Autologous Endothelial Progenitor Cell Therapy for Reversal of Liver Cirrhosis

Sponsor

National University Hospital, Singapore (Other)

Overall Status

Recruiting

CT.gov ID

NCT03109236

Collaborator

Singapore General Hospital (Other), Tan Tock Seng Hospital (Other), Changi General Hospital (Other)

Enrollment

Location

Arms

76.2

Anticipated Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
End Stage Liver Disease	Drug: GCSF Procedure: CD133 Cells Transplantation	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

66 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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 GCSFThis 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 (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.

Primary Purpose:

Treatment

Official Title:

Autologous Endothelial Progenitor Cell Therapy for Reversal of Liver Cirrhosis

Actual Study Start Date :

Aug 24, 2017

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment 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 5 doses of GCSF injection will be injected under the skin on the abdomen to mobilize the bone marrow cells. Procedure: CD133 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. Other Names: Endothelial Progenitor cells
Active Comparator: Control Non-Transplant Arm: Patients will receive 5 doses of GCSF	Drug: GCSF 5 doses of GCSF injection will be injected under the skin on the abdomen to mobilize the bone marrow cells.

Arm

Intervention/Treatment

Experimental: Treatment

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

5 doses of GCSF injection will be injected under the skin on the abdomen to mobilize the bone marrow cells.

Procedure: CD133 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.

Other Names:

Endothelial Progenitor cells

Active Comparator: Control

Non-Transplant Arm: Patients will receive 5 doses of GCSF

Drug: GCSF

5 doses of GCSF injection will be injected under the skin on the abdomen to mobilize the bone marrow cells.

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

Overall Survival and Improvement [1 year]
Overall Survival
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
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 Improvement of MELD score [1 year]
Rate of deterioration of MELD score (Kaplan Meier analysis)

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National University Hospital	Singapore		Singapore	119074

Sponsors and Collaborators

National University Hospital, Singapore
Singapore General Hospital
Tan Tock Seng Hospital
Changi General Hospital

Investigators

Principal Investigator: Dan Yock Young, National University Hospital, Singapore
Principal Investigator: Mark Muthiah, National University Hospital, Singapore

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

National University Hospital, Singapore

ClinicalTrials.gov Identifier:

NCT03109236

Other Study ID Numbers:

2016/00711

First Posted:

Apr 12, 2017

Last Update Posted:

Jan 19, 2021

Last Verified:

Jan 1, 2021

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Liver Diseases

Liver Cirrhosis

End Stage Liver Disease

Study Results

No Results Posted as of Jan 19, 2021