Metabolic DiseasesPhase 1NCT01345578
Hepatocyte Transplantation for Liver Based Metabolic Disorders
A Phase 1 study testing human hepatocyte transplantation and Preparative Radiation Therapy in people with Metabolic Diseases, run by Ira Fox at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages Up to 21 years
- Conditions the study is for
- Metabolic Diseases
- What is being tested?
- human hepatocyte transplantation and Preparative Radiation Therapy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2011to 31 Mar 2022
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
Who cannot join
- 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:
- Subject has active malignancy.
- Subject has allergy to immunosuppression medications that are required post transplant procedure for the prevention of rejection.
- Subject has sepsis, pneumonia, other active infection or other secondary life-threatening organ dysfunction.
- 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.
- Subject is pregnant or breastfeeding.
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, 15201
About this study
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.
Read the detailed 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.
- Conditions
- Metabolic Diseases
- Being tested
- human hepatocyte transplantation, Preparative Radiation Therapy
- Keywords
- Urea Cycle Disorders, Carbamoyl-Phosphate Synthase I Deficiency Disease, Citrullinemia, Ornithine Carbamoyltransferase Deficiency Disease, Crigler-Najjar Syndrome
- Medical subject headings
- Metabolic Diseases, Urea Cycle Disorders, Inborn, Carbamoyl-Phosphate Synthase I Deficiency Disease, Citrullinemia, Ornithine Carbamoyltransferase Deficiency Disease, Crigler-Najjar Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
human hepatocyte transplantationDrug
Also called hepatocyte transplant
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.
Preparative Radiation TherapyRadiation
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).
| Study group | Role | What they receive |
|---|---|---|
| Hepatocyte Transplantation | Experimental | See Below Receives: Drug: human hepatocyte transplantation; Radiation: Preparative Radiation Therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 6 months post hepatocyte transplant
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 May 2011 (estimated)
- Study startMar 2011
- Primary completion31 Mar 2022
- Study completion31 Mar 2022
Why it stopped: seeking additional funding
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Metabolic DiseasesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ira Fox
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Ira Fox, University of Pittsburgh
- Investigators
- Ira J Fox, MD, Principal investigator, University of Pittsburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01345578
- Sponsor's protocol ID
- PRO09040497
- Status last verified
- Dec 2022
- First submitted
- 26 Apr 2011
- Last updated
- 7 Dec 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Horslen SP, Fox IJ. Hepatocyte transplantation. Transplantation. 2004 May 27;77(10):1481-6. doi: 10.1097/01.tp.0000113809.53415.c2.
PubMed 15239608Horslen 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.
PubMed 12777539Fox 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.
PubMed 9580649Dhawan 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.
PubMed 15614156Sokal 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.
PubMed 12973120Jorns C, Ellis EC, Nowak G, Fischler B, Nemeth A, Strom SC, Ericzon BG. Hepatocyte transplantation for inherited metabolic diseases of the liver. J Intern Med. 2012 Sep;272(3):201-23. doi: 10.1111/j.1365-2796.2012.02574.x. Epub 2012 Aug 20.
PubMed 22789058
Study at a glance
From the registry record, last updated by the sponsor on 7 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Hepatocyte Transplantation for Liver Based Metabolic Disorders
- ClinicalTrials.gov ID
- NCT01345578
- Acronym / sponsor ID
- PRO09040497
- Conditions
- Metabolic Diseases
- Keywords
- Urea Cycle Disorders, Carbamoyl-Phosphate Synthase I Deficiency Disease, Citrullinemia, Ornithine Carbamoyltransferase Deficiency Disease, Crigler-Najjar Syndrome
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: seeking additional funding
- Enrolment
- 5 participants (actual)
- Lead sponsor
- Ira FoxUniversity, hospital or other
- Study start
- Mar 2011
- Primary completion
- 31 Mar 2022 (actual)
- Study completion
- 31 Mar 2022 (actual)
- First posted
- 2 May 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Hepatocyte Transplantation | Experimental | Drug: human hepatocyte transplantation, Radiation: Preparative Radiation TherapySee Below |
Who may qualify
- Ages
- Up to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (7 listed)
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| human hepatocyte transplantationAlso: hepatocyte transplantTransplantation 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. | Drug | Hepatocyte Transplantation |
| Preparative Radiation TherapyJust 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). | Radiation | Hepatocyte Transplantation |
Primary outcome
Improvement in enzyme physiologic function at 6 months
Time frame: 6 months post hepatocyte transplant
After infusing donor allogeneic hepatocytes through the portal vein following preparative hepatic irradiation, improvement in enzyme physiologic function will be assessed at 6 months.
Results and safety
The study was stopped early (reason given: seeking additional funding). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Dec 2022.
- Background: PubMed 15239608Horslen SP, Fox IJ. Hepatocyte transplantation. Transplantation. 2004 May 27;77(10):1481-6. doi: 10.1097/01.tp.0000113809.53415.c2.
- Background: PubMed 12777539Horslen 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.
- Background: PubMed 9580649Fox 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.
- Background: PubMed 15614156Dhawan 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.
- Background: PubMed 12973120Sokal 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.
- Derived from this study: PubMed 22789058Jorns C, Ellis EC, Nowak G, Fischler B, Nemeth A, Strom SC, Ericzon BG. Hepatocyte transplantation for inherited metabolic diseases of the liver. J Intern Med. 2012 Sep;272(3):201-23. doi: 10.1111/j.1365-2796.2012.02574.x. Epub 2012 Aug 20.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ira J Fox, MD principal investigator
University of Pittsburgh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing human hepatocyte transplantation and Preparative Radiation Therapy in people with Metabolic Diseases, run by Ira Fox at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 7 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: seeking additional funding). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Improvement in enzyme physiologic function at 6 months (time frame: 6 months post hepatocyte transplant). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01345578, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Dec 2022.