End Stage Liver Disease
Conditions
Brief summary
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
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.
Interventions
DRUGGCSF
5 doses of GCSF injection will be injected under the skin on the abdomen to mobilize the bone marrow cells.
PROCEDURECD133 Cells Transplantation
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.
Sponsors
Singapore General Hospital
Tan Tock Seng Hospital
Changi General Hospital
National University Hospital, Singapore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Blinding will be maintained by investigators performing analysis of the results. Given the invasive procedure of percutaneous transhepatic cannulation, the investigators felt that it will be unethical to perform sham procedure on control arm patients. Both managing doctors and patient will know which arm they are on but where not inevitable, data collection such as quality of life and results interpretation such as histology and laboratory analysis of results will be performed anonymously.
Intervention 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
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
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: 1. MELD score 10-27 2. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement of Fibrosis Staging (Ishak) | 3 months | Improvement of Fibrosis Staging (Ishak) \> 1 point |
| Improvement of liver fibrosis on MRE (magnetic resonance elastography) | 6 months | Improvement of liver fibrosis on MRE (magnetic resonance elastography) \> 2 point |
| Improvement of MELD (Model of End stage Liver Disease) score or Child Pugh State | 6 months | Improvement of MELD (Model of End stage Liver Disease) score or Child Pugh State by at least 2 points |
| Improvement of quantitative fibrosis | 1 year | Improvement of quantitative fibrosis on histology \> 10% |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Improvement of Patient Reported outcome | 6 months | Improvement of Patient Reported outcome (quality of life Short Form Health Survey SF-36 for liver cirrhosis) |
| Overall Survival and Improvement | 1 year | Overall Survival |
| Overall Improvement of MELD score | 1 year | Rate of deterioration of MELD score (Kaplan Meier analysis) |
| Overall Improvement in Liver Function Tests | 1 year | Improvement in Liver Function Tests, especially Total Bilirubin, Albumin and Prothrombin Time |
| Improvement of Hepatic Venous Pressure | 3 months | Improvement of Hepatic Venous Pressure |
| Incidence of clinical decompensation | 1 year | Frequency of Incidence of clinical decompensation |
Countries
Singapore
Contacts
Primary ContactNur Halisah
Backup ContactDan Yock Young
Outcome results
None listed