Chinese Chronic Liver Failure Consortium Acute-on-Chronic Liver Disease and Failure Study --a Prospective Multi-center Study in China, the Largest Hepatitis B Virus High-endemic Region.
Conditions: Liver Failure, Acute on Chronic
Sponsor: Hai Li

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STUDY PROTOCOL 
 
Chinese Chronic Liver Failure Consortium Acute-on-
Chronic Liver Disease and Failure Study  
——a Prospective Multi-center Study in China, the 
Largest Hepatitis B Virus High-endemic Region 
 
 
 
 
 
 
 
 
 
 
 
 
Clinicaltrials.gov ID: NCT02457637 
 
Last updated date: 10 August 2018 
 

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OUTLINE 
Abbreviations:........................................................................................ 3 
Background ............................................................................................ 4 
Objective ................................................................................................. 6 
Methods .................................................................................................. 7 
Period I Recruitment: ....................................................................... 7 
Period II 28-Days Hospitalization and Observation: ............. 8 
Period III Clinic or Telephone Follow-up: ............................... 10 
Statistical Analysis Plan ..................................................................... 11 
Trial size .............................................................................................. 11 
Statistical methods ......................................................................... 11 
Outcome Measures ........................................................................... 12 
Primary Outcome Measures: ....................................................... 12 
Secondary Outcome Measures: ................................................. 12 
Criteria: .................................................................................................. 14 
Inclusion Criteria: ............................................................................. 14 
Exclusion Criteria: ............................................................................ 14 
Contacts/Locations ............................................................................ 16 
Reference .............................................................................................. 17 

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Abbreviations: 
 
ACLF           Acute-on Chronic Liver Failure 
CLIF           Chronic Liver Failure 
CLIF-C OFs     Liver-chronic liver failure-Consortium Organ Failure score  
HBV           Hepatitis B Virus  
CANONIC      Chronic Liver Failure (CLIF) Acute-on Chronic Liver Failure 
in Cirrhosis  
OFs            Organ Failure 
AASLD        the America Association for the Study of Liver Disease 
AD            Acute Decompensation 
SOFA          Sequential Organ Failure Assessment Score 
INR            International Normalized Ratio 
 
 
 
 
 
 
 
 

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Background 
Acute-on chronic liver failure (ACLF) was first described by Japanese 
researchers in 1995[1]. In 2011, the American Association for the Study of 
Liver Disease (AASLD) and the European Association for the Study of the 
Liver (EASL) concluded that the core characteristics of ACLF were multiple 
organ failures and high short-term mortality[2]. In 2013, the EASL-CLIF (the 
European Association for the Study of The Liver-chronic liver failure) 
established the CLIF-SOFA[3] (chronic liver failure-sequential organ failure 
assessment) criteria of ACLF through a prospective multicenter study at 29 
liver units in eight European countries for 1 year, with a focus on patients 
with alcoholic cirrhosis with acute decompensation (AD)[4]. In China, 
patients with acute deterioration of previously chronic liver disease were 
diagnosed with chronic severe hepatitis, until 2008 these patients had been 
termed "ACLF", due to the APASL reached a consensus of diagnostic criteria 
of ACLF[5, 6]. In the Asia-Pacific region, the majority of liver disease is viral 
hepatitis, while in western countries, it is alcoholic liver disease[7]. There is 
a sharp east-west divide with respect to the definition of ACLF, especially in 
the definition of chronic liver disease and its precipitating events[8, 9]. 
The investigators analyzed 6 years' data of hepatitis B virus (HBV)-related 
chronic liver disease in patients with AD in two affiliated hospitals of 
Shanghai Jiao Tong University School of Medicine. These data were also 

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quantified and sent to the EASL-CLIF center for analysis. 80% of whole 
patients were clinically diagnosed with cirrhosis, 30% of which had 
pathological diagnosis. Through analysis of the liver tissues of the liver 
transplantation (LT) patients, 95% had pseudo-lobules. The residual 5% of 
liver tissues were in the S3 stage of progressive liver fibrosis[10]. Compared 
with the CANONIC (EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis), 
there are many similarities between ACLF patients with alcoholic cirrhosis 
or HBV induced cirrhosis: (1) The age of ACLF patients is younger than that 
of cirrhotic patients with AD. (2) ACLF is exist at any stage of liver fibrosis. 
(3) The number of organ failures decides the severity of the disease and is 
related to mortality of the patient. (4) Predisposition to acute liver injury 
(ALI) does not correlate with the history of the disease and outcome of the 
patient. (5) The 90-day mortality rate of ACLF is 45-50%, which is obviously 
higher than that of non-ACLF patients (5%). (6) Eastern and western types 
of ACLF can have similar SOFA scores as a diagnostic criterion (CLIF-OF or 
CLIF-SOFA), and a similar prognostic model to predict the outcomes of 
ACLF and non-ACLF patients[11]. ACLF patients with cirrhosis induced by 
HBV or alcoholism differ in main types of organ failure. The former group 
is liver failure (total bilirubin ≥12mg/dl) and coagulation failure 
(international normalized ratio; INR≥2.5), whereas the latter group is renal 
failure (creatinine ≥2mg/dl or use of renal replacement therapy) and 
nervous system failure (hepatic encephalopathy; HE≥III grade)[4, 12]. 

