A Phase II Clinical Trial to Evaluate the Safety and Efficacy of Injectable AS1501 in the Treatment of Acute-on-chronic Liver Failure (ACLF)
\*\*Document Name: This Trial is a Phase II Clinical Study.docx\*\* \*\*Document Content:\*\* * This trial is a Phase II clinical study, conducted in two stages: * \*\*Phase IIa:\*\* A sentinel, single-arm design will be employed. A total of 12 early ACLF subjects are expected to be enrolled in the 0.5 mg/kg dose group. The first 2 subjects will serve as sentinels and be enrolled sequentially to receive a single intravenous dose. If no drug-related SAEs (Serious Adverse Events) occur in these 2 sentinel subjects within 2 weeks after the first dose, the remaining 10 subjects will be enrolled. Otherwise, the dose will be reduced for further exploration. After receiving a single intravenous dose, subjects will undergo a 20-day washout period. If no drug-related ≥Grade 3 AEs (Adverse Events) occur during this 20-day washout period, and safety/tolerability is jointly confirmed by the investigator and sponsor, the subject will enter the multiple-dose phase (once weekly \[Day 21 as the first dose of multiple administration\], for 4 consecutive weeks). If any drug-related ≥Grade 3 AE occurs, the dose will be reduced for further exploration, with the specific dose determined by the sponsor and investigator. If a subject drops out during the washout period after a single dose, additional subjects may be enrolled to ensure at least 12 subjects enter the multiple-dose phase. * After all 12 early ACLF subjects in the 0.5 mg/kg dose group complete continuous dosing, the DMC (Data Monitoring Committee) will assess the safety of this dose group. If any of the following occur in the 0.5 mg/kg group, the DMC will discuss whether to proceed with dose escalation: \> 1) ≥1/3 of subjects experience drug-related Grade 3 SAEs; \> 2) Any drug-related Grade 4 or higher SAEs. * If the DMC determines that dose escalation criteria are met, an additional 12 early ACLF subjects will be enrolled to receive the 1 mg/kg dose group. The same enrollment rules as the 0.5 mg/kg group apply: the first 2 subjects are sentinels receiving a single intravenous dose. If no drug-related SAEs occur in these sentinels within 2 weeks post-dose, the remaining 10 subjects will be enrolled. Post-single-dose administration, subjects will undergo a 20-day washout period. If no drug-related ≥Grade 3 AEs occur during this period, and safety/tolerability is confirmed, subjects will enter the multiple-dose phase (once weekly \[Day 21 as the first dose\], for 4 consecutive weeks). Dropouts during the washout period may be replaced to ensure at least 12 subjects enter the multiple-dose phase. * After completing the 0.5 mg/kg and 1 mg/kg dose exploration studies, the investigator and sponsor may determine the recommended dose for Phase IIb based on cumulative safety, efficacy, and potential PK/PD results. Additional dose groups or alternative administration frequencies may also be explored. * \*\*Phase IIb:\*\* A randomized (1:1), double-blind, placebo-controlled design will be used. A total of 72 ACLF subjects are expected to receive either AS1501 at the appropriate dose/frequency or placebo to further evaluate the efficacy and safety of AS1501 injection. The specific design will be finalized based on Phase IIa results and agreed upon by the investigator and sponsor.
• The age of the signatories to the informed consent form must range from 18 to 75 years old (including the boundary values).
• 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.
• 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.
• Can comprehend the informed consent form, voluntarily participate in it, and sign it;
• Capable of completing the trial in accordance with the study protocol;
• 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.
• The age of the signatories to the informed consent form must range from 18 to 75 years old (including the boundary values).
• 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.
• 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.
• Can comprehend the informed consent form, voluntarily participate in it, and sign it;
• Can comply with the study protocol and complete the trial.
• 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.