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Hepatocyte Transplantation for Acute Decompensated Liver Failure

Primary Purpose

Liver Failure Acute

Status

Withdrawn

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

human hepatocytes

About this trial

This is an interventional treatment trial for Liver Failure Acute focused on measuring fulminant hepatic failure

Eligibility Criteria

undefined - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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:

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.
Hemodynamically significant gastrointestinal bleeding causing a systolic blood pressure <70mmHg at the time of transplantation.
Uncorrectable coagulopathy despite use of plasmapheresis that would preclude any invasive procedures.
Leukopenia at the time of cell transplant, defined as an absolute neutrophil count of <500/µL.
Known allergy to immunosuppression medications that are required post transplant procedure for the prevention of rejection.
Active malignancy except those with acute liver failure during treatment with estimated life expectancies of >1 year if the malignancy is controlled.
Sepsis or other active infection except those without evidence of hemodynamically significant uncontrollable systemic sepsis with positive blood or tissue cultures.
Intrauterine pregnancy. All females of childbearing potential will receive a pregnancy test prior to enrollment.

Sites / Locations

Children's Hospital of Pittsburgh of UPMC

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Hepatocyte Transplantation

Arm Description

See Below

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

Full Information

NCT ID

NCT01345565

First Posted

April 26, 2011

Last Updated

January 18, 2019

Sponsor

Ira Fox

1. Study Identification

Unique Protocol Identification Number

NCT01345565

Brief Title

Hepatocyte Transplantation for Acute Decompensated Liver Failure

Official Title

Hepatocyte Transplantation for Acute Decompensated Liver Failure

Study Type

Interventional

2. Study Status

Record Verification Date

January 2019

Overall Recruitment Status

Withdrawn

Why Stopped

A funding mechanism is not identified at this time

Study Start Date

March 2011 (undefined)

Primary Completion Date

January 2019 (Actual)

Study Completion Date

January 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Ira Fox

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Liver Failure Acute

Keywords

fulminant hepatic failure

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Hepatocyte Transplantation

Arm Type

Experimental

Arm Description

See Below

Intervention Type

Drug

Intervention Name(s)

human hepatocytes

Intervention Description

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.

Primary Outcome Measure Information:

Title

Improvement in evidence of liver function at two weeks after hepatocyte transplant

Description

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.

Time Frame

Two weeks after hepatocyte transplant

Secondary Outcome Measure Information:

Title

Immune Response

Description

Time Frame

two weeks after hepatocyte transplant and monthly thereafter post hepatocyte transplant

Title

Quality and Quantity of Hepatocytes

Description

The relationship between number and quality of donor hepatocytes infused and engraftment in the livers of patients with the acute liver injury.

Time Frame

Two weeks after hepatocyte transplant

10. Eligibility

Sex

All

Maximum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ira J Fox, MD

Organizational Affiliation

University of Pittsburgh

Official's Role

Principal Investigator

Facility Information:

Facility Name

Children's Hospital of Pittsburgh of UPMC

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15201

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

9580649

Citation

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.

Results Reference

background

PubMed Identifier

9671059

Citation

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.

Results Reference

background

PubMed Identifier

7940741

Citation

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.

Results Reference

background

PubMed Identifier

2066062

Citation

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.

Results Reference

background

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Hepatocyte Transplantation for Acute Decompensated Liver Failure

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