F573 for Injection for the Treatment of Liver Injury/Failure

Acute-On-Chronic Liver Failure Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05689645
• Other study ID #: KDN-F573-202202
• Status: Recruiting
• Phase: Phase 2
• Start date: March 24, 2023
• Est. completion date: March 31, 2026

Study information

• Verified date: February 2024
• Source: Beijing Continent Pharmaceutical Co, Ltd.
• Contact: ling zhang, Dr
• Phone: 13501209210
• Email: zhangling[@]bjcontinent.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

The primary objective of this study was to evaluate the safety of F573 for injection in patients with liver injury (drug-induced liver injury (DILI), chronic hepatitis B (CHB), etc.).

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: Twenty-five patients with liver injury (DILI patients and other types of patients with the same degree of liver injury) were enrolled. The trial was first conducted in 16 participants, who were treated with 0.5,1.0,2.0 mg/kg of the experimental drug or placebo in a 1:1:1:1 ratio. Then, 9 patients with CHB were treated with the experimental drug, and the dose was determined according to the efficacy and safety test results of the 16 patients enrolled first.

The second stage:Twenty-four patients with liver injury (DILI patients and other patients with the same degree of liver injury) were enrolled, and eligible subjects were treated with the experimental drug or placebo in a ratio of 3:1, once a day for 14 days. The dosage was determined based on the results of phase I efficacy and safety trials.

After obtaining subject consent, pharmacokinetic blood samples will be collected for 9 CHB patients and all CHB patients in Phase 2.

The Third stage:

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

Eligible subjects received the trial drug or placebo at a ratio of 3:1 once a day, even Continued administration for 28 days, the dose was comprehensively considered according to the efficacy and safety test results of the first and second phases Yes. Subjects also received the drug acetyl cysteine injection (NAC). After stopping the medication, Participants were followed for 90 days for safety. During the study, subjects will be visited at planned sites Clinical laboratory examination, vital signs, physical examination, 12-lead electrocardiogram examination, and abdominal B were performed Ultrasound, cardiac color ultrasound, biomarker detection, MELD score, AARC score, survival status assessment, AE was also monitored and concomitant/concomitant medication was recorded.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 97
• Est. completion date: March 31, 2026
• Est. primary completion date: September 25, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:The first stage:

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

1. Age is 18 and 60 years old, gender is unlimited;

2. Patients with clinical diagnosis of hepatocyte injury or combination of liver injury or CHB who have been infected with hepatitis B virus for more than 6 months (refer to the "Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2019 edition)"), CHB patients may be screened for etiology (HBsAg positive and/or HBV DNA positive) or clinical or pathological evidence (liver tissue biopsy results).Indicates that hepatitis B virus infection has been more than 6 months);

3. Serum ALT: 2~ 10×ULN, TBil:< 5 x ULN;

4. DILI patients: the abnormal duration of liver biochemical indexes [ALT, AST, ALP, ? -glutamyl-transpeptidase (GGT), TBil, albumin, and prothrombin time] is not more than 90 days;

5. 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;

6. 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:

1. Age is 18 and 60 years old, and gender is unlimited;

2. Patients with clinical diagnosis of hepatocyte injury or combination of liver injury or CHB who have been infected with hepatitis B virus for more than 6 months (refer to the "Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2019 edition)"), CHB patients may be screened for etiology (HBsAg positive and/or HBV DNA positive) or clinical or pathological evidence (liver tissue biopsy results).Indicates that hepatitis B virus infection has been more than 6 months);

3. Subject serum ALT: 5~20 × upper limit of normal value (ULN), TBil: <10 × ULN;

4. DILI patients: the abnormal duration of liver biochemical indexes [ALT, AST, ALP, ? -glutamyl-transpeptidase (GGT), TBil, albumin, and prothrombin time] is not more than 90 days;

5. 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;

6. 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:

1. Age is 18 and 70 years old, gender is unlimited;

2. 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);

3. 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.

