Autologous Endothelial Progenitor Cell Therapy for Reversal of Liver Cirrhosis

Study Overview
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Brief Summary
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This proposal translates a hypothesis driven basic research into clinical setting to determine the potential of using autologous CD133+ cells to reverse fibrosis and improve clinical outcome for patients with end stage cirrhosis. This has significant impact on the management of cirrhosis.

Detailed Description
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This is a 2 arm randomised study patients with decompensated liver cirrhosis involving minimum of 23 and maximum of 33 patients in each arm. The investigators propose that transplantation of mobilized autologous CD133+ cells harvested from the bone marrow directly into the liver has the ability to replace and regenerate the damaged sinusoidal endothelium as well as normalize macrophage and Natural Killer (NK) cell function. The niche provided by the refenestrated endothelium can polarize the macrophage to antifibrotic phenotype as well as directly inactivate the activated myofibroblast, resulting in reversal of liver fibrosis and improvement in liver function. Transplantation of cells will be via intraportal route delivered by percutaneous cannulation of the portal vein system.

Official Title
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Autologous Endothelial Progenitor Cell Therapy for Reversal of Liver Cirrhosis

Conditions
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End Stage Liver Disease

Intervention / Treatment
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* Drug: GCSF
* Procedure: CD133 Cells Transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Liver cirrhosis of any aetiology but where active disease is controlled Childs A/B/C with Child-Pugh score >= 5 And either one of the following: MELD score 10-27 Clinically significant portal hypertension as evidenced by gastroesophageal varices or ascites Exclusion Criteria: MELD score >27 INR>2.5 HIV History of hematological or hepatic malignancy within 5 years from consent Other underlying malignancy with <1 year survival Presence of systemic diseases that may impact survival within 1 year. Listed for liver transplant

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a 2 arm randomised study patients with decompensated liver cirrhosis involving 33 patients in each arm. Randomisation will be done by statistician to determine which arm patients will be in (control / treatment). Treatment arm: Patient will undergo CD133+ cells transplantation at stable compensated state. 5 dose Granulocyte Colony Stimulating Factor (GCSF) will be administered 5 days consecutively before bone marrow harvesting. Approximately 250ml of bone marrow will be harvested and subjected to CD133 isolation using clinimacs (Miltenyi Biotec) in a closed system Under ultrasound guidance, 50 mls of 50-100 million CD133 cells will be infused directly through transhepatic route into portal venous circulation of the liver over 5 mins. Control Arm: Patients will receive 5 doses of GCSF
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Patient will undergo CD133+ cells transplantation at stable compensated state. 5 dose GCSF will be administered 5 days consecutively before bone marrow harvesting. Approximately 250ml of bone marrow will be harvested and subjected to CD133 isolation using clinimacs (Miltenyi Biotec) in a closed system. Under ultrasound guidance, 50 mls of 50-100 million CD133 cells will be infused directly through transhepatic route into portal venous circulation of the liver over 5 mins. | Drug: GCSF<br>* 5 doses of GCSF injection will be injected under the skin on the abdomen to mobilize the bone marrow cells.<br>Procedure: CD133 Cells Transplantation<br>* Endothelial progenitor cells are harvested by CD133+ MACS (magnetic activated cell sorting) sort selection of bone marrow and a minimum of 1x 10^6 and up to 50-100 x 10^6 cells are transplanted to one lobe of the liver via a percutaneous catheter inserted into the portal venous system by percutaneous transhepatic approach for engraftment.<br>* Other names: Endothelial Progenitor cells;|
| Active Comparator: Control<br>Non-Transplant Arm: Patients will receive 5 doses of GCSF | Drug: GCSF<br>* 5 doses of GCSF injection will be injected under the skin on the abdomen to mobilize the bone marrow cells.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of Fibrosis Staging (Ishak) | Improvement of Fibrosis Staging (Ishak) > 1 point | 3 months | 
| Improvement of liver fibrosis on MRE (magnetic resonance elastography) | Improvement of liver fibrosis on MRE (magnetic resonance elastography) > 2 point | 6 months | 
| Improvement of MELD (Model of End stage Liver Disease) score or Child Pugh State | Improvement of MELD (Model of End stage Liver Disease) score or Child Pugh State by at least 2 points | 6 months | 
| Improvement of quantitative fibrosis | Improvement of quantitative fibrosis on histology > 10% | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival and Improvement | Overall Survival | 1 year | 
| Overall Improvement in Liver Function Tests | Improvement in Liver Function Tests, especially Total Bilirubin, Albumin and Prothrombin Time | 1 year | 
| Improvement of Hepatic Venous Pressure | Improvement of Hepatic Venous Pressure | 3 months | 
| Incidence of clinical decompensation | Frequency of Incidence of clinical decompensation | 1 year | 
| Overall Improvement of Patient Reported outcome | Improvement of Patient Reported outcome (quality of life Short Form Health Survey SF-36 for liver cirrhosis) | 6 months | 
| Overall Improvement of MELD score | Rate of deterioration of MELD score (Kaplan Meier analysis) | 1 year |