F573 for Injection for the Treatment of Liver Injury/failure

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), intrahepatic cholestatic liver injury, etc.).

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 the experimental drug or placebo at a 1:1:1:1 ratio of 0.5, 1.0, and 2.0 mg/kg. Then, 9 patients with CHB were treated with the experimental drug, and the dose was determined to be 2.0 mg/kg according to the efficacy and safety test results of the 16 patients enrolled first.After subject consent is obtained, pharmacokinetic blood samples will be collected from 9 CHB patients subsequently enrolled in Phase I.

The second stage:A total of 24 patients with liver injury (DILI patients and intrahepatic cholestasis type liver injury) were enrolled, and qualified 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 to be 0.5 mg/kg and 2.0 mg/kg based on the results of phase I efficacy and safety trials. First, a trial was conducted in the 0.5 mg/kg dose group, and 12 subjects were enrolled and treated with the test drug or placebo at a ratio of 3:1, once a day for 14 days. After the 0.5 mg/kg dose group was completed, the experiment of 2.0 mg/kg dose group was carried out. 12 subjects were also enrolled and received the test drug or placebo in a ratio of 3:1, once a day for 14 days.

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 were given the experimental drug or placebo in a ratio of 3:1, once a day for 28 days, and the dose was determined according to the efficacy and safety results of phase I and Phase II trials. Subjects also received the drug acetyl cysteine injection (NAC). After discontinuation, participants were followed for 90 days for safety. During the study, subjects were visited at planned sites for clinical laboratory examination, vital signs, physical examination, 12-lead electrocardiography, abdominal B-ultrasonography, cardiac color ultrasonography, biomarker testing, MELD score, AARC score, survival status assessment, monitoring of AE, and recording of subjects' concomitant/concomitant medications.

Eligibility Criteria:
Inclusion Criteria:

（1）The first stage:

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

1. Age ≥18 and ≤60 years old, gender is not limited;
2. Patients with liver injury clinically diagnosed with hepatocyte injury or mixed liver injury or CHB patients with hepatitis B virus infection for more than 6 months (refer to the "Chronic Hepatitis B Prevention and Treatment Guidelines (2019 edition)"). Screening patients with CHB may provide etiological (HBsAg positive and/or HBV DNA positive) or clinical or pathological evidence (liver tissue biopsy results) that HBV infection has been present for more than 6 months.
3. Serum ALT: 2\~ 10× upper limit of normal (ULN), TBil: \<5×ULN;
4. DILI patients: the abnormal duration of liver biochemical indexes \[ALT, AST, ALP, gamma-glutamyltranspeptides (GGT), TBil, albumin, prothrombin time\] does not exceed 90 days;
5. The subject (including the partner) is willing to take effective contraceptive measures from the screening until 6 months after the last test drug administration;
6. Sign informed consent and be able to comply with the requirements of the program; If the subject is unable to sign the informed consent form, it must be signed by a legal guardian or witness as required by the regulations.

(2)The second stage:

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

1. Age ≥18 and ≤60 years old, gender is not limited;
2. Patients clinically diagnosed with drug-induced liver injury or intrahepatic cholestatic liver injury according to the Chinese Guidelines for Diagnosis and Treatment of drug-induced Liver Injury (2023 edition);
3. Serum ALT of subjects: 5\~20× upper limit of normal (ULN), TBil: 1\~5×ULN (ULN of TBil according to the international standard value of 17.1μmol /L);
4. DILI patients: Abnormal duration of liver biochemical indexes (ALT, AST, ALP, TBil) is notMore than 60 days;
5. Patients with intrahepatic cholestasis liver injury: ALP≥1.5×ULN and ≤10×ULN;
6. The subject (including the partner) is willing to take effective contraceptive measures from the screening until 6 months after the last trial drug administration;
7. Sign informed consent and be able to comply with the requirements of the program; If the subject is unable to sign the informed consent form, it must be signed by a legal guardian or witness as required by the regulations.

