Micro-encapsulated Hepatocyte Intraperitoneal Transplantation in Liver Failure Adults

Study Overview
=================
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.

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

Conditions
-----------------
Acute-On-Chronic Liver Failure, Chronic Liver Failure

Intervention / Treatment
-----------------
* Biological: a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy


Participation Criteria
=================
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;

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 1<br>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<br>* 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.<br>|
| Experimental: Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 2<br>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<br>* 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.<br>|
| Experimental: Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 3<br>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<br>* 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.<br>|
| Experimental: Micro-encapsulated Hepatocyte Intraperitoneal Transplantation Cohort 4<br>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<br>* 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.<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute-On-Chronic Liver Failure, Chronic Liver Failure, cell transplantation, hepatocyte transplantation, micro-encapsulate