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Micro-encapsulated Hepatocyte Intraperitoneal Transplantation in Liver Failure Adults

Primary Purpose

Acute-On-Chronic Liver Failure, Chronic Liver Failure

Status
Not yet recruiting
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy
Sponsored by
RenJi Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute-On-Chronic Liver Failure focused on measuring Acute-On-Chronic Liver Failure, Chronic Liver Failure, cell transplantation, hepatocyte transplantation, micro-encapsulate

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: A. Chronic liver failure (CLF) group: The progressive liver function decline or decompensation after liver cirrhosis: Body weight>40kg; Aged between 18 to 65 years old; Serum Total bilirubin was higher than the normal range and lower than 10 times the upper limit of normal value (ULN); With or without significantly decreased serum albumin value, lower than 35; With or without significantly decreased platelet (PLT) value, prothrombin activity (PTA)≤40% (or international normalized ratio (INR)≥1.5), other reasons excluded; With or without refractory ascites or portal hypertension; With or without a stage I or II hepatic encephalopathy; 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). Body weight>40kg; Aged between 18 to 65 years old; With obvious fatigue, accompanied by other gastrointestinal symptoms such as anorexia, vomiting, and abdominal distension; Complicated with ascites and/or hepatic encephalopathy within 4 weeks after being diagnosed; Progressive aggravation of jaundice, total serum bilirubin≥85umol/L; Coagulation disorders, INR>1.5 or PTA<40%; No obvious improvement after more than 3 days' regular clinical treatments. Exclusion Criteria: With obvious brain edema, cerebral hernia, or indicated intracranial hemorrhage; Diagnosed or suspected as primary or metastatic liver cancer; With uncorrectable oxygenation index (PaO2/FiO2)<200; With disseminated intravascular coagulation; Active hemorrhage; Uncontrollable infection, including ascites infection such as spontaneous bacterial peritonitis; Uncorrectable decrease in PLT (<20×109/L); HIV and/or SARS-CoV-Ⅱ positive; Drug abuse within 1 year; Systemic hemodynamic instability; Combined with pregnancy or lactation; Other situations excluded by clinician;

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm Type

    Experimental

    Experimental

    Experimental

    Experimental

    Arm Label

    Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 1

    Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 2

    Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 3

    Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 4

    Arm Description

    Participants will each be administered the dosage of 0.15×10^9 for one time, with 60 days follow-up after the cell infusion.

    Participants will each be administered the dosage of 0.5×10^9 for one time, with 60 days follow-up after the cell infusion.

    Participants will each be administered the dosage of 1.5×10^9 for one time, with 60 days follow-up after the cell infusion.

    Participants will each be administered the dosage of 4.5×10^9 for one time, with 60 days follow-up after the cell infusion.

    Outcomes

    Primary Outcome Measures

    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)
    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.

    Secondary Outcome Measures

    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.
    The survival rates compared with historical controls
    The life table method was used to calculate the survival rate of patients.
    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.
    Incidence of Clinical improvement
    diagnosed refer to Chapter 2.6.2.2 of Guidelines for the Diagnosis and Management of Liver Failure (2018, China).

    Full Information

    First Posted
    November 23, 2022
    Last Updated
    February 13, 2023
    Sponsor
    RenJi Hospital
    Collaborators
    Shanghai Institute of Biochemistry and Cell Biology
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05727722
    Brief Title
    Micro-encapsulated Hepatocyte Intraperitoneal Transplantation in Liver Failure Adults
    Official Title
    A Phase I Safety and Tolerability Dose Escalation Study of Micro-encapsulated Hepatocytes Intraperitoneal Transplantation Therapy for Adult Liver Failure Patients.
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    February 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    March 1, 2023 (Anticipated)
    Primary Completion Date
    March 31, 2024 (Anticipated)
    Study Completion Date
    June 30, 2024 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    RenJi Hospital
    Collaborators
    Shanghai Institute of Biochemistry and Cell Biology

