Fatty liver disease is a hepatic manifestation, mainly featured with hepatocytic steatosis, without excess alcohol intake history; the condition is called nonalcoholic fatty liver disease (NAFLD) [
The mechanisms under fatty liver are still elusive; insulin resistance, which is the most widely accepted pathogenesis, is proposed to be associated with hepatic steatosis [
Jiang Zhi Granule (JZG) is a clinically-used herbal formula designed for treating patients with fatty liver disease applyed in Longhua Hospital for more than a decade. It processes favorable treatment effects which have been testified by substantial laboratory researches [
The primary aim of this study was to compare the efficacy and safety of JZG in patients of NAFL with those of placebo. It is the first multicenter, double-blind, randomized controlled study of JZG for NAFL. The trial was approved by State Food and Drug Administration (SFDA) with certification (no. 2008L11181) and the Ethics Committee of Shanghai University of Traditional Chinese Medicine (no. [2010]-353).
The study was carried out on 245 patients with NAFL, randomized in 6 hospitals. Patients were considered for the trial if they had an identified diagnosis of NAFL and performed for 24 weeks of recruitment. The diagnosis criterion was based on the guidelines for the diagnosis and treatment of nonalcoholic fatty liver [
Patients were meant to be excluded in the following circumstances. (1) Positive testing for hepatotropic viruses, hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E, and drug-induced liver disease or autoimmunity liver disease also included; (2) with a history of daily alcohol consumption ≥20 g for a period longer than 2 years at any time in the past 10 years; (3) combined with severe primary disease in heart, brain, kidney, endocrine, blood, metabolism, and gastrointestinal tract or suffered from mental disease; presence of other major diseases including type 1 diabetes; (4) serum creatinine (Cr) value exceeding upper limit; (5) currently taking medicine to lose weight or keep fit; (6) planned to be pregnant and in lactation or in contraception with other medicine; (7) patients with allergies, multidrug sensitivity, and hypersensitivity of test drug or its compositions; (8) seriously ill and could not give exact evaluation of efficacy and safety of the test drug; (9) unwilling to cooperate; (10) presumed to have taken other drugs forbidden in the trial.
The study was designed as a multicenter, randomized, paralleled, double-blinded, placebo-controlled clinical trial. Protocol and patient consent forms were designed by the coordinating center and reviewed by all participating centers. The protocol conformed to ethical guidelines of the 2000 Declaration of Helsinki and Chinese Good Clinical Practice (CGCP), based on the Consolidated Standards of Reporting Trials (CONSORT) statement [
According to the demands of SFDA, while considering 20% for drop-off and allocated proportion of the 2 groups (1 : 1), we determined 120 patients for each group and 40 for every participating center. The randomization was stratified and allocation sequences were based on random digits table generated by SAS 8.1 software. Patients and investigators were double-blinded to treatment throughout the duration of the trial. All data were imputed, then blocked, and managed by the statistical department, and no revision would be allowed to be performed on the data.
As reported previously, JZG is composed of Jiaogulan (
Liver biopsy is the gold standard for diagnosing fatty liver; because of the invasive operation and potential risks, it is not applicable in all patients. As a substitute, we chose an imaging method for this study. It was reported that the ratio of computerized tomography (CT) numbers for the liver and the spleen shows a good inverse correlation with the degree of steatosis shown on histology (
Compliance was assessed with sachet counts. Patients with less than 80% treatment compliance or who missed a visit were withdrawn. Meanwhile, all the patients were provided with standard advice on diet and physical exercise at each follow-up visit by physicians and dieticians.
Clinical data containing heart rate, respiration, blood pressure electrocardiogram (ECG), and related symptoms were recorded at each visit. Patients underwent routine blood and urine tests including red cell count (RBC), white cell count (WBC), platelet count, and hemoglobin (HB). Patients were also demanded to detect ALT, aspartate aminotransferase (AST), blood urea nitrogen (BUN), Cr, and glucose at both entry and end of the trial. The occurrence of adverse events (AEs) was monitored and recorded at every follow-up for safety set (SS) analysis.
