Study on the Optimal Strategy for Acute-on-chronic Liver Failure Combined With Traditional Chinese and Modern Medicine: a Multi-center, Randomized and Controlled Study
Phase: NA
Conditions: Acute on Chronic Liver Failure, Traditional Chinese Medicine, Hepatitis B
Sponsor: Beijing 302 Hospital

 
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Study Protocol 
 
 
Official Title of the study: Effectiveness and safety of Chinese herbal medicine 
for hepatitis B virus-related acute-on-chronic liver failure: A multi-center, 
randomized and controlled trial 
 
 
NCT number: not yet assigned 
 
 
Date of the document: June 21, 2018 
 
 

 
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This prospective, multi-center, parallel, centrally randomized controlled trial was 
designed in accordance with the Consolidated Standards of Reporting Trials 
(CONSORT) and Standard Protocol Items: Recommendations for Interventional 
Trials (SPIRIT) guideline, which is led by the principal investigator from 302 
military hospital in Beijing, will be carried out from September 2018 and 
December 2020 among 16 tertiary academic hospitals in China. Patients with 
hepatitis B virus (HBV) related Acute-on-chronic liver failure (ACLF) will be 
randomly allocated to the Chinese herbal medicine (CHM) group or the standard 
medical treatment (SMT) group in a 1:1 ratio. The last patient will be enrolled 
before August 2019 to make sure the availability of 48 week’s survival status by 
the end of this study. We will decide whether to expand additional institutions to 
guarantee adequate enrolments after interim assessment of effective participant 
numbers around December 2018. Patients in the SMT group will receive the 
standard medical treatment, and patients in the CHM group will receive rhubarb 
decoction enema for 1 week and CHM for 8 weeks additionally. All patients will 
be followed at pre-designed time points after 8 weeks’ observational period until 
August 30, 2020 for the primary outcome and secondary outcomes. 
The study is consistent with Good Clinical Practice(GCP) guidelines and has 
been approved by 302 military hospital ethics review committee (2018007D). 
Written informed consent is requisite to be signed by the patients or the 
authorized person under the willingness. The privacy and data of all participants 
will be protected carefully before, during and after the trial. 
Patients will be consented and enrolled by co-principal investigators at each 
institution and managed by care providers including residents, attending 
physicians and nurses according to the protocol. Most of the patients will be 
treated in hospital for 8 weeks so clinicians can supervise the administration of 
CHM, in addition, the policy of reimbursement filed by the lab results at 
determined time points will boost the regular follow-up of this study. 
 
Diagnostic criteria 
The diagnosis of HBV-ACLF refers to the guideline of liver failure issued by 
Chinese Group on the Study of Severe Hepatitis B (COSSH) in 2012. In this 
guideline, HBV-ACLF was described as acute decompensation of liver function 
within short time (28 days usually) in patients with previously diagnosed or 
undiagnosed chronic liver disease, reaching the following obligatory criteria: (1) 
asthenia combined with obvious symptoms of digestive tract, (2) quick progress 
of jaundice defined as total bilirubin (TBIL) greater than 10 mg/dl or increase 
1mg/dl daily, (3) coagulopathy with prothrombin activity less than or equal to 40% 
or international normalized ratio (INR) greater or equal to 1.5 except other 
extrahepatic reasons and another dispensable item of decompensated ascites 
and/or hepatic encephalopathy. There are three grades classified by the degree of 
coagulopathy and liver complications. 

 
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The TCM syndrome was judged by two qualified senior TCM physicians 
simultaneously based on the published criteria to decide what CHM will be given, 
and the discrepancy will be solved by consulting another senior physician. 
 
Inclusion criteria 
(1) In-patients with ACLF. (2) Patients with chronic hepatitis B or compensated 
cirrhosis caused by HBV. (3) Patients who are willing to sign the informed 
consent. (4) Patients aged from16 to 65 years old. 
 
