F573 for Injection for the Treatment of Liver Injury/Failure

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.

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. -