Liver Cell Transplant for Phenylketonuria

NCT01465100 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: STUDY19030291
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Phenylketonuria

Keywords

phenylketonuria; hepatocyte

Outcome Measures

Primary Outcomes (1)

• Improvement/reversal of characteristics of PKU

  Measured as a 50% decrease in Phe from baseline study level.

  24 months post hepatocyte transplant

Secondary Outcomes (30)

• Engraftment of Hepatocytes

  3 months

• Engraftment of Hepatocytes

  12 months

• Engraftment of Hepatocytes

  up to 24 months

• Wechsler Abbreviated Scale of Intelligence-third edition (WASI-III)

  6 months

• Wechsler Abbreviated Scale of Intelligence-third edition (WASI-III)

  12 months

Study Arms (1)

Hepatocyte Transplantation

EXPERIMENTAL

See Below.

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

Interventions

Preparative Radiation Therapy RADIATION

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 Transplantation

Hepatocyte Transplant PROCEDURE

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.

Hepatocyte Transplantation

Immunosuppression DRUG

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.

Hepatocyte Transplantation

Liver Evaluation OTHER

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.

Hepatocyte Transplantation

Neuro-psychological Assessment BEHAVIORAL

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.

Hepatocyte Transplantation

Whole body Phe oxidation testing DIAGNOSTIC_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.

Hepatocyte Transplantation

Liver Biopsy PROCEDURE

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.

Hepatocyte Transplantation

Eligibility Criteria

• Age: 14 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Ira Fox: lead

Study Sites (1)

UPMC Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

MeSH Terms

Conditions

Phenylketonurias

Interventions

Immunosuppression Therapy

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Immunotherapy; Immunomodulation; Biological Therapy; Therapeutics; Immunologic Techniques; Investigative Techniques

Study Officials

• Ira J Fox, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Surgery

Study Record Dates

• First Submitted: October 20, 2011
• First Posted: November 4, 2011
• Study Start: October 12, 2011
• Primary Completion: August 21, 2015
• Study Completion: June 17, 2016
• Last Updated: August 16, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)