Hepatocyte Transplantation for Liver Based Metabolic Disorders

Metabolic Diseases Clinical Trial

Official title:

Hepatocyte Transplantation for Liver Based Metabolic Disorders

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01345578
• Other study ID #: PRO09040497
• Status: Terminated
• Phase: Phase 1
• Start date: March 2011
• Est. completion date: March 31, 2022

Study information

• Verified date: December 2022
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this research study is to determine whether partial irradiation of the liver and liver cell transplantation can provide help for patients with life-threatening liver-based metabolic diseases who are unlikely to survive without extensive medical therapy or transplant. The goal of this research study is to determine if liver cell transplants can be effective as an alternative to organ transplantation. At the present time, liver cell transplants are experimental and have been done in a limited number of human subjects.

Description:

Management of patients with hepatic failure and liver-based metabolic disorders is complex and expensive. Hepatic failure results in impaired coagulation, altered consciousness and cerebral function, a heightened risk of multiple organ system failure, and sepsis. Liver transplantation is often the only available treatment option for severe, even if transient, hepatic failure. Patients with life-threatening liver-based metabolic disorders similarly require organ transplantation even though their metabolic diseases are typically the result of a single enzyme deficiency, and the liver otherwise functions normally. More than 17,000 patients currently await liver transplantation in the United States, a number that seriously underestimates the number of patients that need treatment, as it has been estimated that more than a million patients in the United States could benefit from transplantation. Unfortunately, use of whole liver transplantation to treat these disorders is limited by a severe shortage of donors and by the risks associated with major surgery. Hepatocyte transplantation holds great promise as an alternative to organ transplantation for the treatment of liver diseases, and numerous studies in rodents indicate that transplants consisting of isolated liver cells can correct various metabolic deficiencies of the liver and can reverse hepatic failure. The transplant procedure, which involves injection of isolated hepatocytes into the liver through the portal vein, is far less intrusive than transplantation of the whole liver and could be performed on severely ill patients with relatively low risk. In the presence of normal host liver architecture, the transplanted cells integrate into the host liver, providing considerable restorative potential. Because the native liver is not removed, the transplanted hepatocytes need only improve some of the functions of the failing liver and need not replace all hepatic functions. Although clinical trials of hepatocyte transplantation have demonstrated the long-term safety of the procedure, only partial correction of metabolic disorders has been achieved, and the degree to which donor hepatocytes have restored failing livers has not been adequate to circumvent the need for organ replacement.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: March 31, 2022
• Est. primary completion date: March 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 21 Years

Eligibility

Inclusion Criteria:

• Patients will have life-threatening liver-based metabolic disorders who are candidates for organ transplantation where hepatocyte transplantation is considered theoretically curative.
• In addition to child subjects less than 18 years of age, for purposes of this protocol, adults up to age 21 years will be enrolled since this is the upper age limit of patients which are seen at Children's Hospital of Pittsburgh.

Exclusion Criteria:

• Patients with liver based metabolic disorders not theoretically treatable with organ transplantation.
• Subjects who meet any of the following criteria will be excluded from participation in

this protocol:

1. Subject has active malignancy.

2. Subject has allergy to immunosuppression medications that are required post transplant procedure for the prevention of rejection.

3. Subject has sepsis, pneumonia, other active infection or other secondary life-threatening organ dysfunction.

4. Significant liver fibrosis determined by biopsy (if clinically indicated). Significant liver fibrosis will be defined by the Ishak Staging, Stage 5: bridges with occasional nodules.

5. Subject is pregnant or breastfeeding.

Related Conditions & MeSH terms

• Metabolic Diseases

Intervention

Drug:
• human hepatocyte transplantation
Transplantation of hepatocytes into the liver will be through the portal vein. The portal vein will be accessed transhepatically, by umbilical vein, or surgically by a peripheral mesenteric vein. The subject will be evaluated de novo and if they are a candidate for orthotopic liver transplantation they will receive the transplant. Even if the subject receives the hepatocyte transplant and it does not work, they will be evaluated for orthotopic liver transplantation as if they never received the hepatocyte transplant. If at 6 months we see an improvement in disease, we will recommend a re-transplantation with a goal of complete correction of disease and until the subject is no longer required to be a candidate for organ transplantation. Subjects will be re-evaluated every 6 months for re-transplantation. Subjects will remain on the waiting list for organ transplantation. Further radiation therapy will not be needed prior to re-transplantation.

Radiation:
• Preparative Radiation Therapy
Just prior to the hepatocyte transplant, a portion of the right hepatic lobe comprising between 35-50% of the entire liver volume will be irradiated to a dose of 7.5-10 Gy in a single fraction using a linear accelerator-based stereotactic radiosurgery system with intensity-modulated radiation therapy planning (IMRT).

Locations

Country	Name	City	State
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Ira Fox

Country where clinical trial is conducted

United States, 

References & Publications (5)

Dhawan A, Mitry RR, Hughes RD, Lehec S, Terry C, Bansal S, Arya R, Wade JJ, Verma A, Heaton ND, Rela M, Mieli-Vergani G. Hepatocyte transplantation for inherited factor VII deficiency. Transplantation. 2004 Dec 27;78(12):1812-4. doi: 10.1097/01.tp.0000146386.77076.47. — View 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. — View Citation

Horslen SP, Fox IJ. Hepatocyte transplantation. Transplantation. 2004 May 27;77(10):1481-6. doi: 10.1097/01.tp.0000113809.53415.c2. — View Citation

Horslen SP, McCowan TC, Goertzen TC, Warkentin PI, Cai HB, Strom SC, Fox IJ. Isolated hepatocyte transplantation in an infant with a severe urea cycle disorder. Pediatrics. 2003 Jun;111(6 Pt 1):1262-7. doi: 10.1542/peds.111.6.1262. — View Citation

Sokal EM, Smets F, Bourgois A, Van Maldergem L, Buts JP, Reding R, Bernard Otte J, Evrard V, Latinne D, Vincent MF, Moser A, Soriano HE. Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis disease: technique, safety, and metabolic follow-up. Transplantation. 2003 Aug 27;76(4):735-8. doi: 10.1097/01.TP.0000077420.81365.53. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Improvement in enzyme physiologic function at 6 months	After infusing donor allogeneic hepatocytes through the portal vein following preparative hepatic irradiation, improvement in enzyme physiologic function will be assessed at 6 months.	6 months post hepatocyte transplant