F573 for Injection for the Treatment of Liver Injury/Failure

Sponsor

Beijing Continent Pharmaceutical Co, Ltd. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05689645

Collaborator

(none)

120

Enrollment

Arms

38.4

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This study was a randomized, double-blind, placebo-controlled PhaseⅡ clinical trial .

The main objective of this study was to confirm the efficacy and safety of F573 for injection in the treatment of liver injury/failure.

Condition or Disease	Intervention/Treatment	Phase
Acute Liver Failure Acute-On-Chronic Liver Failure	Drug: F573 for injection Drug: Sterilizing water for injection	Phase 2

Detailed Description

In a randomized, double-blind, placebo-controlled design, the study was divided into two phases according to the subjects' risk of liver failure due to liver injury.

The first stage: The 36 patients with 1/2 grade DILI and 12 patients with CHB were enrolled,Firstly, DILI patients were treated with trial drug 0.5, 1.0, 2.0 mg/kg or placebo in a 1:1:1:1 ratio,CHB patients received the trial drug or placebo in a 3:1 ratio, and the dose was determined based on the efficacy and safety results of the DILI patients.

The second stage:The 2/3 grade DILI patients and CHB patients were enrolled, 12 cases in each group, and they were assigned to the experimental group and the control group in a ratio of 3:1.the drug dose given was determined by the combination of efficacy and safety results in the first stage.

The study was divided into screening period (14 days), treatment period (14 days) and follow-up period (28 days).

Screening eligible subjects received the trial drug or placebo in a 3:1 ratio once daily for 14 consecutive days.

DILI subjects and CHB subjects should also use Diammonium glycyrrhizate enteric-coated capsules for basic treatment.After withdrawal, the subjects were followed up for 28 days for safety.

After obtaining subject consent, pharmacokinetic blood samples will be collected for CHB patients in stages 1 and 2 in this trial.

The Third stage:

This study used a randomized, double-blind, placebo-controlled design. The study was divided into screening period (14 days), treatment period (28 days) and follow-up period (90 days).

48 screen eligible subjects received trial drug or placebo in a ratio of 3:1, once a day for 28 days. The dose was determined according to the results of the efficacy and safety of the first and second stages. Subjects should also receive concurrent drug acetylcysteine injection (NAC). After withdrawal, the subjects were followed up for 90 days for safety.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

F573 for Injection for the Treatment of Liver Injury/Failure : Randomized, Double-blind, Placebo-controlled Phase Ⅱa Clinical Trial

Anticipated Study Start Date :

Jan 18, 2023

Anticipated Primary Completion Date :

Sep 25, 2025

Anticipated Study Completion Date :

Mar 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: F573 for injection groups The first stage : The dose of 1/2 grade DILI patients was 0.5, 1.0, 2mg / kg, the dose of CHB patients was based on the efficacy and safety results of DILI patients, The second stage:The dose was determined by the comprehensive consideration of the efficacy and safety trial results in the first stage ,both the dose volume was 2 mL, intramuscular injection (IM), once a day for 14 consecutive days, and the dose was calculated by the weight results of the last visit. basic treatment: receive Diammonium glycyrrhizate enteric-coated capsules at a dose of 150 mg 3 times a day. The Third stage: The dose of the Screen eligible subjects was determined by the results of the efficacy and safety trials in the first and second stages. The dose volume was 2 mL, intramuscular injection (IM), once a day for 28 consecutive days. The dose was calculated by the body weight results of the last visit. basic treatment: receive acetylcysteine injection (NAC),the dose was 8 g/d, once a day.	Drug: F573 for injection The first stage: DILI patients were given doses of 0.5, 1.0, 2.0mg/kg. The dose for CHB patients was determined based on the efficacy and safety test results of DILI patients. The dosages of the second and third stages were determined according to the results of the first stage. The dosage volume was 2mL for intramuscular injection. Medication course: The first and second stages were administered once a day for 14 days. The third stage was administered once a day for 28 consecutive days
Placebo Comparator: Placebo Comparator The first stage: the 1/2 grade DILI patients and CHB patients and The second stage: the 2/3 grade DILI patients and CHB patients were treated with Sterilizing water for injection , the dose volume was 2 mL, intramuscular injection (IM), once a day for 14 consecutive days, and the dose was calculated by the weight results of the last visit. Basic treatment: receive Diammonium glycyrrhizate enteric-coated capsules at a dose of 150 mg 3 times a day. The third stage: the Screen eligible subjects were treated with Sterilizing water for injection. The dose volume was 2 mL, intramuscular injection (IM), once a day for 28 consecutive days. The dose was calculated by the body weight results of the last visit. Basic treatment: receive acetylcysteine injection at a dose of 8 g / d once a day.	Drug: Sterilizing water for injection The composition of this product is water for injection, and the dosage volume is 2mL for intramuscular injection. Medication course: The first and second stages were administered once a day for 14 days. The third stage was administered once a day for 28 days.

