PhenylketonuriaPhase 1/2NCT01465100
Liver Cell Transplant for Phenylketonuria
A Phase 1/2 study testing Preparative Radiation Therapy, Hepatocyte Transplant and Immunosuppression in people with Phenylketonuria, run by Ira Fox at 1 site in United States.
Trial summary
Human phenylketonuria (PKU) results from phenylalanine hydroxylase (PAH) deficiency, and represents one of the most common and extensively studied single-gene Mendelian disorders in humans. Read more about this study
- Who is it for?
- Ages 14 to 55 years
- Conditions the study is for
- Phenylketonuria
- What is being tested?
- Preparative Radiation Therapy, Hepatocyte Transplant and Immunosuppression
- Type of treatment
- Injection or infusion, Surgery or procedure, Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1 participants
- Where
- 1 siteUnited States
- Study dates
- 12 Oct 2011to 17 Jun 2016
- Phase
- Phase 1/2
- 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 14 to 55 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Previous diagnosis of classical PKU, as determined by a PAH mutation known to cause classical PKU, or a Phe >20 mg/dL at any time.
- Patients must have poor control on standard therapy (i.e. Kuvan or diet alone) as defined by two consecutive Phe levels of > 12 mg/dL in the past six months. This is two times the recommended level. If the patient is being treated with Palynziq, they must discontinue treatment for at least two months before participating in this trial.
- Baseline I.Q. ≥70 as assessed by Wechsler Abbreviated Scale of Intelligence (4-subtest IQ)
- Must have a complete evaluation, including dietary records, in a PKU clinic in the past twelve months
- Age between 14 and 55 years
- Stated willingness to comply with all study procedures and availability for the duration of the study
- Sexually active female subjects must agree to use two highly effective forms of contraception for the duration of the study
Who cannot join
- I.Q. <70
- Known biopterin synthesis defects
- Subject has active malignancy
- Subject has known allergy or other contraindication to immune suppression medications (and their alternatives) required post transplant for the prevention of rejection
- Subject has sepsis, pneumonia, other active infection, or other secondary life-threatening organ dysfunction at Screening or Baseline Visits. Subject may be re-screened once infection has cleared.
- Subject is pregnant or breastfeeding
Show all 10Show fewer
- Subject has positive HIV serostatus
- Liver biopsy shows significant fibrosis, defined by the Ishak Stage 5: bridges with occasional nodules, or higher. Liver biopsy will be performed if, in the clinical judgment of the investigators, subject has clinical signs of liver failure, or increased risk of liver fibrosis.
- Any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or not completing the required study follow-up
- Concurrent disease or condition that would interfere with study participation or safety
Trial locations and contacts
1 site in 1 country.
United States1 site
UPMC Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, 15224
About this study
Official title: Hepatocyte Transplantation for Phenylketonuria
Human phenylketonuria (PKU) results from phenylalanine hydroxylase (PAH) deficiency, and represents one of the most common and extensively studied single-gene Mendelian disorders in humans. Unfortunately, optimum clinical outcome demands lifelong dietary restriction through adherence to an unpalatable and expensive artificial diet. Challenges in maintaining traditional therapy lead to increasing phenylalanine (Phe) levels in patients as they approach adulthood with an incumbent severe burden of psychosocial and intellectual difficulties. The recent introduction of the new medication Sapropterin for treatment of PKU has improved Phe control and dietary tolerance in some patients, but at enormous cost to patients and insurers for the FDA designated orphan product. Thus, there is an unmet need for novel therapies to correct PKU. PAH is almost exclusively expressed in the liver in humans. The main objective of the current proposal is to examine the safety and efficacy of hepatocyte transplantation in patients with PKU.
Read the detailed description
Hepatocytes from more than one donor may be required to provide sufficient numbers of cells for transplantation to correct the disease process. We have previously estimated that the hepatic mass of a recipient approaches 4 x 10 to the 9th power hepatocytes/kg. However, this is just an estimate and the true mass may be twice this number. Our goal is to attempt to infuse at least 2x10 to the 8th power cells/kg. Once it has been determined that IND release criteria for the hepatocytes has been met, the patient will then receive Intensity-Modulated Radiation Therapy (IMRT), and the hepatocyte transplant will begin.