The third stage:

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

1. Age ≥18 and ≤70 years old, gender is not limited; 2. Patients diagnosed with chronic and acute liver failure with TBil≥5×ULN according to the "Guidelines for Diagnosis and Treatment of Liver Failure (2018 Edition)" may have hepatic encephalopathy (Grade 1-2) or ascites (grade 1-2) 4 weeks before subject screening. And 5≤AARC score ≤10 (AARC rating I-II); 3. The subject (including the partner) is willing to take effective contraceptive measures from the screening until 6 months after the last trial drug administration; 4. Sign informed consent and comply with the requirements of the program; If the subject is unable to sign the informed consent form, it must be signed by a legal guardian or witness as required by the regulations.

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Exclusion Criteria:

The first stage:

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

1. According to the investigator's judgment, the subjects were patients with cholestatic liver injury;
2. Previous diagnosis of cirrhosis or liver hardness determination (LSM) at screening ≥ 12.4kPa;
3. Patients with severe or life-threatening heart, lung, brain, kidney, gastrointestinal and systemic diseases, and patients with malignant tumors;
4. There are the following laboratory test values or abnormal test values:

   1. Blood routine: platelet (PLT) \<75× 109/L, hemoglobin (HGB) \<90 g/L;
   2. Prothrombin activity \<40%, prothrombin time (PT) extended \>5 s;
   3. Left ventricular ejection fraction (LVEF) \<50%;
5. Allergic or intolerant to the investigational drug, or allergic;
6. The subject is unable to express his main complaint, such as mental illness and severe neurosis;
7. Poor compliance can not partner;
8. Pregnant women, breastfeeding women or women of childbearing age who are trying to conceive;
9. Participants in other clinical trials within 3 months;
10. Patients who had used liver protection drugs other than ursodeoxycholic acid or adenosylmethionine within 3 days before randomization;
11. The researcher considers any circumstances unsuitable for inclusion.

The second stage:

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

1. Previous diagnosis of cirrhosis or liver hardness determination (LSM) at screening ≥ 12.4kPa;
2. Patients with severe or life-threatening heart, lung, brain, kidney, gastrointestinal and systemic diseases are malignantTumor patients;
3. There are the following laboratory test values or abnormal test values:

   1. Blood routine: platelet (PLT) \<100×109/L, hemoglobin (HGB) \<100 g/L;
   2. INR\>1.4, or as determined by the investigator to meet the criteria for severe hepatitis;
   3. Left ventricular ejection fraction (LVEF) \<50%;
4. Allergic or intolerant to the investigational drug, or allergic;
5. The subject is unable to express his main complaint, such as mental illness and severe neurosis;
6. Poor compliance can not partner;
7. Pregnant women, breastfeeding women or women of childbearing age who are trying to conceive;
8. Participants in other clinical trials within 3 months;
9. Patients who had used liver protection drugs other than ursodeoxycholic acid or adenosylmethionine and basic therapeutic drugs (polyene phosphatidylcholines and glutathione drugs) within 3 days before randomization;
10. Patients who had used glucocorticoids or interferon drugs within 3 days before randomization;
11. The researcher considers any circumstances unsuitable for inclusion.

The third stage:

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

1. Patients who have completed liver transplantation or plan to undergo liver transplantation within 1 month;
2. Severe grade 3 ascites or stubborn ascites;
3. Patients with ≥ grade 3 hepatic encephalopathy;
4. Patients who received artificial liver treatment within 1 week before screening;
5. Patients with severe underlying diseases, such as respiratory system, digestive system, circulatory system, endocrine and other diseases and malignant tumors, and patients with severe infections that cannot be controlled by drugs;
6. During the screening period or within 1 month before screening, the results of gastroscopy or imaging (abdominal B-ultrasound, CT or MRI) examination suggest severe varicose veins with bleeding risk;
7. Patients with acute kidney injury (AKI), defined as meeting one of the following conditions:

   1. Serum creatinine (Scr) increased ≥26.5 μmol/L (0.3 mg/dL, 1 mg/dL=88.4 μmol/L) within 48 h;
   2. The Scr increase exceeds 1.5 times or more of the base value within 7 days;
   3. Decreased urine volume (\<0.5 mL/kg/h) for more than 6 hours;
8. Allergic or intolerant to the investigational drug, or allergic;
9. The subject is unable to express his main complaint, such as mental illness and severe neurosis;
10. Poor compliance can not partner; 11 Pregnant women, breastfeeding women or women of childbearing age who are trying to conceive;

12. Participants in other clinical trials within 3 months; 13. The researcher considers any circumstances unsuitable for inclusion.