Arm

Intervention/Treatment

Experimental: F573 for injection groups

The first stage : The dose of 1/2 grade DILI patients was 0.5, 1.0, 2mg / kg, the dose of CHB patients was based on the efficacy and safety results of DILI patients, The second stage:The dose was determined by the comprehensive consideration of the efficacy and safety trial results in the first stage ,both the dose volume was 2 mL, intramuscular injection (IM), once a day for 14 consecutive days, and the dose was calculated by the weight results of the last visit. basic treatment: receive Diammonium glycyrrhizate enteric-coated capsules at a dose of 150 mg 3 times a day. The Third stage: The dose of the Screen eligible subjects was determined by the results of the efficacy and safety trials in the first and second stages. The dose volume was 2 mL, intramuscular injection (IM), once a day for 28 consecutive days. The dose was calculated by the body weight results of the last visit. basic treatment: receive acetylcysteine injection (NAC),the dose was 8 g/d, once a day.

Drug: F573 for injection

The first stage: DILI patients were given doses of 0.5, 1.0, 2.0mg/kg. The dose for CHB patients was determined based on the efficacy and safety test results of DILI patients. The dosages of the second and third stages were determined according to the results of the first stage. The dosage volume was 2mL for intramuscular injection. Medication course: The first and second stages were administered once a day for 14 days. The third stage was administered once a day for 28 consecutive days

Placebo Comparator: Placebo Comparator

The first stage: the 1/2 grade DILI patients and CHB patients and The second stage: the 2/3 grade DILI patients and CHB patients were treated with Sterilizing water for injection , the dose volume was 2 mL, intramuscular injection (IM), once a day for 14 consecutive days, and the dose was calculated by the weight results of the last visit. Basic treatment: receive Diammonium glycyrrhizate enteric-coated capsules at a dose of 150 mg 3 times a day. The third stage: the Screen eligible subjects were treated with Sterilizing water for injection. The dose volume was 2 mL, intramuscular injection (IM), once a day for 28 consecutive days. The dose was calculated by the body weight results of the last visit. Basic treatment: receive acetylcysteine injection at a dose of 8 g / d once a day.

Drug: Sterilizing water for injection

The composition of this product is water for injection, and the dosage volume is 2mL for intramuscular injection. Medication course: The first and second stages were administered once a day for 14 days. The third stage was administered once a day for 28 days.