Preparative Liver Irradiation: A portion of the right hepatic lobe comprising between 35-50% of the entire liver volume will be irradiated to a dose of 10 Gy in a single fraction using a linear accelerator-based stereotactic radiosurgery system with intensity-modulated radiation therapy planning (IMRT). Respiratory gating will be used to further increase the accuracy of delivering the dose to a specified volume and limiting the exposure to adjacent tissues. After hepatic irradiation, the right or main portal vein will be occluded transiently (0-90 min) to provide a compensatory mitotic signal to donor hepatocytes. Transient portal vein occlusion or embolization has been shown in primates to provide the appropriate mitotic signals necessary for donor cell proliferation. At that time, donor hepatocytes will be transplanted into the irradiated portion of the recipient's liver.
The number of infusions from each donor liver will depend on the tolerance of the patient to infusion (avoidance of portal vein thrombosis and portal vein to systemic venous system shunting), and viability of donor hepatocytes. The hepatocytes from each donor liver will be given over three to four infusions, every 6 to 8 hours, until the cells are no longer viable, approximately twenty-four hours after initial preparation. Ideally, the infusion catheter will be maintained just outside the portal circulation in the umbilical vein remnant so the patient can be potentially discharged from the hospital until the next donor liver is available. Since we do not yet know from our experience the number of cells needed for transplant in order to improve function so that a metabolic disease is cured, we will continue to infuse hepatocytes as donors become available until reaching the goal volume of hepatocytes and until viability of cells has expired. Using hepatocytes from multiple donors will help to ensure that an adequate number of cells is infused while maintaining portal pressure in the normal range.Phe levels will be collected once a week by the subject, using a capillary blood sample on a newborn screening filter paper, and mailed to CHP. Phe levels will also be collected in a venous sample monthly. During months when a Follow-Up Visit is scheduled, both a venous and capillary sample will be collected.
Subjects will receive careful dietary observation post-transplant through the UPMC Children's Hospital of Pittsburgh Division of Medical Genetics research dietician. Three-day diet records will be completed once a month for six months, then every three months thereafter. Diet should remain unchanged throughout the study, unless directed by study staff.
Subjects will undergo a repeat neuropsychological assessment at 6, 12 and 24 months post-transplant (Visits 4 and 6 and the End of Study Visit) which will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Isotopic monitoring of whole body Phe oxidation will be performed at every follow-up visit following the final hepatocyte infusion. An additional Phe oxidation test may also be completed in the event of suspected graft rejection.
Liver biopsies will be performed at 3 and 12 months post-transplant to assess for the presence of donor hepatocytes, and may be completed in the event of suspected graft rejection.
- Conditions
- Phenylketonuria
- Being tested
- Preparative Radiation Therapy, Hepatocyte Transplant, Immunosuppression, Liver Evaluation, Neuro-psychological Assessment
- Keywords
- phenylketonuria, hepatocyte
- Medical subject headings
- Phenylketonurias
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Preparative Radiation TherapyRadiation
Subjects will undergo CT-based simulation and treatment planning for radiation therapy. Once a suitable hepatocyte donor is found and the cell count and viability is acceptable for transplantation, patients will receive Intensity-Modulated Radiation Therapy (IMRT) in one fraction(10 Gy)to the right lobe of the liver (but not exceeding 50% of the liver mass).
Hepatocyte TransplantProcedure or surgery
Transplantation of hepatocytes into the liver will be through the portal vein, either accessed transhepatically, or by umbilical vein. After cell transplantation, measures will be taken to provide chronic access to the portal venous circulation system. If chronic access is achieved, patients will be seen in the PCTRC once a week to assess the site.
Hepatocytes from more than one donor may be required to provide sufficient numbers of cells for transplantation to correct the disease process and to optimize Phe tolerance. Hepatocytes will be infused until the goal number of hepatocytes is infused. If viable hepatocytes remain after the goal number has been infused, the remaining cells will also be infused, as tolerated by the patient.
ImmunosuppressionDrug
Following transplantation, patients will be treated with conventional immune suppression, as is used following whole organ liver transplantation. Patients will be followed as routinely performed following organ transplantation and also followed as would normally be performed for their PKU.
Liver EvaluationOther
Prior to the hepatocyte transplant subjects will undergo a liver evaluation which is standard for all patients who have whole organ transplants at Children's Hospital of Pittsburgh of UPMC. The evaluation includes immunosuppression medication education, psychological assessment, bloodwork to assess blood count, blood and tissue type, blood chemistries, immune system function and certain infectious diseases, EKG, chest x-ray, and abdominal ultrasound to assess blood flow to the blood vessels in the liver. A liver biopsy may be performed if, in the clinical judgment of the investigators, the subject shows clinical signs of liver failure, or is at increased risk for liver fibrosis.