4. 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:

1. According to the researchers, the subjects were patients with cholestatic liver injury.

2. Previous diagnosis of cirrhosis or the liver hardness determination in the screening time (LSM)=12.4kPa;

3. Severe severe or life-threatening heart, lung, brain, kidney, gastrointestinal and systemic diseases, patients with malignant tumors;

4. The following laboratory inspection values or inspection values are abnormal:

1. Blood routine: Platelet (PLT) < 75×109/L , Hemoglobin (HGB) < 90 g / L;

2. Prothrombin activity was < 40%, and prothrombin time (PT) was prolonged for > 5s;

3. Left ventricular ejection fraction (LVEF) was <50%;

5. Allergic or intolerant to trial drugs, or allergic constitution;

6. Subjects were unable to express their own complaints, such as psychosis and severe neurosis;

7. Poor compliance and they cannot collaborate;

8. Pregnant women, lactating women, or women of childbearing age preparing to conceive;

9. Participating in other clinical trials within 3 months;

10. Patients who have used ursodeoxycholic acid other than adenosine methionine within 3 days before randomization;

11. 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:

1. According to the researchers, the subjects were patients with cholestatic liver injury.

2. Previous diagnosis of cirrhosis or the liver hardness determination in the screening time (LSM)=9.0 kPa;(LSM exclusion criteria may be based onThe first stage test results are adjusted);

3. Severe severe or life-threatening heart, lung, brain, kidney, gastrointestinal and systemic diseases, patients with malignant tumors;

4. The following laboratory inspection values or inspection values are abnormal:

1. Blood routine: Platelet (PLT) < 75×109/L , Hemoglobin (HGB) < 90 g / L;

2. Prothrombin activity was < 40%, and prothrombin time (PT) was prolonged for > 5s;

3. Left ventricular ejection fraction (LVEF) was < 50%;

5. Allergic or intolerant to trial drugs, or allergic constitution;

6. Subjects were unable to express their own complaints, such as psychosis and severe neurosis;

7. Poor compliance and they cannot collaborate;

8. Pregnant women, lactating women, or women of childbearing age preparing to conceive;

9. Participating in other clinical trials within 3 months;

10. Patients who have used ursodeoxycholic acid other than adenosine methionine within 3 days before randomization;

11. 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:

1. Those who have completed the liver transplantation, or plan to do it within 1 month;

2. Severe grade 3 ascites or refractory ascites;

3. Patients with associated grade 3 hepatic encephalopathy;

4. Those who had received artificial liver treatment within 1 week prior to screening period;

5. 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;

6. 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;

7. The following acute kidney injury (AKI) patients are defined as meeting one of the following conditions:

1. 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;

2. the Scr increased by more than 1.5 times or more than the base value within 7 days ;

3. Urinary volume was decreased (<0.5 ml/kg / h) and lasted for more than 6 hours;

8. Allergic or intolerant to trial drugs, or allergic constitution;

9. Subjects were unable to express their own complaints, such as psychosis and severe neurosis;

10. Poor compliance and they cannot collaborate;

11. Pregnant women, lactating women, or women of childbearing age preparing to conceive;

12. Participating in other clinical trials within 3 months;

13. The investigator considered any circumstances unsuitable for inclusion. -

Related Conditions & MeSH terms

• Acute Liver Failure
• Acute-On-Chronic Liver Failure
• End Stage Liver Disease
• Hepatic Insufficiency
• Liver Failure
• Liver Failure, Acute

Intervention

Drug:
• F573 for injection
The first 16 patients with liver injury were given doses of 0.5, 1.0 and 2.0 mg/kg,2 mL,intramuscular injection (IM),once a day for 7 daysand. the subsequent 9 patients with CHB were given doses of 2 mL intramuscular injection (IM), once a day for 7 days, according to the results of the efficacy and safety trials of the first 16 patients. The dose of the second stage was determined according to the results of the efficacy and safety trials in the first stage. The dose volume was 2 mL, and was administered intramuscular injection (IM) once a day for 14 days. The dosage of the third stage was determined according to the results of the first and second stage efficacy and safety trials. The dosage volume was 2 mL and intramuscular injection (IM) was administered once a day for 28 consecutive days. The dosage of the above three stages of administration was calculated according to the weight of the most recent visit
• 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 stages were administered once a day for 7 days and second stages were administered once a day for 14 days. The third stage was administered once a day for 28 days.

