Fluorodeoxyglucose Positron Emission Tomography (FDG PET) Findings in Patients With Phenylketonuria Before and After KUVAN Therapy

NCT ID: NCT00986973

Last Updated: 2015-06-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-03-31
• Study Completion Date: 2011-09-30

Brief Summary

The aim of this pilot study is to determine if there are any changes in brain glucose metabolism in the gray matter of patients with Phenylketonuria (PKU) and whether administration of Sapropterin (KUVAN) therapy can improve such deficits.

Detailed Description

Phenylketonuria (PKU) is an autosomal recessive disorder resulting from a deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Phenylalanine hydroxylase is one of the three aromatic amino acid hydroxylases that utilizes tetrahydrobiopterin (BH4) as cofactor. The published reports indicate that there is altered energy metabolism in the brain of patients with PKU. Phenylalanine and its metabolites appear to impair several aspects of brain energetics including: (1) Inhibition of glucose uptake; (2) diminished glycosylation of cytoskeletal proteins; (3) Inhibition of pyruvate kinase; and (4) reduced flux through the glycolysis. Studies in vivo with magnetic resonance spectroscopy have demonstrated phenylalanine-responsive abnormalities in cerebral energy metabolism.

Positron Emission Tomography (PET) scanning with fluorodeoxyglucose (FDG-PET) is a non-invasive method that measures regional glucose metabolic rate with high resolution and absolute quantitation. To date this technology has been used only for single case reports or the investigation of white matter abnormalities in small numbers of patients with PKU.

The aim of this pilot study is to determine if there are any changes in brain glucose metabolism in the gray matter of patients with PKU and whether Sapropterin (KUVAN) can improve such deficits. This study will also elucidate the relationship between hyperphenylalaninemia, phenylalanine intake in diet, altered brain glucose handling and the neurocognitive profile of the patients with PKU before and after KUVAN therapy.

Conditions

Phenylketonuria

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Sapropterin (KUVAN)

All subjects will receive Sapropterin (KUVAN) therapy at a dose of 20/mk/kg/day for four months.

Group Type: EXPERIMENTAL

Sapropterin

Intervention Type: DRUG

All subjects will receive 20 mg/kg/day Sapropterin (KUVAN) for four months. Subjects will be examined with fluorodeoxyglucose positron emission tomography (FDG-PET) brain imaging, physical and neurological exam, blood tests for phenylalanine (Phe) and tyrosine levels, and neuropsychological testing before and 4 months after KUVAN therapy. Subjects Phe and tyrosine levels will be monitored weekly during the study and subjects will keep 3-day diet records to allow for calculation of Phe intake.

Interventions

Sapropterin

All subjects will receive 20 mg/kg/day Sapropterin (KUVAN) for four months. Subjects will be examined with fluorodeoxyglucose positron emission tomography (FDG-PET) brain imaging, physical and neurological exam, blood tests for phenylalanine (Phe) and tyrosine levels, and neuropsychological testing before and 4 months after KUVAN therapy. Subjects Phe and tyrosine levels will be monitored weekly during the study and subjects will keep 3-day diet records to allow for calculation of Phe intake.

Intervention Type: DRUG

Other Intervention Names

KUVAN; BH4

Eligibility Criteria

Inclusion Criteria

1. Males or females over the age of 18 years

2. Subject must be able to give independent informed consent

3. Girls must have a negative urine pregnancy test and must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the duration of the study.

4. Subject must have a confirmed diagnosis of PKU

5. Subjects with Phenylalanine (Phe) levels over 10 mg/dL

6. Subjects naïve to KUVAN therapy or has not received KUVAN in the 6 months before screening

Exclusion Criteria

1. Pregnancy

2. Cognitive deficits resulting from physical trauma (e.g. subject with history of severe birth trauma).

3. Neurologic comorbidities including a history of a stroke or a seizure disorder.

4. Laboratory abnormalities that indicate clinically significant hepatic disease Aspartate aminotransferase (AST)> 2.0 times the upper limit of normal, Alanine transaminase (ALT) > 2.0 times the upper limit of normal, Prothrombin Time (PT) > 2.0 times the upper limit of normal, Partial Thromboplastin Time(PTT) > 2.0 times the upper limit of normal

5. Subjects using medications such as steroids, insulin and glucagons that may interfere with the results of PET scan.

6. Subjects using medications that inhibit folate metabolism such as methotrexate

7. Subjects using medications known to affect nitric oxide-mediated vasorelaxation.

8. Subjects using Levodopa

9. Treatment with KUVAN in the past 6 months before study entry.

10. Treatment with any investigational product in the last 90 days before study entry

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Children's Hospital of Philadelphia

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Can Ficicioglu, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Philadelphia,University of Pennsylvania

Locations

Children's Hospital of Philadelphia, Section of Metabolism,PKU program

Philadelphia, Pennsylvania, United States

Countries

United States

Other Identifiers

IRB 09-007154

Identifier Type: -

Identifier Source: org_study_id