Overview
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.
Eligibility
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;
- 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);
- Serum ALT: 2~ 10×ULN, TBil:< 5 x 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 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);
- 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.
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Exclusion Criteria:
The first stage:
Subjects meeting one of the following conditions will not be included in the trial:
- According to the researchers, the subjects were patients with cholestatic liver injury.
- Previous diagnosis of cirrhosis or the liver hardness determination in the screening time (LSM)≥12.4kPa;
- 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:
- According to the researchers, the subjects were patients with cholestatic liver injury.
- 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);
- 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. -