Trial record 7 of 171 for:    Open Studies | "Brain Diseases, Metabolic, Inborn"

Liver Cell Transplant for Phenylketonuria

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2012 by University of Pittsburgh
Sponsor:
Information provided by (Responsible Party):
University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT01465100
First received: October 20, 2011
Last updated: July 5, 2012
Last verified: July 2012
  Purpose

The purpose of this research study is to determine whether partial irradiation of the liver and liver cell transplantation can reduce the need for dietary and medical management or could possibly eliminate the need for a special diet and medications to treat this disease for patients with phenylketonuria (PKU) by normalizing phenylalanine levels in the body. Phenylalanine (Phe) is a substance needed in the body that can only be obtained from the foods the investigators eat. People with PKU cannot get rid of Phe in their body. Large amounts of Phe can cause problems, such as deterioration of mental function. At the present time, liver cell transplants are experimental and have been done in only a limited number of human subjects.


Condition Intervention Phase
Phenylketonuria
Radiation: Preparative Radiation Therapy
Procedure: Hepatocyte Transplant
Drug: Immunosuppression
Other: Liver Evaluation
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Hepatocyte Transplantation for Phenylketonuria

Resource links provided by NLM:


Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • Improvement/reversal of characteristics of PKU [ Time Frame: 6 months post hepatocyte transplant ] [ Designated as safety issue: Yes ]
    Measured as a 50% decrease in Phe from baseline study level.


Secondary Outcome Measures:
  • Engraftment of Hepatocytes [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Liver biopsy samples may be obtained if a response is ascertained after 6 months. (The approach used, surgical vs percutaneous needle biopsy, will be determined by the clinical setting.)

  • Engraftment of Hepatocytes [ Time Frame: up to one year ] [ Designated as safety issue: Yes ]
    Laboratory tests of hepatic function


Estimated Enrollment: 10
Study Start Date: December 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Radiation: Preparative Radiation Therapy
    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).
    Procedure: Hepatocyte Transplant
    Within a maximum of two days after hepatic irradiation,the right or main portal vein will be occluded transiently (60-90 min)to provide a compensatory mitotic signal to donor hepatocytes. Directly following this transient occlusion of the portal vein, donor hepatocytes will be transplanted into the irradiated portion of the recipient's liver.
    Drug: Immunosuppression
    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.
    Other: Liver Evaluation
    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 and abdominal ultrasound to assess blood flow to the blood vessels in the liver.
Detailed Description:

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 determine the feasibility of hepatocyte transplantation to correct the biochemical (and ultimately, clinical) features of PKU.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Previous diagnosis of classical PKU (Phe >20 mg/dl) Phe level greater than 10 mg/dl in past 6 months or any measure of Phe >20 mg/dl in past 6 months.
  2. Psychological assessment in the past year
  3. I.Q. >70 as assessed by Wechsler Abbreviated Scale of Intelligence (2-subtest IQ)
  4. Must have careful dietary management for one month in PKU clinic.

Exclusion Criteria:

  1. I.Q. <70
  2. No biopterin synthetase defects
  3. Subject has severe cardiovascular or respiratory disease at baseline and at the time of hepatocyte transplant as defined by:

    a) Central venous pressure >25 mm Hg or if known, pulmonary capillary wedge pressure of >30 mg Hg or 2) Oxygen saturation of <90% on > 50% oxygen.

  4. Subject has evidence of major ongoing gastrointestinal bleeding defined as any bleeding causing >3 g fall in hemoglobin or cardiovascular compromise with systolic blood pressure <90 mm Hg in the week preceding transplantation.
  5. Subject has thrombocytopenia at the time of hepatocyte transplant, defined as a platelet count of <50,000/µL (result may be obtained after giving subject platelets to increase count).
  6. Subject has creatinine >2.0 mg/dl (unless patient is chronically dialysis dependent) at the time of cell transplant.
  7. Subject has leukopenia at the time of cell transplant, defines as neutrophils <500/µL.
  8. Subject has active malignancy.
  9. Subject has allergy to immune suppression medications that are required post transplant procedure for the prevention of rejection.
  10. Subject has sepsis, pneumonia or other active infection as determined by urine and blood cultures and/or chest x-ray.
  11. Significant liver fibrosis determined by biopsy. Significant liver fibrosis will be defined by the Ishak Staging, Stage 5: bridges with occasional nodules.
  12. Subject is pregnant or breastfeeding.
  13. Subject has positive HIV serostatus.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01465100

Contacts
Contact: Rachel Sada, MS 412-692-7673 novoselre@upmc.edu
Contact: Maria Bond 412-692-7133 bondma@upmc.edu

Locations
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15201
Contact: Rachel E Sada, MS    412-692-7673    novoselre@upmc.edu   
Contact: Maria Bond    412-692-7133    bondma@upmc.edu   
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15201
Contact: Rachel E Sada, MS, CIP    412-692-7673    novoselre@upmc.edu   
Contact: Maria Bond    412-692-7133    bondma@upmc.edu   
Principal Investigator: Ira J Fox, MD         
Sub-Investigator: Kyle Soltys, MD         
Sub-Investigator: George Mazariegos, MD         
Sub-Investigator: Rakesh Sindhi, MD         
Sub-Investigator: Geoffrey Bond, MD         
Sub-Investigator: Gerard Vockley, MD         
Sub-Investigator: Georgianne Arnold, MD         
Sub-Investigator: Steve Strom, PhD         
Sub-Investigator: John Crowley, MD         
Sub-Investigator: Melvin Deutsch, MD         
Sub-Investigator: Ken Dorko         
Sub-Investigator: Ben Shneider, MD         
Sub-Investigator: Robert Squires, MD         
Sub-Investigator: Charles Fitz, MD         
Sub-Investigator: David Finegold, MD         
Sub-Investigator: Suneeta Madan-Kheterpal, MD         
Sub-Investigator: Robert Stough, MD         
Sub-Investigator: Diana Shellmer, PhD         
Sub-Investigator: Hilary Feldman, MD         
Sponsors and Collaborators
University of Pittsburgh
Investigators
Principal Investigator: Ira J Fox, MD University of Pittsburgh
  More Information

No publications provided

Responsible Party: University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01465100     History of Changes
Other Study ID Numbers: PRO10100525
Study First Received: October 20, 2011
Last Updated: July 5, 2012
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Pittsburgh:
phenylketonuria
hepatocyte

Additional relevant MeSH terms:
Phenylketonurias
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases

ClinicalTrials.gov processed this record on July 20, 2014