per the two sample rate calculation formula: n= ((Zα/2√ (p(1-p)(Q1-1+Q2-1)) +Zβ√((p1 (1-p1)/Q1) + (p2 (1-p2)/Q2))/(p1-p2)) 2, we can conclude that n≈94. Taking into account patients’ withdrawal and loss during follow-up, we also assumed that the drop-out rate in each group will be 15%, implying that n=80, namely 40 cases in the treatment group and the control group, respectively.
Statistical analysis
All data will be entered and counted by professional statisticians using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and SPSS 26.0 (IBM, Armonk, NY, USA). If the data is normally distributed and the variance is uniform, the measurement data will be expressed as mean ± standard deviation (x±s). The paired t-test will be adopted for intra-group comparison before and after treatment, and the independent sample t-test will be adopted for inter-group comparison before and after treatment. If the data does not follow a normal distribution or has an uneven variance, the measurement data will be expressed as median (quartile interval) [M (Q)], and the Wilcoxon rank sum test will be employed for data analysis before and after treatment. The Chi-square test will be adopted to compare the rates between both groups. P<0.05 means that the difference is statistically significant.