JianPi HuaZhuo XingNao formula (Chinese herbal medicine) for the treatment of minimal hepatic encephalopathy: a protocol for a randomized, placebo-controlled pilot trial

Abstract Background: Minimal hepatic encephalopathy (MHE) is a subclinical state of hepatic encephalopathy with the possibility of developing into overt hepatic encephalopathy (OHE) and having adverse outcomes. However, no preventative medicine for MHE has been recommended so far. The aim is to evaluate the therapeutic effect of the JianPi HuaZhuo XingNao formula (JPHZXN) on MHE, specifically whether JPHZXN decreases OHE occurrence, through a randomized controlled trial. Method: Seventy-two patients with MHE are enrolled and allocated in a 1:1 ratio in an experimental group and a control group. JPHZXN granules and placebos are dispatched to the experimental group and control group, respectively, for 24 weeks. The primary outcome is the incidence of developing OHE. The secondary outcomes are the patients’ performances in number connection test A and the digital sign test as well as results from the health survey and chronic liver disease questionnaire. Results: This study will provide proof regarding the therapeutic effect of JPHZXN among patients with MHE. Conclusion: The outcomes could grant clinicians an alternative choice when treating potentially progressive patients with MHE.


Background
Minimal hepatic encephalopathy (MHE) is a unique disease stage of covert hepatic encephalopathy (CHE), and it is one of the complications caused by liver dysfunction. [1] As it is in a subclinical state, it is difficult to identify, and it has no apparent psychologic or neurologic clinical manifestation. However, symptoms can be detected through sophisticated neuropsychologic and neurophysiologic tests. [2] MHE debases patients' quality of life by, for example, restricting their abilities to drive and work, and it is highly possible that MHE will further develop into overt hepatic encephalopathy (OHE). [3] Therefore, MHE poses a significant potential hazard to individuals and society. [4] Thus, it is significant to diagnose MHE and CHE and to prevent MHE from progressing to OHE. According to epidemiologic surveys, MHE or CHE occurs in 20% to 80% of patients with cirrhosiss. [5][6][7][8] Therapies including lactulose, lactitol, probiotics, and rifaximin have been applied in the treatment and research of MHE, and they have shown the effect of preventing OHE from the first attack. [9,10] However, none of these therapies is adequate for recommendation as a routine or preventive treatment. According to the 2014 Practice Guideline by the American Association for the Study of Liver Diseases, routine or preventive medicine is not recommended for MHE. [11] The medical community lacks a clear consensus regarding how to treat the disease. The study is funded by the '111' Collaborative Innovation Project, Dongzhimen Hospital affiliated to BUCM (2016-DZM111-JC016). This funding source and drug provider did not participate in the design of this study and will not have any role in its analyses or decision to submit results.
Liver cirrhosis is the most critical cause of hepatic decompensation, and chronic hepatitis B (CHB) is a principal cause of cirrhosis in China, which is a mid-high endemic region. [12] The cure for hepatic encephalopathy, as an essential complication of cirrhosis, shall be systematic and multidimensional. The treatment for CHB is as necessary as the treatment for MHE itself. The JianPi HuaZhuo XingNao (JPHZXN) formula adopted in this research was refined from therapeutic drugs for CHB used in former studies (the Shuanghu qinggan granule and Yigan yiqi jieyu granule), [13] having a defined effect for both the treatment of CHB and hepatic encephalopathy. In the situation with the lack of agreement regarding the treatment of MHE, the use of the JPHZXN formula with high-risk patients suffering from MHE that originated from CHB-induced cirrhosis can restrict primary diseases and reduce the possibility of OHE attacks. Moreover, the therapy avoids overtreatment by combining CHB and MHE therapies into a single formula of traditional Chinese medicine.

Trial design
We designed this trial as a double-blinded, randomized, and controlled exploratory trial. We will implement simple randomization with a 1:1 allocation ratio in 72 eligible patients. The primary endpoint is the occurrence of OHE within 24 weeks.

Study setting
Seventy-two patients from the clinic and inpatient department of the Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, are recruited for this pilot study.

Criteria
All patients should provide a signed informed consent form before enrollment.

Inclusion criteria.
Participants should meet all the following criteria: 1. Be diagnosed with CHB, referring to the guideline of prevention and treatment for CHB (2015 version) [

Research personnel
Experienced physicians (attending physicians, with a minimum 5 years of clinical experience in the department of hepatology or gastroenterology) will be responsible for supervising the recruitments and performing host interviews and physical examinations. Postgraduate students who majored in hepatology will be trained by the principal investigator before participating in the study. They will dispatch drugs, fill in case report forms, and input electronic case report forms.
2.4. Interventions 2.4.1. Trial drugs. Both groups will be treated with trial drugs for 24 weeks. The experimental group will receive 1 dose per day of the JPHZXN formula, whereas the control group will be given the JPHZXN formula placebo. The real drugs and placebos are consistent in shape, color, and taste.
The patients will be allowed to continue their basic treatment for hepatocirrhosis and CHB. In addition to receiving the trial drugs for MHE (Detailed in 2.4.4 Relevant interventions).
The major ingredients of the JPHZXN formula are listed in Table 1.

