Umbilical Cord Mesenchymal Stem Cells for Patients With Primary Biliary Cirrhosis

Study Overview
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Brief Summary
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Primary biliary cirrhosis (PBC) is a slowly progressive disease that causes substantial loss of intrahepatic bile ducts, ultimately resulting in cholestasis, advanced fibrosis, cirrhosis, liver failure and even hepatocellular carcinoma. Histologically, the disease is characterized by chronic portal inflammation with infiltration, destruction and loss of the epithelial cells in the small-sized and medium-sized bile ducts. Currently, Ursodeoxycholic acid (UDCA) in a dose of 13-15mg/kg/day is recommended as therapeutic drugs for PBC by AASLD and is approved for this indication by the U.S. Food and Drug Administration (FDA). Treatment with UDCA may delay disease progression and prolong survival free of liver transplantation. However, one out of three patients does not adequately respond to UDCA therapy and many need additional medical therapy or liver transplantation, or both. UC-MSC has been application for the treatment of several severe autoimmune diseases, such as immune thrombocytopenia, systemic lupus erythematosus, and therapy-resistant rheumatoid arthritis. In this study, the safety and efficacy of UC-MSC transplantation for PBC patients will be evaluated.

Detailed Description
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Primary biliary cirrhosis (PBC) is a slowly progressive cholestatic disease associated with the development of cirrhosis and liver failure that may justify liver transplantation. Ursodeoxycholic acid (UDCA) is currently the only drug approved specifically for the treatment of PBC. However, one out of three patients does not adequately respond to UDCA therapy and many need additional medical therapy or liver transplantation, or both. The potential for stem cells to differentiate into biliary epithelial cells was recently confirmed. In particular, bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation has been applicated in the clinic for treat several human disease such as GVHD, cardiac injury and brain injury, and displayed good tolerance and efficiency. Recently, umbilical cord-derived MSCs (UC-MSC) has also been used to treat severe autoimmune diseases, such as therapy-resistant rheumatoid arthritis and multiple sclerosis. The purpose of this study is to learn whether and how UC-MSC can improve the disease condition in patients with primary biliary cirrhosis. This study will also look at how well UC-MSC is tolerated and its safety in PBC patients Participants in the study will be randomly assigned to one of two treatment arms: Arm A: Participants will receive 12 weeks of UC-MSC treatment plus UDCA. Arm B: Participants will receive 12 weeks of placebo plus UDCA. UC-MSC will be prepared according to standard procedures and is collected in plastic bags containing anticoagulant. UC-MSCs are given via i.v. under sonography monitoring. After cell therapy, patients are followed up at week 4,8,12,24,36 and 48. The evaluation of some clinical parameters such as the level of serum alkaline phosphatase (ALP), alanine aminotransferase(ALT) aspartate aminotransferase (AST) and total bilirubin (TB), prothrombin time(PT), albumin(ALB), prealbumin(PA), are detected at these time points. Mayo risk score, portal hypertension, Liver histology, MELD score and clinical symptoms were also observed simultaneously.

Official Title
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Phase 1/2 Study of UC-MSC Treatment for Evaluation the Efficacy and Safety in Patients With Primary Biliary Cirrhosis

Conditions
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Primary Biliary Cirrhosis

Intervention / Treatment
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* Other: conventional plus UC-MSC treatment
* Other: Conventional plus placebo treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Primary Biliary Cirrhosis (according to the criteria defined by AASLD practice guidelines , Hepatology, 2009;50:291-308 ) Negative pregnancy test (female patients in fertile age) Exclusion Criteria: Hepatocellular carcinoma or other Malignancies Pregnant or lactating women Viral Hepatitis ( HAB, HBV, HCV, et al ) Vital organs failure (Cardiac, Renal or Respiratory, et al) Sepsis Active thrombosis in the portal or hepatic veins

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conventional plus UC-MSC treatment<br>Participants will receive conventional treatment plus a dose of UC-MSC from day 0 through the week 12 study visit. Participants will then be followed until the week 48 study visit. | Other: conventional plus UC-MSC treatment<br>* Received conventional treatment and taken i.v., once per 4 week, at a dose of 1*10E6 UC-MSC/kg body weight for 12 weeks.<br>|
| Placebo Comparator: Conventional plus placebo treatment<br>Participants will receive conventional plus placebo treatment from day 0 through the week 12 study visit. Participants will then be followed until the week 48 study visit. | Other: Conventional plus placebo treatment<br>* Received conventional treatment and taken i.v., once per 4 week, at 50 ml saline for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum alkaline phosphatase (ALP) |  | 0, 4, 8,12, 24, 36,48 weeks after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histological changes in liver biopsies |  | baseline and 48 weeks | 
| Serum Bilirubin |  | At base line and at week 4,8,12,24,36 and 48 | 
| Serum AST |  | At base line and at week 4,8,12,24,36 and 48 | 
| Mayo risk score |  | At base line and at week 4,8,12,24,36 and 48 | 
| Number of patients with Portal Hypertension after 12 weeks treatment |  | At base line and at week 12,24,36 and 48 | 
| MELD score |  | At base line and at week 4,8,12,24,36 and 48 | 
| Number of participants with improvement of clinical symptoms | clinical symptoms including fatigue (Fatigue Impact Score, FIS) and pruritus ( Visual Analog Scale ,VAS) | At base line and at week 4,8,12,24,36 and 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary Biliary Cirrhosis, Mesenchymal Stem Cells, Serum alkaline phosphatase, Serum Bilirubin