Outcome Measures

Primary Outcome Measures

Adverse events (AE), serious adverse events (SAE) [14 days of administration in the first and second stages]
to record Adverse events and serious adverse events in the trial
Adverse events (AE), serious adverse events (SAE) [28 days of follow-up in the first and second stages]
to record Adverse events and serious adverse events in the trial
clinical laboratory tests ：blood routine [14 days of administration in the first and second stages]
blood routine report contains the following values: RBC,WBC,NE%,LY%,HGB,PLT.
clinical laboratory tests ：blood routine [28 days of follow-up in the first and second stages]
blood routine report contains the following values: RBC,WBC,NE%,LY%,HGB,PLT.
clinical laboratory tests ：blood biochemistry [14 days of administration in the first and second stages]
blood biochemistry report contains the following values: DBIL,TBIL,Urea，BUN,Cr，AST，ALT，GGT, TP, ALB, GLU,TG, TC, K,Na,CI, UA,LDH, ALP, PAB, RBP, AFP.
clinical laboratory tests ：blood biochemistry [28 days of follow-up in the first and second stages]
blood biochemistry report contains the following values: DBIL,TBIL,Urea，BUN,Cr，AST，ALT，GGT, TP, ALB, GLU,TG, TC, K,Na,CI, UA,LDH, ALP, PAB, RBP, AFP.
clinical laboratory tests : urine routine [14 days of administration of follow-up in the first and second stages]
urine routine report contains the following values: GLU,PRO,RBC,WBC.
clinical laboratory tests : urine routine [28 days of follow-up in the first and second stages]
urine routine report contains the following values: GLU,PRO,RBC,WBC.
clinical laboratory tests ：blood coagulation function [14 days of administration in the first and second stages]
blood coagulation function report contains the following values: TT, APTT, PT, INR.
clinical laboratory tests ：blood coagulation function [28 days of follow-up in the first and second stages]
blood coagulation function report contains the following values: TT, APTT, PT, INR.
12-lead electrocardiogram (ECG) [14 days of administration in the first and second stages]
12-lead electrocardiogram (ECG) report contains the following values: HR, BP,DP,PR intervals,QRS intervals,QT intervals,QTc intervals.
12-lead electrocardiogram (ECG) [28 days of follow-up in the first and second stages]
12-lead electrocardiogram (ECG) report contains the following values: HR, BP,DP,PR intervals,QRS intervals,QT intervals,QTc intervals.
All-cause mortality [28 days after completion of dosing in the third stage]
All-cause mortality within 28 days after completion of dosing.
All-cause mortality [90 days after completion of dosing in the third stage]
All-cause mortality within 90 days after completion of dosing.

