This study is designed as a randomized, controlled, blind and multicenter trial. Trained researchers introduce the trial to patients, give them information sheets and consent forms. All patients have to obtain “Ethics approval and consent to participate” section and give their written informed consents prior to enrolment. The study’s flow chart is shown in Figure 1.
The trial protocol is conducted in accordance with the Good Clinical Practice Guidelines and the Declaration of Helsinki (2008). Central ethical approval has been confirmed from the group leader's ethic committee of Affiliated Hospital of Nanjing University of Chinese Medicine (ref approval no. 2019NL-158-02) and four sub-centers ethical will comply with the group leader's ethics approval. Written informed consent will be obtained from each patient.
A total of 240 Chinese patients who fulfill the screening criteria will be recruited at five hospitals in China: 1) Group leader, Affiliated Hospital of Nanjing University of Chinese Medicine, will recruit 64 patients through posters, 2) Sub-center, Changzhou Hospital of Traditional Chinese Medicine, will recruit 60 patients through posters, 3) Sub-center, Suzhou Hospital of Traditional Chinese Medicine, will recruit 60 patients through posters, 4) Sub-center, Xuyi Hospital of Traditional Chinese Medicine, will recruit 28 patients through posters, 5) Sub-center, Wujin Hospital of Traditional Chinese Medicine, will recruit 28 patients through posters.
According to the literature search results, bleeding was used as the primary outcome measure for the treatment of HD by diosmin. It was estimated that Liang-Xue-Di-Huang Decoction treatment is not inferior to that of diosmin treatment. According to the non-inferiority test sample size calculation formula, for a two-sided significance level of 0.05, the standard deviation is 0.4, (α=0.05, β=0.2, δ=0.15), the non-inferiority bound is 0.15 when the degree of grasp (1-β)=80%, the sample size is calculated using the formula: (See Formula 1 in the Supplemental Files)
Considering a 10% loss to follow-up, the sample size is 240 cases (n=120 in each group).
Block randomization was used. Stratification was carried out according to the center. With the help of SAS 9.4 statistical software, the random number table of central coding was generated for a given number of seeds. The subjects were randomly divided into Liang-Xue-Di-Huang Decoction with the addition of Diosmine mimetic agent, or Diosmine with the addition of Liang-Xue-Di-Huang Decoction mimetic agent. An independent person (Zhao-feng Shen), who is not involved in observation or assessment of the patients possesses the computer-generated randomization sequence.
The randomization procedure will be conducted by research assistants using an online computerized randomization system (https://sci.medroad.cn/).
This trial is a double-blind trial, divided into the Liang-Xue-Di-Huang Decoction with the addition of Diosmine mimetic agent, or Diosmine with the addition of Liang-Xue-Di-Huang Decoction mimetic agent. The double levels of blinding are sealed separately. Treatments are blinded to the patients and investigators (including statisticians) until the entire study is completed. Each hospital receives an emergency letter, along with these test drugs, properly preserved until the end of the trial.
Code-breaking should occur only in the case of serious adverse events happen or further intervention of the patient needs to know the actual medication situation, with the permission of the person in charge of the research center, and a report should be submitted to the leader of the trial within 24 hours
1.Comply with hemorrhoids standards diagnosis (stage I, Ⅱ, Ⅲ);
2.Comply with "Traditional Chinese Medicine Disease and Syndrome, Diagnosis and Curative Effect Standard" damp-heat syndrome:bleeding hemorrhoids, bright red blood;
3.Patient signed the informed consent form;
4. Patient agreed to avoid taking study agents outside the trial;
1.Patient had accompanied by severe liver, kidney, heart, brain, or lung dysfunction;
2.Patient had a history of inflammatory bowel disease, or a history of colorectal cancer, or had a history of any cancer;
4.Patient had a perianal abscess, anal fistula, rectal polyp, intestinal tumor or intestinal infectious disease;
5.Patient will plan pregnancy during this study;
6.Patient is pregnant or lactating women at the time;
7.Patient was allergic to test drugs and their ingredients;
8.Patient had unability to understand the nature of the study and follow the doctor’s recommendations.
9. Patient purchase or take other hemorrhoids medicine during this study period.
10. Patient had a history of bleeding disorders other than HD.
Test drugs include Liang-Xue-Di-Huang Decoction, Liang-Xue-Di-Huang Decoction mimetic agent, Diosmine and Diosmine mimetic agent. Liang-Xue-Di-Huang Decoction mimetic agent was consisted of 5％Liang-Xue-Di-Huang Decoction materials, as well as maltodextrin, food coloring, and bitters. Liang-Xue-Di-Huang Decoction and Liang-Xue-Di-Huang Decoction mimetic agent are provided by Tianjiang Pharmaceutical Group Co. Ltd, Wuxi, China. Diosmine mimetic agent was consisted of 5％ Diosmine materials, as well as maltodextrin, and food coloring. Diosmine and Diosmine mimetic agent are provided by NANJING CHIA TAI TIANQING Group Co. Ltd, Nanjing, China. All these mimetic agents have the same shape, size, taste, colour, package and Lot number.
Liang-Xue-Di-Huang Decoction with the addition of Diosmine mimetic agent
Patients will take one Liang-Xue-Di-Huang Decoction per day, 2 times a day, be took 1 hour after lunch and dinner meals. Diosmine mimetic agent, 0.45g each time, 2 times a day, be took 2 hours after lunch and dinner meals. The course of treatment will last 7 days, unless there is a loss of follow-up. Patients will be contacted by telephone in 7 and 14 days, and queried regarding adherence to study agents, illnesses, medication and supplement use. The assessment that needs to be performed at visit are listed in Figure 2.
Diosmine with the addition of Liang-Xue-Di-Huang Decoction mimetic agent
Diosmine with the addition of Liang-Xue-Di-Huang Decoction mimetic agent group's treatments and measurements will be in accordance with Liang-Xue-Di-Huang Decoction with the addition of Diosmine mimetic agent group.
According to the latest treatment guidelines for HD, the primary outcome measure of this study is the French Bleeding Score (Table 2) in 7 and 14 days. The Secondary outcome measure are Goligher Prolapse Score (Table 3) and Quality-of-Life Score (Table 4) in 7 and 14 days[available online at www.jvir.org].
Emergency symptomatic treatment (serious bleeding)
If patients have the following problems during this trial, such as a large amount of ejection bleeding accompanied by a significant decrease in hemoglobin, increased heart rate, and decreased blood pressure, patients will be discontinued and hospitalized.
All adverse events, including toxicity and side effects, such as gastrointestinal reaction, liver damage, and renal failure will be recorded and graded in detail throughout the study. When a severe adverse event occurs, researchers will provide every necessary treatment, and report the adverse event to the ethic committee of Affiliated Hospital of Nanjing University of Chinese Medicine.
A blood routine examination, routine urine test, liver function test, renal function test, electrocardiograph, and urine pregnancy test (women only) will be administered for safety outcomes, which are monitored both before and after clinical intervention.
Information from the clinical examination, as well as evaluation of treatment efficacy, will be recorded in each patient’s case report form (CRF). The study record is the source document of clinical study subject and should be kept in group leader's hospital. Each center will design designated personnel to be the electronic CRF input staff. Upon completion of each subject observation, the investigator will promptly submit the study record to the CRF inputter. The electronic CRF encoder must review whether the project record of the study notes is complete and report on time.
Data monitoring committee
This clinical data monitoring committee was composed by Affiliated Hospital of Nanjing University of Chinese Medicine and Jiangsu Famous Medical Technology Co., Ltd, Nanjing, China.
Patient's privacy protection
Only researchers and arbitrator who will sign the confidentiality commitment in this clinical trial may come into contact with the participants' personal health records. Drug regulatory departments have the right to inspect the records of clinical trials. Data will be processed anonymously, and information identifying individual subjects will be omitted. Patient's medical records will be stored in group leader's data archives
Frequency, median, and mean±standard deviation of the bleeding score, goligher prolapse score and quality-of-life score will be used for descriptive statistics. The statistical analysis will be performed using SAS 9.4. P<0.05 is considered statistically significant.