Umbilical Cord Mesenchymal Stem Cells for Patients With Primary Biliary Cirrhosis

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

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.

Study Overview

• Status: Unknown
• Conditions: Primary Biliary Cirrhosis
• Intervention / Treatment: Other: Conventional plus placebo treatment; Other: conventional plus UC-MSC treatment

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.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100039
      • Recruiting
      • Beijing 302 Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Conventional plus UC-MSC treatment; 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; 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.
PLACEBO_COMPARATOR: Conventional plus placebo treatment; 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; Received conventional treatment and taken i.v., once per 4 week, at 50 ml saline for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Beijing 302 Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (ANTICIPATED): October 1, 2013
• Study Completion (ANTICIPATED): October 1, 2013

Study Registration Dates

• First Submitted: August 5, 2012
• First Submitted That Met QC Criteria: August 9, 2012
• First Posted (ESTIMATE): August 13, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): May 31, 2013
• Last Update Submitted That Met QC Criteria: May 30, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: Mesenchymal Stem Cells; Primary Biliary Cirrhosis; Serum alkaline phosphatase; Serum Bilirubin
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Cholestasis; Fibrosis; Liver Cirrhosis; Liver Cirrhosis, Biliary
• Other Study ID Numbers: Beijing302-005