Locations

Country	Name	City	State
China	First Hospital of Jilin University	Changchun	Ji Lin
China	Heze Municipal Hospital	Heze	Shandong
China	Affiliated Hospital of Southwest Medical University	Luzhou	Sichuan
China	Pingxiang Second People's Hospital	Pingxiang	Jiangxi P
China	Qingyuan People's Hospital (Sixth Affiliated Hospital of Guangzhou Medical University)	Qingyuan	Guangdong
China	Shiyan City Taihe Hospital	Shiyan	Hubei

Sponsors (1)

Lead Sponsor	Collaborator
Beijing Continent Pharmaceutical Co, Ltd.

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events (AE), serious adverse events (SAE)	to record Adverse events and serious adverse events in the trial	7 days of administration in the first stage and 14 days of administration in the second stage
Primary	Adverse events (AE), serious adverse events (SAE)	to record Adverse events and serious adverse events in the trial	28 days of follow-up in the first and second stages
Primary	clinical laboratory tests :blood routine	blood routine report contains the following values: RBC,WBC,NE%,LY%,HGB,PLT.	7 days of administration in the first stage and 14 days of administration in the second stage
Primary	clinical laboratory tests :blood routine	blood routine report contains the following values: RBC,WBC,NE%,LY%,HGB,PLT.	28 days of follow-up in the first and second stages
Primary	clinical laboratory tests :blood biochemistry	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.	7 days of administration in the first stage and 14 days of administration in the second stage
Primary	clinical laboratory tests :blood biochemistry	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.	28 days of follow-up in the first and second stages
Primary	clinical laboratory tests : urine routine	urine routine report contains the following values: GLU,PRO,RBC,WBC.	7 days of administration in the first stage and 14 days of administration in the second stage
Primary	clinical laboratory tests : urine routine	urine routine report contains the following values: GLU,PRO,RBC,WBC.	28 days of follow-up in the first and second stages
Primary	clinical laboratory tests :blood coagulation function	blood coagulation function report contains the following values: TT, APTT, PT, INR.	7 days of administration in the first stage and 14 days of administration in the second stage
Primary	clinical laboratory tests :blood coagulation function	blood coagulation function report contains the following values: TT, APTT, PT, INR.	28 days of follow-up in the first and second stages
Primary	12-lead electrocardiogram (ECG)	12-lead electrocardiogram (ECG) report contains the following values: HR, BP,DP,PR intervals,QRS intervals,QT intervals,QTc intervals.	7 days of administration in the first stage and 14 days of administration in the second stage
Primary	12-lead electrocardiogram (ECG)	12-lead electrocardiogram (ECG) report contains the following values: HR, BP,DP,PR intervals,QRS intervals,QT intervals,QTc intervals.	28 days of follow-up in the first and second stages
Primary	All-cause mortality	All-cause mortality within 28 days after completion of dosing.	28 days after completion of dosing in the third stage
Primary	All-cause mortality	All-cause mortality within 90 days after completion of dosing.	90 days after completion of dosing in the third stage
Secondary	Basin alanine aminotransferase (ALT)	ALT values reflect hepatocyte injury	after 7 days of administration in the first and second stages
Secondary	Basin alanine aminotransferase (ALT)	ALT values reflect hepatocyte injury	after 14 days of administration in the first and second stages
Secondary	Basin alanine aminotransferase (ALT)	ALT values reflect hepatocyte injury	28 days of follow-up in the first and second stages.
Secondary	peak concentration (Cmax)	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 (AUC0-8). Clearance rate (CL / F), apparent distribution volume (Vz / F), average retention time (MRT), etc.	12 hours after administration in the first and second stages
Secondary	Peak-reaching time (Tmax)	Pharmacokinetic parameters: Peak-reaching time (Tmax)	12 hours after administration in the first and second stages
Secondary	half-life period (T1/2)	Pharmacokinetic parameters: half-life period (T1/2)	12 hours after administration in the first and second stages
Secondary	Blood concentration-area (AUC)	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 (AUC0-8).	12 hours after administration in the first and second stages
