Human Fetal Liver Cell Transplantation in Chronic Liver Failure

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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Human Fetal Liver Cell Transplantation for Treatment of Chronic Liver Failure

Conditions
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Liver Cirrhosis

Intervention / Treatment
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* Other: Human Fetal Liver Cell Transplantation


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treated patients<br>Cirrhotic patients treated with Human Fetal Liver Cell Transplantation. | Other: Human Fetal Liver Cell Transplantation<br>* 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.<br>|
| No Intervention: Control patients<br>Cirrhotic patients on Standard therapy. | |

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver cirrhosis, Fetal stem cells, Stem cell transplantation, Liver transplant candidate