Exclusion criteria 
(1) Acute liver failure, sub-acute liver failure, or chronic liver failure. (2) ACLF 
caused by another disease such as autoimmune disorder, drug, alcohol, toxin, 
parasites other than HBV. (3) Pregnant or lactating women. (4) Primary liver 
cancer. (5) Combined with other severe systemic diseases or mental disease. (6) 
Anti-HIV positive or combined with infection of hepatitis A, C, D, E virus or 
cytomegalovirus, Epstein-Barr virus. (7) Patients participating in other clinical 
trials three months back. (8) Patients unwilling to cooperate. (9) Poor compliance, 
unable to guarantee to complete the protocol. (10) Complicated by severe cerebral 
edema, severe infection, type I hepatorenal syndrome (HRS), and gastrointestinal 
hemorrhage. (11) Patients allergic to one of the Chinese herbs in this protocol. 
 
Criteria for discontinuing or modifying allocated interventions 
The study will end at once if severe adverse events associated with CHM occurs 
or sufficient evidence indicates that adding CHM is not superior to the SMT 
group. Besides, CHM will discontinue and the final status will be censored in the 
condition of liver transplantation or the onset of liver cancer. Allocated 
interventions can be changed upon participant’s request. All these changes will 
be recorded and analyzed based on intention-to-treat (ITT). 
 
Intervention 
Standard medical treatment 
The SMT include a high-calorie diet; nucleoside analogues for HBV DNA-
positive patients; sodium restriction, diuretics and paracentesis combined with 
albumin infusion for ascites; lactulose and L-ornithine aspartate and lactulose for 
HE and hyper-ammonia; hemostatic treatment for gastrointestinal hemorrhage; 
antibiotics for infections and renal replacement for HRS and uremic symptoms. 
CHM formulas, whatever routes of administration, are prohibited in the SMT 
group. 
 
Chinese herbal medicine formula 
There are two kinds of CHM based on traditional Chinese Medicines (TCM) 
syndromes. The common components of the two CHM formulas include 
Artemisiacapillaris Thunb (30g), Salvia miltiorrhiza Bge (30g), Rhizoma 

 
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Atractylodis 
Macroce- 
phalae 
(30g), 
Rubia 
cordifolia 
L 
(30g), 
Sieyesbeckiaorientalis L (30g). Additional four components of Paeoniae Radix 
Rubra (60g), Gardenia jasminoides Ellis (9g), Hedyotis diffusa Willd (30g), 
Bletilla striata (15g) are involved for excess syndrome, and five other components 
of Astragalus membranaceus (30g), Radix Pseudostellariae (15g), Radix Aconiti 
Lateralis Praeparata (10g), Galli Gigeriae Endothelium Corneum (20g), 
Polygonum cuspidatum Sieb.et Zucc (15g) are involved for deficiency syndrome. 
All ingredients are manufactured as a Chinese herbal granule in a specific weight 
ratio to the raw herb (Beijing Kang Rentang Pharmaceutical Co., Ltd, Beijing, 
China) in accordance with the quality criteria of Chinese pharmacopoeia in 2015. 
Patients will take one dosage of CHM granule per day for 8 weeks. For patients 
who cannot take oral medicine can be switched to colon route by the colonic 
therapy system（IMS-100A produced by Sunny Medical in Beijing China). 
In addition, patients in the CHM group will also receive daily herbal enema of 
100 microliter decoction composed by Radix et Rhizoma Rhei Palmati (Dahuang) 
30g and Fructus Mume (Wumei) 30g for 7 days expect the following 
contraindications: (1) severe hemorrhoid, (2) female patients during menstruation, 
(3) anal stenosis, (4) artificial anal and (5) cardiac disease. 
 
Outcome measurements 
Primary outcome 
The primary outcome is transplant-free survival at week 12. 
 
Secondary outcomes 
Secondary outcomes include (1) transplant-free survival at week 24, (2) the 
inﬂuence on liver function assessed by MELD score (involving levels of serum 
bilirubin, creatinine, INR and sodium) at week 12, (3) the inﬂuence on liver 
function assessed by Child-Pugh score (involving the serum bilirubin, 
coagulation function, albumin and the complication of hepatic encephalopathy 
and ascites) at week 12. (4) quality of life assessed by WHOQOL-BRIEF at week 
12 and (5) the incidence of serious complications (including infections, 
encephalopathy, HRS, and gastrointestinal bleeding) from week 1 to week 24. 
 
