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

Primary Biliary Cirrhosis Clinical Trial

— MSCsTreatPBC  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01440309
• Other study ID #: 2008BAI59B03/2011AA020119
• Status: Recruiting
• Phase: Phase 1
• First received: September 20, 2011
• Last updated: August 1, 2012
• Start date: November 2011
• Est. completion date: December 2013

Study information

• Verified date: September 2011
• Source: Chinese Academy of Medical Sciences
• Contact: Fengchun Zhang, MD
• Phone: 0086-10-65296891
• Email: zhangfccra[@]yahoo.com.cn
• Is FDA regulated: No
• Health authority: China: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: December 2013
• Est. primary completion date: November 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Liver Cirrhosis
• Liver Cirrhosis, Biliary
• Primary Biliary Cirrhosis

Intervention

Biological:
• Biological: mesenchymal stem cell
Mesenchymal stem cells,5-50 million/kg, Intravenous infusion, One dosage,whether to give another dosage depending on patients' condition

Drug:
• ursodeoxycholic acid
13-15 mg/kg/day, to the end of the study

Locations

Country	Name	City	State
China	Peking Union Medical College Hospital	Beijing

Sponsors (2)

Lead Sponsor	Collaborator
Robert Chunhua Zhao, MD, PhD	Peking Union Medical College Hospital

Country where clinical trial is conducted

China, 

References & Publications (10)

Chen L, Zhang W, Yue H, Han Q, Chen B, Shi M, Li J, Li B, You S, Shi Y, Zhao RC. Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells. Stem Cells Dev. 2007 Oct;16(5):719-31. — View Citation

Deng W, Han Q, Liao L, Li C, Ge W, Zhao Z, You S, Deng H, Zhao RC. Allogeneic bone marrow-derived flk-1+Sca-1- mesenchymal stem cells leads to stable mixed chimerism and donor-specific tolerance. Exp Hematol. 2004 Sep;32(9):861-7. — View Citation

Deng W, Han Q, Liao L, You S, Deng H, Zhao RC. Effects of allogeneic bone marrow-derived mesenchymal stem cells on T and B lymphocytes from BXSB mice. DNA Cell Biol. 2005 Jul;24(7):458-63. — View Citation

Fang B, Shi M, Liao L, Yang S, Liu Y, Zhao RC. Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice. Transplantation. 2004 Jul 15;78(1):83-8. — View Citation

Liao L, Zhao RC. An overview of stem cell-based clinical trials in China. Stem Cells Dev. 2008 Aug;17(4):613-8. doi: 10.1089/scd.2008.0183. Review. — View Citation

Shi D, Liao L, Zhang B, Liu R, Dou X, Li J, Zhu X, Yu L, Chen D, Zhao RC. Human adipose tissue-derived mesenchymal stem cells facilitate the immunosuppressive effect of cyclosporin A on T lymphocytes through Jagged-1-mediated inhibition of NF-?B signaling. Exp Hematol. 2011 Feb;39(2):214-224.e1. doi: 10.1016/j.exphem.2010.10.009. Epub 2010 Nov 13. — View Citation

Sun Z, Han Q, Zhu Y, Li Z, Chen B, Liao L, Bian C, Li J, Shao C, Zhao RC. NANOG has a role in mesenchymal stem cells' immunomodulatory effect. Stem Cells Dev. 2011 Sep;20(9):1521-8. doi: 10.1089/scd.2010.0366. Epub 2011 Feb 26. — View Citation

Wang J, Bian C, Liao L, Zhu Y, Li J, Zeng L, Zhao RC. Inhibition of hepatic stellate cells proliferation by mesenchymal stem cells and the possible mechanisms. Hepatol Res. 2009 Dec;39(12):1219-28. doi: 10.1111/j.1872-034X.2009.00564.x. Epub 2009 Sep 25. — View Citation

Zhang B, Liu R, Shi D, Liu X, Chen Y, Dou X, Zhu X, Lu C, Liang W, Liao L, Zenke M, Zhao RC. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population. Blood. 2009 Jan 1;113(1):46-57. doi: 10.1182/blood-2008-04-154138. Epub 2008 Oct 2. — View Citation

Zhang W, Ge W, Li C, You S, Liao L, Han Q, Deng W, Zhao RC. Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev. 2004 Jun;13(3):263-71. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	The occurrence of cirrhosis and its complications		24 months after therapy	No
Secondary	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	No
Secondary	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	No