Mesenchymal Stem Cell Therapy for Liver Cirrhosis

Study Overview
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Brief Summary
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MSCs have been studied for the treatment of liver diseases as well as non-liver diseases. MSCs have been successful in treating conditions like acute steroid-resistant GVHD in hematopoietic stem cell transplanted patients and also have shown to improve the MELD score in end-stage liver disease. There were no severe side effects observed in using autologous MSCs as a treatment option. The outcome of the studies done so far have been positive and it is encouraged to study the use of MSCs as cell therapy for treating liver diseases. The estimated rate of cirrhosis in HBV patients in Singapore is about 1.6% per year, rate of hepatocellular carcinoma is about 0.8% per year overall and 3.0% per year in cirrhotic patients. Knowing that there are not many options currently available for Liver Cirrhosis patients and that they have a poor prognosis with an average life expectancy of < 12 months, this study uses autologous MSCs to treat Liver Cirrhosis patients in Singapore. The objective of the study is to demonstrate that autologous bone marrow is safe to be used in patients with liver cirrhosis as well as demonstrate that bone marrow MSC may improve liver function and prolong patient survival.

Detailed Description
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Liver cirrhosis refers to extreme scarring of the liver, resulting in suboptimal function of the liver. It can result from a variety of causes, ranging from hepatitis B and C infection, excessive alcohol consumption, autoimmune causes, fatty liver and others. Irrespective of the cause, once the liver becomes cirrhotic, it is a downhill course. Liver cirrhosis is irreversible and most patients will progressively worsen over time. Once liver cirrhosis has reached the stage of decompensation, that is, development of jaundice, ascites, variceal bleeding, hepatic encephalopathy and coagulopathy the two-year survival drops to about 50%. The definitive treatment of decompensated cirrhosis is liver transplantation. While a liver transplantation is potentially curative, the high costs, lack of a donor, treatment-related mortality and the immunosuppression complications make this option possible only for a limited number of patients. The vast majority do not have an effective option at all, thus the need to develop alternative therapies. Various types of Stem Cells had been investigated as a regenerative therapy for liver cirrhosis. These stem cells include bone marrow mesenchymal stem cells (MSC), bone marrow mononuclear cells (MNC) and peripheral CD34 positive cells. Some early studies have shown encouraging results in patients who had autologous bone marrow stem cell transplantation. There was improved liver function in these patients with cirrhotic livers. The sponsor is proposing a study to look into the role of MSC therapy for patients with liver cirrhosis in Singapore. This will be a Phase I/II study with the main emphasis on the safety profile first. The trial will be conducted in compliance with the protocol, GCP and local regulatory requirement(s).

Official Title
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Mesenchymal Stem Cell Therapy for Liver Cirrhosis: A Phase I/II Study

Conditions
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Liver Cirrhosis

Intervention / Treatment
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* Biological: Autologous BM MSC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all the inclusive criteria to participate in the study: with definite liver cirrhosis, irrespective of aetiology must have Child's B or C stage must have signed an informed consent form Exclusion Criteria: Subjects with any of the following criteria are regarded as an exclusion from the study and will not be permitted to participate: age ≤21 years and >70 years old with life expectancy of < 6 months cancers and bone marrow malignancies patients with an active infection or multiple infections patients with uncontrolled hypertension and diabetes immunosuppressed patients (IST must have stopped at least 4 weeks prior to trial enrolment) patients who are HIV positive patients who are pregnant or lactating

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 69 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
Intervention Model: Single Group Assignment
Interventional Model Description: As the primary objective of the study is to assess safety of MSC infusion, a single arm non-blinded study design has been adopted.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>A single dose of 0.5 to 1 x 10^6/kg autologous BM MSCs (Total volume: 30 - 50 ml) will be infused via peripheral venous access. | Biological: Autologous BM MSC<br>* A total of 100-200ml will be harvested from the subject, in either a single or multiple punctures. This will be processed for autologous MSC infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Examination | To observe for the following: absence of grade IV anaphylactic reactions (in reference to CTCAE 4.03) absence of grade IV febrile reactions or septic/ infective complications (in reference to CTCAE 4.03). | Up to 34 weeks | 
| MR Elastography | To detect liver stiffness | Up to 34 weeks | 
| The level of serum alanine aminotransferase (ALT) | To ensure the absence of deterioration of liver function. | Up to 34 weeks | 
| The level of glomerular filtration rate (GFR) | To ensure the absence of deterioration of renal function. | Up to 34 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The level of serum prothrombin time (PT) | To assess the efficacy of treatment | Up to 6 months, post-infusion | 
| The level of serum total bilirubin (TB) | To assess the efficacy of treatment | Up to 6 months, post-infusion | 
| The level of serum albumin (ALB) | To assess the efficacy of treatment | Up to 6 months, post-infusion | 
| MELD Score | To assess the efficacy of treatment | Up to 6 months, post-infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver, Cirrhosis, Child B, Child C, Advance, Advanced, Singapore, MSC, Mesenchymal, Stem Cell, Cell Therapy, MSC Therapy, Treatment