Autologous Endothelial Progenitor Cell Therapy for Reversal of Liver Cirrhosis

Phase 3

• Conditions: End Stage Liver Disease
• Interventions: Drug: GCSF; Procedure: CD133 Cells Transplantation

• Registration Number: NCT03109236
• Lead Sponsor: National University Hospital, Singapore

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.

Study Timeline

• Study First Submitted: 2017-03-06
• Study First Submitted QC: 2017-04-05
• Study First Posted: 2017-04-12
• Study Start: 2017-08-24
• Status Verified: 2021-01
• Last Update Submitted: 2021-01-14
• Last Update Posted: 2021-01-19
• Primary Completion: 2022-12-31
• Study Completion: 2023-12-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 66

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment	CD133 Cells Transplantation	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.
Control	GCSF	Non-Transplant Arm: Patients will receive 5 doses of GCSF
Treatment	GCSF	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.

Primary Outcome Measures

Name	Time	Method
Improvement of liver fibrosis on MRE (magnetic resonance elastography)	6 months	Improvement of liver fibrosis on MRE (magnetic resonance elastography) \> 2 point
Improvement of quantitative fibrosis	1 year	Improvement of quantitative fibrosis on histology \> 10%
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 Fibrosis Staging (Ishak)	3 months	Improvement of Fibrosis Staging (Ishak) \> 1 point

Secondary Outcome Measures

Name	Time	Method
Overall Survival and Improvement	1 year	Overall Survival
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)
Overall Improvement in Liver Function Tests	1 year	Improvement in Liver Function Tests, especially Total Bilirubin, Albumin and Prothrombin Time

Trial Locations

Locations (1)

National University Hospital; 🇸🇬 Singapore, Singapore