Shenzhen Zhongke Ai Shen Pharmaceutical Co Ltd

**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.

主要目的： 评价注射用AS1501在中国健康受试者中单次静脉注射给药的耐受性和安全性，为后期临床研究推荐合理的给药方案； 次要目的： （1）评价注射用AS1501在中国健康受试者中的药代动力学特征； （2）评价注射用AS1501在中国健康受试者中的免疫原性； 探索性目的： 初步探索注射用AS1501静脉注射给药前后血清中TRAIL表达水平的变化。