A Phase I Safety and Tolerability Dose Escalation Study of Micro-encapsulated Hepatocytes Intraperitoneal Transplantation Therapy for Adult Liver Failure Patients.
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose (MTD)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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;
研究组 & 干预措施
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.
干预措施: a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy (Biological)
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.
干预措施: a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy (Biological)
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.
干预措施: a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy (Biological)
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.
干预措施: a single course of micro-encapsulated hepatocytes intraperitoneal transplantation therapy (Biological)
结局指标
主要结局
Maximum tolerated dose (MTD)
时间窗: 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
时间窗: 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)
次要结局
- The survival rates compared with historical controls(the 60th day after cell transplantation therapy)
- Model for end-stage liver disease (MELD) score system(baseline to 60 days after cell transplantation therapy)
- Incidence of Clinical improvement(baseline to 60 days after cell transplantation therapy)
- Serum antibodies against human leukocyte antigen (HLA) Class I and II(baseline to 60 days after cell transplantation therapy)