Secondary Outcome Measures

Basin alanine aminotransferase (ALT) [after 7 days of administration in the first and second stages]
ALT values reflect hepatocyte injury
Basin alanine aminotransferase (ALT) [after 14 days of administration in the first and second stages]
ALT values reflect hepatocyte injury
Basin alanine aminotransferase (ALT) [28 days of follow-up in the first and second stages.]
ALT values reflect hepatocyte injury
peak concentration (Cmax) [12 hours after administration in the first and second stages]
Pharmacokinetic parameters: peak concentration (Cmax). Peak-reaching time (Tmax), half-life period (T1/2), Blood concentration-area (AUC) under the time curve from zero to t0-t), Area under the blood concentration-time curve from 0 to infinite time (AUC0-∞). Clearance rate (CL / F), apparent distribution volume (Vz / F), average retention time (MRT), etc.
Peak-reaching time (Tmax) [12 hours after administration in the first and second stages]
Pharmacokinetic parameters: Peak-reaching time (Tmax)
half-life period (T1/2) [12 hours after administration in the first and second stages]
Pharmacokinetic parameters: half-life period (T1/2)
Blood concentration-area (AUC) [12 hours after administration in the first and second stages]
Blood concentration-area (AUC) under the time curve from zero to t0-t), Area under the blood concentration-time curve from 0 to infinite time (AUC0-∞).
Clearance rate (CL / F) [12 hours after administration in the first and second stages]
Pharmacokinetic parameters: Clearance rate (CL / F).
apparent distribution volume (Vz / F) [12 hours after administration in the first and second stages]
Pharmacokinetic parameters: apparent distribution volume (Vz / F).
average retention time (MRT) [12 hours after administration in the first and second stages]
Pharmacokinetic parameters: average retention time (MRT)
Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [after 7 days of administration in the first and second stages]
Changes in biomarkers from baseline include ALT, aspartate aminotransferase (AST).
total bilirubin (TBil) [after 7 days of administration in the first and second stages]
Changes in biomarkers from baseline include total bilirubin (TBil).
prothrombin activity (PTA) [after 7 days of administration in the first and second stages]
Changes in biomarkers from baseline include prothrombin activity (PTA).
international normalized ratio (INR) [after 7 days of administration in the first and second stages]
Changes in biomarkers from baseline include international normalized ratio (INR).
alkaline phosphatase (ALP) [after 7 days of administration in the first and second stages]
Changes in biomarkers from baseline include alkaline phosphatase (ALP)
Alpha-fetoprotein(AFP) [after 7 days of administration in the first and second stages]
Changes in biomarkers from baseline include Alpha-fetoprotein (AFP).
CK-18 M30 [after 7 days of administration in the first and second stages]
Changes in biomarkers from baseline include c aspase digested keratin 18M 30 (CK-18 M30)
caspase 3 / 7 [after 7 days of administration in the first and second stages]
Changes in biomarkers from baseline include caspase 3 / 7.
caspase 1 [after 7 days of administration in the first and second stages]
Changes in biomarkers from baseline include caspase 1.
hepatocyte growth factor (HGF) [after 7 days of administration in the first and second stages]
Changes in biomarkers from baseline include hepatocyte growth factor (HGF)
the end-stage liver disease model (MELD) score [7 days of administration in the third stage secondary outcome]
Changes of the end-stage liver disease model (MELD) score. Higher scores indicate more severe disease.
the end-stage liver disease model (MELD) score [14 days of administration in the third stage secondary outcome]
Changes of the end-stage liver disease model (MELD) score. Higher scores indicate more severe disease.
the end-stage liver disease model (MELD) score [28 days of administration in the third stage secondary outcome]
Changes of the end-stage liver disease model (MELD) score. Higher scores indicate more severe disease.
the end-stage liver disease model (MELD) score [28 days of follow-up in the third stage secondary outcome]
Changes of the end-stage liver disease model (MELD) score. Higher scores indicate more severe disease.
the end-stage liver disease model (MELD) score [90 days of follow-up in the third stage secondary outcome]
Changes of the end-stage liver disease model (MELD) score. Higher scores indicate more severe disease.
ACLF Research Consortium (AARC) score [7 days of administration in the third stage]
Changes of ACLF Research Consortium (AARC) score. Higher scores indicate more severe disease.
ACLF Research Consortium (AARC) score [14 days of administration in the third stage]
Changes of ACLF Research Consortium (AARC) score. Higher scores indicate more severe disease.
ACLF Research Consortium (AARC) score [28 days of administration in the third stage]
Changes of ACLF Research Consortium (AARC) score. Higher scores indicate more severe disease.
ACLF Research Consortium (AARC) score [28 days of follow-up in the third stage]
Changes of ACLF Research Consortium (AARC) score. Higher scores indicate more severe disease.
ACLF Research Consortium (AARC) score [90 days of follow-up in the third stage]
Changes of ACLF Research Consortium (AARC) score. Higher scores indicate more severe disease.
Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [7 days of administration in the third stage]
Changes in biomarkers compared to baseline include ALT and AST.
Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [14 days of administration in the third stage]
Changes in biomarkers compared to baseline include ALT and AST.
Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [28 days of administration in the third stage]
Changes in biomarkers compared to baseline include ALT and AST.
Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [28 days of follow-up in the third stage]
Changes in biomarkers compared to baseline include ALT and AST.
Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [90 days of follow-up in the third stage]
Changes in biomarkers compared to baseline include ALT and AST.
total bilirubin (TBil) [7 days of administration in the third stage]
Changes in biomarkers compared to baseline include TBil.
total bilirubin (TBil) [14 days of administration in the third stage]
Changes in biomarkers compared to baseline include TBil.
total bilirubin (TBil) [28 days of administration in the third stage]
Changes in biomarkers compared to baseline include TBil.
total bilirubin (TBil) [28 days of follow-up in the third stage]
Changes in biomarkers compared to baseline include TBil.
total bilirubin (TBil) [90 days of follow-up in the third stage]
Changes in biomarkers compared to baseline include TBil.
prothrombin activity (PTA) [7 days of administration in the third stage]
Changes in biomarkers compared to baseline include PTA.
prothrombin activity (PTA) [14 days of administration in the third stage]
Changes in biomarkers compared to baseline include PTA.
prothrombin activity (PTA) [28 days of administration in the third stage]
Changes in biomarkers compared to baseline include PTA.
