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Autologous Endothelial Progenitor Cell Therapy for Reversal of Liver Cirrhosis

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ClinicalTrials.gov Identifier: NCT03109236
Recruitment Status : Recruiting
First Posted : April 12, 2017
Last Update Posted : April 12, 2017
Sponsor:
Collaborators:
Singapore General Hospital
Tan Tock Seng Hospital
Changi General Hospital Singapore
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
End Stage Liver Disease Drug: Neupogen 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 Type : Interventional  (Clinical Trial)
Estimated 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 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
Estimated Study Start Date : April 15, 2017
Estimated Primary Completion Date : March 31, 2020
Estimated Study Completion Date : March 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment

Patient will undergo CD133+ cells transplantation at stable compensated state. 5 dose GCSF (Neupogen) 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: Neupogen
5 doses of GCSF injection will be injected under the skin on the abdomen to mobilize the bone marrow cells.
Other Name: GCSF

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 Name: Endothelial Progenitor cells

Active Comparator: Control

Non-Transplant Arm:

Patients will receive 5 doses of GCSF (Neupogen)

Drug: Neupogen
5 doses of GCSF injection will be injected under the skin on the abdomen to mobilize the bone marrow cells.
Other Name: GCSF




Primary Outcome Measures :
  1. Improvement of Fibrosis Staging (Ishak) [ Time Frame: 3 months ]
    Improvement of Fibrosis Staging (Ishak) > 1 point

  2. Improvement of liver fibrosis on MRE (magnetic resonance elastography) [ Time Frame: 6 months ]
    Improvement of liver fibrosis on MRE (magnetic resonance elastography) > 2 point

  3. Improvement of MELD (Model of End stage Liver Disease) score or Child Pugh State [ Time Frame: 6 months ]
    Improvement of MELD (Model of End stage Liver Disease) score or Child Pugh State by at least 2 points

  4. Improvement of quantitative fibrosis [ Time Frame: 1 year ]
    Improvement of quantitative fibrosis on histology > 10%


Secondary Outcome Measures :
  1. Overall Survival and Improvement [ Time Frame: 1 year ]
    Overall Survival

  2. Overall Improvement in Liver Function Tests [ Time Frame: 1 year ]
    Improvement in Liver Function Tests, especially Total Bilirubin, Albumin and Prothrombin Time

  3. Improvement of Hepatic Venous Pressure [ Time Frame: 3 months ]
    Improvement of Hepatic Venous Pressure

  4. Incidence of clinical decompensation [ Time Frame: 1 year ]
    Frequency of Incidence of clinical decompensation

  5. Overall Improvement of Patient Reported outcome [ Time Frame: 6 months ]
    Improvement of Patient Reported outcome (quality of life Short Form Health Survey SF-36 for liver cirrhosis)

  6. Overall Improvement of MELD score [ Time Frame: 1 year ]
    Rate of deterioration of MELD score (Kaplan Meier analysis)



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Ages Eligible for Study:   40 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Liver cirrhosis of any aetiology but where active disease is controlled
  • Childs B/C with Child-Pugh score > 8
  • MELD score 13-27
  • Platelet>50 000/mls

Exclusion Criteria:

  • MELD score >27
  • Abdominal ascites precluding percutaneous transhepatic cannulation.
  • HIV
  • History of hematological or hepatic malignancy
  • Other underlying malignancy with <1 year survival
  • Absence of systemic diseases that may impact survival within 1 year.
  • Listed or potential for liver transplant
  • Pregnant women

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03109236


Contacts
Contact: Nur Halisah 66015193 mdcnhj@nus.edu.sg
Contact: Dan Yock Young 67727641 yock_young_dan@nuhs.edu.sg

Locations
Singapore
National University Hospital Recruiting
Singapore, Singapore, 119074
Principal Investigator: Dan Yock Young         
Sub-Investigator: Mark Muthiah         
Sponsors and Collaborators
National University Hospital, Singapore
Singapore General Hospital
Tan Tock Seng Hospital
Changi General Hospital Singapore
Investigators
Principal Investigator: Dan Yock Young National University Hospital, Singapore
Principal Investigator: Mark Muthiah National University Hospital, Singapore

Responsible Party: National University Hospital, Singapore
ClinicalTrials.gov Identifier: NCT03109236     History of Changes
Other Study ID Numbers: 2016/00711
First Posted: April 12, 2017    Key Record Dates
Last Update Posted: April 12, 2017
Last Verified: February 2017

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Liver Diseases
Liver Cirrhosis
End Stage Liver Disease
Digestive System Diseases
Liver Failure
Hepatic Insufficiency