Safety outcomes 
Primary vital signs, physical examinations, electrocardiogram and some 
laboratory tests such as routine blood test, urine test, renal function will be 
assessed before and after treatment to monitor the safety of this study. 
Furthermore, adverse events are also recorded in a predesigned case report form 
(CRF) through the whole study period. An independent safety committee will 
analyze the incidence and severity of adverse events to identify any unexpected 
adverse events or mortality in the CHM groups. 
 
Other assessed parameters 

 
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Epidemiological characteristics, the details of nucleoside/nucleotide analog 
therapy, family history of liver disease were collected from patient medical record, 
the level of HBV DNA, endotoxin, and lymphocyte subsets were tested as well 
as CLIP-C-ACLF score were computed at week 24 and 48. The plasma level of 
HBV DNA, endotoxin, and cytokines were tested in ADICO clinical laboratories 
(Shanghai, China) which is blind to the allocation information. Remnant plasma 
will be stored at -80˚C for ancillary studies. Women of childbearing age will 
undergo pregnancy test for the eligibility. 
 
Sample size 
The proposed -12% superiority margin of 8-week mortality rate was chosen based 
on our previous results of 30.87% in the SMT group. Considering a power of 0.80 
and 10% of attrition rate, 255 subjects are needed for each group to achieve the 
significance level of 0.05 in assessing the difference between the two groups. 
 
Randomization 
The eligible patients will be randomly allocated to the SMT group and CHM 
group in a 1:1 ratio. The sealed numbers are generated by a computerized random 
number generator with statistical analysis system (SAS) software by an 
independent statistician from the center of clinical evaluation in China Academy 
of Chinese medical sciences (Beijing, China) and are concealed using opaque 
envelopes. 
 
Trial monitoring 
Trial monitoring is assumed by an independent Contract Research Organization 
so as to verify that: (1) The rights and well-being of human subjects are protected. 
(2) The reported trial data are accurate, complete, and verifiable from source 
documents. (3) The conduct of the trial is in compliance with the currently 
approved protocol/amendment(s), with GCP, and with the applicable regulatory 
requirement(s). Monitors should be appropriately trained and have the scientific 
and/or clinical knowledge needed to monitor the trial adequately. A risk-based 
monitoring strategy is developed in this trial, which includes on-site and 
centralized monitoring, which is more likely than routine visits to all clinical sites 
and 100% data verification to ensure subject protection and overall study quality. 
On-site monitoring is an in-person evaluation carried out by the monitor at the 
sites at which the clinical investigation is being conducted. Centralized 
monitoring is a remote evaluation carried out at a location other than the sites at 
which the clinical investigation is being conducted. Key monitoring processes 
include subject inclusion process; implementation of the inclusion criteria; source 
data verification; data integrity, etc. 
 
Data management and Statistical methods 

 
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Data entry will be conducted by two independent administrators using online 
electronic CRF for accuracy and consistency. At the end of the study, the database 
will be locked and analyzed under the agreement of principal investigator and 
statistician, who are privileged to access the final trial dataset. 
The randomized subjects who take at least one dose of CHM or SMT constitute 
the full analysis set (FAS) and those who complete all the visits constitute the 
per-protocol set (PPS). An efficacy assessment will be analyzed using FAS and 
PPS based on the principle of ITT. Subjects who have taken the CHM and been 
evaluated the safety at least once constitute the safety set (SS), which is used for 
safety evaluation. The statistical analysis will be performed using SAS 9.0 
software (SAS Institute, Cary, NC, USA) by independent data management 
committee who are blind to the interventions. 
Comparison of the two groups is conducted for the continuous variables with 
t-test and the categorical variables or rates with the chi-square test. The Kaplan-
Meier overall survival curves will be generated and tested by log-rank. Cox 
proportional hazards regression model will be adopted to determine the 
prognostic factors associated with transplant-free survival. Multivariate logistic 
regression analyses will be adopted to explore factors associated with the 
incidence of liver-related complications. Subgroup analyses will be done based 
on the diagnostic criteria of Asian Pacific Association for the Study of the Liver 
(APASL) and European Association for the Study of the Liver (EASL) guideline. 
The last observation carried forward approach was used for missing values. The 
statistical significance is defined as a two-sided P <0.05.