prothrombin activity (PTA) [28 days of follow-up in the third stage]
Changes in biomarkers compared to baseline include PTA.
prothrombin activity (PTA) [90 days of follow-up in the third stage]
Changes in biomarkers compared to baseline include PTA.
international normalized ratio (INR) [7 days of administration in the third stage]
Changes in biomarkers compared to baseline include international normalized ratio (INR).
international normalized ratio (INR) [14 days of administration in the third stage]
Changes in biomarkers compared to baseline include international normalized ratio (INR).
international normalized ratio (INR) [28 days of administration in the third stage]
Changes in biomarkers compared to baseline include international normalized ratio (INR).
international normalized ratio (INR) [90 days of follow-up in the third stage]
Changes in biomarkers compared to baseline include international normalized ratio (INR).
alkaline phosphatase (ALP) [7 days of administration in the third stage]
Changes in biomarkers compared to baseline include alkaline phosphatase (ALP).
alkaline phosphatase (ALP) [14 days of administration in the third stage]
Changes in biomarkers compared to baseline include alkaline phosphatase (ALP).
alkaline phosphatase (ALP) [28 days of administration in the third stage]
Changes in biomarkers compared to baseline include alkaline phosphatase (ALP).
alkaline phosphatase (ALP) [28 days of follow-up in the third stage]
Changes in biomarkers compared to baseline include alkaline phosphatase (ALP).
alkaline phosphatase (ALP) [90 days of follow-up in the third stage]
Changes in biomarkers compared to baseline include alkaline phosphatase (ALP).
Alpha-fetoprotein(AFP) [7 days of administration in the third stage]
Changes in biomarkers compared to baseline include Alpha-fetoprotein(AFP) .
Alpha-fetoprotein(AFP) [14 days of administration in the third stage]
Changes in biomarkers compared to baseline include Alpha-fetoprotein(AFP) .
Alpha-fetoprotein(AFP) [28 days of administration in the third stage]
Changes in biomarkers compared to baseline include Alpha-fetoprotein(AFP) .
Alpha-fetoprotein(AFP) [28 days of follow-up in the third stage]
Changes in biomarkers compared to baseline include Alpha-fetoprotein(AFP) .
Alpha-fetoprotein(AFP) [90 days of follow-up in the third stage]
Changes in biomarkers compared to baseline include Alpha-fetoprotein(AFP) .
CK-18 M30 [7 days of administration in the third stage]
Changes in biomarkers from baseline include c aspase digested keratin 18M 30 (CK-18 M30)
CK-18 M30 [14 days of administration in the third stage]
Changes in biomarkers from baseline include c aspase digested keratin 18M 30 (CK-18 M30)
CK-18 M30 [28 days of administration in the third stage]
Changes in biomarkers from baseline include c aspase digested keratin 18M 30 (CK-18 M30)
CK-18 M30 [28 days of follow-up in the third stage]
Changes in biomarkers from baseline include c aspase digested keratin 18M 30 (CK-18 M30)
CK-18 M30 [90 days of follow-up in the third stage]
Changes in biomarkers from baseline include c aspase digested keratin 18M 30 (CK-18 M30)
caspase 3 / 7 [7 days of administration in the third stage]
Changes in biomarkers from baseline include caspase 3 / 7.
caspase 3 / 7 [14 of administration in the third stage]
Changes in biomarkers from baseline include caspase 3 / 7.
caspase 3 / 7 [28 days of administration in the third stage]
Changes in biomarkers from baseline include caspase 3 / 7.
caspase 3 / 7 [28 days of follow-up in the third stage]
Changes in biomarkers from baseline include caspase 3 / 7.
caspase 3 / 7 [90 days of follow-up in the third stage]
Changes in biomarkers from baseline include caspase 3 / 7.
caspase 1 [7 days of administration in the third stage]
Changes in biomarkers from baseline include caspase 1.
caspase 1 [14 days of administration in the third stage]
Changes in biomarkers from baseline include caspase 1.
caspase 1 [28 days of administration in the third stage]
Changes in biomarkers from baseline include caspase 1.
caspase 1 [28 days of follow-up in the third stage]
Changes in biomarkers from baseline include caspase 1.
caspase 1 [90 days of follow-up in the third stage]
Changes in biomarkers from baseline include caspase 1.
hepatocyte growth factor (HGF) [7 days of administration in the third stage]
Changes in biomarkers from baseline include hepatocyte growth factor (HGF)
hepatocyte growth factor (HGF) [14 days of administration in the third stage]
Changes in biomarkers from baseline include hepatocyte growth factor (HGF)
hepatocyte growth factor (HGF) [28 days of administration in the third stage]
Changes in biomarkers from baseline include hepatocyte growth factor (HGF)
hepatocyte growth factor (HGF) [28 days of follow-up in the third stage]
Changes in biomarkers from baseline include hepatocyte growth factor (HGF)
hepatocyte growth factor (HGF) [90 days of follow-up in the third stage]
Changes in biomarkers from baseline include hepatocyte growth factor (HGF)
Adverse events (AE), serious adverse events (SAE) [28 days of follow-up in the third stage.]
Adverse events (AE), serious adverse events (SAE) in the third stage at 28 days
Adverse events (AE), serious adverse events (SAE) [90 days of follow-up in the third stage.]
Adverse events (AE), serious adverse events (SAE) in the third stage at 28 days
clinical laboratory tests ：blood routine [28 days of follow-up ihe third stage.]
blood routine report contains the following values: RBC,WBC,NE%,LY%,HGB,PLT.
clinical laboratory tests ：blood routine [90 days of follow-up ihe third stage.]
blood routine report contains the following values: RBC,WBC,NE%,LY%,HGB,PLT.
clinical laboratory tests ：blood biochemistry [28 of follow-up ihe third stage.]
blood biochemistry report contains the following values: DBIL,TBIL,Urea，BUN,Cr，AST，ALT，GGT, TP, ALB, GLU,TG, TC, K,Na,CI, UA,LDH, ALP, PAB, RBP, AFP.
clinical laboratory tests ：blood biochemistry [90 days of follow-up ihe third stage.]
blood biochemistry report contains the following values: DBIL,TBIL,Urea，BUN,Cr，AST，ALT，GGT, TP, ALB, GLU,TG, TC, K,Na,CI, UA,LDH, ALP, PAB, RBP, AFP.
clinical laboratory tests ：urine routine [28 days of follow-up ihe third stage.]
urine routine report contains the following values: GLU,PRO,RBC,WBC.
clinical laboratory tests ：urine routine [90 days of follow-up ihe third stage.]
urine routine report contains the following values: GLU,PRO,RBC,WBC.
clinical laboratory tests ：blood coagulation function [28 days of follow-up ihe third stage.]
blood coagulation function report contains the following values: TT, APTT, PT, INR.
clinical laboratory tests ：blood coagulation function [90 days of follow-up ihe third stage.]
blood coagulation function report contains the following values: TT, APTT, PT, INR.
12-lead electrocardiogram (ECG) [28 days of follow-up ihe third stage.]
12-lead electrocardiogram (ECG) report contains the following values: HR, BP,DP,PR intervals,QRS intervals,QT intervals,QTc intervals.
12-lead electrocardiogram (ECG) [90 days of follow-up ihe third stage.]
12-lead electrocardiogram (ECG) report contains the following values: HR, BP,DP,PR intervals,QRS intervals,QT intervals,QTc intervals.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:The first stage:

