Hepatitis B virus (HBV) infection is a major health problem in China. It is one of the important reasons for virus-related liver diseases, such as chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC) [
Fuzheng-Huayu tablet (FZHY), a Chinese herbal medicine formula, affected liver fibrosis in clinical trials [
The clinical efficacy evaluation in traditional Chinese medicine (TCM) is based on TCM syndrome, which also known as ZHENG or TCM pattern, is a characteristic profile in clinical symptoms and signs [
In this study, a multicenter, double-blind, randomized, placebo-controlled trail was carried out. The aim was to evaluate and predict FZHY efficacy on HBC with or without TCM syndrome differentiation through the outcome assessment of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid(HA), Child-Pugh score and TCM syndrome score, and the prediction of FZHY efficacy using Bayes forecasting method.
The study was designed to a multi-center, double-blind, equal-randomized, placebo-controlled trial and was carried out to evaluate the efficacy of FZHY, reported in accordance to the 2010 CORSORT statements. With intervention allocation ratio 1 : 1, participants randomized to the intervention group would be given FZHY, while the others randomized to the control group would be given placebo.
The study was conducted according to the guidelines of the Declaration of Helsinki and the principles of Good Clinical Practice (China), and obtained the approval of medical ethics committee in Shanghai Shuguang Hospital. The full trial protocol was drawn up and taken care by Center for Drug ClincalReserch of Shanghai University of TCM.
Because of first exploration for FZHY treatment on HBC, there were not any basic parameters provided as references, and we tried to carry out the study with 200 participants and the same participant number in FZHY group and placebo group. In the process of enrollment, 20 participants were excluded considering not meeting inclusion criteria, participating in another study, and some other reasons.
According to layering subsection random method using DAS statistical software by Center for Drug ClincalReserch of Shanghai University of TCM, random number table was generated on the basis of random proportion. And the table was safely kept by the executive and persons in charge. Placebo treatment group was designed as control group in the study, and placebos were matched to study drugs for taste, color, and size. Drugs and placebos were numbered according to random number table, which was unknown to both doctors and patients. Based on the sequence of participants and the number of drugs and placebos, the interventions were administered.
The study would include adults if they met the following criteria: clinical diagnosis of post-hepatitis B cirrhosis; male or female patients between 18~65 years old; written informed consent.
The participants would be excluded if they met one of the following criteria: Child-Pugh C above 12, or ALT > 2 * ULN, TBiL > 2 * ULN, or combined with hepatic encephalopathy, Obstinate ascites, bleeding tendency, hepatorenal syndrome, or primary liver cancer; combine with severe heart, gallbladder, kidney, endocrine system, hemopoietic system, or nervous system disease; deformed man by the law; pregnancy or breast feeding women, or unwilling to have contraception; irritability body constitution, or irritability of the FZHY; enter other trials lately one month; other cause of cirrhosis.
The assessor (gastroenterologists) was conducted at 4 centers including Shuguang, Longhua, Yueyang, and Putuo hospitals in Shanghai in China (Table
Allocation information of patients with CHB-caused cirrhosis.
Allocation information | Patients (%) |
---|---|
Research centers | |
Shuguang hospital | 54 (30) |
Longhua hospital | 56 (31.11) |
Yueyang hospital | 30 (16.67) |
Putuo hospital | 40 (22.22) |
Treatment groups | |
FZHY | 90 (50%) |
Placebo | 90 (50%) |
FZHY (SFDA approval no: Z20050546) and placebo (2% FZHY) were prepared and provided by Shanghai Sundise Medicine Technology Development Co., Ltd. (Shanghai, China). There were the same appearance and smell and 0.4 g per tablet in both FZHY and placebo. The quality control and preparing standardization of FZHY was established and enforced according to previous report [
180 HBC patients were randomly divided to receive FZHY treatment group (FZHY group, 90 cases) and placebo treatment group (placebo group, 90 cases). The patients were given FZHY or placebo, every day 3 times oral, every time 1.6 g, and a total of taking 6 months.
The study was designed to evaluate the therapeutic efficacy of FZHY and placebo treatment for 6 months on HBC. FZHY efficacy was evaluated as the outcome assessment of ALT, AST, HA, Child-Pugh score, and TCM syndrome sore, and predicted by an established forecasting model based on the Bayes classification method. The Bayes classification method was added after trial commencement.
The levels of ALT and AST were detected by velocity method, the levels of TBil were detected by endpoint method, and the level of albumin (Alb) was detected by one point method. The detection of PT was carried out by coagulation method. The agents were from STAGO Company (Parsippany, NJ, USA). HA was detected using Hyaluronic Acid Test Kit from Corgenix, Inc. (Westminster, CO, USA).