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Research on hepatic pathology in HBV-induced ACLF patients after LT in 
RenJi Hospital demonstrated that the pathological characteristics of ACLF 
may be MHN/SMHN (massive hepatic necrosis/submassive hepatic 
necrosis) in the background of liver pseudo-lobules. Regeneration of 
hepatic progenitor cells, cholestasis, and sepsis are other possible 
pathological features of ACLF[13]. 
 
 
Objective 
The overall objective is to build a prospective multicenter clinical patient 
cohort representing Eastern-type ACLF in patients with chronic liver 
disease (cirrhotic and non-cirrhotic) of various etiologies, accompanied by 
AD or ALI, to characterize disease progression and establish appropriate 
diagnostic criteria. 
 
 
 

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Methods 
Period I Recruitment: 
The investigators plan to enroll 2000-3000 consecutive patients from 
January to December 2015. The research will be carried out in about 14 
Chinese national wide liver centers each of whose total beds are around 
500. Only chronic liver disease patients of various etiologies with AD or ALI 
will be enrolled. Then we will scan all of the enrolled patients and exclude 
those who fit our exclusion criteria.  
Every patient remained will have a unique number. As soon as they are 
hospitalized, name, age, sex, ID (identification) number, telephone number, 
e-mail address, WeChat (a popular mobile phone text and voice messaging 
communication service) number, family address, and degree of education 
will be collected. The investigators will get the history and etiology of their 
liver disease, such as hepatitis B, alcoholic liver disease, and autoimmune 
liver disease. For viral hepatitis, the investigators will ask how antiviral 
therapy is conducted. The investigators will ascertain if the patients have a 
history of cirrhosis and for how long. The investigators will ascertain if the 
patients have any of the following predisposing factors: HBV reactivation, 
bacterial infection, active alcohol intake, HBV superimposed by other 
hepatitis viruses, gastrointestinal bleeding, portal vein thrombosis, surgery, 
intake of hepatotoxic drugs or herbs, or physiological exhaustion. The 

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investigators will establish the main cause of admission: gastrointestinal 
bleeding, hepatic encephalopathy, ascites, bacterial infection, jaundice or 
ALI. The investigators will determine whether the patients have chronic 
disease such as hypertension, coronary heart disease, diabetes, chronic 
renal disease, or connective tissue disease. 
Period II 28-Days Hospitalization and Observation: 
During hospitalization, data will be collected at 1, 4, 7,14, 21 and 28 days 
(or last visit date, if the patient is hospitalized less than 28 days), and 24h 
prior to death or LT (if the patient dies or has LT) and focus on the following 
three aspects. 
The first aspect is evaluation of organ failure. The circulatory system will be 
evaluated by measuring heart rate and blood pressure and use of 
vasopressors. Renal function will be evaluated by serum creatinine or renal 
replacement therapy. Coagulation function will be evaluated by INR 
(international normalized ratio of prothrombin time). Liver function will be 
evaluated by serum total bilirubin. The respiratory system will be evaluated 
by the ratio of oxyhemoglobin saturation and fraction of inspired oxygen. 
The nervous system will be evaluated by the grade of hepatic 
encephalopathy. Bacterial infection, including pneumonia, urinary tract 
infection, spontaneous bacterial peritonitis, spontaneous bacteremia, and 
cellulitis will be evaluated by positive culture results or imaging findings. 