Subjects who meet all of the following criteria will be enrolled in the study:

Age is 18 and 60 years old, gender is unlimited;
Clinically diagnosed as hepatocyte injury type DILI patients or CHB patients infected with HBV for more than 6 months, the subject population is defined as follows:

Grade 1/2 DILI patients: refer to the "Guidelines for the Diagnosis and Treatment of Drug-induced Liver Injury, 2015 edition", Drug-induced liver injury refers to the liver injury induced by various kinds of prescribed or over-the-counter chemical drugs, biological agents, traditional Chinese medicine, natural drugs, health care products, dietary supplements and their metabolites and even auxiliary materials; (1) The patient presented with elevated serum ALT, ALP, GGT, and TBil; (2) Liver ultrasound has no obvious changes or only mild enlargement; (3) After tracing the history of suspected drug application and other causes of liver injury, necessarily, the patients take other measures such as liver biopsy to confirm the diagnosis of DILI; (4) Clinical classification is hepatocyte injury type (defined as ALT ≥3 ×ULN and R value ≥5, R value = [ALT / ULN]÷ [ALP /

ULN]); (5) Severity level is level 1 or level 2 (where level 1 is defined as:

TBil < 2.5 ×ULN and INR <1.5, Accompanied with or without accompanying clinical symptoms; Level 2 is defined as: TBil ≥2.5×ULN, Or, although without elevated TBil but with INR ≥1.5, Severe clinical symptoms).

