AS1501 in ACLF: a two-stage dose study in adults with acute-on-chronic liver failure

Stage IIa - Main inclusion criteria

1. The age of the signatories to the informed consent form must range from 18 to 75 years old (including the boundary values).
2. During screening, chronic plus acute liver failure was diagnosed based on the Guidelines for Diagnosis and Treatment of Liver Failure (2018 Edition) issued by the Liver Failure and Artificial Liver Group of the Infectious Diseases Branch of the Chinese Medical Association and the Severe Liver Disease and Artificial Liver Group of the Hepatology Branch of the Chinese Medical Association. Patients were in the early stage of acute liver failure (ACLF) and did not meet the criteria for liver transplantation.

   Early manifestations of ACLF:

   Severe fatigue accompanied by significant gastrointestinal symptoms such as marked anorexia, vomiting, and abdominal distension; ALT and/or AST levels remain significantly elevated, with progressive worsening of jaundice (TBil ≥ 171 μmol/L or daily increase ≥ 17.1 μmol/L); Hemorrhagic tendency is present in 30% of cases with PTA values ranging from \<30% to ≤40% (or INR values between 1.5 and \<1.9).

   No complications or other extrahepatic organ failures were observed.
3. During the screening phase, serum TRAIL levels are elevated to ≥2 times that of normal individuals, or NK cell membrane-type TRAIL expression is increased.
4. Can comprehend the informed consent form, voluntarily participate in it, and sign it;
5. Capable of completing the trial in accordance with the study protocol;
6. Participants (including their partners) are willing to voluntarily adopt effective contraceptive measures from the screening stage through 6 months after the last administration of the investigational drug.

Stage IIb - Main inclusion criteria Individuals who do not meet any of the following criteria shall not be enrolled as subjects.

1. The age of the signatories to the informed consent form must range from 18 to 75 years old (including the boundary values).
2. The screening criteria were based on the "Guidelines for Diagnosis and Treatment of Liver Failure (2018 Edition)" issued by the Liver Failure and Artificial Liver Group of the Infectious Diseases Branch of the Chinese Medical Association and the Severe Liver Disease and Artificial Liver Group of the Hepatology Branch of the Chinese Medical Association, requiring a diagnosis of chronic plus acute liver failure at an early or intermediate stage of ACLF (Acute Complicated Liver Failure) and failure to meet the eligibility criteria for liver transplantation.

   Early manifestations of liver failure:

   Severe fatigue accompanied by significant gastrointestinal symptoms such as marked anorexia, vomiting, and abdominal distension; ALT and/or AST levels remain significantly elevated, with progressive worsening of jaundice (TBil ≥ 171 μmol/L or daily increase ≥ 17.1 μmol/L); Hemorrhagic tendency is present in 30% of cases with PTA values ranging from \<30% to ≤40% (or INR values between 1.5 and \<1.9).

   No complications or other extrahepatic organ failures were observed.

   Mid-stage manifestations of liver failure:

   Based on the early manifestations of liver failure, the condition further progresses.

   ALT and/or AST levels decline rapidly, while TBil continues to rise. The bleeding is evident (with petechiae or ecchymoses), with 20% \<PTA ≤ 30% (or 1.9 ≤ INR \<2.6).

   Associated with one complication and/or one extrahepatic organ failure.
3. During the screening phase, serum TRAIL levels are elevated to ≥2 times that of normal individuals, or NK cell membrane-type TRAIL expression is increased.
4. Can comprehend the informed consent form, voluntarily participate in it, and sign it;
5. Can comply with the study protocol and complete the trial.
6. Participants (including their partners) are willing to voluntarily adopt effective contraceptive measures from the screening stage through 6 months after the last administration of the investigational drug.

