Human Fetal Liver Cell Transplantation in Chronic Liver Failure (hFLCTx)

Human Fetal Liver Cell Transplantation for Treatment of Chronic Liver Failure

The herein study consists in the transplantation of liver progenitor cells isolated from human fetal liver tissue with the aim of improving conventional liver therapy and broadening therapeutical options other than liver transplantation.

Study Overview

• Status: Completed
• Conditions: Liver Cirrhosis
• Intervention / Treatment: Other: Human Fetal Liver Cell Transplantation

Detailed Description

One of the major clinical problems in transplantation medicine is the discrepancy between the growing number of liver chronic disease patients and the lack of organs. Research and development of new liver failure treatments thus have a high clinical significance. Regenerative medicine and results recently achieved in the field of stem cell biology may provide a remedy to this emerging problem.

Our project aims at developing new generation cell transplantation methodologies through an interdisciplinary research project created from a collaboration between ISMETT, Palermo and the University of Pittsburgh (UPMC-USA).

Adult hepatocyte transplantation has been in use for several years already and has proved to be safe for patients and able, especially in pediatric patients, to improve liver function indices and delay the need for liver transplantation. Studies have been limited until now by the use of already differentiated hepatocytes and therefore unable to proliferate and develop a suitable liver mass to support a decompensated liver.

The hypothesis of our project, supported by in vitro studies and studies on experimental animal models, is based on the possibility to generate an ectopic liver system in the spleen through the experimental use of hepatic cell progenitors obtained from human fetal liver tissues. Human fetal liver cell transplantation will be performed in the spleen through arterial injection.

The final endpoint of the project is to develop an innovative and safe treatment for patients with end-stage chronic liver failure

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Palermo, Italy, 90127
    • ISMETT

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Clinical diagnosis (evidence of chronic liver disease, presence of ascites and/or esophageal varices upon superior digestive endoscopy and/or ultrasound evidence of portal hypertension) or histological diagnosis of liver cirrhosis with any etiology.
• Serious liver failure documented by a score ≥ B8 based on the Child-Pugh-Turcotte classification and/or MELD score ≥ 14.
• Informed consent to the study signed by the patient.

Exclusion Criteria:

• MELD score ≥ 25
• Hepatocellular carcinoma (HCC)
• Portal vein thrombosis
• Serious cardiovascular or respiratory disease, or other medical condition which may threaten patient's life in the subsequent three months
• Admission to the Intensive Care Unit (ICU)
• Hemodynamic instability (MAP < 55 mmHg)
• Use of vasoactive drugs (Epinephrine, Norepinephrine, Vasopressin, Dopamine, Terlipressine
• Type-1 (acute) hepatorenal syndrome
• Levels of serum creatinine >2 mg/dl and/or creatinine clearance <30-40 ml/min
• Sepsis, active infection or spontaneous bacterial peritonitis
• Active gastrointestinal bleeding or recent gastrointestinal bleeding episode (in the previous 4 weeks)
• Active alcohol abuse
• Severe alcoholic hepatitis
• Pulmonary hypertension (PAP > 35 mmHg)
• History of neoplasia
• Pregnancy
• Non Sicilian residency
• HBV DNA positive
• HIV infection
• Drug addiction
• Age < 18 years
• Transjugular intrahepatic portosystemic shunt (TIPS) placed in the previous month
• Contraindications to the procedure (e.g., related to the splenic artery: aneurysm, kinking, thrombosis, splenic-renal shunt; related to the spleen: large angioma).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treated patients; Cirrhotic patients treated with Human Fetal Liver Cell Transplantation.	Other: Human Fetal Liver Cell Transplantation; Human Fetal Liver Cell Transplantation. Cell source: Non-purified and non-selected fetal liver cells from fetuses aborted between the 16th and 26th week of gestation. Infusion technique: Isolation and incannulation of the femoral artery.Splenic artery infusion under radiological guidance. Cell infusion: between 5 and 10x10^8 cells. Number of sessions: up to 2.
NO_INTERVENTION: Control patients; Cirrhotic patients on Standard therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Survival	Assessment of treated and control patients survival at 1 year follow-up	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of Child-Pugh Score From Baseline to 1 Year Follow-up	Assessment of the efficacy of human fetal liver progenitor cell transplantation on Child-Pugh score. The Child-Pugh (CP) classification is a scoring system used for the classification of the severity of cirrhosis. It includes three continuous variables (bilirubin, albumin and INR) and two discrete variables (ascites and encephalopathy). Each variable is scored 1-3 with 3 indicating most severe derangement. The determination of CP score may range from 5 to 15 and the final score allows to categorize patients in Child-Pugh A (5-6 points), B (7-9 points) and C (10-15 points). The highest is the score the sickest is the patient.	Baseline and 1 year Follow-up
Analysis of Meld Score From Baseline to 1 Year Follow-up	Assessment of the efficacy of human fetal liver progenitor cell transplantation on Meld score. The Model for End-stage Liver Disease (MELD) scoring system aims at stratifying recipients by their disease severity according to a score estimating the 3-month probability of death on the waiting list. The calculation of an individual's MELD score is based on three objective lab parameters (bilirubin, serum creatinine and prothrombin time expressed as international normalized ratio, INR) and it includes logarithmic transformations and multiplication by several factors. It ranges between 6 and 40. The highest is the score the lower is the patient's survival.	Baseline and 1 year Follow-up

Collaborators and Investigators

• Sponsor: The Mediterranean Institute for Transplantation and Advanced Specialized Therapies
• Collaborators: University of Pittsburgh
• Investigators: Principal Investigator: Bruno Gridelli, MD, ISMETT-UPMC

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (ACTUAL): April 1, 2011
• Study Completion (ACTUAL): July 1, 2011

Study Registration Dates

• First Submitted: November 11, 2009
• First Submitted That Met QC Criteria: November 12, 2009
• First Posted (ESTIMATE): November 13, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): November 3, 2015
• Last Update Submitted That Met QC Criteria: October 2, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: Stem cell transplantation; Liver cirrhosis; Fetal stem cells; Liver transplant candidate
• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Pathologic Processes; Liver Diseases; End Stage Liver Disease; Fibrosis; Liver Failure; Liver Cirrhosis
• Other Study ID Numbers: IRRB/01/06