The Chinese herbal formula Huoxiang Zhengqi for diarrhea-predominant irritable bowel syndrome (CHAIRS): a study protocol for a double-blinded randomized controlled trial

This study is a multi-center, double-blind, randomized placebo-controlled trial. A flowchart of the trial is shown in Fig. 1. This trial will be conducted at 11 first-class hospitals in China in accordance with the principles of good clinical practice and the Declaration of Helsinki. The study protocol was approved by the ethics committees of the participating hospitals. The trial was registered with the Chinese Clinical Trial Registry (ID: ChiCTR1900026837). The protocol reporting follows the Standard Protocol Items for Clinical Trials 2013 (SPIRIT 2013) [16].

All participants will be recruited from the following 11 research centers: Guangdong Provincial Hospital of Chinese Medicine, Chongqing Traditional Chinese Medicine Hospital, Peking University Third Hospital, Beijing Friendship Hospital of Capital Medical University, Shaanxi University of Traditional Chinese Medicine, Shuguang Hospital of Shanghai University of TCM, Chongqing Red Cross Hospital, Shenzhen Second People’s Hospital, Yuncheng Center Hospital, Xiangyang 1st People’s Hospital, and Hebei Provincial Hospital of Traditional Chinese Medicine.

Participants will be recruited through social media and recruiting advertisements in hospitals. After patients are screened for eligibility with the following criteria and sign informed consent, they will be enrolled in the study. During screening, enrolling, and withdrawing from the trial, all personal patient information will be kept strictly confidential within the scope of the law, except for the inspection or monitoring of the source data.

The diagnosis of CM dampness pattern refers to the Standard of Diagnosis and Curative Effect of Chinese Medicine Syndrome and Diseases [17] and the textbook of CM colleges and universities, the Diagnostics of Chinese Medicine [18]. Diagnosis of CM dampness pattern will be made by senior CM professional practitioner according to the characteristics of the disease based on the following criteria.

Patients with two primary symptoms and one secondary symptom are considered to have the CM dampness pattern, as well as patients with one primary symptom plus two disease characteristics.

Patients who meet all of the following conditions will be included.

Patients with one of the following conditions will be excluded.

The sample size was calculated based on the primary outcome of the proportion of responders of adequate relief (AR). Calculations were made with PASS 11.0 (NCSS, LLC, Kaysville, UT, USA). According to the results of similar clinical trials [9, 19], we assume that HXZQ’s AR response rate is 60% and that the placebo’s is 30%. Thus, we estimated that for 80% power to detect a superiority margin of 10% on the RA response rates at a given 2-tailed type I error of 0.05, 106 patients will be needed in each group, after allowing for a 15% dropout rate. A total of 212 patients will be randomly allocated to the two groups at an equal ratio.

A center-stratified block randomization sequence generated by using SAS 9.2 (SAS Institute Inc., Cary, USA) has been completed by the Institute of Basic Research in Clinical Medicine (IBRCM), China Academy of Chinese Medical Science. All eligible participants will be randomly assigned to either the HXZQ group or the placebo group at a ratio of 1:1 through an interactive web response system. Investigators will log into the system to acquire participants’ treatment allocation. The randomization results will be kept confidential and maintained by IBRCM.

All patients and researchers, including investigators, study assistants, outcome assessors, statisticians, and other staff members will know neither patients’ allocation nor their treatment. The placebo should be identical to HXZQ in appearance, taste, weight, labeling, and packaging, but contain no active ingredients. HXZQ oral liquid and the matching placebo will also be examined based on appearance, taste, and weight by the triangulation method.

In the experimental group, participants will receive 20 ml of HXZQ oral liquid twice a day for 4 weeks. Participants in the control group will receive 20 ml of a placebo oral liquid twice a day for 4 weeks. After the treatment, all participants will be followed up for 4 weeks. During the study period, patients will not be allowed to receive other IBS-D treatments.

The HXZQ and placebo oral liquids will be manufactured by Taiji Group Chongqing Fuling Pharmaceutical Co. Ltd. (Chongqing, China) according to the requirements of good manufacturing practice. The placebo will be made from glycyrrhizin, bitterant, caramel color, and trace amounts of cinnamon extract and ginger juice. It will meet the hygienic requirements of the oral liquid product.

