Study design
This is a prospective, non-randomized, controlled study. One-hundred and thirty two AIH patients visited in Guangdong provincial hospital of Chinese medicine at the first time will be enrolled and divided into two groups with a case: control ratio of approximately 1:1. While patients in the control group received the steroid standard therapy, patients in the case group are treated with combination treatment of SGJP decoction and the steroid therapy. Both of the treatment and follow-up period will be for 24 weeks. The details of the flow chart of this trial are shown in Fig. 1.
Patient population
A total of 132 AIH patients, who fulfill the screening criteria, is being enrolled and followed up between October 2015 and June 2017. According to the patients’ preference, the eligible AIH patients will be divided into two groups: the case group (to receive SGJP Decoction combined with low dose prednisone and azathioprine, n = 66) or a control group (to receive low dose prednisone and azathioprine, n = 66).
Diagnostic criteria
The patients’ western medicine diagnostic criteria are based on AIH guideline which was established by American Association for the Study of Liver Diseases (AASLD) [12]. The TCM diagnosis of AIH patients is based on “Clinic terminology of traditional Chinese medicine medical diagnosis and treatment-Syndromes [13]”.
Inclusion criteria
(1) All the patients had either a first diagnosis of AIH or were experiencing relapse after a previous diagnosis of AIH based on histology findings within 12 months before screening. (2) TCM syndrome type: liver stagnation and spleen deficiency. (3) Patients fulfill indications for treatment: serum aspartate aminotransferase (AST) ≥ 10-fold upper limit of normal (ULN) levels; or Serum AST ≥ 5-fold ULN and gammaglobulins ≥ twice ULN; or Bridging necrosis or multiacinar necrosis on histopathological examination (4) aged from 18 to 65 years.
Exclusion criteria
(1) co-infection with hepatitis virus or human immunodeficiency virus; (2) evidence of advanced liver diseases, such as decompensated cirrhosis, severe hepatitis, or hepatic carcinoma; (3) evidence of serious uncontrollable diseases, such as heart, brain, kidney or gastrointestinal primary disease, etc.; (4) recent treatment with drugs with known liver toxicity; (5) pregnancy or lactation; (6) parenteral administration of blood or blood products within 6 months before screening.
Interventions
While patients in the control group received the steroid standard therapy, patients in the case group are treated with combination treatment of SGJP decoction and the steroid therapy. The primary and secondary outcomes are assessed and analyzed after 24-week treatment.
Steroid standard therapy
The steroid standard therapy, recommended by the AASLD AIH Guidelines [12], was as follows: prednisone (starting dose 30 mg/day, tapered to 10 mg/day) plus Azathioprine (administered at a dose of 50 mg/day). More details are shown in Fig. 1. According to the changes of patients’ conditions, doctors could adjust the specific agents and the doses, but the groups are not allowed to be changed until week 24.
SGJP decoction
The formula comprises 11 herbs, including Radix Bupleuri (Chai Hu) 5 g, radices paeoniae alba (Bai Shao) 10 g, Tuckahoe (Fu Ling) 15 g, Turmeric Root Tuber (Yu Jin) 10 g, etc. The indication of the formula is liver stagnation and spleen deficiency pattern, including symptoms of fatigue, chest tightness, poor appetite, and abdominal distension, depressed, irritable and wiry and slippery pulse.
The procedure of preparing the SGJP decoction is as follows: firstly, all herbs are tipped into an earthenware pot with 1000 mL cold water and soaked for about half an hour. Secondly, give a boil with strong fire and then turn soft fire to simmer about 30 min until decoction reduces to 200 mL. Thirdly, the decoction is poured out and the same herbs with same water are boiled again for another 200 mL decoction over heat. Finally, these two times of decoction is mixed well together. Patients in the case group should take 200 mL of the decoction two times a day.
Outcome measurements
Primary outcome
The primary outcome was complete response to therapy, defined as complete biochemical remission at the patient’s last visit of observation period and the absence of predefined steroid-specific side effects throughout observation period (moon face, central obesity, buffalo hump, diabetes and increased intraocular pressure, etc.). Biochemical remission was defined as complete normalization of aminotransferase levels including IgG.
Secondary outcomes
Secondary outcomes include the proportion of patients whose g-glutamyl transpeptidase (GGT) and total bilirubin (TBIL) levels decrease more than 50% after 4-week treatment as well as the GGT and TBIL normalization rate, the remission rate of patients’ clinical symptoms and the occurrence rate of the immunosuppressive agents’ side effects after 24-week treatment.
Safety outcomes
The results of a routine blood test, routine urine test, routine stool test, renal function test and electrocardiogram are assessed before and after the treatment to ensure the safety of this study. Further more, a urine pregnancy test or serum human chorionic gonadotropin test must be done before enrolling a women patient of childbearing age.
Data monitoring board
Two supervisors who are not members of the end-point committee should be assigned to contact and visit the researchers regularly to supervise the trial progress. Through this monitoring process, it can be ensured that it is conducted, recorded and reported in accordance with the protocol and standard operating procedures. In addition, the researchers should agree to cooperate with the supervisors to ensure that any problems found and resolved.
Ethics, consent and permission
Written informed consents will be obtained from all patients before enrollment. The study is being conducted in accordance with the Declaration of Helsinki (2008) [14] and has been approved by the ethics committees of Guangdong Provincial hospital of Chinese medicine. In addition, the study is registered with the Chinese Clinical Trial Registry (ChiCTR-OOC-15006155).
Sample size and statistical methods
This prospective study is intended to evaluate the efficacy and safety of the combination treatment of SGJP Decoction and steroid standard therapy on AIH. Since there is still no enough reliable data to accurately calculate the sample size for our study, 20 hepatology experts in Chinese medicine or integrative medicine with more than 20 years clinical experience were asked for advice. After two rounds of meetings with these experts, we agreed that 110 patients should be sufficient to gather enough information in order to plan such a clinical trial. And 132 cases are needed if there is a dropout rate of 15%.
The statistical analysis for this study will be performed using SPSS software version 19.0 (SPSS Inc., Chicago, IL, USA). Data will be presented as mean and standard deviation, or frequency and percentages. Comparisons will be conducted between the case group and the control group, also between pre-treatment and post-treatment in each group. For normally distributed variables, means will be compared by using t-tests (two-tailed), and nonparametric variables will be analyzed using Pearson chi-squared tests or Fisher exact tests. All P-values will be two-tailed. A P-value of less than 0.05 will be considered statistically significant.