Outcomes
The primary therapeutic outcome is the incidence measure of OHE within 24 weeks. An OHE attack is defined an adverse outcome. The secondary outcomes are the results of the NCT-A, DST, SF-36, and CLDQ. The NCT-A and DST will be applied to measure patients' neuropsychology performances, and an extended completion time will indicate cognition impairments. [15,16] The SF-36 [17] and CLDQ [18] are regular measurements of life quality among patients with hepatocirrhosis, and reduced scores for these tests designate impaired life quality.

Participant time line
The enrollment will begin in September and finish by approximately December 2018. The clinical observation will be completed by June 2019. The scheduled timeframe is displayed in Figure 1.

Sample size
Currently, the scientific community has inadequate information about the incidences of OHE that developed from MHE within a specified duration. In this pilot study, we set the sample size to 36 for each group, with 72 participants in total.

Recruitment
Internal physicians will screen eligible patients from the clinic and inpatient department. The principal investigator will introduce the protocol as well as the benefits and risks of the study to the participants. An informed consent form is mandatory for enrollment.

Allocation concealment
The ethics committee will generate a random number table (containing the patients' IDs) using Microsoft Excel to settle the grouping plan; each group will be assigned 36 IDs, which will be in a disorganized sequence. Each eligible patient will be given a sealed envelope with an ID after enrollment.

Blinding
The interviewers and patients will both be blinded to the grouping information of each participant. The trial drugs and placebos are consistent in color and taste. The ethics committee and data management committee will keep the allocation sequence and grouping information, which they will not release until final analysis or emergency unblinding.

Interviews
Patients will be interviewed every 4 weeks after enrollment in the clinic, where they should return the used packages and remaining Only a single type of these antiviral drugs is allowed at the same time. drugs. Adequate trial drugs for 28 days will be dispatched during each interview. A series of tests will be conducted in different weeks (Fig. 1).

Data management
Information obtained from each visit and the laboratory results will be recorded on printed case report forms. Electronic data will be manually inputted into double entries in electronic case report forms generated by EPIDATA software. Case report forms and data sets will be stored in the local archive center at Dongzhimen Hospital.

Statistical methods
We will carry out efficacy analyses with the full analysis set, which will include those who provided baseline data and at least one post-treatment assessment. Safety analyses will assess all of the randomly assigned patients. We will apply a chi-square test to compare the occurrence of OHE attacks among groups.
We will assess the secondary outcomes with the Shapiro-Wilk test. We will assess the normally distributed data with t tests. We will assess data that were not normally distributed with nonparametric Wilcoxon rank-sum testing.

Data monitoring
The Centre for Evidence-Based Chinese Medicine at the Beijing University of Chinese Medicine will commit to the data monitoring-including recruitment supervision, allocation administration, integrity checks of the case report forms, and the overseeing of the unblinding. Interim analysis is not applicable for this pilot study.

Safety monitoring
At each visit, physicians will document any adverse events. When severe adverse events occur or the patient suffers from progressive OHE and needs intensive medical care, the event will be reported to the ethics committee and data management committee to determine whether an emergency unblinding is necessary for the patient. The data management committee is also authorized to perform the unblinding, access the final data set, and evaluate the outcomes.

Ethics approval
The ethics committee of Dongzhimen Hospital, affiliated to Beijing University of Chinese Medicine, approved this protocol on August 8, 2017 (DZMEC-KY-2017-23).

Protocol amendments
The principal investigator is responsible for presenting protocol modifications to the ethics committee and data management committee before the modifications are implemented. The ethics committee and data management committee should agree upon significant changes to the protocol-including changes to the objectives, sample size, interventions, and study procedures-before their implementation. We will formally document minor changessuch as corrections of typos and clarifications-in the memorandum.

Confidentiality
We will write the names of all the participants in abbreviated Pinyin on the case report forms. The participants' identities, personal information, and medical records obtained from the study are confidential and can only be accessed by the data management committee and ethics committee when necessary. Examined laboratory specimens will be destroyed following clinical regulations (30 days after collection). Informed consent forms, which contain the patients' signatures, will be stored separately in the archive center.

Policies of data sharing and distributions
During the trial, only the data management committee will be authorized to access the full data set (including the grouping information). The principal investigator is allowed to view all intrastudy medical records but not the allocation data. The ethics committee can acquire the patients' information only if a severe adverse event occurs and premature unblinding is necessary.
The patients' ID numbers and medical records will be available from the study leader upon reasonable request after the study is complete. Each patient will obtain a copy of his/her case report form after the unblinding.

Discussion
Research on the treatment of MHE through traditional Chinese medicine is insufficient. With the features of treatment being based on symptom differentiation, traditional Chinese medicine therapy can act as an early intervention in diseases with insidious manifestations (or subclinical diseases) such as MHE, but the evidence does not sufficiently address the lack of consistent diagnostic criteria and has the confirmation of a randomized placebo-controlled trial. We believe this pilot trial might provide a promising approach to treating CHB-induced MHE in antiviral aspects and preventing OHE.
Agree on the final protocol Approve significant amendments to the protocol Determine the allocation plans by generating the random number table Agree on suspending the study and prematurely unblinding Data management committee Design case report form and electronic case report form Supervise the recruitment Administer the allocation Oversee the unblinding Data management will be executed by the Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine. Data curation: Ying Li.