Clinical trial NCT01662973: Umbilical Cord Mesenchymal Stem Cells for Patients With Primary Biliary Cirrhosis
Official title: Phase 1/2 Study of UC-MSC Treatment for Evaluation the Efficacy and Safety in Patients With Primary Biliary Cirrhosis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Primary Biliary Cirrhosis
Keywords: Primary Biliary Cirrhosis
Mesenchymal Stem Cells
Serum alkaline phosphatase
Serum Bilirubin
Lead sponsor: Beijing 302 Hospital
Sponsor class: OTHER
First posted: 2012-08-13
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: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent
2. Primary Biliary Cirrhosis (according to the criteria defined by AASLD practice guidelines , Hepatology, 2009;50:291-308 )
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 ( HAB, 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: Serum alkaline phosphatase (ALP)
timeFrame: 0, 4, 8,12, 24, 36,48 weeks after treatment
Secondary outcomes:
measure: Histological changes in liver biopsies
timeFrame: baseline and 48 weeks
measure: Serum Bilirubin
timeFrame: At base line and at week 4,8,12,24,36 and 48
measure: Serum AST
timeFrame: At base line and at week 4,8,12,24,36 and 48
measure: Mayo risk score
timeFrame: At base line and at week 4,8,12,24,36 and 48
measure: Number of patients with Portal Hypertension after 12 weeks treatment
timeFrame: At base line and at week 12,24,36 and 48
measure: MELD score
timeFrame: At base line and at week 4,8,12,24,36 and 48
measure: Number of participants with improvement of clinical symptoms
timeFrame: At base line and at week 4,8,12,24,36 and 48
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: Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997 Sep;113(3):884-90. doi: 10.1016/s0016-5085(97)70183-5.
citation: Kuiper EM, Hansen BE, de Vries RA, den Ouden-Muller JW, van Ditzhuijsen TJ, Haagsma EB, Houben MH, Witteman BJ, van Erpecum KJ, van Buuren HR; Dutch PBC Study Group. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009 Apr;136(4):1281-7. doi: 10.1053/j.gastro.2009.01.003. Epub 2009 Jan 14.
citation: Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol. 2010 May;52(5):745-58. doi: 10.1016/j.jhep.2009.11.027. Epub 2010 Feb 18.
citation: Silveira MG, Brunt EM, Heathcote J, Gores GJ, Lindor KD, Mayo MJ. American Association for the Study of Liver Diseases endpoints conference: design and endpoints for clinical trials in primary biliary cirrhosis. Hepatology. 2010 Jul;52(1):349-59. doi: 10.1002/hep.23637. No abstract available.