Secondary	Clearance rate (CL / F)	Pharmacokinetic parameters: Clearance rate (CL / F).	12 hours after administration in the first and second stages
Secondary	apparent distribution volume (Vz / F)	Pharmacokinetic parameters: apparent distribution volume (Vz / F).	12 hours after administration in the first and second stages
Secondary	average retention time (MRT)	Pharmacokinetic parameters: average retention time (MRT)	12 hours after administration in the first and second stages
Secondary	Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST)	Changes in biomarkers from baseline include ALT, aspartate aminotransferase (AST).	after 7 days of administration in the first and second stages
Secondary	total bilirubin (TBil)	Changes in biomarkers from baseline include total bilirubin (TBil).	after 7 days of administration in the first and second stages
Secondary	prothrombin activity (PTA)	Changes in biomarkers from baseline include prothrombin activity (PTA).	after 7 days of administration in the first and second stages
Secondary	international normalized ratio (INR)	Changes in biomarkers from baseline include international normalized ratio (INR).	after 7 days of administration in the first and second stages
Secondary	alkaline phosphatase (ALP)	Changes in biomarkers from baseline include alkaline phosphatase (ALP)	after 7 days of administration in the first and second stages
Secondary	Alpha-fetoprotein(AFP)	Changes in biomarkers from baseline include Alpha-fetoprotein (AFP).	after 7 days of administration in the first and second stages
Secondary	CK-18 M30	Changes in biomarkers from baseline include c aspase digested keratin 18M 30 (CK-18 M30)	after 7 days of administration in the first and second stages
Secondary	caspase 3	Changes in biomarkers from baseline include caspase 3	after 7 days of administration in the first and second stages
Secondary	caspase 1	Changes in biomarkers from baseline include caspase 1.	after 7 days of administration in the first and second stages
Secondary	hepatocyte growth factor (HGF)	Changes in biomarkers from baseline include hepatocyte growth factor (HGF)	after 7 days of administration in the first and second stages
Secondary	the end-stage liver disease model (MELD) score	Changes of the end-stage liver disease model (MELD) score. Higher scores indicate more severe disease.	7 days of administration in the third stage secondary outcome
Secondary	the end-stage liver disease model (MELD) score	Changes of the end-stage liver disease model (MELD) score. Higher scores indicate more severe disease.	14 days of administration in the third stage secondary outcome
Secondary	the end-stage liver disease model (MELD) score	Changes of the end-stage liver disease model (MELD) score. Higher scores indicate more severe disease.	28 days of administration in the third stage secondary outcome
Secondary	the end-stage liver disease model (MELD) score	Changes of the end-stage liver disease model (MELD) score. Higher scores indicate more severe disease.	28 days of follow-up in the third stage secondary outcome
Secondary	the end-stage liver disease model (MELD) score	Changes of the end-stage liver disease model (MELD) score. Higher scores indicate more severe disease.	90 days of follow-up in the third stage secondary outcome
Secondary	ACLF Research Consortium (AARC) score	Changes of ACLF Research Consortium (AARC) score. Higher scores indicate more severe disease.	7 days of administration in the third stage
Secondary	ACLF Research Consortium (AARC) score	Changes of ACLF Research Consortium (AARC) score. Higher scores indicate more severe disease.	14 days of administration in the third stage
Secondary	ACLF Research Consortium (AARC) score	Changes of ACLF Research Consortium (AARC) score. Higher scores indicate more severe disease.	28 days of administration in the third stage
Secondary	ACLF Research Consortium (AARC) score	Changes of ACLF Research Consortium (AARC) score. Higher scores indicate more severe disease.	28 days of follow-up in the third stage
Secondary	ACLF Research Consortium (AARC) score	Changes of ACLF Research Consortium (AARC) score. Higher scores indicate more severe disease.	90 days of follow-up in the third stage
Secondary	Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST)	Changes in biomarkers compared to baseline include ALT and AST.	7 days of administration in the third stage
Secondary	Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST)	Changes in biomarkers compared to baseline include ALT and AST.	14 days of administration in the third stage
