Efficacy and Safety Study of Allogenic Mesenchymal Stem Cells for Patients With Refractory Primary Biliary Cirrhosis

Study Overview
=================
Brief Summary
-----------------
The study is designed to evaluate the safety and efficacy of intravenous administration of bone marrow derived mesenchymal stem cells for patients with refractory primary biliary cirrhosis (PBC).

Detailed Description
-----------------
Primary biliary cirrhosis (PBC) is an organ-specific inflammatory disease and characterized by immune mediated destruction of intrahepatic bile ducts, then lead to liver cirrhosis and eventually failure.Currently, ursodeoxycholic acid (UDCA) is the only drug approved by the Food and Drug Administration (FDA). Novel treatment is urgently needed for patients who have an incomplete response to UDCA. Mesenchymal stem cells (MSC) represent a promising tool for cell-based therapies of autoimmune diseases. To explore the therapeutic effect of MSCs for PBC, the investigators plan to conduct an open-label, randomized clinical trial. Patients with PBC will be enrolled and randomly divided into two groups which will receive MSCs and UDCA respectively. The investigators will evaluate the efficacy and safety of MSCs for PBC by comparison of symptom improvement, survival rate and side effects in the two groups.

Official Title
-----------------
Phase I Clinical Trial, Randomized, Controlled, to Evaluate the Efficacy and Safety of Therapy With Allogenic Mesenchymal Stem Cells From Bone Marrow for Patients With Refractory Primary Biliary Cirrhosis

Conditions
-----------------
Primary Biliary Cirrhosis

Intervention / Treatment
-----------------
* Biological: Biological: mesenchymal stem cell
* Drug: ursodeoxycholic acid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: There must be at least two of the following: a concentration in serum of AMAs at titres of 1:40 or higher; an unexplained rise in the amount of alkaline phosphatase of at least 1•5 times the upper limit of normal for more than 24 weeks; and compatible liver histological findings, specifically non-suppurative cholangitis and interlobular bile duct injury. Incomplete response to UDCA at 13-15 mg/kg/day, Criteria for the group of complete responders is including: concentrations of alkaline phosphatase less than three times the upper limit of normal, aspartate aminotransferase less than twice the upper limit of normal, and bilirubin less than 17 μmol/L;and normalisation of abnormal concentrations of bilirubin, albumin, or both. Liver pathological staging in 2 or3, Histological staging is based on Ludwig's and Scheuer's classifications Exclusion Criteria: Patients are receiving any other investigational agents within 4 weeks of study entry Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (defined as invasive fungal infection and progressive CMV viremia), symptomatic congestive heart failure (NYH class III and IV), unstable angina pectoris, or cardiac arrhythmia In pregnancy or lactation Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible HCVpositive ，HBSAg positive or with other liver diseases Combined with other autoimmune disease Expected survival time is less than one year Decompensation of liver function（Child B or C） Have a history of allergy or Allergic constitution

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: allogenic mesenchymal stem cells (MSCs)<br>Patients who have primary biliary cirrhosis. | Biological: Biological: mesenchymal stem cell<br>* Mesenchymal stem cells,5-50 million/kg, Intravenous infusion, One dosage，whether to give another dosage depending on patients' condition<br>* Other names: regenerative medicine:MSCs;|
| Active Comparator: ursodeoxycholic acid (UDCA)<br>Patients who have primary biliary cirrhosis. | Drug: ursodeoxycholic acid<br>* 13-15 mg/kg/day, to the end of the study<br>* Other names: UDCA;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| serum level of alkaline phosphatase | Serum level of alkaline phosphatase will be measured at entry, 1 months，3 months, 6 months and 24 months after therapy | 24 months after MSCs administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| histological changes in liver biopsies | Liver biopsy of each patient will be taken before entry into therapeutic trials and at 6 months after therapy. | 6 months after therapy | 
| Serum levels of TNF-alpha | serum levels of TNF-alpha will be assessed before entry into therapeutic trials and at 6 months after therapy | 6 months after therapy | 
| changes in fatigue | changes in fatigue will be evaluated before test (baseline), 1 month,3 months and 6 months after theraphy by PBC-40 score. | 6 months after theraphy | 
| The occurrence of cirrhosis and its complications |  | 24 months after therapy | 
| Serum levels of Interleukin | serum levels of Interleukin will be assessed before entry into therapeutic trials and at 6 months after therapy | 6 months after therapy | 
| changes in pruritus severity | changes in pruritus severity will be evaluated before test (baseline), 1 month,3 months and 6 months after theraphy by VAS score. | 6 months after therapy | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
biliary cirrhosis