F573 for Injection for the Treatment of Liver Injury/Failure

Official title

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

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), intrahepatic cholestatic liver injury, etc.).

Detailed 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 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.

Interventions

• Drug F573 for injection
  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, th
• Drug 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.

Primary outcome measures

• Adverse events (AE), serious adverse events (SAE) [Time frame: 7 days of administration in the first stage and 14 days of administration in the second stage]
• Adverse events (AE), serious adverse events (SAE) [Time frame: followed up for 28 days in the first stage and followed up for 14 days in the second stage]
• clinical laboratory tests ：blood routine [Time frame: 7 days of administration in the first stage and 14 days of administration in the second stage]
• clinical laboratory tests ：blood routine [Time frame: followed up for 28 days in the first stage and followed up for 14 days in the second stage]
• clinical laboratory tests ：blood biochemistry [Time frame: 7 days of administration in the first stage and 14 days of administration in the second stage]
• clinical laboratory tests ：blood biochemistry [Time frame: followed up for 28 days in the first stage and followed up for 14 days in the second stage]
• clinical laboratory tests : urine routine [Time frame: 7 days of administration in the first stage and 14 days of administration in the second stage]
• clinical laboratory tests : urine routine [Time frame: followed up for 28 days in the first stage and followed up for 14 days in the second stage]
• clinical laboratory tests ：blood coagulation function [Time frame: 7 days of administration in the first stage and 14 days of administration in the second stage]
• clinical laboratory tests ：blood coagulation function [Time frame: followed up for 28 days in the first stage and followed up for 14 days in the second stage]

Secondary outcome measures (12)

• Basin alanine aminotransferase (ALT) [Time frame: after 7 days of administration in the first and second stages]
• Basin alanine aminotransferase (ALT) [Time frame: after 14 days of administration in the second stages]
• Basin alanine aminotransferase (ALT) [Time frame: followed up for 28 days in the first stage and followed up for 14 days in the second stage]
• peak concentration (Cmax) [Time frame: 12 hours after administration in the first and second stages]
• Peak-reaching time (Tmax) [Time frame: 12 hours after administration in the first and second stages]
• half-life period (T1/2) [Time frame: 12 hours after administration in the first and second stages]
• Blood concentration-area (AUC) [Time frame: 12 hours after administration in the first and second stages]
• Clearance rate (CL / F) [Time frame: 12 hours after administration in the first and second stages]
• apparent distribution volume (Vz / F) [Time frame: 12 hours after administration in the first and second stages]
• average retention time (MRT) [Time frame: 12 hours after administration in the first and second stages]
• Aspartate aminotransferase (AST) [Time frame: after 7 days of administration in the first and 14 days of administration in second stages]
• total bilirubin (TBil) [Time frame: after 7 days of administration in the first and 14 days of administration in second stages]

Eligibility criteria

Inclusion criteria

（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; 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:

• 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; 13. The researcher considers any circumstances unsuitable for inclusion.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

China · 10 centers

• Beijing You 'an Hospital, Capital Medical University — Beijing
• Qingyuan People's Hospital (Sixth Affiliated Hospital of Guangzhou Medical University) — Qingyuan
• Shiyan City Taihe Hospital — Shiyan
• Hunan Medical College General Hospital (formerly Huaihua City First People's Hospital) — Huaihua
• Pingxiang Second People's Hospital — Pingxiang
• First Hospital of Jilin University — Changchun
• The Affiliated Hospital of Binzhou Medical University — Binzhou
• Heze Municipal Hospital — Heze
• … and 2 more centers

Identifiers

NCT: NCT05689645 · KDN-F573-202202

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