HCL001 Cell Injection for Decompensated Cirrhosis: A Phase I/II Trial

A Phase I/II Clinical Trial to Evaluate the Safety, Tolerability, and Preliminary Efficacy of HCL001 Cell Injection in Patients With Decompensated Cirrhosis

Three sequential dose cohorts are predefined for single administration: Cohort 1 (1.0 × 10⁶ cells/kg), Cohort 2 (2.0 × 10⁶ cells/kg), and Cohort 3 (4.0 × 10⁶ cells/kg). Escalation proceeds from Cohort 1 to Cohort 3 according to a "3 + 3" algorithm, with each subject receiving a single assigned dose. To ensure maximal subject safety, the first subject in every cohort must complete ≥ 14 days of post-dose observation within the DLT evaluation window before additional subjects in that cohort may be dosed. After the last subject in a cohort has completed the entire DLT observation period (from dosing through Day 29), the Safety Review Committee (SRC) will review the cumulative safety data and, by consensus, determine whether escalation to the first subject of the subsequent cohort may commence. Concurrent enrollment into two or more cohorts is prohibited.

Upon completion of the Week 12 assessment in the last subject enrolled in Phase I, one or two dose levels will be selected for Phase II expansion based on the safety and preliminary efficacy data obtained during Phase I.

A single SRC will be convened during the Phase I dose-escalation stage to conduct dynamic safety oversight. The SRC will comprise investigators, the Sponsor, and/or medically qualified personnel designated by the Sponsor's delegate (contract research organization [CRO]). Detailed SRC procedures are provided in a separate SRC charter.

• Begin with three subjects in the lowest cohort.

• If zero of three subjects experience a DLT during the observation period, escalate to the next cohort.

• If one of three subjects experiences a DLT, enroll an additional three subjects at the same dose level.

  • If ≤ 1/6 total subjects in the expanded cohort experience a DLT, escalate to the next cohort.
  • If > 1/6 experience a DLT, dose escalation is terminated.

• If ≥ 2 of the initial three subjects experience a DLT, escalation is stopped; the preceding dose level is declared the maximum tolerated dose (MTD).

• If > 1 subject experiences a DLT at any dose level, no further escalation will occur per protocol, and the preceding cohort will be designated the MTD.

• If no DLT is observed at the highest predefined dose (4 × 10⁶ cells/kg), the investigator and the Sponsor will jointly determine whether exploration of higher doses is warranted.

Upon completion of the Week 12 assessment in the last subject enrolled in Phase I, one or two dose levels will be selected for Phase II expansion based on the safety and preliminary efficacy data obtained during Phase I.

Eligible subjects will be randomized to an investigational arm or a control arm.

• If only one investigational dose is selected, the randomization ratio will be investigational arm : control arm = 2 : 1.
• If two investigational doses are selected, the randomization ratio will be low-dose group : high-dose group : control group = 2 : 2 : 1.

Each investigational cohort will enroll 20-30 subjects, and the control cohort will enroll 10-15 subjects; the control group will receive standard-of-care treatment only. The total anticipated enrollment for Phase II is 30-75 subjects.

Inclusion Criteria:

• Age ≥ 18 years at the time of informed consent; sex unrestricted.
• Diagnosis of decompensated cirrhosis established according to the Chinese Guidelines for the Diagnosis and Treatment of Liver Cirrhosis (2019 Edition) and attributable to: hepatitis B, hepatitis C, alcohol, autoimmune disease, metabolic-associated fatty liver disease, or other less common aetiologies when deemed appropriate by the investigator.
• Karnofsky Performance Status (KPS) ≥ 60 (see Appendix 6).
• Presence of a vascular access route judged safe for selective catheterisation of the proper hepatic artery.
• For subjects with hepatitis B or C cirrhosis: HBV-DNA ≤ 50 IU/mL and HCV-RNA below the limit of quantification at screening; for alcohol-related cirrhosis: documented abstinence for ≥ 6 months.
• Ability to understand the study procedures and willingness to comply; written informed consent obtained from the subject or legally authorised representative.

Exclusion Criteria:

• Known hypersensitivity to HCL001 Cell Injection or any of its excipients.
• Child-Pugh score ≥ 13 (see Appendix 1 for scoring and classification).
• Cavernous transformation of the portal vein.
• Serum total bilirubin > 10 × the upper limit of normal (ULN).
• Hepatocellular carcinoma or any other concurrent malignancy.
• Inability to cooperate or unwillingness to comply with protocol requirements.
• Bleeding diathesis (e.g., haemophilia) or platelet count < 40 × 10⁹/L despite platelet-raising therapy.
• Use of anticoagulant or antiplatelet agents within 7 days prior to dosing.
• Grade ≥ 3 hepatic encephalopathy within 3 months before dosing (grading criteria in Appendix 2).
• Previous transjugular intrahepatic portosystemic shunt (TIPS) or requirement/planned TIPS during the study.
• History of venous thrombosis, including portal vein thrombosis (PVT) Grade ≥ 2 (grading criteria in Appendix 9), deemed unsuitable by the investigator.
• Severe dysfunction of vital organs (heart, lung, brain, kidney):

Pulmonary: severe emphysema, pulmonary embolism, or any pulmonary disorder significantly impairing pulmonary function.

Cardiac history meeting any of the following:

1. Decompensated heart failure (NYHA Class III-IV);

2. Unstable angina within 6 months before dosing. Chronic kidney disease (CKD) Stage 4-5.

   • Inadequately controlled diabetes despite treatment: HbA1c ≥ 8 % or fasting plasma glucose ≥ 10 mmol/L.
   • Pregnancy or lactation women; or inability/unwillingness to use Investigator-approved contraceptive methods during the study and for 6 months after study completion.
   • Participation in another interventional clinical trial within 3 months before screening, or prior receipt of any stem-cell therapy.
   • Positive human immunodeficiency virus (HIV) antibody.
   • Active infection (defined as an infection, other than intra-abdominal, requiring intravenous antibiotics) within 2 weeks before screening, deemed unsuitable by the investigator.
   • Ascites with concurrent intra-abdominal infection [defined as: 1. Positive ascitic fluid culture; or 2. Ascitic polymorphonuclear neutrophil (PMN) count ≥ 250 × 10⁶/L], deemed by the Investigator as unsuitable for trial participation.
   • History of drug abuse or psychiatric disorders.
   • Any other condition or circumstance-including concomitant disease, therapy, procedure, surgery, or clinically significant laboratory abnormality-that, in the opinion of the investigator, could interfere with study conduct, impose additional risk to the subject, or preclude safe participation or completion of the study.