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Acute-On-Chronic Liver Failure, Chronic Liver Failure
    Keywords
    Acute-On-Chronic Liver Failure, Chronic Liver Failure, cell transplantation, hepatocyte transplantation, micro-encapsulate

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1
    Interventional Study Model
    Sequential Assignment
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    10 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 1
    Arm Type
    Experimental
    Arm Description
    Participants will each be administered the dosage of 0.15×10^9 for one time, with 60 days follow-up after the cell infusion.
    Arm Title
    Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 2
    Arm Type
    Experimental
    Arm Description
    Participants will each be administered the dosage of 0.5×10^9 for one time, with 60 days follow-up after the cell infusion.
    Arm Title
    Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 3
    Arm Type
    Experimental
    Arm Description
    Participants will each be administered the dosage of 1.5×10^9 for one time, with 60 days follow-up after the cell infusion.
    Arm Title
    Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 4
    Arm Type
    Experimental
    Arm Description
    Participants will each be administered the dosage of 4.5×10^9 for one time, with 60 days follow-up after the cell infusion.
    Intervention Type
    Biological
    Intervention Name(s)
    a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy
    Intervention Description
    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.
    Primary Outcome Measure Information:
    Title
    Incidence of Adverse events
    Description
    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)
    Time Frame
    baseline to 60 days after cell transplantation therapy
    Title
    Maximum tolerated dose (MTD)
    Description
    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.
    Time Frame
    baseline to 60 days after cell transplantation therapy
    Secondary Outcome Measure Information:
    Title
    Model for end-stage liver disease (MELD) score system
    Description
    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.
    Time Frame
    baseline to 60 days after cell transplantation therapy
    Title
    The survival rates compared with historical controls
    Description
    The life table method was used to calculate the survival rate of patients.
    Time Frame
    the 60th day after cell transplantation therapy
    Title
    Serum antibodies against human leukocyte antigen (HLA) Class I and II
    Description
    The serum antibodies against HLA Class I and II are used to for immunogenicity evaluation.
    Time Frame
    baseline to 60 days after cell transplantation therapy
    Title
    Incidence of Clinical improvement
    Description
    diagnosed refer to Chapter 2.6.2.2 of Guidelines for the Diagnosis and Management of Liver Failure (2018, China).
    Time Frame
    baseline to 60 days after cell transplantation therapy

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    65 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: A. Chronic liver failure (CLF) group: The progressive liver function decline or decompensation after liver cirrhosis: Body weight>40kg; Aged between 18 to 65 years old; Serum Total bilirubin was higher than the normal range and lower than 10 times the upper limit of normal value (ULN); With or without significantly decreased serum albumin value, lower than 35; With or without significantly decreased platelet (PLT) value, prothrombin activity (PTA)≤40% (or international normalized ratio (INR)≥1.5), other reasons excluded; With or without refractory ascites or portal hypertension; With or without a stage I or II hepatic encephalopathy; 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). Body weight>40kg; Aged between 18 to 65 years old; With obvious fatigue, accompanied by other gastrointestinal symptoms such as anorexia, vomiting, and abdominal distension; Complicated with ascites and/or hepatic encephalopathy within 4 weeks after being diagnosed; Progressive aggravation of jaundice, total serum bilirubin≥85umol/L; Coagulation disorders, INR>1.5 or PTA<40%; No obvious improvement after more than 3 days' regular clinical treatments. Exclusion Criteria: With obvious brain edema, cerebral hernia, or indicated intracranial hemorrhage; Diagnosed or suspected as primary or metastatic liver cancer; With uncorrectable oxygenation index (PaO2/FiO2)<200; With disseminated intravascular coagulation; Active hemorrhage; Uncontrollable infection, including ascites infection such as spontaneous bacterial peritonitis; Uncorrectable decrease in PLT (<20×109/L); HIV and/or SARS-CoV-Ⅱ positive; Drug abuse within 1 year; Systemic hemodynamic instability; Combined with pregnancy or lactation; Other situations excluded by clinician;

    12. IPD Sharing Statement

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    Micro-encapsulated Hepatocyte Intraperitoneal Transplantation in Liver Failure Adults

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