Neuro-psychological AssessmentBehavioural
Subjects will undergo a repeat neuropsychological assessment at 6, 12 and 24 months post-transplant (Visits 4 and 6 and the End of Study Visit) which will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Whole body Phe oxidation testingDiagnostic test
Patient will again be asked to not eat or drink for at least four hours prior to testing. Isotopic monitoring of whole body Phe oxidation will be performed pre-transplant and at every follow-up visit following the final hepatocyte infusion. An additional Phe oxidation test may also be completed in the event of suspected graft rejection.
Liver BiopsyProcedure or surgery
Liver biopsies will be performed at 3 and 12 months post-transplant to assess for the presence of donor hepatocytes, and may be completed in the event of suspected graft rejection.
| Study group | Role | What they receive |
|---|---|---|
| Hepatocyte Transplantation | Experimental | See Below. Receives: Radiation: Preparative Radiation Therapy; Procedure: Hepatocyte Transplant; Drug: Immunosuppression; Other: Liver Evaluation; Behavioral: Neuro-psychological Assessment; Diagnostic Test: Whole body Phe oxidation testing; Procedure: Liver Biopsy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Improvement/reversal of characteristics of PKU
Measured as a 50% decrease in Phe from baseline study level.
Measured: 24 months post hepatocyte transplant
Secondary outcomes (30)
Engraftment of Hepatocytes
Liver biopsy will be performed at 3 months post-transplant to assess for the presence of donor hepatocytes, and may be completed in the event of suspected graft rejection.
Measured: 3 months
Engraftment of Hepatocytes
Liver biopsy will be performed at 12 months post-transplant to assess for the presence of donor hepatocytes, and may be completed in the event of suspected graft rejection.
Measured: 12 months
Engraftment of Hepatocytes
Laboratory tests of hepatic function
Measured: up to 24 months
Wechsler Abbreviated Scale of Intelligence-third edition (WASI-III)
Subjects will undergo this neuropsychological assessment at 6 months post-transplant (Visits 4). T-scores ranging from 20-80 with higher scores reflecting better functioning. Scores are transformed to standard scores ranging from 50-150 again with higher scores representing better functioning. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 6 months
Wechsler Abbreviated Scale of Intelligence-third edition (WASI-III)
Subjects will undergo a repeat neuropsychological assessment at 12 months post-transplant (Visit 6) T-scores ranging from 20-80 with higher scores reflecting better functioning. Scores are transformed to standard scores ranging from 50-150 again with higher scores representing better functioning. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 12 months
Wechsler Abbreviated Scale of Intelligence-third edition (WASI-III)
Subjects will undergo a repeat neuropsychological assessment at 24 months post-transplant (End of Study Visit) T-scores ranging from 20-80 with higher scores reflecting better functioning. Scores are transformed to standard scores ranging from 50-150 again with higher scores representing better functioning. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 24 months
Delis Kaplan Executive Functioning System (D-KEFS)
Subjects will undergo this neuropsychological assessment at 6 months post-transplant (Visit 4). 16 subtests. Test scores vary depending on primary interest and comparisons. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 6 months
Delis Kaplan Executive Functioning System (D-KEFS)
Subjects will undergo a repeat neuropsychological assessment at 12 months post-transplant (Visit 6) 16 subtests. Test scores vary depending on primary interest and comparisons. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 12 months
Delis Kaplan Executive Functioning System (D-KEFS)
Subjects will undergo a repeat neuropsychological assessment at 24 months post-transplant (End of Study Visit). 16 subtests. Test scores vary depending on primary interest and comparisons. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 24 months
Connors Continuous Performance Test-third edition (CPT-III)
Subjects will undergo this neuropsychological assessment at 6 months post-transplant (Visit 4). T scores ranging from <40 to 90 with higher scores reflecting worse function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 6 months
Connors Continuous Performance Test-third edition (CPT-III)
Subjects will undergo this neuropsychological assessment at 12 months post-transplant (Visit 6). T scores ranging from <40 to 90 with higher scores reflecting worse function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 12 months
Connors Continuous Performance Test-third edition (CPT-III)
Subjects will undergo this neuropsychological assessment at 24 months post-transplant (End of Study Visit). T scores ranging from <40 to 90 with higher scores reflecting worse function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 24 months
Adaptive Behavior Assessment System-third edition (ABAS-III)
Subjects will undergo this neuropsychological assessment at 6 months post-transplant (Visit 4). Subtests scaled scores range from 1-15, composite transform to standard scores ranging from 40-120. Higher scores for all reflect better function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 6 months
Adaptive Behavior Assessment System-third edition (ABAS-III)
undergo this neuropsychological assessment at 12 months post-transplant (Visit 6). Subtests scaled scores range from 1-15, composite transform to standard scores ranging from 40-120. Higher scores for all reflect better function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 12 months
Adaptive Behavior Assessment System-third edition (ABAS-III)
