Chinese Classical Prescription(Liang-Xue-Di-Huang Decoction)for Hemorrhoidal Disease: study protocol for a randomized controlled trial

Abstract Background: Hemorrhoidal disease (HD) is one of the commonest proctologic condition in the general population. Medical therapy for HD has not been formally conrmed due to the inconsistent of results. Liang-Xue-Di-Huang Decoction, a kind of ancient Chinese classical prescription, has been used to treat HD from the 19th century in China. However, clinical research of Liang-Xue-Di-Huang Decoction in the treatment of HD is lack. We designed this study to evaluate the ecacy and safety of Liang-Xue-Di-Huang Decoction in the treatment of HD. Methods/Design: A randomized, controlled, double blind, double-mimetic agent and multicenter trial to evaluate the ecacy and safety of Liang-Xue-Di-Huang Decoction is proposed. HD patients (stage I, (cid:0), (cid:0)) will be randomly assigned into Liang-Xue-Di-Huang Decoction with the addition of Diosmine mimetic agent group and Diosmine with the addition of Liang-Xue-Di-Huang Decoction mimetic agent group. Patients will receive a 7-day treatments and a 7-day follow-up. The primary outcome measure is the French Bleeding Score in 7 and 14 days. The Secondary outcome measures are Goligher Prolapse Score and Quality-of-Life Score in 7 and 14 days. Discussion: This study will provide objective evidence to evaluate the ecacy and safety of Liang-Xue-Di-Huang Decoction in treatment of HD. Trial registration: Chinese Clinical Trial Registry. ChiCTR-1900022531.Registered


Background
Hemorrhoidal disease (HD), one of the oldest and commonest proctologic condition in the general population, is more frequent in industrialized countries [1] . The true prevalence of HD in the general population is unknown and probably differents from country to country [2] . In the United States, HD is the third most common outpatient gastrointestinal diagnosis, affecting between 20 to 50% of the population and resulting in 4 million emergency visits annually [3] .
HD exists in two forms-an external and an internal disease. External hemorrhoids are laid below the dentate line. Internal hemorrhoids are located above the dentate line, which are characterized by dilatation and engorgement of the hemorrhoidal plexuses and vascular hyperplasia. Chronic bleeding is the main symptom of internal hemorrhoids [4] .
Treatments for HD include medical therapies and surgery [5] . Medical therapies for HD have not been formally studied where the results have been inconsistent [3] . Increased ber and fluid intake has been shown to improve symptoms of mild-to-moderate bleeding, whereas symptoms such as prolapse and pain show a tendency toward no effect [6] . The ber is not recommended as primary treatment of moderate-to-severe prolapse [7] . Another common medical prescription in patients with bleeding hemorrhoids is micronized puri ed avonoid fraction. These drugs include diosmin, hesperidin, and cumarin. Each of these treatments has advantages and drawbacks, which are mild gastrointestinal disturbances [2] . There is still no evidence from well-designed studies to support the use of any of the overthe-counter preparations [8] .
Liang-Xue-Di-Huang Decoction, a kind of Chinese herbal medicine, listed in Table 1, which has been approved by the National Administration of Traditional Chinese Medicine of People's Republic of China in 2018 [9] , has been used for HD from the 19th century in China with good effects and few adverse events. However, it was still necessary to prove the e cacy and safety of this ancient Chinese classical prescription. The aim of the present study is to evaluate Liang-Xue-Di-Huang Decoction in the treatment of HD using a randomized, controlled, blind and multicenter trial among o cially registered Chinese colorectal consultants, fellows and residents in China.

Design
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 ow chart is shown in Figure 1.

Ethics
The trial protocol is conducted in accordance with the Good Clinical Practice Guidelines and the Declaration of Helsinki (2008) [10] . Central ethical approval has been con rmed from the group leader's ethic committee of A liated 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.

Recruitment
A total of 240 Chinese patients who ful ll the screening criteria will be recruited at ve hospitals in China: 1) Group leader, A liated Hospital of Nanjing University of Chinese Medicine, will recruit 64 patients through posters, 2) Sub-center, Changzhou a liated Hospital of Nanjing University of Chinese Medicine, will recruit 60 patients through posters, 3) Sub-center, Suzhou a liated Hospital of Nanjing University of Chinese Medicine, will recruit 60 patients through posters, 4) Sub-center, Xuyi a liated Hospital of Nanjing University of Chinese Medicine, will recruit 28 patients through posters, 5) Sub-center, Wujin a liated Hospital of Nanjing University of Chinese Medicine, will recruit 28 patients through posters.

Sample size
According to the literature search, bleeding hemorrhoids was used as the scoring criteria for the treatment of HD. It is expected that the use of Liang-Xue-Di-Huang Decoction treatment is not inferior to diosmine treatment. For a two-sided signi cance level of 0.05 and power of 80% (α=0.05, β=0.2, δ=0.15), the sample size is calculated using the formula: Considering a 10% loss to follow-up, the sample size is 240 cases (n=120 in each group).

Randomization
Block randomization was used. Strati cation 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 group, and Diosmine with the addition of Liang-Xue-Di-Huang Decoction mimetic agent group. 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/).

Blinding
This trial is a double-blind trial, divided into the Liang-Xue-Di-Huang Decoction with the addition of Diosmine mimetic agent group,and Diosmine with the addition of Liang-Xue-Di-Huang Decoction mimetic agent group. The double levels of blinding are sealed separately, and given to the leader and the sponsor of the clinical research. Each hospital receives an emergency letter, along with these test drugs, properly preserved until the end of the trial. Treatments are blinded to the patients and investigators (including statisticians) until the entire study is completed.
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.

Eligibility criteria
Inclusion criteria: 1.Comply with hemorrhoids standards diagnosis (stage I, , ) [2] ; 2.Comply with "Traditional Chinese Medicine Disease and Syndrome, Diagnosis and Curative Effect Standard" damp-heat syndrome: bleeding hemorrhoids, bright red blood [11] ; 3.Patient signed the informed consent form; 4.Patient agreed to avoid taking study agents outside the trial; Exclusion criteria: 1.Patient had accompanied by severe liver, kidney, heart, brain, or lung dysfunction; 2.Patient had a history of in ammatory bowel disease, or a history of colorectal cancer, or had a history of any cancer; 4.Patient had a perianal abscess, anal stula, 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.

Test drugs
Test drugs are Liang-Xue-Di-Huang Decoction, Liang-Xue-Di-Huang Decoction mimetic agent, Diosmine and Diosmine mimetic agent. Liang-Xue-Di-Huang Decoction and Liang-Xue-Di-Huang Decoction mimetic agent are provided by Tianjiang Pharmaceutical Group Co. Ltd, Wuxi, China. Diosmine and Diosmine mimetic agent are provided by NANJING CHIA TAI TIANQING Group Co. Ltd, Nanjing, China. The mimetic agent has the same shape, size, taste, colour, package and Lot number.

Interventions
Liang-Xue-Di-Huang Decoction with the addition of Diosmine mimetic agent group 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 group 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.

Outcome measures
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 (

Safety evaluation
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.

Data management
Information from the clinical examination, as well as evaluation of treatment e cacy, 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 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.

Adverse events
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 A liated Hospital of Nanjing University of Chinese Medicine.

Statistical analysis
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 signi cant.

Discussion
HD is a well-de ned clinical and pathophysiological placement between benign conditions but with high impact on quality of life [12] . Chronic bleeding is the main symptom of HD [4] . It is estimated that 50% of people over 50 years of age have experienced symptoms of HD at least once in their life, and one-third of patients affected by HD seek medical attention [13,14] . Excessive bleeding can lead to an emergency situation. Hemorrhoidectomy and stapled hemorrhoidopexy are validated and effective surgical techniques, but are associated with long, painful postoperative courses with a signi cant complication rate, still required medical therapy [15] . Contrary to common belief, a nonsurgical treatment is quite effective to manage HD [16] , which can be offered with expectations of minimal harm and a decent potential for relief [6] , suggesting that medical therapy should be the rst-line therapy for this disease [17] .
Liang-Xue-Di-Huang Decoction has been used to treat HD from the 19th century in China. Over this period, rich experience in this medication has been accumulated. In 2018, National Administration of Traditional Chinese Medicine of People's Republic of China published 100 classic prescriptions of ancient Chinese medicine, which contained Liang-Xue-Di-Huang Decoction [9] . In this prescription, Sphora japonica L. (Huaijiao) and Platycladus orientalis(L.)Franco (Cebaiye) are the Jun (emperor) components in Liang-Xue-Di-Huang Decoction. Sphora japonica L. (Huaijiao) ,which was rst recorded in Sheng Nong's herbal classic, is commonly applied in clinical practice for the treatment of hematochezia. It has the effect of cooling blood, stopping bleeding, clearing heat in bowels and eliminating swell and easing pain [18] . Modern pharmacological studies have demonstrated its e cacy for stopping bleeding and antiin ammation [19] . Platycladus orientalis(L.)Franco (Cebaiye) is categorized as a blood-cooling and hematostatic herb, which is usually prescribed with heat-clearing herbs to reinforce the e cacy of hemostasis. The pharmacological study of this herb validated its anti-in ammatory, antioxidant, antimicrobial activities, and considered as not toxic [20] . Although TCM has been clinically practised for thousands of years, most Chinese herbal medicine products do not possess up-to-date data regarding their safety and modern scienti c evidence for their claimed clinical uses. TCM safety research is becoming more standardized and is gradually aligning with international standards. A randomized, controlled, blind, and multicenter trial will be helpful for further prove the e cacy and safety of Liang-Xue-Di-Huang Decoction as an treatment for HD.

Declarations
Ethical approval Central ethical approval has been con rmed from the group leader's ethic committee of A liated 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. All patients have to obtain "Ethics approval and consent to participate" section and give their written informed consents prior to enrolment.

Trial status
The protocol version number is NO.2 and the date is January 10, 2019. At the time of manuscript submission, patient's recruitment for the trial is on-going. The clinical study will begin from Sept, 2019 and end in Dec, 2020. A total of 240 Chinese patients will be recruited in this clinical study.

Funding
This study is supported by the Key Laboratory of Famous Doctors' Proved Recipe Evaluation and Transformation Under State Administration of Traditional Chinese Medicine (NZYJDMF-2018002). This funding source provided test drugs, but it had no role in the design of this study and did not have any responsibility for analyses, interpretation of the data or the decision to submit results. Tables   Table 1 Standard Figure 1 Study ow chart. The ow chart of enrolment, allocation, intervention and assessment. Study schedule for patients. After the enrolment and allocation, participants will receive a 7-day treatment and a 7-day follow-up. The time-points of assessment are shown in the schedule.