Secondary	Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST)	Changes in biomarkers compared to baseline include ALT and AST.	28 days of administration in the third stage
Secondary	Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST)	Changes in biomarkers compared to baseline include ALT and AST.	28 days of follow-up in the third stage
Secondary	Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST)	Changes in biomarkers compared to baseline include ALT and AST.	90 days of follow-up in the third stage
Secondary	total bilirubin (TBil)	Changes in biomarkers compared to baseline include TBil.	7 days of administration in the third stage
Secondary	total bilirubin (TBil)	Changes in biomarkers compared to baseline include TBil.	14 days of administration in the third stage
Secondary	total bilirubin (TBil)	Changes in biomarkers compared to baseline include TBil.	28 days of administration in the third stage
Secondary	total bilirubin (TBil)	Changes in biomarkers compared to baseline include TBil.	28 days of follow-up in the third stage
Secondary	total bilirubin (TBil)	Changes in biomarkers compared to baseline include TBil.	90 days of follow-up in the third stage
Secondary	prothrombin activity (PTA)	Changes in biomarkers compared to baseline include PTA.	7 days of administration in the third stage
Secondary	prothrombin activity (PTA)	Changes in biomarkers compared to baseline include PTA.	14 days of administration in the third stage
Secondary	prothrombin activity (PTA)	Changes in biomarkers compared to baseline include PTA.	28 days of administration in the third stage
Secondary	prothrombin activity (PTA)	Changes in biomarkers compared to baseline include PTA.	28 days of follow-up in the third stage
Secondary	prothrombin activity (PTA)	Changes in biomarkers compared to baseline include PTA.	90 days of follow-up in the third stage
Secondary	international normalized ratio (INR)	Changes in biomarkers compared to baseline include international normalized ratio (INR).	7 days of administration in the third stage
Secondary	international normalized ratio (INR)	Changes in biomarkers compared to baseline include international normalized ratio (INR).	14 days of administration in the third stage
Secondary	international normalized ratio (INR)	Changes in biomarkers compared to baseline include international normalized ratio (INR).	28 days of administration in the third stage
Secondary	international normalized ratio (INR)	Changes in biomarkers compared to baseline include international normalized ratio (INR).	90 days of follow-up in the third stage
Secondary	alkaline phosphatase (ALP)	Changes in biomarkers compared to baseline include alkaline phosphatase (ALP).	7 days of administration in the third stage
Secondary	alkaline phosphatase (ALP)	Changes in biomarkers compared to baseline include alkaline phosphatase (ALP).	14 days of administration in the third stage
Secondary	alkaline phosphatase (ALP)	Changes in biomarkers compared to baseline include alkaline phosphatase (ALP).	28 days of administration in the third stage
Secondary	alkaline phosphatase (ALP)	Changes in biomarkers compared to baseline include alkaline phosphatase (ALP).	28 days of follow-up in the third stage
Secondary	alkaline phosphatase (ALP)	Changes in biomarkers compared to baseline include alkaline phosphatase (ALP).	90 days of follow-up in the third stage
Secondary	Alpha-fetoprotein(AFP)	Changes in biomarkers compared to baseline include Alpha-fetoprotein(AFP) .	7 days of administration in the third stage
Secondary	Alpha-fetoprotein(AFP)	Changes in biomarkers compared to baseline include Alpha-fetoprotein(AFP) .	14 days of administration in the third stage
Secondary	Alpha-fetoprotein(AFP)	Changes in biomarkers compared to baseline include Alpha-fetoprotein(AFP) .	28 days of administration in the third stage
Secondary	Alpha-fetoprotein(AFP)	Changes in biomarkers compared to baseline include Alpha-fetoprotein(AFP) .	28 days of follow-up in the third stage
Secondary	Alpha-fetoprotein(AFP)	Changes in biomarkers compared to baseline include Alpha-fetoprotein(AFP) .	90 days of follow-up in the third stage
Secondary	CK-18 M30	Changes in biomarkers from baseline include c aspase digested keratin 18M 30 (CK-18 M30)	7 days of administration in the third stage
Secondary	CK-18 M30	Changes in biomarkers from baseline include c aspase digested keratin 18M 30 (CK-18 M30)	14 days of administration in the third stage