Subjects will undergo this neuropsychological assessment at 24 months post-transplant (End of Study Visit). Subtests scaled scores range from 1-15, composite transform to standard scores ranging from 40-120. Higher scores for all reflect better function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 24 months
SF-36 Health Survey
Subjects will undergo this neuropsychological assessment at 6 months post-transplant (Visit 4). scores are transformed to scale scores of 0-100 with higher scores reflecting better function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 6 months
SF-36 Health Survey
Subjects will undergo this neuropsychological assessment at 12 months post-transplant (Visit 6). scores are transformed to scale scores of 0-100 with higher scores reflecting better function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 12 months
SF-36 Health Survey
Subjects will undergo this neuropsychological assessment at 24 months post-transplant (End o Study Visit). scores are transformed to scale scores of 0-100 with higher scores reflecting better function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 24 months
Beck Depression Inventory
Subjects will undergo this neuropsychological assessment at 6 months post-transplant (Visit 4). scores range from 0-63 with higher scores representing poorer function/more prominent depression. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 6 months
Beck Depression Inventory
Subjects will undergo this neuropsychological assessment at 12 months post-transplant (Visit 6). scores range from 0-63 with higher scores representing poorer function/more prominent depression. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 12 months
Beck Depression Inventory
Subjects will undergo this neuropsychological assessment at 24 months post-transplant (End of Study Visit). scores range from 0-63 with higher scores representing poorer function/more prominent depression. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 24 months
Behavior Rating Inventory of Executive Function (BRIEF-parent version)
Parents of subjects will undergo this neuropsychological assessment at 6 months post-transplant (Visit 4) regarding the behavior of their child. scores are converted to T-scores ranging from 40-90 with higher scores representing greater dysfunction. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 6 months
Behavior Rating Inventory of Executive Function (BRIEF-parent version)
Parents of subjects will undergo this neuropsychological assessment at 12 months post-transplant (Visit 6) regarding the behavior of their child. scores are converted to T-scores ranging from 40-90 with higher scores representing greater dysfunction. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 12 months
Behavior Rating Inventory of Executive Function (BRIEF-parent version)
Parents of subjects will undergo this neuropsychological assessment at 24 months post-transplant (End of Study Visit) regarding the behavior of their child. scores are converted to T-scores ranging from 40-90 with higher scores representing greater dysfunction. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 24 months
Behavior Assessment System for Children-second edition (BASC-II)
Subjects will undergo this neuropsychological assessment at 6 months post-transplant (Visit 4). Scores converted to T-scores 40-90 with higher scores representing poorer function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 6 months
Behavior Assessment System for Children-second edition (BASC-II)
Subjects will undergo this neuropsychological assessment at 12 months post-transplant (Visit 6). Scores converted to T-scores 40-90 with higher scores representing poorer function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 12 months
Behavior Assessment System for Children-second edition (BASC-II)
Subjects will undergo this neuropsychological assessment at 24 months post-transplant (End of Study Visit). Scores converted to T-scores 40-90 with higher scores representing poorer function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 24 months
Child Health Questionnaire (CHQ)
Subjects will undergo this neuropsychological assessment at 6 months post-transplant (Visit 4). Scores converted to a 0-100 scale with higher scores evidencing better function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 6 months
Child Health Questionnaire (CHQ)
Subjects will undergo this neuropsychological assessment at 12 months post-transplant (Visit 6). Scores converted to a 0-100 scale with higher scores evidencing better function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 12 months
Child Health Questionnaire (CHQ)
Subjects will undergo this neuropsychological assessment at 24 months post-transplant (End of Study Visit). Scores converted to a 0-100 scale with higher scores evidencing better function. Results will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 2011 (estimated)
- Study start12 Oct 2011
- Primary completion21 Aug 2015
- Study completion17 Jun 2016
Why it stopped: Study was funded by NIH grant; grant funding ended in June 2023 without enrollment of additional subjects; the only subject enrolled was in 2011.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for PhenylketonuriaStudies 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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 1 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
- NCT01465100
- Sponsor's protocol ID
- STUDY19030291
- Status last verified
- Aug 2023
- First submitted
- 20 Oct 2011
- Last updated
- 16 Aug 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 Aug 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Hepatocyte Transplantation for Phenylketonuria
- ClinicalTrials.gov ID
- NCT01465100
- Acronym / sponsor ID
- STUDY19030291
- Conditions
- Phenylketonuria
- Keywords
- phenylketonuria, hepatocyte
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study was funded by NIH grant; grant funding ended in June 2023 without enrollment of additional subjects; the only subject enrolled was in 2011.