The comparison between treatment groups was evaluated by Student’s
Before and after of FZHY and placebo treated for 6 months, the TCM symptoms, the levels of ALT, AST, HA, Child-Pugh score, and TCM syndrome sore were evaluated. The Child-Pugh scores of HBC patients were recorded and calculated by rating the following five parameters including serum levels of TBil, A1b, PT, ascites, and encephalopathy, and divided into classes A (5-6 points), B (7–9 points), and C (10–15 points) [
Based on the Naïve Bayes classification [
In the classification prediction, firstly based on a lot of reliable history material put forward a training samples, and calculates
In order to make readers understand our design better, a flow diagram (Figure
Flow diagram of a multicenter, randomized, controlled, double-blind trial for evaluating therapeutic efficacy of FZHY. The diagram includes information on the excluded participants.
Age-eligible HBC patients were recruited from September 2007. Participants enrolled attended clinic visits at the time of randomisation (baseline), one-month interval, three-month interval, and six-month interval. And the study was completed on June 2009.
All of 180 patients were Chinese yellow race. As shown in Table
Clinical data of patients with CHB-caused cirrhosis.
Patients (%) | |
---|---|
Mean age (yr) | 50.91 ± 8.36 |
Male (%) | 124 (68.89) |
Female (%) | 56 (31.11) |
Child-Pugh classification | |
A | 149 (82.78) |
B | 28 (15.56) |
C | 3 (1.67) |
To evaluate the therapeutic efficacy of FZHY and placebo treatment for 6 months on HBC, the parameters of liver function such as ALT and AST, liver fibrosis such as HA, and Child-Pugh score were analyzed. Because of the lack of some parameters, 75 cases in FZHY group and 72 cases in placebo group were analyzed. As shown in Table
Efficacy of FZHY on ALT, AST, HA, and Child-Pugh score in HBC.
Index | Treatment | FZHY group | Placebo group |
|
---|---|---|---|---|
(mean ± SD) | (mean ± SD) | |||
( |
( |
|||
ALT (U/L) | Before |
|
|
0.5996 |
After |
|
|
0.9602 | |
|
0.1088 | 0.2229 | ||
| ||||
AST (U/L) | Before |
|
|
0.8700 |
After |
|
|
0.5421 | |
|
0.2757 | 0.0614 | ||
| ||||
HA (ng/mL) | Before |
|
|
0.3969 |
After |
|
|
0.1613 | |
|
|
0.3980 | ||
| ||||
Child-Pugh (score) | Before |
|
|
0.0468 |
After |
|
|
0.5354 | |
|
0.9746 | 0.1939 |
The formation of liver fibrosis is one of the characteristics of LC. HA is a parameter of liver fibrosis and an independent predictor of LC [
Furthermore, in 75 cases of FZHY group, there were Child-Pugh score class A, 68 cases; B, 7 cases; C, 0 cases. After FZHY treatment for 6 months, Child-Pugh score class A, 71 cases; B, 4 cases; C, 0 cases. Child-Pugh scores classes were decreased to 22 cases, not changed 43 cases, and increased 10 cases. In 72 cases of placebo group, there were Child-Pugh score class A, 57 cases; B, 13 cases; C, 2 cases. After FZHY treatment for 6 months, Child-Pugh score class A, 53 cases; B, 18 cases; C, 1 cases. Child-Pugh score classes were decreased to 19 cases, not changed 33 cases, and increased 20 cases.
Child-Pugh classification is the common liver reserve function classification standard of cirrhosis, guides treatment, prognosis, and drug efficacy evaluation, and has very important reference value [
Because of the first exploration of FZHY treatment for HBC, the limitation of the trial design without sample size calculation could not be neglected. This study was carried out as a reference for further related studies. The evaluation of FZHY efficacy including Child-Pugh classification evaluation needs much evidence through further clinical trial, with more reasonable sample size and a long-term treatment (more than 12 months).
In HBC as a chronic disease, the symptoms of patients are also an important index of efficacy evaluation in TCM. TCM syndrome sore, a semiquantitative evaluation method for symptoms and signs, has been used in the efficacy evaluation in TCM clinical practice [
Efficacy of FZHY on TCM syndrome score in HBC.