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Systemic inflammatory reactive syndrome, sepsis, severe sepsis and septic 
shock will also be assessed. Gastrointestinal bleeding before and after 
admission, treatment with diuretics, and paracentesis will be recorded. The 
investigators will establish whether ascites and hepatic encephalopathy 
can be medically controlled. 
The second aspect is laboratory examinations. Tests at admission will 
include routine blood, urine and stool tests, liver and renal function tests, 
blood electrolytes, blood-gas analysis, blood glucose, coagulation test, C-
reactive protein (CRP), procalcitonin (PCT), HBV antibodies and antigens, 
anti-hepatitis A (IgM), HBV-DNA, anti-hepatitis E (IgM), anti-hepatitis C, 
and immunoglobulins (IgA, IgG, IgM and IgM-4). Tests at other times will 
include blood, urine and stool routine tests, liver and renal function tests, 
blood electrolytes, blood glucose, coagulation test, CRP and PCT 
(procalcitonin). Tests optionally done during hospitalization will include 
autoantibody measurement, blood culture (if the patients have fever and 
shivering), sputum culture (if there is suspicion of pulmonary infection), 
middle urine cultivation (when there is suspicion of urinary tract infection) 
and ascites culture (when there is suspicion of spontaneous bacterial 
peritonitis). 
The third aspect is imaging. During hospitalization, thoracic X ray or 
computed tomography (CT) will be done to diagnose pulmonary infection. 
Abdominal CT (enhanced when necessary), B ultrasound and Fibro-Scan or 

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other elastography will be done to diagnose cirrhosis (or fibrosis), portal 
thrombosis, esophageal and gastric varices and hepatocellular carcinoma. 
Period III Clinic or Telephone Follow-up: 
Patients will be followed up regularly after discharge. When the patients die 
during follow-up, the time of death and main cause of death will be noted. 
When the patients undergo LT during follow-up, the time of LT and the 
results of hepatic pathology will be noted. 
Follow-up is by clinical visiting or telephone call depending on whether the 
patient can attend the clinic. Clinical follow-up is once a month for 2 years 
adding to 24 visits. The time of visit will be recorded. Antiviral therapy and 
alcohol intake will be monitored (if the patient has). Laboratory tests 
include routine blood tests, liver and renal function test, coagulation test, 
CRP and PCT. B ultrasound will be done to monitor cirrhosis (or fibrosis) and 
hepatocellular carcinoma. Telephone follow-up will be at 28 days, 3, 6,9, 12, 
15, 18, 21 and 24 months. The investigators will determine whether there 
are 
new 
complications 
(e.g. 
gastrointestinal 
bleeding, 
hepatic 
encephalopathy, ascites, bacterial infection) and hepatocellular carcinoma. 
 
 
 
 

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Statistical Analysis Plan 
Trial size 
This is an exploratory, observational study, and anticipated size for this 
study is 2000-3000 patients. 
Statistical methods 
Refer to the CANONIC study, at the beginning we will focus on (but not 
limit in) the relationship between 6 parameters (TB, INR, Creatinine, 
SpO2/FiO2, mean arterial pressure and West-Haven grade), one for each 
organ/system, from CLIF-C OFs and 28-days or 90-days mortality and LT 
rate. Descriptive statistics, mean and standard difference, will be used to 
describe continuous variables, and frequency and percent will be to 
describe categorical variables (such as gender). Statistical significance (P < 
0.05). In univariate statistical comparisons, the chi-square test will be used 
for categorical variables, T-test and Mann-Whitney test for continuous 
variables. Risk ratio (RR) will be used to evaluate and establish the cutoff 
value for each organ/system. Multivariate logistic regression, Cox’s PH 
models and other exploratory models would be used in the establishment 
of our ACLF prognostic scoring systems. The area under the ROC (AUC) will 
be used to compare the predictive value of ours with others. LT patients will 
be considered as censored and the survival function would be adjusted for 
the risk of liver transplantation at each study time point. 

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Outcome Measures 
Primary Outcome Measures: 
1. Short Term Mortality & Liver Transplantation Rate  
Description: Mortality & Liver Transplantation Rate will be calculated and 
reported at 28 days,90 days,180 days,1 year ,2 year and 3 years after 
enrollment. Among them, the 28-day and 90-day mortality rates are the 
focus of our observation. 
Time Frame: up to 3 years. 
Secondary Outcome Measures: 
2. The appearance and number of organ failure 
Description: The appearance and number of organ failure（including liver, 
coagulation, renal, circulation, brain, respiratory system） will be evaluated 
and reported at 1, 4, 7, 14, 21 and 28 days (or last visit)during patients' 
hospitalization.  
Time Frame: Up to 28 days. 
3. Biochemical Parameters 
Description: Serum bilirubin, international normalized ratio, serum 
creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, γ-Glutamyltransferase, white blood cell count, neutrophil 
count and hemoglobin will be collected and reported at 1, 4, 7, 14, 21 and 
28 days (or last visit) during patients' hospitalization. 