CHB patients: refer to the "Chronic hepatitis B Prevention Guidelines (2019 edition)", screening period can provide etiological evidence (HBsAg positive and / or HBV DNA positive) or clinical or pathological evidence (liver tissue biopsy results) that hepatitis B virus infection for more than 6 months;

Subject serum ALT: 2~10 × upper limit of normal value (ULN), TBil: < 5×ULN;
DILI patients: the abnormal duration of liver biochemical indexes [ALT, AST, ALP, γ -glutamyl-transpeptidase (GGT), TBil, albumin, and prothrombin time] is not more than 90 days;
Subjects (including their partners) are willing to voluntarily take effective contraception within 6 months from the screening period until the last trial drug was given;
Subjects can sign the informed consent and comply with the requirements of the protocol; If the subject cannot sign the informed consent, it shall be signed by the legal guardian or witness who required by regulations.

(2)The second stage:

Subjects who meet all of the following criteria will be enrolled in the study:

Age is 18 and 60 years old, and gender is unlimited;
Patients with a clinical diagnosis of hepatocellular injury-type DILI or patients with

HBV infection for more than 6 months, the subject population is defined as follows:

Grade 2 / 3 DILI patients: refer to the Guidelines for the Diagnosis and Treatment of Drug-induced Liver Injury (2015 edition). Drug-induced liver injury refers to the liver injury induced by various kinds of prescribed or over-the-counter chemical drugs, biological agents, traditional Chinese medicine, natural drugs, health care products, dietary supplements and their metabolites and even auxiliary materials; (1) The patient presented with elevated serum ALT, ALP, GGT, and TBil; (2) Liver ultrasound has no obvious changes or only mild enlargement; (3) After tracing the history of suspected drug application and other causes of liver injury, necessarily, the patients take other measures such as liver biopsy to confirm the diagnosis of DILI; (4) Clinical classification is the hepatocyte injury type (defined as ALT ≥3×ULN with an R value ≥5.0, R value = [ALT / ULN]÷ [ALP / ULN]); (5) The Severity level is Level 2 or Level 3 (where Level 2 is defined as: TBil ≥2.5×ULN, Or, although without elevated TBil but with INR ≥1.5, Clinical symptoms are aggravated; Level 3 is defined as a TBil ≥5×ULN, With or without an INR ≥1.5, Clinical symptoms worsen to require hospitalization).
CHB patients: refer to the "Chronic hepatitis B Prevention Guidelines (2019 edition)", screening period can provide etiological evidence (HBsAg positive and / or HBV DNA positive) or clinical or pathological evidence (liver tissue biopsy results) that hepatitis B virus infection for more than 6 months;

Subject serum ALT: 5~20 × upper limit of normal value (ULN), TBil: <10 × ULN;
DILI patients: the abnormal duration of liver biochemical indexes [ALT, AST, ALP, γ -glutamyl-transpeptidase (GGT), TBil, albumin, and prothrombin time] is not more than 90 days;
Subjects (including their partners) are willing to voluntarily take effective contraception within 6 months from the screening period until the last trial drug was given;
Subjects can sign the informed consent and comply with the requirements of the protocol; If the subject cannot sign the informed consent, it shall be signed by the legal guardian or witness who required by regulations.