TCM Syndrome | Treatment | FZHY group | Placebo group |
|
---|---|---|---|---|
(mean ± SD) | (mean ± SD) | |||
LSS ( |
Before |
|
|
0.5135 |
After |
|
|
|
|
|
|
0.2000 | ||
| ||||
SDDOS ( |
Before |
|
|
0.7237 |
After |
|
|
0.9071 | |
|
|
0.2351 | ||
| ||||
DHAS ( |
Before |
|
|
0.9863 |
After |
|
|
0.9688 | |
|
|
0.0515 | ||
| ||||
LKYDS ( |
Before |
|
|
0.2997 |
After |
|
|
|
|
|
|
0.0524 | ||
| ||||
BSS ( |
Before |
|
|
0.1338 |
After |
|
|
0.3240 | |
|
0.0871 | 0.0105 | ||
| ||||
SKYDS ( |
Before |
|
|
0.5989 |
After |
|
|
0.8868 | |
|
0.0783 | 0.2462 |
What is more, in the TCM syndrome score evaluation, there were 53 effective and 22 invalid patients in FZHY group, but 26 effective and 47 invalid patients in placebo group; there was significant difference between FZHY and placebo groups (
As a clinical manifestation, the symptoms reflecting feels and mental state of patients usually were rejected in the efficacy evaluation of current drugs. However, because of embodying the holistic situation of patients, the classification and the characteristic finding from symptoms and signs of patients is the basis of diagnosis of diseases and efficacy evaluation or prediction in TCM clinical practice. So we further demonstrated the possibility of efficacy prediction by symptoms and signs of patients compared with Child-Pugh score evaluation.
For the Bayes prediction analysis of FZHY efficacy, it took training set 147 cases (FZHY group, 75 cases and placebo group, 72 cases) and test set 20 cases (FZHY and placebo group, each 10 cases). While Child-Pugh score in the grading difference between before and after treatments was as the classification events, the probabilities of FZHY and placebo efficacies were able to indicate as the changed situation of Child-Pugh score classification. As shown in Table
Prediction probability of Child-Pugh score, TCM symptoms, and clinical parameters in FZHY and placebo groups.
Treatment groups |
Child-Pugh |
Prediction probability (%) | ||
---|---|---|---|---|
Child-Pugh score | TCM symptom score | Clinical parameters | ||
FZHY group ( |
Decreased | 30 | 20 | 60 |
Not changed | 60 | 80 | 38 | |
Increased | 10 | 0 | 3 | |
| ||||
Placebo group ( |
Decreased | 10 | 10 | 12 |
Not changed | 60 | 70 | 15 | |
Increased | 30 | 20 | 73 |
Moreover, the efficacy prediction from 84 of TCM symptoms showed that the posteriori probability of Child-Pugh score decreased 99.99% in FZHY group and increased 98.69% in placebo groups, indicated the possibility of FZHY treated HBC. These predicted results were similar with the statistical results of Child-Pugh score.
Bayesian classification model is a kind of classification model in statistical method. Bayes’ theorem is one of the most important formulas in Bayesian theory, and it is the theoretical basis of Bayesian learning method. The Bayesian classification model subtly links up the prior probability and posterior probability of events, using prior information and sample data information to determine events of the posterior probability [
However, Bayes methods were confined to analyze the probability of clinical efficacy evaluation events, and have known the prior probability, and then calculate its posterior probability. It limits the application of Bayes methods in the clinical efficacy evaluation.
The study was a multicenter, double-blind, randomized, and controlled trial research, which the therapeutic efficacy of FZHY on HBC for 6 months was evaluated as a clinical outcome assessment. FZHY therapy improved HA and TCM syndrome score in HBC. Among, FZHY therapy has better efficacy on HA in LSS, and on TCM syndrome score in LSS, SDDOS, DHAS, and LKYDS than other TCM syndromes. There were not any adverse reactions in patients. Moreover, the therapeutic efficacy of FZHY based on Child-Pugh score can be predicted by TCM symptoms using Bayes forecasting method. The results suggested there is a possibility of FZHY efficacy on HBC, and FZHY treatment-based TCM syndrome differentiation is useful to improve the life quality of HBC patients.
The authors declare that they have no financial and personal relationships with other people or organizations that can inappropriately influence their work. And there is no potential conflict of interests including employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications and registrations, and grants or other funding.
This work was supported by National S and T Major Project of China (no. 2009ZX09311-003 and no. 2012ZX10005001-004), Leading Academic Discipline Project of Shanghai Municipal Education Commission (no. J50301), and E-institutes of Shanghai Municipal Education Commission (E 03008). The clinical trial registration number was NCT00543426 which could be found on