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Time Frame: Up to 28 days  
4. Models for Disease Severity 
Description: MELD score, MELD-Na score, CLIF-SOFA score, SOFA score 
and APACHE scores will be calculated and reported at 1, 4, 7, 14, 21 and 28 
days (or last visit) during patients' hospitalization. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Criteria: 
Inclusion Criteria: 
1.Inpatient (hospitalization >1 days) (including patient in emergency 
observation wards); 
2.Chronic liver disease patients including non-alcoholic fatty liver disease 
patients, chronic liver hepatitis patients without cirrhosis, compensated 
cirrhosis patients and decompensated cirrhosis patients; 
3.Having acute liver injury [ALT (alanine aminotransferase)>3NL(normal 
level),AST(aspartate aminotransferase)>3NL or TB(total bilirubin)>2NL 
within 1 week before enrollment] or acute decompensation[having ascites, 
hepatic encephalopathy, bacterial infection ,gastrointestinal bleeding or 
jaundice(TB>5NL)within 1 month]. 
Exclusion Criteria: 
1.pregnancy; 
2.hepatocellular carcinoma or other liver malignancies; 
3.malignancy of other organs; 
4.severe chronic extrahepatic disease including chronic obstructive 
pulmonary disease combined with respiratory failure, coronary heart 
disease with cardiac function level 3 (NYHA), myocardial infarction in the 3 
months before admission, diabetes with severe complications and chronic 
kidney disease with end-stage renal failure; 

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5.receiving immunosuppressive drugs for reasons other than chronic liver 
disease; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Contacts/Locations 
 
Professor Hai Li, MD & PhD 
Study Director  
Digestive Department of Renji Hospital, Shanghai Jiao Tong University 
School of Medicine 
Shanghai, China, 200001   
Telephone: +86-13818525494     
E-mail: haili_17@126.com 
 
 
 
 
 
 
 
 
 
 
 
 

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Reference 
1. 
Ohnishi, H., et al., [Acute-on-chronic liver failure]. Ryoikibetsu Shokogun Shirizu, 1995(7): 
p. 217-9. 
2. 
Olson, J.C., et al., Intensive care of the patient with cirrhosis. Hepatology, 2011. 54(5): p. 
1864-72. 
3. 
Vincent, J.L., et al., The SOFA (Sepsis-related Organ Failure Assessment) score to describe 
organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems 
of the European Society of Intensive Care Medicine. Intensive Care Med, 1996. 22(7): p. 
707-10. 
4. 
Moreau, R., et al., Acute-on-chronic liver failure is a distinct syndrome that develops in 
patients with acute decompensation of cirrhosis. Gastroenterology, 2013. 144(7): p. 1426-
37, 1437.e1-9. 
5. 
Sarin, S.K., et al., Acute-on-chronic liver failure: consensus recommendations of the Asian 
Pacific Association for the study of the liver (APASL). Hepatol Int, 2009. 3(1): p. 269-82. 
6. 
Sarin, S.K., et al., Acute-on-chronic liver failure: consensus recommendations of the Asian 
Pacific Association for the Study of the Liver (APASL) 2014. Hepatol Int, 2014. 8(4): p. 453-
71. 
7. 
Dusheiko, G. and K. Agarwal, Delineating the global challenges of hepatitis B virus 
infection. Lancet Gastroenterol Hepatol, 2018. 3(6): p. 372-373. 
8. 
Hernaez, R., et al., Acute-on-chronic liver failure: an update. Gut, 2017. 66(3): p. 541-553. 
9. 
Wu, T., et al., Development of diagnostic criteria and a prognostic score for hepatitis B 
virus-related acute-on-chronic liver failure. Gut, 2017. 
10. 
Li, H., et al., Characteristics, Diagnosis and Prognosis of Acute-on-Chronic Liver Failure in 
Cirrhosis Associated to Hepatitis B. Sci Rep, 2016. 6: p. 25487. 
11. 
Arroyo, V. and R. Jalan, Acute-on-Chronic Liver Failure: Definition, Diagnosis, and Clinical 
Characteristics. Semin Liver Dis, 2016. 36(2): p. 109-16. 
12. 
Arroyo, V., et al., Acute-on-chronic liver failure: A new syndrome that will re-classify 
cirrhosis. J Hepatol, 2015. 62(1 Suppl): p. S131-43. 
13. 
Li, H., et al., Submassive hepatic necrosis distinguishes HBV-associated acute on chronic 
liver failure from cirrhotic patients with acute decompensation. J Hepatol, 2015. 63(1): p. 
50-9.