Micro-encapsulated Hepatocyte Intraperitoneal Transplantation in Liver Failure Adults

A Phase I Safety and Tolerability Dose Escalation Study of Micro-encapsulated Hepatocytes Intraperitoneal Transplantation Therapy for Adult Liver Failure Patients.

This is a prospective single-center dose escalation study of the administration of the microencapsulated hepatocyte therapy in adult liver failure. The purpose of the study is to determine the maximum tolerated dose of microencapsulated hepatocytes in liver failure patients and its effectiveness in treating the disease. We previously generated proliferating human hepatocytes (ProliHH) through dedifferentiation of PHH and engineered them into encapsulated liver organoids (eLO), providing an unlimited cell source for hepatocyte transplantation.

Study Overview

• Status: Recruiting
• Conditions: Acute-On-Chronic Liver Failure; Chronic Liver Failure
• Intervention / Treatment: Biological: a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy

Detailed Description

This study is a single-center unblinded single-arm study comprised of a dose escalation phase and a preliminary assessment of efficacy. Subjects who were diagnosed with liver failure (including chronic liver failure and acute-on-chronic liver failure) received 3 days' regular treatment with no beneficial effect and volunteered to participate in micro-encapsulated hepatocytes intraperitoneal transplantation therapy will be enrolled. Before the clinical research, the recruitment criteria and micro-encapsulated hepatocytes transplantation protocol will be confirmed. To minimize the number of patients receiving unbeneficial therapeutic dosage, the accelerated titration design and "3+3" design will be used to decide the dosage group. All micro-encapsulated hepatocytes transplantation patients will be monitored after 1, 3, 7, 14, 28, and 60 days after treatment for safety and primary efficacy analyses. The patients could still receive regular clinical treatment including liver transplantation.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai, China
    • Recruiting
    • Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine
    • Contact: Qiang Xia, MD, PhD; Phone Number: +86-21-58752345; Email: xiaqiang@shsmu.edu.cn
    • Contact: Ping Wan, MD, PhD; Phone Number: +86-15721069636; Email: gufeng182@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

A. Chronic liver failure (CLF) group:

The progressive liver function decline or decompensation after liver cirrhosis:

1. Body weight>40kg;
2. Aged between 18 to 65 years old;
3. Serum Total bilirubin was higher than the normal range and lower than 10 times the upper limit of normal value (ULN);
4. With or without significantly decreased serum albumin value, lower than 35;
5. With or without significantly decreased platelet (PLT) value, prothrombin activity (PTA)≤40% (or international normalized ratio (INR)≥1.5), other reasons excluded;
6. With or without refractory ascites or portal hypertension;
7. With or without a stage I or II hepatic encephalopathy;
8. No obvious improvement after more than 3 days' regular clinical treatments.

OR B. Acute-on-chronic liver failure (ACLF) group:

With known or unknown basic liver diseases, subjects undergoing acute liver failure syndrome (clinical manifestations indicated as an early stage liver failure).

1. Body weight>40kg;
2. Aged between 18 to 65 years old;
3. With obvious fatigue, accompanied by other gastrointestinal symptoms such as anorexia, vomiting, and abdominal distension;
4. Complicated with ascites and/or hepatic encephalopathy within 4 weeks after being diagnosed;
5. Progressive aggravation of jaundice, total serum bilirubin≥85umol/L；
6. Coagulation disorders, INR>1.5 or PTA<40%;
7. No obvious improvement after more than 3 days' regular clinical treatments.

Exclusion Criteria:

