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.

Overview

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.

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.

Interventions

• 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\^

Primary outcome measures

• Incidence of Adverse events [Time frame: baseline to 60 days after cell transplantation therapy]
• Maximum tolerated dose (MTD) [Time frame: baseline to 60 days after cell transplantation therapy]

Secondary outcome measures (4)

• Model for end-stage liver disease (MELD) score system [Time frame: baseline to 60 days after cell transplantation therapy]
• The survival rates compared with historical controls [Time frame: the 60th day after cell transplantation therapy]
• Serum antibodies against human leukocyte antigen (HLA) Class I and II [Time frame: baseline to 60 days after cell transplantation therapy]
• Incidence of Clinical improvement [Time frame: baseline to 60 days after cell transplantation therapy]

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;

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine — Shanghai

Publications

• Yang T, Zhu X, Long M, Hui L, Yuan X, Sun Z, Zhang L, Xia Q, Wan P. Phase I safety and tolerability dose escalation study of microencapsulated hepatocyte intraperitoneal transplantation therapy in adult patients with liver failure: a study protocol. BMJ Open. 2025 Apr 15;15(4):e087828. doi: 10.1136/bmjopen-2024-087828. PMID 40233953

Identifiers

NCT: NCT05727722 · IIT02-ProliHH-I

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