- Enrolment
- 1 participants (actual)
- Lead sponsor
- Ira FoxUniversity, hospital or other
- Study start
- 12 Oct 2011 (actual)
- Primary completion
- 21 Aug 2015 (actual)
- Study completion
- 17 Jun 2016 (actual)
- First posted
- 4 Nov 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.
Human phenylketonuria (PKU) results from phenylalanine hydroxylase (PAH) deficiency, and represents one of the most common and extensively studied single-gene Mendelian disorders in humans. Unfortunately, optimum clinical outcome demands lifelong dietary restriction through adherence to an unpalatable and expensive artificial diet. Challenges in maintaining traditional therapy lead to increasing phenylalanine (Phe) levels in patients as they approach adulthood with an incumbent severe burden of psychosocial and intellectual difficulties. The recent introduction of the new medication Sapropterin for treatment of PKU has improved Phe control and dietary tolerance in some patients, but at enormous cost to patients and insurers for the FDA designated orphan product. Thus, there is an unmet need for novel therapies to correct PKU. PAH is almost exclusively expressed in the liver in humans. The main objective of the current proposal is to examine the safety and efficacy of hepatocyte transplantation in patients with PKU.
Detailed description
Hepatocytes from more than one donor may be required to provide sufficient numbers of cells for transplantation to correct the disease process. We have previously estimated that the hepatic mass of a recipient approaches 4 x 10 to the 9th power hepatocytes/kg. However, this is just an estimate and the true mass may be twice this number. Our goal is to attempt to infuse at least 2x10 to the 8th power cells/kg. Once it has been determined that IND release criteria for the hepatocytes has been met, the patient will then receive Intensity-Modulated Radiation Therapy (IMRT), and the hepatocyte transplant will begin.
Preparative Liver Irradiation: A portion of the right hepatic lobe comprising between 35-50% of the entire liver volume will be irradiated to a dose of 10 Gy in a single fraction using a linear accelerator-based stereotactic radiosurgery system with intensity-modulated radiation therapy planning (IMRT). Respiratory gating will be used to further increase the accuracy of delivering the dose to a specified volume and limiting the exposure to adjacent tissues. After hepatic irradiation, the right or main portal vein will be occluded transiently (0-90 min) to provide a compensatory mitotic signal to donor hepatocytes. Transient portal vein occlusion or embolization has been shown in primates to provide the appropriate mitotic signals necessary for donor cell proliferation. At that time, donor hepatocytes will be transplanted into the irradiated portion of the recipient's liver.
The number of infusions from each donor liver will depend on the tolerance of the patient to infusion (avoidance of portal vein thrombosis and portal vein to systemic venous system shunting), and viability of donor hepatocytes. The hepatocytes from each donor liver will be given over three to four infusions, every 6 to 8 hours, until the cells are no longer viable, approximately twenty-four hours after initial preparation. Ideally, the infusion catheter will be maintained just outside the portal circulation in the umbilical vein remnant so the patient can be potentially discharged from the hospital until the next donor liver is available. Since we do not yet know from our experience the number of cells needed for transplant in order to improve function so that a metabolic disease is cured, we will continue to infuse hepatocytes as donors become available until reaching the goal volume of hepatocytes and until viability of cells has expired. Using hepatocytes from multiple donors will help to ensure that an adequate number of cells is infused while maintaining portal pressure in the normal range.Phe levels will be collected once a week by the subject, using a capillary blood sample on a newborn screening filter paper, and mailed to CHP. Phe levels will also be collected in a venous sample monthly. During months when a Follow-Up Visit is scheduled, both a venous and capillary sample will be collected.