Secondary	CK-18 M30	Changes in biomarkers from baseline include c aspase digested keratin 18M 30 (CK-18 M30)	28 days of administration in the third stage
Secondary	CK-18 M30	Changes in biomarkers from baseline include c aspase digested keratin 18M 30 (CK-18 M30)	28 days of follow-up in the third stage
Secondary	CK-18 M30	Changes in biomarkers from baseline include c aspase digested keratin 18M 30 (CK-18 M30)	90 days of follow-up in the third stage
Secondary	caspase 3	Changes in biomarkers from baseline include caspase 3	7 days of administration in the third stage
Secondary	caspase 3	Changes in biomarkers from baseline include caspase 3	14 of administration in the third stage
Secondary	caspase 3 / 7	Changes in biomarkers from baseline include caspase 3	28 days of administration in the third stage
Secondary	caspase 3	Changes in biomarkers from baseline include caspase 3	28 days of follow-up in the third stage
Secondary	caspase 3	Changes in biomarkers from baseline include caspase 3	90 days of follow-up in the third stage
Secondary	caspase 1	Changes in biomarkers from baseline include caspase 1.	7 days of administration in the third stage
Secondary	caspase 1	Changes in biomarkers from baseline include caspase 1.	14 days of administration in the third stage
Secondary	caspase 1	Changes in biomarkers from baseline include caspase 1.	28 days of administration in the third stage
Secondary	caspase 1	Changes in biomarkers from baseline include caspase 1.	28 days of follow-up in the third stage
Secondary	caspase 1	Changes in biomarkers from baseline include caspase 1.	90 days of follow-up in the third stage
Secondary	hepatocyte growth factor (HGF)	Changes in biomarkers from baseline include hepatocyte growth factor (HGF)	7 days of administration in the third stage
Secondary	hepatocyte growth factor (HGF)	Changes in biomarkers from baseline include hepatocyte growth factor (HGF)	14 days of administration in the third stage
Secondary	hepatocyte growth factor (HGF)	Changes in biomarkers from baseline include hepatocyte growth factor (HGF)	28 days of administration in the third stage
Secondary	hepatocyte growth factor (HGF)	Changes in biomarkers from baseline include hepatocyte growth factor (HGF)	28 days of follow-up in the third stage
Secondary	hepatocyte growth factor (HGF)	Changes in biomarkers from baseline include hepatocyte growth factor (HGF)	90 days of follow-up in the third stage
Secondary	Adverse events (AE), serious adverse events (SAE)	Adverse events (AE), serious adverse events (SAE) in the third stage at 28 days	28 days of follow-up in the third stage.
Secondary	Adverse events (AE), serious adverse events (SAE)	Adverse events (AE), serious adverse events (SAE) in the third stage at 28 days	90 days of follow-up in the third stage.
Secondary	clinical laboratory tests :blood routine	blood routine report contains the following values: RBC,WBC,NE%,LY%,HGB,PLT.	28 days of follow-up ihe third stage.
Secondary	clinical laboratory tests :blood routine	blood routine report contains the following values: RBC,WBC,NE%,LY%,HGB,PLT.	90 days of follow-up ihe third stage.
Secondary	clinical laboratory tests :blood biochemistry	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.	28 of follow-up ihe third stage.
Secondary	clinical laboratory tests :blood biochemistry	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.	90 days of follow-up ihe third stage.
Secondary	clinical laboratory tests :urine routine	urine routine report contains the following values: GLU,PRO,RBC,WBC.	28 days of follow-up ihe third stage.
Secondary	clinical laboratory tests :urine routine	urine routine report contains the following values: GLU,PRO,RBC,WBC.	90 days of follow-up ihe third stage.
Secondary	clinical laboratory tests :blood coagulation function	blood coagulation function report contains the following values: TT, APTT, PT, INR.	28 days of follow-up ihe third stage.
Secondary	clinical laboratory tests :blood coagulation function	blood coagulation function report contains the following values: TT, APTT, PT, INR.	90 days of follow-up ihe third stage.
Secondary	12-lead electrocardiogram (ECG)	12-lead electrocardiogram (ECG) report contains the following values: HR, BP,DP,PR intervals,QRS intervals,QT intervals,QTc intervals.	28 days of follow-up ihe third stage.
Secondary	12-lead electrocardiogram (ECG)	12-lead electrocardiogram (ECG) report contains the following values: HR, BP,DP,PR intervals,QRS intervals,QT intervals,QTc intervals.	90 days of follow-up ihe third stage.