Any medications which might treat IBS-D and drugs to relieve abdominal pain and diarrhea will be prohibited. Other prohibited drugs and therapies include any traditional Chinese medicine except for the study drugs, non-pharmaceutical therapy of CM, such as acupuncture, moxibustion, massage, or cupping for IBS-D.

During the trial, if patients develop intolerable abdominal pain or diarrhea, they can take rescue medications as directed by their doctors. The name and dosage of the rescue medication will be recorded in the patient's diary.

Participants will be requested to record the weekly number of HXZQ they consume in the patient diaries. Any unused HXZQ oral liquid must be returned at each visit. The quantity of consumed and returned HXZQ will then be recorded in the CRF to measure compliance. Patients with compliance rates equal to or greater than 80% will be considered as having high compliance.

All patients will be asked about the occurrence of any unfavorable or unintended effects, or any adverse events (AEs). AEs will be recorded on a case report form (CRF) and addressed appropriately. Before and after the treatment (weeks 0 and 4), all participants will undergo electrocardiogram and laboratory testing including a routine blood test, kidney function test, liver function tests, urine and stool tests. Investigators will pay attention to any abnormal changes indicated by the above examination results. All AEs will be assessed and analyzed, and causality between the study drugs will be evaluated according to the WHO Uppsala Monitoring Center System for Standardized Case Causality Assessment [26]. An independent Data Safety and Monitoring Committee (DSMC) will also assess the safety data during the trial. Severe AEs or severe adverse reactions should also be reported to the DSMC, the hospital ethics committee, and the research team, within 24 h. The content and timing of the enrollment, intervention, and evaluation are shown in Table 1.

Prior to the study, relevant personnel involved in data collection and management, including investigators, study assistants, nurses, and other staffs, will receive at least 4 h of training, in order to maintain protocol implementation compliance. The completed CRFs will be reviewed by the monitor, and then transferred to the data manager for data entry. An electronic data management system will be adopted for data entry and management. The system will be equipped with a series of logical consistency checks for data entry, and the data manager will also be able to check the data manually through the system. Investigators will return the feedback for the query to the data manager to ensure that the data can be uploaded to the data management system in a timely, accurate and complete manner. Trial monitoring will be conducted regularly with SOPs by the Beijing Yaohai Ningkang Pharmaceutical Technology Co. Ltd. (Beijing, China). Audits will be executed regularly by IBRCM at the China Academy of Chinese Medical Sciences.

Data analysis will be conducted in accordance with a statistical analysis plan prepared in advance. Statistical analysis will adhere to the intent-to-treat (ITT) and per protocol (PP) principles, and be performed with either SPSS 18.0 (IBM SPSS Inc, Armonk, New York, USA) or SAS 9.2 (SAS Institute Inc., Cary, USA) by independent statisticians at IBRCM. Statistical analyses will be conducted with a two-sided significance level of 0.05.

Patients’ baseline characteristics will be reported with descriptive statistics. Baseline data will be presented using frequencies, percentages, mean, standard deviation (SD), median and interquartile range according to the scales of the measurement and distributions. For primary outcome, AR responder rate, the data analysis will be performed on the ITT set, defined as all patients randomized to study treatment. AR responder rate will be compared between both groups at 4 weeks and 8 weeks after treatment considering superiority comparison between two groups by 95% confidence interval (CI) method. A chi-square test will be used for categorical data, and a t-test will be used for continuous data if the data distribution is appropriate. Missing data caused by withdrawal, loss to follow-up, or dropout will be addressed with multiple imputation methods. Sex, age, course of disease, and center effect will be considered covariates in a logistic regression or general linear model. If necessary, various sensitivity analyses will be conducted to assess the unimputation methods and complete case analyses. A safety analysis set (SS) will be used for safety evaluation and analysis. For safety analysis, the two groups’ incidence of adverse reactions will be compared by using a chi-square test or Fisher’s exact test. The AEs’ severity and the causality between AEs and the study drug should also be considered. If there is a significant amount of adverse reactions, the relationship with medication duration and baseline characteristics should be analyzed.