F573 for Injection for the Treatment of Liver Injury/Failure : Randomized, Double-blind, Placebo-controlled Phase Ⅱa Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 97
- 试验地点
- 10
- 主要终点
- Adverse events (AE), serious adverse events (SAE)
研究概览
简要总结
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.).
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •（1）The first stage:
- •Participants who meet all of the following criteria will be enrolled in the study:
- •Age ≥18 and ≤60 years old, gender is not limited;
- •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.
- •Serum ALT: 2~ 10× upper limit of normal (ULN), TBil: <5×ULN;
- •DILI patients: the abnormal duration of liver biochemical indexes [ALT, AST, ALP, gamma-glutamyltranspeptides (GGT), TBil, albumin, prothrombin time] does not exceed 90 days;
- •The subject (including the partner) is willing to take effective contraceptive measures from the screening until 6 months after the last test drug administration;
- •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 meeting all of the following criteria will be included in the study:
- •Age ≥ 18 and ≤ 65 years old, with no gender restrictions;
- •According to the "Chinese Guidelines for the Diagnosis and Treatment of Drug-Induced Liver Injury (2023 Edition)", patients diagnosed with drug-induced liver injury (DILI) or those diagnosed with intrahepatic cholestasis type liver injury. Patients with DILI and intrahepatic cholestasis type liver injury need to meet the following criteria separately;
- •Patients with DILI need to simultaneously meet the following conditions: ① Serum ALT > 3 times the upper limit of normal (ULN), and TBil > 2 times the ULN (the ULN of TBil refers to 17.1 μmol/L according to international standards); ② Abnormal liver biochemical indicators (ALT, AST, ALP, TBil) persist for no more than 60 days;
- •Patients with intrahepatic cholestasis type liver injury need to simultaneously meet the following conditions: ① TBil > 2 times the ULN (the ULN of TBil refers to 17.1 μmol/L); ② ALP > 1.5 times the ULN; ③ALT>1×ULN;
- •The subjects (including their partners) are willing to voluntarily adopt effective contraceptive measures from the time of the initial screening until 6 months after the last administration of the investigational drug;
- •They have signed the informed consent form and can comply with the requirements of the protocol; if the subjects are unable to sign the informed consent form, it must be signed by a legal guardian or a 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;
- •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);
- •The subject (including the partner) is willing to take effective contraceptive measures from the screening until 6 months after the last trial drug administration;
- •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.
排除标准
- •The first stage:
- •Subjects meeting one of the following conditions will not be included in the trial:
- •According to the investigator's judgment, the subjects were patients with cholestatic liver injury;
- •Previous diagnosis of cirrhosis or liver hardness determination (LSM) at screening ≥ 12.4kPa;
- •Patients with severe or life-threatening heart, lung, brain, kidney, gastrointestinal and systemic diseases, and patients with malignant tumors;
- •There are the following laboratory test values or abnormal test values:
- •Blood routine: platelet (PLT) <75× 109/L, hemoglobin (HGB) <90 g/L;
- •Prothrombin activity <40%, prothrombin time (PT) extended >5 s;
- •Left ventricular ejection fraction (LVEF) <50%;
- •Allergic or intolerant to the investigational drug, or allergic;
- •The subject is unable to express his main complaint, such as mental illness and severe neurosis;
- •Poor compliance can not partner;
- •Pregnant women, breastfeeding women or women of childbearing age who are trying to conceive;
- •Participants in other clinical trials within 3 months;
- •Patients who had used liver protection drugs other than ursodeoxycholic acid or adenosylmethionine within 3 days before randomization;
- •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:
- •The diagnosis is advanced liver cirrhosis (with complications such as ascites and hepatic encephalopathy), or liver cancer, or when liver stiffness measurement (LSM) is ≥ 18.0 kPa during screening.
- •Patients with severe or life-threatening heart, lung, brain, kidney, gastrointestinal and systemic diseases are malignantTumor patients;
- •There are the following laboratory test values or abnormal test values:
- •Blood routine: platelet (PLT) <100×109/L, hemoglobin (HGB) <100 g/L;
- •INR>1.4, or as determined by the investigator to meet the criteria for severe hepatitis;
- •Left ventricular ejection fraction (LVEF) <50%;
- •Allergic or intolerant to the investigational drug, or allergic;
- •The subject is unable to express his main complaint, such as mental illness and severe neurosis;
- •Poor compliance can not partner;
- •Pregnant women, breastfeeding women or women of childbearing age who are trying to conceive;
- •Participants in other clinical trials within 3 months;
- •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;
- •Patients who had used glucocorticoids or interferon drugs within 3 days before randomization;
- •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:
- •Patients who have completed liver transplantation or plan to undergo liver transplantation within 1 month;
- •Severe grade 3 ascites or stubborn ascites;
- •Patients with ≥ grade 3 hepatic encephalopathy;
- •Patients who received artificial liver treatment within 1 week before screening;
- •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;
- •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;
- •Patients with acute kidney injury (AKI), defined as meeting one of the following conditions:
- •Serum creatinine (Scr) increased ≥26.5 μmol/L (0.3 mg/dL, 1 mg/dL=88.4 μmol/L) within 48 h;
- •The Scr increase exceeds 1.5 times or more of the base value within 7 days;
- •Decreased urine volume (<0.5 mL/kg/h) for more than 6 hours;
- •Allergic or intolerant to the investigational drug, or allergic;
- •The subject is unable to express his main complaint, such as mental illness and severe neurosis;
- •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;
- •The researcher considers any circumstances unsuitable for inclusion.