The statistical significance was defined as two-sided
The trial was conducted from March 1, 2010, to September 30, 2011. Patient screening, enrollment, and retention by treatment process were detailed in Figure
Patient flow diagram of the 2 trial groups.
221 patients entered the trial (JZG group, male/female 94/17; placebo group, male/female 83/27). The baseline characteristics of the participants under FAS analysis were summarized in Table
Baseline characteristics of patients (FAS analysis).
Parameter | JZG ( |
Placebo ( |
|
---|---|---|---|
Age, y |
|
|
0.1178 |
Male sex, |
94 (84.68) | 83 (75.45) | 0.0858 |
Weight (male), kg |
|
|
0.7280 |
Weight (female), kg |
|
|
0.5334 |
Systolic pressure, mmHg/L |
|
|
0.0724 |
Diastolic pressure, mmHg/L |
|
|
0.5732 |
L/S ratio |
|
|
0.0856 |
BMI |
|
|
0.6994 |
Course of NAFL, month |
|
|
0.6004 |
Comorbidity (with), |
4 (3.60) | 4 (3.64) | 1.0000 |
History of drug hypersensitivity (yes), |
2 (1.80) | 1 (0.91) | n.s. |
Combined medicine using (yes), |
2 (1.82) | 3 (2.73) | n.s. |
Serum glucose, mmol/L |
|
|
1.0000 |
ALT, IU/L |
|
|
>0.05 |
AST, IU/L |
|
|
>0.05 |
BUN, mmol/L |
|
|
>0.05 |
Serum Cr, |
|
|
>0.05 |
Data were presented as mean ± standard deviation.
At week 12, the mean L/S ratio increased from
(a) Primary outcome (L/S ratio) comparison between groups. (b) ANCOVA for mean change in L/S ratio from baseline to end of treatment.
Follow-ups | FAS | PPS | ||||
---|---|---|---|---|---|---|
JZG | Placebo |
|
JZG | Placebo |
| |
Baseline |
|
|
0.0856 |
|
|
0.1366 |
Week 12 |
|
|
|
|
||
Week 12-baseline |
|
|
0.0003 |
|
|
0.0015 |
Week 24 |
|
|
|
|
||
Week 24-baseline |
|
|
0.0011 |
|
|
0.0003 |
FAS | PPS | |||
---|---|---|---|---|
|
|
|
| |
Group | 38.85 | <0.0001 | 36.19 | <0.0001 |
Baseline | 13.69 | 0.0003 | 11.35 | 0.0009 |
Center | 7.25 | 0.0076 | 10.15 | 0.0017 |
Placebo group* (95% CI) | 0.07 (0.03, 0.11) | 0.07 (0.03, 0.12) | ||
JZG group* (95% CI) | 0.24 (0.20, 0.28) | 0.25 (0.21, 0.30) | ||
Mean change between |
−0.18 (−0.24, −0.12) | −0.18 (−0.24, −0.12) |
Furthermore, the difference in mean change from baseline between JZG and placebo was estimated using adjusted means together with the 95% CI from the ANCOVA model (Table
The changes in BMI, serum TG, and TC from baseline to week 4, week 12, and week 24 were illustrated in Figure
Changes in secondary outcomes (FAS) of the treatment. (a) BMI: body mass index.
All patients were assessed with good compliance. Patients followed the direction of treatment strictly with an assessment value of 100%. Other combined medications not the patients took during the treatment were used for an identified diagnosis of disease and with allowance for trial protocol.
