Autologous Endothelial Progenitor Cell Therapy for Reversal of Liver Cirrhosis

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.

Study Overview

• Status: Recruiting
• Conditions: End Stage Liver Disease
• Intervention / Treatment: Drug: GCSF; Procedure: CD133 Cells Transplantation

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 Type: Interventional
• Enrollment (Anticipated): 66
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Nur Halisah; Phone Number: 66015193; Email: mdcnhj@nus.edu.sg
• Study Contact Backup: Name: Dan Yock Young; Phone Number: 67727641; Email: yock_young_dan@nuhs.edu.sg

Study Locations

• Singapore
  • Singapore, Singapore, 119074
    • Recruiting
    • National University Hospital
    • Principal Investigator: Dan Yock Young
    • Sub-Investigator: Mark Muthiah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: Singapore General Hospital; Tan Tock Seng Hospital; Changi General Hospital
• Investigators: Principal Investigator: Mark Muthiah, National University Hospital, Singapore

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 24, 2017
• Primary Completion (ANTICIPATED): December 31, 2022
• Study Completion (ANTICIPATED): December 31, 2023

Study Registration Dates

• First Submitted: March 6, 2017
• First Submitted That Met QC Criteria: April 5, 2017
• First Posted (ACTUAL): April 12, 2017

Study Record Updates

• Last Update Posted (ACTUAL): January 19, 2021
• Last Update Submitted That Met QC Criteria: January 14, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Failure; Hepatic Insufficiency; Pathologic Processes; Fibrosis; Liver Diseases; End Stage Liver Disease; Liver Cirrhosis
• Other Study ID Numbers: 2016/00711

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No