研究组 & 干预措施
F573 for injection groups
The first stage:the first 16 patients with liver injury were given doses of 0.5, 1.0 and 2.0 mg/kg, and the subsequent 9 patients with CHB were given doses of 2.0 mg/kg, with an administration volume of 2 mL and intramuscular injection (IM) according to the efficacy and safety test results of the first 16 patients. The dose was given once a day for 7 days and calculated according to the weight of the last visit.
The second stage:According to the results of Phase I efficacy and safety trials, the dosage was determined to be 0.5 mg/kg and 2.0 mg/kg, the dosage volume was 2 mL, intramuscular injection (IM), once a day for 14 days, and the dosage was calculated according to the weight of the latest visit.
The third stage:The dosage was determined according to the results of the first and second phase efficacy and safety trials. The dosage volume was 2 mL, intramuscular injection (IM), once a day for 28 consecutive days, and the dosage was calculated according to the weight of the latest
干预措施: F573 for injection (Drug)
Placebo Comparator
- The first stage: The dosage was 2 mL by intramuscular injection (IM) once a day for 7 days.
Basic treatment: enteric-coated diammonium glycyrrhizinate capsules were administered at a dose of 150 mg 3 times a day. 2. The second stage: The dosage was 2 mL by intramuscular injection (IM) once a day for 14 days.
Basic treatment: Polyene phosphatidylcholines and glutathione drugs (no restricted dosage forms) are accepted as basic treatment. 3. 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. Basic treatment: receive acetylcysteine injection at a dose of 8 g / d once a day.
干预措施: Sterilizing water for injection (Drug)
结局指标
主要结局
Adverse events (AE), serious adverse events (SAE)
时间窗: followed up for 28 days in the first stage and followed up for 14 days in the second stage
to record Adverse events and serious adverse events in the trial
clinical laboratory tests ：blood routine
时间窗: followed up for 28 days in the first stage and followed up for 14 days in the second stage
blood routine report contains the following values: RBC,WBC,NE%,LY%,HGB,PLT.
clinical laboratory tests ：blood biochemistry
时间窗: followed up for 28 days in the first stage and followed up for 14 days in the second 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
时间窗: followed up for 28 days in the first stage and followed up for 14 days in the second stage
urine routine report contains the following values: GLU,PRO,RBC,WBC.
clinical laboratory tests ：blood coagulation function
时间窗: followed up for 28 days in the first stage and followed up for 14 days in the second stage
blood coagulation function report contains the following values: TT, APTT, PT, INR.
12-lead electrocardiogram (ECG)
时间窗: followed up for 28 days in the first stage and followed up for 14 days in the second stage
12-lead electrocardiogram (ECG) report contains the following values: HR, BP,DP,PR intervals,QRS intervals,QT intervals,QTc intervals.
All-cause mortality
时间窗: 90 days after completion of dosing in the third stage
All-cause mortality within 90 days after completion of dosing.
次要结局
- Basin alanine aminotransferase (ALT)(followed up for 28 days in the first stage and followed up for 14 days in the second stage)
- peak concentration (Cmax)(12 hours after administration in the first and second stages)
- Peak-reaching time (Tmax)(12 hours after administration in the first and second stages)
- half-life period (T1/2)(12 hours after administration in the first and second stages)
- Blood concentration-area (AUC)(12 hours after administration in the first and second stages)
- Clearance rate (CL / F)(12 hours after administration in the first and second stages)
- apparent distribution volume (Vz / F)(12 hours after administration in the first and second stages)
- average retention time (MRT)(12 hours after administration in the first and second stages)
- Aspartate aminotransferase (AST)(after 7 days of administration in the first and 14 days of administration in second stages)
- total bilirubin (TBil)(90 days of follow-up in the third stage)
- prothrombin activity (PTA)(90 days of follow-up in the third stage)
- international normalized ratio (INR)(90 days of follow-up in the third stage)
- alkaline phosphatase (ALP)(90 days of follow-up in the third stage)
- Alpha-fetoprotein(AFP)(90 days of follow-up in the third stage)
- CK-18 M30(90 days of follow-up in the third stage)
- caspase 3(90 days of follow-up in the third stage)
- caspase 1(90 days of follow-up in the third stage)
- hepatocyte growth factor (HGF)(90 days of follow-up in the third stage)
- the end-stage liver disease model (MELD) score(90 days of follow-up in the third stage secondary outcome)
- ACLF Research Consortium (AARC) score(90 days of follow-up in the third stage)
- Basin alanine aminotransferase (ALT) and aspartate aminotransferase (AST)(90 days of follow-up in the third stage)
- caspase 3 / 7(28 days of administration in the third stage)
- Adverse events (AE), serious adverse events (SAE)(90 days of follow-up in the third stage.)
- clinical laboratory tests ：blood routine(90 days of follow-up ihe third stage.)
- clinical laboratory tests ：blood biochemistry(90 days of follow-up ihe third stage.)
- clinical laboratory tests ：urine routine(90 days of follow-up ihe third stage.)
- clinical laboratory tests ：blood coagulation function(90 days of follow-up ihe third stage.)
- 12-lead electrocardiogram (ECG)(90 days of follow-up ihe third stage.)