Subjects will receive careful dietary observation post-transplant through the UPMC Children's Hospital of Pittsburgh Division of Medical Genetics research dietician. Three-day diet records will be completed once a month for six months, then every three months thereafter. Diet should remain unchanged throughout the study, unless directed by study staff.
Subjects will undergo a repeat neuropsychological assessment at 6, 12 and 24 months post-transplant (Visits 4 and 6 and the End of Study Visit) which will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.
Isotopic monitoring of whole body Phe oxidation will be performed at every follow-up visit following the final hepatocyte infusion. An additional Phe oxidation test may also be completed in the event of suspected graft rejection.
Liver biopsies will be performed at 3 and 12 months post-transplant to assess for the presence of donor hepatocytes, and may be completed in the event of suspected graft rejection.
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 | Radiation: Preparative Radiation Therapy, Procedure: Hepatocyte Transplant, Drug: Immunosuppression, Other: Liver Evaluation, Behavioral: Neuro-psychological Assessment, Diagnostic Test: Whole body Phe oxidation testing, Procedure: Liver BiopsySee Below. |
Who may qualify
- Ages
- 14 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (7 listed)
- Previous diagnosis of classical PKU, as determined by a PAH mutation known to cause classical PKU, or a Phe >20 mg/dL at any time.
- Patients must have poor control on standard therapy (i.e. Kuvan or diet alone) as defined by two consecutive Phe levels of > 12 mg/dL in the past six months. This is two times the recommended level. If the patient is being treated with Palynziq, they must discontinue treatment for at least two months before participating in this trial.
- Baseline I.Q. ≥70 as assessed by Wechsler Abbreviated Scale of Intelligence (4-subtest IQ)
- Must have a complete evaluation, including dietary records, in a PKU clinic in the past twelve months
- Age between 14 and 55 years
Key exclusion criteria (10 listed)
- I.Q. <70
- Known biopterin synthesis defects
- Subject has active malignancy
- Subject has known allergy or other contraindication to immune suppression medications (and their alternatives) required post transplant for the prevention of rejection
- Subject has sepsis, pneumonia, other active infection, or other secondary life-threatening organ dysfunction at Screening or Baseline Visits. Subject may be re-screened once infection has cleared.
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 |
|---|---|---|
| Preparative Radiation TherapySubjects will undergo CT-based simulation and treatment planning for radiation therapy. Once a suitable hepatocyte donor is found and the cell count and viability is acceptable for transplantation, patients will receive Intensity-Modulated Radiation Therapy (IMRT) in one fraction(10 Gy)to the right lobe of the liver (but not exceeding 50% of the liver mass). | Radiation | Hepatocyte Transplantation |
| Hepatocyte TransplantTransplantation of hepatocytes into the liver will be through the portal vein, either accessed transhepatically, or by umbilical vein. After cell transplantation, measures will be taken to provide chronic access to the portal venous circulation system. If chronic access is achieved, patients will be seen in the PCTRC once a week to assess the site. Hepatocytes from more than one donor may be required to provide sufficient numbers of cells for transplantation to correct the disease process and to optimize Phe tolerance. Hepatocytes will be infused until the goal number of hepatocytes is infused. If viable hepatocytes remain after the goal number has been infused, the remaining cells will also be infused, as tolerated by the patient. | Procedure or surgery | Hepatocyte Transplantation |
| ImmunosuppressionFollowing transplantation, patients will be treated with conventional immune suppression, as is used following whole organ liver transplantation. Patients will be followed as routinely performed following organ transplantation and also followed as would normally be performed for their PKU. | Drug | Hepatocyte Transplantation |
| Liver EvaluationPrior to the hepatocyte transplant subjects will undergo a liver evaluation which is standard for all patients who have whole organ transplants at Children's Hospital of Pittsburgh of UPMC. The evaluation includes immunosuppression medication education, psychological assessment, bloodwork to assess blood count, blood and tissue type, blood chemistries, immune system function and certain infectious diseases, EKG, chest x-ray, and abdominal ultrasound to assess blood flow to the blood vessels in the liver. A liver biopsy may be performed if, in the clinical judgment of the investigators, the subject shows clinical signs of liver failure, or is at increased risk for liver fibrosis. | Other | Hepatocyte Transplantation |
| Neuro-psychological AssessmentSubjects will undergo a repeat neuropsychological assessment at 6, 12 and 24 months post-transplant (Visits 4 and 6 and the End of Study Visit) which will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure. | Behavioural | Hepatocyte Transplantation |
| Whole body Phe oxidation testingPatient will again be asked to not eat or drink for at least four hours prior to testing. Isotopic monitoring of whole body Phe oxidation will be performed pre-transplant and at every follow-up visit following the final hepatocyte infusion. An additional Phe oxidation test may also be completed in the event of suspected graft rejection. | Diagnostic test | Hepatocyte Transplantation |
| Liver BiopsyLiver biopsies will be performed at 3 and 12 months post-transplant to assess for the presence of donor hepatocytes, and may be completed in the event of suspected graft rejection. | Procedure or surgery | Hepatocyte Transplantation |
Primary outcome
Improvement/reversal of characteristics of PKU
Time frame: 24 months post hepatocyte transplant
Measured as a 50% decrease in Phe from baseline study level.