The occurrence of AEs was monitored and recorded throughout the study, and no severe adverse events occurred during the process. There were 221 patients under SS analysis. 38 cases (of 30 patients) were reported with AEs (Table
The frequency of adverse effects/events (SS,
Items | Placebo ( |
JZG ( |
---|---|---|
ALT increase | 9 (8.18) | 4 (3.60) |
AST increase | 2 (1.82) | 0 (0.00) |
Serum TG increase | 0 (0.00) | 2 (1.80) |
Sloppy stool | 1 (0.91) | 1 (0.90) |
Exhaustion/dizziness | 0 (0.00) | 1 (0.90) |
Dull pain in belly | 1 (0.91) | 0 (0.00) |
Diarrhea | 1 (0.91) | 0 (0.00) |
Cold | 1 (0.91) | 2 (1.80) |
Cough | 0 (0.00) | 1 (0.90) |
Expectoration | 1 (0.91) | 0 (0.00) |
Yellow urine | 1 (0.91) | 3 (2.70) |
Flush face | 1 (0.91) | 0 (0.00) |
Sense of hunger | 1 (0.91) | 0 (0.00) |
Injury | 0 (0.00) | 1 (0.90) |
Stomach illness | 0 (0.00) | 1 (0.90) |
Abnormal EKG | 0 (0.00) | 1 (0.90) |
WBC increase | 0 (0.00) | 1 (0.90) |
Dry throat | 0 (0.00) | 1 (0.90) |
| ||
Total | 19 (17.27) | 19 (17.12) |
Adverse effects/events (SS analysis).
Placebo ( |
JZG ( |
| |||||
---|---|---|---|---|---|---|---|
Patients | Cases | Incidence (%) | Patients | Cases | Incidence (%) | ||
Total AEs | 14 | 19 | 12.73 | 16 | 19 | 14.41 | 0.7149 |
AEs related to study | 0 | 0 | 0.00 | 2 | 2 | 1.80 | 0.4977 |
The epidemic of NAFLD is prevailing in China; the morbidity has risen to 15–30% in some cities [
As more and more clinical trials were conducted in NAFLD, several consensuses were formed in the methodologies. NAFLD is composed of a spectrum of diseases including NAFL, NASH, fibrosis, and HCC; each stage has its specific methods of diagnosis, evaluation, and treatment. For the consideration of safety and quality control, the initial attempt of TCM application in NAFLD is mainly focusing on the early stage of the disease (NAFL). To perform fatty liver clinical trial, liver biopsy is the gold standard for diagnosing. However, due to the invasive operation and potential risks, it could not be applicable in all patients. Imaging techniques, including ultrasound (US), CT, and magnetic Resonance (MR), are now widely used. It was reported that CT attenuation values of the liver were strongly correlated with histological evidence of hepatic steatosis; the ratio of CT numbers for the liver and the spleen shows a good inverse correlation with the degree of steatosis shown on histology (
According to TCM theory, fatty liver is corresponding to pathogens including dampness, heat, and stasis interacted in the liver with spleen deficiency as the basis. To target its pathomechanism, JZG has been applied in clinic for more than fifty years; it was designed to invigorate spleen, remove phlegm, eliminate dampness, activate blood flow, and clear heat. JZG is composed of Jiaogulan (
This is a randomed, double-blinded, and placebo-controlled clinical trial to assess the effect of TCM medication in NAFL patients. In this trial, JZG was found to significantly reduce hepatic steatosis in NAFL patients compared to placebo control; major improvements were demonstrated through CT evaluation, with the change of L/S ratio. In addition, BMI was also markedly decreased after 24-week JZG intervention compared with the baseline.
Although our findings indicated that JZG was superior to placebo in some outcomes, the tentatively positive effects shown in the present study should be interpreted with caution. There are a number of limitations in this study. Firstly, the diagnosis of NAFL was through CT evaluation and lack of the histology evidence. Secondly, to be convenient for the patients, we used standard dosing of JZG according to the latest Chinese Medicine Recipe Dictionary (1997); thus, the dosage was not so exact when it was applied to people with different bodyweights and heights. Thirdly, the lifestyle deviations among patients may have influence on the results more or less, and some factors are uncontrollable.
We have found in our study that JZG is superior to placebo in increasing L/S ratio of CT evaluation and reducing BMI. This randomized, placebo-controlled, and double-blind clinical trial further consolidated evidence for the safety and effectiveness of JZG in treating patients with NAFL.
There is no conflict of interests involved in this paper.
The authors thank the doctors and nurses, laboratory personnel, nutrition staff, and other personnels at all participating centers for their valuable efforts as part of this project. This work was supported by the National Nature Science Foundation of China (nos. 81001508 and 81273727) and by Shanghai Discipline Project (no. ZYSNXD-CC-ZDYJ042).