Hepatocyte Transplantation for Acute Decompensated Liver Failure

The purpose of this research study is to determine whether liver cell transplantation can provide help for patients with liver failure who are unlikely to survive without some form of liver support. The goal of this research study is to determine if liver cell transplants can be effective until a liver transplant is received or until patients recover from their liver failure.

Study Overview

• Status: Withdrawn
• Conditions: Liver Failure Acute
• Intervention / Treatment: Drug: human hepatocytes

Detailed Description

Orthotopic liver transplantation has become the treatment of choice for patients with acute liver failure with poor prognostic signs. Survival following hepatic transplantation has improved in the last decade for a number of reasons. These include improvement in immunosuppression, improved methods for preserving and transporting organs, use of donors which had been previously considered unacceptable, use of reduced-sized grafts , and the use of living-donor hepatic transplantation. Despite encouraging survival statistics, there continues to be significant morbidity and mortality associated with hepatic transplantation. In addition, the success of hepatic transplantation has broadened the indications for this form of therapy without a concomitant increase in the number of donors available for these patients.

Since the development of a method for isolating primary hepatocytes by collagenase perfusion, many investigators have demonstrated the efficacy of hepatocyte transplantation in the treatment of liver failure and inherited metabolic disorders in experimental animals. Treatment of liver diseases with transplantation of isolated hepatocytes rather than the whole liver has several theoretical advantages. Unlike the whole liver, isolated hepatocytes could be cryopreserved for instant availability and could be modified genetically or otherwise to enhance specific functions, stimulate proliferation or abrogate allograft rejection. Hepatocyte transplantation should be less stressful than whole liver transplantation because the host organ remains intact. Since the transplanted cells integrate into the host liver, they could provide restorative potential and the consequences of graft loss would be relatively minor. In addition, hepatocyte transplantation would not interfere with subsequent liver transplantation, should that become necessary.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15201
      • Children's Hospital of Pittsburgh of UPMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects will include those patients with ALF who are potential conventional liver transplant recipient candidates based on PELD criteria as well as those who would not be considered candidates for orthotopic liver transplantation (e.g. patients who appear to be too small or too ill for solid organ transplant or those who have a diagnosis that is a contradiction for whole organ transplantation, for example, systemic mitochondrial hepatopathy).
• If the patient is a candidate for orthotopic liver transplantation (per standard clinical criteria), they will be officially listed for liver transplantation as well as hepatocyte transplantation.
• If a subject is a potential conventional liver transplant recipient candidate and a donor liver is available; the patient will receive a solid organ transplant.
• Subjects ages 0-21 years old will be included in this study.

Exclusion Criteria:

The patient has:

1. Severe cardiovascular or respiratory disease at baseline and at the time of hepatocyte transplant as defined by

   1. Central venous pressure >25 mm Hg or if known, pulmonary capillary wedge pressure of >30 mg Hg or
   2. Oxygen saturation of <90% on > 60% oxygen OR a P/F ratio (Po2/FiO2) of <1.
2. Hemodynamically significant gastrointestinal bleeding causing a systolic blood pressure <70mmHg at the time of transplantation.
3. Uncorrectable coagulopathy despite use of plasmapheresis that would preclude any invasive procedures.
4. Leukopenia at the time of cell transplant, defined as an absolute neutrophil count of <500/µL.
5. Known allergy to immunosuppression medications that are required post transplant procedure for the prevention of rejection.
6. Active malignancy except those with acute liver failure during treatment with estimated life expectancies of >1 year if the malignancy is controlled.
7. Sepsis or other active infection except those without evidence of hemodynamically significant uncontrollable systemic sepsis with positive blood or tissue cultures.
8. Intrauterine pregnancy. All females of childbearing potential will receive a pregnancy test prior to enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Hepatocyte Transplantation; See Below

Drug: human hepatocytes; The intrahepatic site for liver cell transplantation has been associated with the best engraftment and function based on animal experiments. Several approaches for access to the portal vein will be considered. The technique used will be determined based on what is considered best for the child based on risk/benefit at the time. We propose to attempt to infuse approximately 5-10% of the hepatic mass in order to provide improved hepatic function. Since we do not yet know from our experience so far the correct number of cells to transplant in order to improve function, we will continue to infuse hepatocytes as donors become available until the patient improves to the point where they are no longer meet the criteria for organ transplantation. The subject will be evaluated de novo and if they are a candidate for orthotopic liver transplantation they will receive the transplant.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in evidence of liver function at two weeks after hepatocyte transplant	The extent to which hepatocyte transplantation can elicit evidence of improvement in liver function in patients with acute decompensated liver failure not responding to medical management.	Two weeks after hepatocyte transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune Response	The extent to which the standard immune suppression medications used for solid organ transplantation can effectively control rejection and preserve the function of transplanted hepatocytes without leading to overwhelming infection or other medication related toxicities in the face of hepatic failure.	two weeks after hepatocyte transplant and monthly thereafter post hepatocyte transplant
Quality and Quantity of Hepatocytes	The relationship between number and quality of donor hepatocytes infused and engraftment in the livers of patients with the acute liver injury.	Two weeks after hepatocyte transplant

Collaborators and Investigators

• Sponsor: Ira Fox
• Investigators: Principal Investigator: Ira J Fox, MD, University of Pittsburgh

Publications and helpful links

General Publications

• Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, Dorko K, Sauter BV, Strom SC. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med. 1998 May 14;338(20):1422-6. doi: 10.1056/NEJM199805143382004. No abstract available.
• Roger V, Balladur P, Honiger J, Baudrimont M, Delelo R, Robert A, Calmus Y, Capeau J, Nordlinger B. Internal bioartificial liver with xenogeneic hepatocytes prevents death from acute liver failure: an experimental study. Ann Surg. 1998 Jul;228(1):1-7. doi: 10.1097/00000658-199807000-00001.
• Habibullah CM, Syed IH, Qamar A, Taher-Uz Z. Human fetal hepatocyte transplantation in patients with fulminant hepatic failure. Transplantation. 1994 Oct 27;58(8):951-2. doi: 10.1097/00007890-199410270-00016. No abstract available.
• Gupta S, Aragona E, Vemuru RP, Bhargava KK, Burk RD, Chowdhury JR. Permanent engraftment and function of hepatocytes delivered to the liver: implications for gene therapy and liver repopulation. Hepatology. 1991 Jul;14(1):144-9. doi: 10.1002/hep.1840140124.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): January 1, 2019
• Study Completion (Actual): January 1, 2019

Study Registration Dates

• First Submitted: April 26, 2011
• First Submitted That Met QC Criteria: April 28, 2011
• First Posted (Estimate): May 2, 2011

Study Record Updates

• Last Update Posted (Actual): January 23, 2019
• Last Update Submitted That Met QC Criteria: January 18, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: fulminant hepatic failure
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency
• Other Study ID Numbers: PRO09020051

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED