Clinical Study of hUC-MSCs Treating Decompensated Liver Cirrhosis With HBV

Study Overview
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Brief Summary
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The purpose of this study was to observe the safety ,tolerability ,Efficacy dose of human umbilical cord mesenchymal stem cells in patients of decompensated liver cirrhosis with HBV.

Detailed Description
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Investigators plan to recruit 24 voluntary patients of decompensate liver cirrhosis with HBV, dividing them into 3 group：1) low-dose group: 100mL with 2.5×10^7 cells；2) medium-dose group: 100mL with 5.0×10^7 cells；3) high-dose group: 100mL with 1.0×10^8 cells. Each group contains 8 patients. Investigators treat the participants with human umbilical cord mesenchymal stem cells via venous transfusion. First investigators arrange a whole test for participants, such as vital sign examination, laboratory test, ECG, CT, MRI, ultrasound etc. Investigators screen these patients with a complete eligibility criteria. Then investigators proceed the therapy in the 1st, 8th and 15th day. There are 8 times of follow-up visit for these patients, 4 times of those are proceeded during the hospitalization, while other 4 times happens after the discharge. The follow-up visit includes vital sign examination, laboratory test, ECG, CT, MRI, ultrasound, Child-Pugh grade, MELD grade, SF-36 test. These follow-up visit last 24 weeks since the first treatment. After that, investigators also arrange a survival visit through phone or clinic each 6 months, lasting another 1.5 years. The main object of this research is investigating the survival rate, promotion of the liver function, improvement of health, safety of hUC-MSCs, tolerability of patients, for exploring a new way for the therapy of decompensated liver cirrhosis with HBV.

Official Title
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Clinical Study of Human Umbilical Cord Mesenchymal Stem Cells for Treating Decompensated Liver Cirrhosis Associated With HBV

Conditions
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HBV

Intervention / Treatment
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* Biological: hUCMSCs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 18 and 65 (including 18 and 65), regardless of gender; Decompensated stage of viral hepatitis B cirrhosis; The effect of conventional medical treatment is not good, and the condition is repeated; ALB < 35g/L, TBIL < 170μmol/L, INR > 30%, Child-pugh score ≥7; MELD score ≤15; Hgb > 70g/L, PLT > 3×109/L; Unconditional acceptance for liver transplantation; 7）Participate in the clinical study voluntarily, cooperate with doctors to carry out the study, and sign informed consent. Exclusion Criteria: With spontaneous peritonitis or other serious infection; Patients with hepatorenal syndrome; Severe hepatic encephalopathy, massive hemorrhage of digestive tract or varicose 4. vein in recent 1 month; Portal vein thrombosis; Complicated with serious diseases of heart, lung, kidney, blood and endocrine system; HIV positive; Positive autoantibodies related to autoimmune liver disease; Presence of liver or any type of malignant tumor; Pregnant women, breast-feeding women or those with recent birth plans; Those who have a history of alcohol and drug abuse and failed to get rid of it effectively; Participated in other clinical trials within 3 months prior to enrollment; Participated in clinical research on stem cells; Unwillingness to sign informed consent; Other conditions that the investigator considers inappropriate for patients to participate in this study.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: We allocate 24 participants into 3 group, low-dose, medium-dose and high-dose group. It is going to proceeded sequential from low-dose group to high-dose group. Next group is allowed to be started only the last group has been finished. Low-dose group: 100mL human umbilical cord mesenchymal stem cell preparation, containing 2.5×10^7 cells; medium-dose group: 100mL human umbilical cord mesenchymal stem cell preparation, containing 5.0×10^7 cells; High-dose group: 100mL human umbilical cord mesenchymal stem cell preparation, containing 1.0×10^8 cells
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low-dose group<br>100mL human umbilical cord mesenchymal stem cell preparation, containing 2.5×10^7 cells. | Biological: hUCMSCs<br>* Human umbilical cord mesenchymal stem cell preparation, 100ml/ bag, containing 2.5×107 cells, 5.0×107 cells, 1.0 x 108 cells<br>|
| Experimental: medium-dose group<br>100mL human umbilical cord mesenchymal stem cell preparation, containing 5.0×10^7 cells. | Biological: hUCMSCs<br>* Human umbilical cord mesenchymal stem cell preparation, 100ml/ bag, containing 2.5×107 cells, 5.0×107 cells, 1.0 x 108 cells<br>|
| Experimental: High-dose group<br>100mL human umbilical cord mesenchymal stem cell preparation, containing 1.0×10^8 cells. | Biological: hUCMSCs<br>* Human umbilical cord mesenchymal stem cell preparation, 100ml/ bag, containing 2.5×107 cells, 5.0×107 cells, 1.0 x 108 cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum albumin in g/L | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| alanine aminotransferase in U/L | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| aspartate aminotransferase in U/L | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| cholinesterase in U/L | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Total bilirubin in μmol/L | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Direct bilirubin in μmol/L | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Serum cholesterol in mmol/L | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Prothrombin activity in percentage | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Antithrombin in mg/L | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| survival rate | survival rate after 2 years since the first therapy | 2 years | 
| Child-Pugh grade | Child-Pugh grade is defined according to hepatic encephalopathy, ascites，serum albumin, total bilirubin, prothrombin time. Score 5-6 is grade A. Score 7-9 is grade B. Score 10-15 is grade C. We compare the Child-Pugh grade in first day, 4th, 8th, 12th and 24th week, to describe its tendency. | 24 weeks | 
| Rate of weight change | We compare the weight in first day, 4th, 8th, 12th and 24th week, to describe its tendency. | 24 weeks | 
| Ascites | We test the ascites via ultrasound, CT and MRI. We classify the ascite level into none, low and high. We compare the Child-Pugh grade in first day, 4th, 8th, 12th and 24th week, to describe its tendency. | 24 weeks | 
| clinical symptoms | Including lower limb edema, hematemesis, jaundice, fatigue, poor appetite. We compare these symptoms in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Th1 cells in percentage | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Th2 cells in percentage | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Natural killer T cells in percentage | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Interleukin-1β cells in pg/mL | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Interleukin-4 cells in pg/mL | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Interleukin-6 cells in pg/mL | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Interleukin-8 cells in pg/mL | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Interleukin-12 cells in pg/mL | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Interleukin-15 cells in pg/mL | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Interleukin-17A cells in pg/mL | We compare this index in first day, 4th, 8th, 12th and 24th week, to describe their tendency. | 24 weeks | 
| Medical images | Ultrasound in first day, 4th, 8th, 12th and 24th; enhanced CT scanning and/or MRI-Primovist scanning in first day, 12th week and 24th week. | 24 weeks | 
| The Medical outcomes study 36-item Short Form Health Survay scale (SF-36 scale) | SF-36 scale is a measurement for patients' living quality. The scores contain 8 parts, including physical functioning, role-physica, bodily pain, general health, vitality, social functioning, role-emotional and mental health. Conversion score=(actual score-minimum score in this part)/(maximum score in this part-minimum score in this part)*100. Score of each part range from 0 to 100. The higher score means more healthy. We proceed SF-36 test in 12th week and 24th week | 24 weeks | 
| MELD score | MELD=3.78*Ln(total bilirubin mg/dL)+11.2*Ln(INR)+9.57*Ln(serum creatine mg/dL)+6.43 (for HBV patient) We compare MELD score in first day, 4th, 8th, 12th and 24th week, to describe its tendency. | 24 weeks |