Umbilical Cord Mesenchymal Stem Cells for Patients With Autoimmune Hepatitis

Study Overview
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Brief Summary
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Autoimmune hepatitis (AIH) is characterized by chronic inflammation of the liver, interface hepatitis, hypergammaglobulinemia, and the presence of autoantibodies. Disease presentation is varied but typically is based on characteristic aminotransferase elevations, histological abnormalities, elevated levels of serum globulins, and the presence of one or more autoantibodies. Two types of juvenile AIH have been identified according to seropositivity for smooth muscle and /or antinuclear antibody (AIH type 1) or liver kidney microsomal antibody (AIH type 2). Standard therapy in clinic consists of a combination of corticosteroids and azathioprine, which displays the efficacy in 80% of patients. However, 7% of patients deteriorate despite compliance with the standard corticosteroid regiments (treatment failure),13% of patients improve but not to a degree that satisfies remission criteria (incomplete response), 13% of patients develop serious drug-induced complications, and 50%-86% of patients will relapse after drug withdrawal. These serious drawbacks counterbalance the benefits of conventional therapy, and they are compelling reasons to refine current treatment strategies and pursue alternative therapies. UC-MSC has been the 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 AIH patients will be evaluated.

Detailed Description
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Autoimmune hepatitis (AIH) is an immune-mediated necroinflammatory disease of the liver characterized by elevation of IgG, presence of characteristic autoantibodies, and histological feature of interface hepatitis. Standard therapy consists of a combination of corticosteroids and azathioprine, which is efficacious in 80% of patients. However, current treatment strategies are complicated by frequent relapse after drug withdrawal, medication intolerance, and refractory disease. Alternative medical therapy may be need for AIH. The potential for stem cells to differentiate into hepatocytes 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 immune thrombocytopenia, systemic lupus erythematosus, and therapy-resistant rheumatoid arthritis. The purpose of this study is to learn whether and how UC-MSC can improve the disease condition in patients with autoimmune hepatitis (AIH). This study will also look at how well UC-MSC is tolerated and its safety in AIH 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 conventional treatment (combination of corticosteroids and azathioprine) Arm B: Participants will receive 12 weeks of placebo plus conventional treatment. (combination of corticosteroids and azathioprine) 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 12, 24, 36, 48, 72, 96. The evaluation of some clinical parameters such as the level of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-globulin, total bilirubin (TB), prothrombin time (PT), albumin (ALB), prealbumin (PA) and IgG, are detected at these time points. MELD score, Liver histology, treatment side effects, relapse rate 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 Autoimmune Liver Disease

Conditions
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Autoimmune Hepatitis

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 Autoimmune hepatitis (according to the criteria defined by the international autoimmune hepatitis Group ,Hepatology, 2008;48:169-176) Negative pregnancy test (female patients in fertile age) Exclusion Criteria: Hepatocellular carcinoma or other Malignancies Pregnant or lactating women Viral Hepatitis ( HAV,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 96 study visit. | Other: conventional plus UC-MSC treatment<br>* Received conventional treatment and taken i.v., once per 4 week, at a dose of 1×106 UC-MSC/kg body weight for 12 weeks.<br>|
| Experimental: 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 96 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 |
| --- | --- | --- |
| Liver Histology change |  | baseline and 96 weeks | 
| Serum alanine aminotransferase (ALT) |  | 0,12, 24, 36, 48, 72, 96 weeks after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum AST |  | At baseline and at week 12, 24, 36, 48, 72, 96 | 
| Serum Tbil |  | At baseline and at week 12, 24, 36, 48, 72, 96 | 
| Serum immunoglobulin G (IgG) |  | At baseline and at week 12, 24, 36, 48, 72, 96 | 
| Serum γ-globulin |  | At baseline and at week 12, 24, 36, 48, 72, 96 | 
| MELD score |  | At base line and at week 12, 24, 36, 48, 72, 96 | 
| Number of participants with treatment side effects | weight gain, acne, facial rounding, dorsal hump formation, hirsutism, osteopenia and diabetes mellitus, et al | At base line and at week 12, 24, 36, 48, 72, 96 | 
| Number of participants with improvement of clinical symptoms | diffuse arthralgias, fatigue, generalized malaise, jaundice, abdominal pain, nausea, and loss of appetite | At base line and at week 12, 24, 36, 48, 72, 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autoimmune Hepatitis, Mesenchymal stem cells, serum albumin, serum Tbil, serum immunoglobulin G(IgG)