The third stage:

Age is 18 and 70 years old, gender is unlimited;
Referring to the "Guidelines for the Diagnosis and Treatment of Liver Failure (2018 edition)" for patients diagnosed with Acute on chronic Liver Failure , TBil ≥5×ULN, 4 weeks with hepatic encephalopathy (grade 1-2) or ascites (grade 1-2) before screening period, and 5≤ AARC score≤10 (AARC rating of grade I-II);
Subjects (including their partners) were willing to voluntarily take effective contraception within 6 months from the screening period until the last trial drug was given.
Subjects can sign the informed consent and comply with the requirements of the protocol; If the subject cannot sign the informed consent, it shall be signed by the legal guardian or witness who required by regulations.

Exclusion Criteria:

The first stage:

Subjects meeting one of the following conditions will not be included in the trial:

For DILI and CHB population, mixed with other liver factors;
Previous diagnosis of cirrhosis or the liver hardness determination in the screening time (LSM)≥9.0 kPa;
Severe severe or life-threatening heart, lung, brain, kidney, gastrointestinal and systemic diseases, patients with malignant tumors;
The following laboratory inspection values or inspection values are abnormal:
Blood routine: Platelet (PLT) < 75×109/L , Hemoglobin (HGB) < 90 g / L;
Prothrombin activity was < 40%, and prothrombin time (PT) was prolonged for > 5s;
Left ventricular ejection fraction (LVEF) was <50%;
Allergic or intolerant to trial drugs, or allergic constitution;
Subjects were unable to express their own complaints, such as psychosis and severe neurosis;
Poor compliance and they cannot collaborate;
Pregnant women, lactating women, or women of childbearing age preparing to conceive;
Participating in other clinical trials within 3 months;
Patients who have used ursodeoxycholic acid other than adenosine methionine within 3 days before randomization;
The investigator considered any circumstances unsuitable for inclusion.

The second stage:

Subjects meeting one of the following conditions will not be included in the trial:

For DILI and CHB population, mixed with other liver factors;
Previous diagnosis of cirrhosis or the liver hardness determination in the screening time (LSM)≥9.0 kPa;
Severe severe or life-threatening heart, lung, brain, kidney, gastrointestinal and systemic diseases, patients with malignant tumors;
The following laboratory inspection values or inspection values are abnormal:
Blood routine: Platelet (PLT) < 75×109/L , Hemoglobin (HGB) < 90 g / L;
Prothrombin activity was < 40%, and prothrombin time (PT) was prolonged for > 5s;
Left ventricular ejection fraction (LVEF) was < 50%;
Allergic or intolerant to trial drugs, or allergic constitution;
Subjects were unable to express their own complaints, such as psychosis and severe neurosis;
Poor compliance and they cannot collaborate;
Pregnant women, lactating women, or women of childbearing age preparing to conceive;
Participating in other clinical trials within 3 months;
Patients who have used ursodeoxycholic acid other than adenosine methionine within 3 days before randomization;
The investigator considered any circumstances unsuitable for inclusion.

The third stage:

Subjects meeting one of the following conditions will not be included in the trial:

Those who have completed the liver transplantation, or plan to do it within 1 month;
Severe grade 3 ascites or refractory ascites;
Patients with associated grade 3 hepatic encephalopathy;
Those who had received artificial liver treatment within 1 week prior to screening period;
Patients with serious basic diseases, such as respiratory system, digestive system, circulatory system, endocrine system and other diseases and malignant tumors, and serious infected persons with uncontrollable drugs;
The results of gastroscopy or imaging (abdominal B ultrasound, CT or MRI) within 1 month before the screening period or during the screening period, that indicate the risk of severe varicose veins with bleeding;
The following acute kidney injury (AKI) patients are defined as meeting one of the following conditions:
Serum creatinine (Scr) was increased by 26.5 μmol/L (0.3 mg/dL, 1 mg/dL=88.4 μ mol / L) within 48 hous;
the Scr increased by more than 1.5 times or more than the base value within 7 days ;
Urinary volume was decreased (<0.5 ml/kg / h) and lasted for more than 6 hours;
Allergic or intolerant to trial drugs, or allergic constitution;
Subjects were unable to express their own complaints, such as psychosis and severe neurosis;
Poor compliance and they cannot collaborate;
Pregnant women, lactating women, or women of childbearing age preparing to conceive;
Participating in other clinical trials within 3 months;
The investigator considered any circumstances unsuitable for inclusion. -