1. With obvious brain edema, cerebral hernia, or indicated intracranial hemorrhage;
2. Diagnosed or suspected as primary or metastatic liver cancer;
3. With uncorrectable oxygenation index (PaO2/FiO2)<200;
4. With disseminated intravascular coagulation;
5. Active hemorrhage;
6. Uncontrollable infection, including ascites infection such as spontaneous bacterial peritonitis;
7. Uncorrectable decrease in PLT (<20×109/L);
8. HIV and/or SARS-CoV-Ⅱ positive;
9. Drug abuse within 1 year;
10. Systemic hemodynamic instability;
11. Combined with pregnancy or lactation;
12. Other situations excluded by clinician;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 1; Participants will each be administered the dosage of 0.15×10^9 for one time, with 60 days follow-up after the cell infusion.	Biological: a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy; A single course will be divided into an "accelerated titration design" phase and a "3+3 design" phase to reduce the number of subjects exposed to potentially ineffective doses that may not benefit from treatment. The "accelerated titration design" phase starts at a starting dose of 0.15x10^9, moving to the "3+3 design" phase at the dose of 0.5x10^9. According to the semi-logarithmic incremental (10^0.5-fold) approach, the treatment dosage was set into four groups at a maximum dose of 4.5×10^9 (allowing for a ±20% difference between the actual dose and the planned dose, considering production specifics). The number or the incremental ratio of subsequent dose groups can be adjusted based on the evaluation of available data in the study, and intermediate doses can be explored.
Experimental: Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 2; Participants will each be administered the dosage of 0.5×10^9 for one time, with 60 days follow-up after the cell infusion.	Biological: a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy; A single course will be divided into an "accelerated titration design" phase and a "3+3 design" phase to reduce the number of subjects exposed to potentially ineffective doses that may not benefit from treatment. The "accelerated titration design" phase starts at a starting dose of 0.15x10^9, moving to the "3+3 design" phase at the dose of 0.5x10^9. According to the semi-logarithmic incremental (10^0.5-fold) approach, the treatment dosage was set into four groups at a maximum dose of 4.5×10^9 (allowing for a ±20% difference between the actual dose and the planned dose, considering production specifics). The number or the incremental ratio of subsequent dose groups can be adjusted based on the evaluation of available data in the study, and intermediate doses can be explored.
Experimental: Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 3; Participants will each be administered the dosage of 1.5×10^9 for one time, with 60 days follow-up after the cell infusion.	Biological: a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy; A single course will be divided into an "accelerated titration design" phase and a "3+3 design" phase to reduce the number of subjects exposed to potentially ineffective doses that may not benefit from treatment. The "accelerated titration design" phase starts at a starting dose of 0.15x10^9, moving to the "3+3 design" phase at the dose of 0.5x10^9. According to the semi-logarithmic incremental (10^0.5-fold) approach, the treatment dosage was set into four groups at a maximum dose of 4.5×10^9 (allowing for a ±20% difference between the actual dose and the planned dose, considering production specifics). The number or the incremental ratio of subsequent dose groups can be adjusted based on the evaluation of available data in the study, and intermediate doses can be explored.
Experimental: Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 4; Participants will each be administered the dosage of 4.5×10^9 for one time, with 60 days follow-up after the cell infusion.	Biological: a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy; A single course will be divided into an "accelerated titration design" phase and a "3+3 design" phase to reduce the number of subjects exposed to potentially ineffective doses that may not benefit from treatment. The "accelerated titration design" phase starts at a starting dose of 0.15x10^9, moving to the "3+3 design" phase at the dose of 0.5x10^9. According to the semi-logarithmic incremental (10^0.5-fold) approach, the treatment dosage was set into four groups at a maximum dose of 4.5×10^9 (allowing for a ±20% difference between the actual dose and the planned dose, considering production specifics). The number or the incremental ratio of subsequent dose groups can be adjusted based on the evaluation of available data in the study, and intermediate doses can be explored.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse events	All adverse events are defined and graded following the National Cancer Institute-Common Terminology Criteria for Adverse Events V.5.0. Adverse events (AE), serious adverse events (SAE), and treatment emergent AEs (TEAE)	baseline to 60 days after cell transplantation therapy
Maximum tolerated dose (MTD)	The maximum tolerated dose (MTD) is defined as the highest dose at which no more than 1 of at least 6 subjects developed dose-limiting toxicity (DLT). During the DLT observation period, another patient should be enrolled if one subject does not complete the DLT observation period due to withdrawal for reasons other than DLT.	baseline to 60 days after cell transplantation therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Model for end-stage liver disease (MELD) score system	Laboratory test results used to calculate the MELD score must be obtained at the same time point, and the results need to be obtained within 6 hours of the blood draw.	baseline to 60 days after cell transplantation therapy
The survival rates compared with historical controls	The life table method was used to calculate the survival rate of patients.	the 60th day after cell transplantation therapy
Serum antibodies against human leukocyte antigen (HLA) Class I and II	The serum antibodies against HLA Class I and II are used to for immunogenicity evaluation.	baseline to 60 days after cell transplantation therapy
Incidence of Clinical improvement	diagnosed refer to Chapter 2.6.2.2 of Guidelines for the Diagnosis and Management of Liver Failure (2018, China).	baseline to 60 days after cell transplantation therapy

Collaborators and Investigators

• Sponsor: RenJi Hospital
• Collaborators: Shanghai Institute of Biochemistry and Cell Biology

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): February 28, 2026

Study Registration Dates

• First Submitted: November 23, 2022
• First Submitted That Met QC Criteria: February 13, 2023
• First Posted (Actual): February 14, 2023

Study Record Updates

• Last Update Posted (Actual): June 27, 2025
• Last Update Submitted That Met QC Criteria: June 23, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Acute-On-Chronic Liver Failure; cell transplantation; Chronic Liver Failure; hepatocyte transplantation; micro-encapsulate
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure, Acute; End Stage Liver Disease; Liver Failure; Hepatic Insufficiency; Acute-On-Chronic Liver Failure
• Other Study ID Numbers: IIT02-ProliHH-I

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No