30 secondary outcomes
Engraftment of Hepatocytes
Time frame: 3 months
Engraftment of Hepatocytes
Time frame: 12 months
Engraftment of Hepatocytes
Time frame: up to 24 months
Wechsler Abbreviated Scale of Intelligence-third edition (WASI-III)
Time frame: 6 months
Wechsler Abbreviated Scale of Intelligence-third edition (WASI-III)
Time frame: 12 months
Wechsler Abbreviated Scale of Intelligence-third edition (WASI-III)
Time frame: 24 months
Delis Kaplan Executive Functioning System (D-KEFS)
Time frame: 6 months
Delis Kaplan Executive Functioning System (D-KEFS)
Time frame: 12 months
Delis Kaplan Executive Functioning System (D-KEFS)
Time frame: 24 months
Connors Continuous Performance Test-third edition (CPT-III)
Time frame: 6 months
Connors Continuous Performance Test-third edition (CPT-III)
Time frame: 12 months
Connors Continuous Performance Test-third edition (CPT-III)
Time frame: 24 months
Adaptive Behavior Assessment System-third edition (ABAS-III)
Time frame: 6 months
Adaptive Behavior Assessment System-third edition (ABAS-III)
Time frame: 12 months
Adaptive Behavior Assessment System-third edition (ABAS-III)
Time frame: 24 months
SF-36 Health Survey
Time frame: 6 months
SF-36 Health Survey
Time frame: 12 months
SF-36 Health Survey
Time frame: 24 months
Beck Depression Inventory
Time frame: 6 months
Beck Depression Inventory
Time frame: 12 months
Beck Depression Inventory
Time frame: 24 months
Behavior Rating Inventory of Executive Function (BRIEF-parent version)
Time frame: 6 months
Behavior Rating Inventory of Executive Function (BRIEF-parent version)
Time frame: 12 months
Behavior Rating Inventory of Executive Function (BRIEF-parent version)
Time frame: 24 months
Behavior Assessment System for Children-second edition (BASC-II)
Time frame: 6 months
Behavior Assessment System for Children-second edition (BASC-II)
Time frame: 12 months
Behavior Assessment System for Children-second edition (BASC-II)
Time frame: 24 months
Child Health Questionnaire (CHQ)
Time frame: 6 months
Child Health Questionnaire (CHQ)
Time frame: 12 months
Child Health Questionnaire (CHQ)
Time frame: 24 months
Results and safety
The study was stopped early (reason given: Study was funded by NIH grant; grant funding ended in June 2023 without enrollment of additional subjects; the only subject enrolled was in 2011.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Aug 2023.
- Individual participant dataSharing planned: No
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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 1/2 study testing Preparative Radiation Therapy, Hepatocyte Transplant and Immunosuppression in people with Phenylketonuria, 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 7 inclusion and 10 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 16 Aug 2023. 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 combined 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.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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: Study was funded by NIH grant; grant funding ended in June 2023 without enrollment of additional subjects; the only subject enrolled was in 2011.). 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/reversal of characteristics of PKU (time frame: 24 months post hepatocyte transplant). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 16 Aug 2023.