Liver Cirrhosis
Conditions
Keywords
Liver cirrhosis, Fetal stem cells, Stem cell transplantation, Liver transplant candidate
Brief summary
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
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
Interventions
OTHERHuman 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.
Sponsors
University of Pittsburgh
The Mediterranean Institute for Transplantation and Advanced Specialized Therapies
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patient Survival | 1 year | Assessment of treated and control patients survival at 1 year follow-up |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Analysis of Child-Pugh Score From Baseline to 1 Year Follow-up | Baseline and 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. |
| Analysis of Meld Score From Baseline to 1 Year Follow-up | Baseline and 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. |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treated Patients Patients with end-stage chronic liver disease in waiting list for liver transplantation treated with non-purified and non-selected fetal liver cells. | 9 |
| Control Patients Patients with end-stage chronic liver disease on standard therapy in waiting list for liver transplantation. | 16 |
| Total | 25 |
Baseline characteristics
| Characteristic | Treated Patients | Control Patients | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 16 Participants | 25 Participants |
| Region of Enrollment Italy | 9 participants | 16 participants | 25 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 6 Participants | 13 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 16 |
| serious Total, serious adverse events | 0 / 9 | 0 / 16 |
Outcome results
Primary
Patient Survival
Assessment of treated and control patients survival at 1 year follow-up
Time frame: 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treated Patients | Patient Survival | Patient survival | 5 participants |
| Treated Patients | Patient Survival | Death/Transplant | 4 participants |
| Control Patients | Patient Survival | Patient survival | 6 participants |
| Control Patients | Patient Survival | Death/Transplant | 10 participants |
p-value: 0.434Fisher Exact
Secondary
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.
Time frame: Baseline and 1 year Follow-up
Population: Baseline Child-Pugh score vs Follow-up
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treated Patients | Analysis of Child-Pugh Score From Baseline to 1 Year Follow-up | Baseline Child-Pugh score | 10.11 units on a scale | Standard Deviation 1.54 |
| Treated Patients | Analysis of Child-Pugh Score From Baseline to 1 Year Follow-up | Follow-up Child-Pugh score | 9.11 units on a scale | Standard Deviation 1.45 |
| Control Patients | Analysis of Child-Pugh Score From Baseline to 1 Year Follow-up | Baseline Child-Pugh score | 10.00 units on a scale | Standard Deviation 1.26 |
| Control Patients | Analysis of Child-Pugh Score From Baseline to 1 Year Follow-up | Follow-up Child-Pugh score | 11.13 units on a scale | Standard Deviation 1.63 |
Comparison: Comparison at 1 year Follow-upp-value: 0.0076t-test, 2 sided
Secondary
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.
Time frame: Baseline and 1 year Follow-up
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treated Patients | Analysis of Meld Score From Baseline to 1 Year Follow-up | Baseline Meld score | 16.00 units on a scale | Standard Deviation 2.96 |
| Treated Patients | Analysis of Meld Score From Baseline to 1 Year Follow-up | Follow-up Meld score | 15.67 units on a scale | Standard Deviation 3.84 |
| Control Patients | Analysis of Meld Score From Baseline to 1 Year Follow-up | Baseline Meld score | 15.31 units on a scale | Standard Deviation 2.5 |
| Control Patients | Analysis of Meld Score From Baseline to 1 Year Follow-up | Follow-up Meld score | 19.06 units on a scale | Standard Deviation 5.7 |
Comparison: Comparison at 1 year Follow-upp-value: 0.0437t-test, 2 sided