Micro-encapsulated Hepatocyte Intraperitoneal Transplantation in Liver Failure Adults

Phase 1

Not yet recruiting

• Conditions: Acute-On-Chronic Liver Failure; Chronic Liver Failure
• Interventions: Biological: a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy

• Registration Number: NCT05727722
• Lead Sponsor: RenJi Hospital

Brief Summary

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.

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 Timeline

• Study First Submitted: 2022-11-23
• Status Verified: 2023-02
• Study First Submitted QC: 2023-02-13
• Last Update Submitted: 2023-02-13
• Study First Posted: 2023-02-14
• Last Update Posted: 2023-02-14
• Study Start: 2023-03-01
• Primary Completion: 2024-03-31
• Study Completion: 2024-06-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 10

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 2	a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy	Participants will each be administered the dosage of 0.5×10\^9 for one time, with 60 days follow-up after the cell infusion.
Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 4	a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy	Participants will each be administered the dosage of 4.5×10\^9 for one time, with 60 days follow-up after the cell infusion.
Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 1	a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy	Participants will each be administered the dosage of 0.15×10\^9 for one time, with 60 days follow-up after the cell infusion.
Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 3	a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy	Participants will each be administered the dosage of 1.5×10\^9 for one time, with 60 days follow-up after the cell infusion.

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose (MTD)	baseline to 60 days after cell transplantation therapy	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.
Incidence of Adverse events	baseline to 60 days after cell transplantation therapy	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)

Secondary Outcome Measures

Name	Time	Method
The survival rates compared with historical controls	the 60th day after cell transplantation therapy	The life table method was used to calculate the survival rate of patients.
Model for end-stage liver disease (MELD) score system	baseline to 60 days after cell transplantation therapy	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.
Incidence of Clinical improvement	baseline to 60 days after cell transplantation therapy	diagnosed refer to Chapter 2.6.2.2 of Guidelines for the Diagnosis and Management of Liver Failure (2018, China).
Serum antibodies against human leukocyte antigen (HLA) Class I and II	baseline to 60 days after cell transplantation therapy	The serum antibodies against HLA Class I and II are used to for immunogenicity evaluation.