Clinical trial NCT01661842: Umbilical Cord Mesenchymal Stem Cells for Patients With Autoimmune Hepatitis
Official title: Phase 1/2 Study of UC-MSC Treatment for Evaluation the Efficacy and Safety in Patients With Autoimmune Liver Disease
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Autoimmune Hepatitis
Keywords: Autoimmune Hepatitis
Mesenchymal stem cells
serum albumin
serum Tbil
serum immunoglobulin G(IgG)
Lead sponsor: Beijing 302 Hospital
Sponsor class: OTHER
First posted: 2012-08-10
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent
2. Autoimmune hepatitis (according to the criteria defined by the international autoimmune hepatitis Group ,Hepatology, 2008;48:169-176)
3. Negative pregnancy test (female patients in fertile age)

Exclusion Criteria:

1. Hepatocellular carcinoma or other Malignancies
2. Pregnant or lactating women
3. Viral Hepatitis ( HAV,HBV,HCV, et al )
4. Vital organs failure (Cardiac, Renal or Respiratory, et al)
5. Sepsis
6. Active thrombosis in the portal or hepatic veins

Primary outcomes:
measure: Liver Histology change
timeFrame: baseline and 96 weeks
measure: Serum alanine aminotransferase (ALT)
timeFrame: 0,12, 24, 36, 48, 72, 96 weeks after treatment
Secondary outcomes:
measure: Serum AST
timeFrame: At baseline and at week 12, 24, 36, 48, 72, 96
measure: Serum Tbil
timeFrame: At baseline and at week 12, 24, 36, 48, 72, 96
measure: Serum immunoglobulin G (IgG)
timeFrame: At baseline and at week 12, 24, 36, 48, 72, 96
measure: Serum γ-globulin
timeFrame: At baseline and at week 12, 24, 36, 48, 72, 96
measure: MELD score
timeFrame: At base line and at week 12, 24, 36, 48, 72, 96
measure: Number of participants with treatment side effects
timeFrame: At base line and at week 12, 24, 36, 48, 72, 96
measure: Number of participants with improvement of clinical symptoms
timeFrame: At base line and at week 12, 24, 36, 48, 72, 96
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing 302 Hospital
state: Beijing
Study officials:
affiliation: Beijing 302 Hospital
name: Fu-Sheng Wang, professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Czaja AJ. Advances in the current treatment of autoimmune hepatitis. Dig Dis Sci. 2012 Aug;57(8):1996-2010. doi: 10.1007/s10620-012-2151-2. Epub 2012 Apr 3.
citation: Montano-Loza AJ, Carpenter HA, Czaja AJ. Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease. Hepatology. 2007 Oct;46(4):1138-45. doi: 10.1002/hep.21787.
citation: Czaja AJ. Promising pharmacological, molecular and cellular treatments of autoimmune hepatitis. Curr Pharm Des. 2011;17(29):3120-40. doi: 10.2174/138161211798157568.
citation: Gossard AA, Lindor KD. Autoimmune hepatitis: a review. J Gastroenterol. 2012 May;47(5):498-503. doi: 10.1007/s00535-012-0586-z. Epub 2012 Apr 17.
citation: Malekzadeh Z, Haghazali S, Sepanlou SG, Vahedi H, Merat S, Sotoudeh M, Nasseri-Moghaddam S, Malekzadeh R. Clinical features and long term outcome of 102 treated autoimmune hepatitis patients. Hepat Mon. 2012 Feb;12(2):92-9. doi: 10.5812/hepatmon.808. Epub 2012 Feb 29.
citation: Yi T, Song SU. Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications. Arch Pharm Res. 2012 Feb;35(2):213-21. doi: 10.1007/s12272-012-0202-z. Epub 2012 Feb 28.
citation: Holbro A, Abinun M, Daikeler T. Management of autoimmune diseases after haematopoietic stem cell transplantation. Br J Haematol. 2012 May;157(3):281-90. doi: 10.1111/j.1365-2141.2012.09070.x. Epub 2012 Feb 24.