Stage IIa - Main exclusion criteria

1. Patients with a history of allergic predisposition or severe hypersensitivity to protein-based drugs (CTCAE v5.0 grade\>3);
2. Patients who have undergone liver transplantation or plan to undergo liver transplantation within 1 month;
3. ACLF patients at intermediate or advanced stages;
4. Severe Grade III ascites or refractory ascites;
5. Associated with stage III-IV hepatic encephalopathy;
6. Patients with concurrent malignant tumors or a history of malignant tumors; those diagnosed with lung cancer, liver cancer, pancreatic cancer, or gastrointestinal tumors through imaging studies (ultrasound, CT, or MRI) and tumor marker tests (e.g., AFP, CEA, CA125, or CA199) during the screening period or within one month prior to it.
7. Patients during the screening period or within 1 month prior to screening whose endoscopic or imaging (abdominal ultrasound, CT, or MRI) findings indicate severe varices with a bleeding risk;
8. The KDIGO criteria for acute kidney injury (AKI) define the following subjects: (1) a serum creatinine (Scr) level increase of ≥26.5 μmol/L (0.3 mg/dL; 1 mg/dL = 88.4 μmol/L) within 48 hours; (2) a Scr increase of ≥1.5 times the baseline value within 7 days; and (3) reduced urine output (\<0.5 ml/kg/h) lasting for more than 6 hours.
9. The following laboratory test values are present or abnormal: a. Complete blood count: platelets (PLT) \<75×10⁹/L, hemoglobin (HGB) \<80 g/L; b. PT-INR ≥1.9 or PTA ≤30%; c. Left ventricular ejection fraction (LVEF) \<50%; serum creatinine\>1.5×ULN.
10. Those with severe respiratory dysfunction, dyspnea, or respiratory failure;
11. Severe infections that cannot be controlled by concomitant medications, including infections of major organs such as the abdominal cavity, lungs, urinary tract, and skin;
12. Individuals who are HIV-positive, or have active pulmonary tuberculosis or syphilis infection;
13. Patients with a history of unstable ischemic heart disease, congestive heart failure, myocardial infarction (MI), stroke, severe arrhythmias, or other related conditions;
14. Patients with severe hypertension or diabetes that cannot be controlled with concomitant medications;
15. Women who are pregnant or breastfeeding, or those with a positive pregnancy test result;
16. Individuals who participated in clinical trials involving other drugs or medical devices within 30 days prior to randomization or during any of the five drug half-life periods;
17. The study subjects must have undergone trauma or major surgery (e.g., requiring general anesthesia) within 28 days prior to the first administration of the investigational drug. Note: Subjects scheduled for surgical procedures under local anesthesia are eligible to participate in the study.
18. Any serious potential medical or psychiatric condition (e.g., alcohol or drug abuse), dementia, or changes in mental status; or any issue that may impair the subject's ability to receive or tolerate the planned treatment at the research center, understand informed consent, or participate in the study, or that investigators consider contraindications for enrollment or potential interference with protocol-defined assessments or study outcomes.
19. The researchers identified other conditions that made participants unsuitable for this study.

Stage IIb - Main exclusion criteria Subjects are ineligible for inclusion in this study if any of the following criteria are met.

1. Patients with a history of allergic predisposition or severe hypersensitivity to protein-based drugs (CTCAE v5.0 grade\>3);
2. Patients who have undergone liver transplantation or plan to undergo liver transplantation within 1 month;
3. Patients with advanced ACLF;
4. Severe Grade III ascites or refractory ascites;
5. Associated with stage III-IV hepatic encephalopathy;
6. Patients with concurrent malignant tumors or a history of malignant tumors; those diagnosed with lung cancer, liver cancer, pancreatic cancer, or gastrointestinal tumors through imaging studies (ultrasound, CT, or MRI) and tumor marker tests (e.g., AFP, CEA, CA125, or CA199) during the screening period or within one month prior to it.
7. Patients during the screening period or within 1 month prior to screening whose endoscopic or imaging (abdominal ultrasound, CT, or MRI) findings indicate severe varices with a bleeding risk;
8. Patients with severe coagulation failure defined as PT-INR ≥ 2.6 or PTA ≤ 20%; complete blood count: platelets (PLT) \<75 × 10⁹/L, hemoglobin (HGB) \<80 g/L;
9. Those with severe respiratory dysfunction, dyspnea, or respiratory failure;
10. Severe infections that cannot be controlled by concomitant medications, including infections of major organs such as the abdominal cavity, lungs, urinary tract, and skin;
11. Individuals who are HIV-positive, or have active pulmonary tuberculosis or syphilis infection;
12. Patients with a history of unstable ischemic heart disease, congestive heart failure, myocardial infarction (MI), stroke, severe arrhythmias, or other related conditions;
13. Patients with severe hypertension or diabetes that cannot be controlled with concomitant medications;
14. Women who are pregnant or breastfeeding, or those with a positive pregnancy test result;
15. Individuals who participated in clinical trials involving other drugs or medical devices within 30 days prior to randomization or during any of the five drug half-life periods;
16. The study subjects must have undergone trauma or major surgery (e.g., requiring general anesthesia) within 28 days prior to the first administration of the investigational drug. Note: Subjects scheduled for surgical procedures under local anesthesia are eligible to participate in the study.
17. Any serious potential medical or psychiatric condition (e.g., alcohol or drug abuse), dementia, or changes in mental status; or any issue that may impair the subject's ability to receive or tolerate the planned treatment at the research center, understand informed consent, or participate in the study, or that investigators consider contraindications for enrollment or potential interference with protocol-defined assessments or study outcomes.

The researchers identified other conditions that made participants unsuitable for this study.