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

Primary Purpose

Phenylketonuria

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Sapropterin

About this trial

This is an interventional treatment trial for Phenylketonuria focused on measuring PKU, BH4, KUVAN, PET scan, Neurodevelopment

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Males or females over the age of 18 years
Subject must be able to give independent informed consent
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.
Subject must have a confirmed diagnosis of PKU
Subjects with Phenylalanine (Phe) levels over 10 mg/dL
Subjects naïve to KUVAN therapy or has not received KUVAN in the 6 months before screening

Exclusion Criteria:

Pregnancy
Cognitive deficits resulting from physical trauma (e.g. subject with history of severe birth trauma).
Neurologic comorbidities including a history of a stroke or a seizure disorder.
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
Subjects using medications such as steroids, insulin and glucagons that may interfere with the results of PET scan.
Subjects using medications that inhibit folate metabolism such as methotrexate
Subjects using medications known to affect nitric oxide-mediated vasorelaxation.
Subjects using Levodopa
Treatment with KUVAN in the past 6 months before study entry.
Treatment with any investigational product in the last 90 days before study entry

Sites / Locations

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

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sapropterin (KUVAN)

Arm Description

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

Outcomes

Primary Outcome Measures

Plasma Phenylalanine Level (mg/dl)

Plasma phenylalanine level (mg/dl) served as the primary means of evaluating brain glucose metabolism before and after sapropterin (KUVAN) therapy. Blood tests for phenylalanine levels (Phe) were collected before and 4 months after sapropterin (KUVAN) therapy. All subjects received KUVAN at a dose of 20/mg/kg/day for four months. The goal was to estimate the change in blood glucose metabolism after treatment with Sapropterin (if any), with the hypothesis that treatment would decrease plasma Phe levels.

Secondary Outcome Measures

Hopkins Verbal Learning Test (HVLT) Total Recall

The Hopkins Verbal Learning Test-Revised (HVLT) is a neuropsychological test designed to assess verbal memory. The test consists of 12 nouns (targets) with four words drawn from each of three semantic categories. Raw scores are derived for Total Recall (across three learning trials), Delayed Recall (after 20-25 minute delay), Retention (% retained), and a Recognition Discrimination Index (true positives minus false positives). The maximum total for each recall trial (Learning Trials 1 to 3, Delayed Recall Trial 4) is 12. Raw scores are converted to "T-scores" by means of age-based tables provided in test manual (T-scores can go from 0 - 100, with higher scores correlating with higher verbal memory function). Median HVLT Total Recall and HVLT Delayed Recall T-scores at baseline and 4 months after Sapropterin therapy were compared.

Hopkins Verbal Learning Test (HVLT) Delayed Recall

Paced Auditory Serial Addition Task (PASAT)

The Adapted Paced Auditory Serial Addition Task (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. For Rates #1 and #2, single digits are presented every 3 seconds and the patient must add each new digit to the one immediately prior to it. The score for PASAT is the total number of correct answers (out of 60, for a total possible score ranging from 0-60 with higher score preferred as it indicates higher auditory processing speed) for each trial. All scores are expressed as "z-scores" which are generated based on norms for 101 healthy adults, with separate norms for <12 years of education versus >12years of education. Using a reference population as a basis of comparison, the "z-score" is the number of standard deviations the score is above (positive) or below (negative) the mean of the reference population (zero). Possible z-scores lie on a continuous scale.

Symbol-Digit Modalities Test (SMTD)

The symbol-digit modalities test (SDMT) was developed to identify individuals with neurological impairment. The SDMT requires individuals to identify nine different symbols corresponding to the numbers 1 through 9, and to practice writing the correct number under the corresponding symbol. Then they manually fill the blank space under each symbol with the corresponding number. A second oral administration is then completed. The participant is given a blank copy of the test and asked to state the correct number for each corresponding symbol. The participant is given 90 s to complete each of these administrations. A written and oral score is calculated by totaling the number of correct answers for each section. The score is the number of correctly coded items from 0-110 in 90 seconds, with a higher score representing less neurological impairment with respect to attention, scanning abilities and motor skills. The total raw score was used for purposes of this study.

Wechsler Adult Intelligence Scale (WAIS-IV)-Digit Span

The Wechsler Adult Intelligence Scale (WAIS) is a test designed to measure intelligence in adults and older adolescents. It is composed of 10 core subtests and five supplemental subtests, with the 10 core subtests comprising the Full Scale intelligence quotient (IQ). Contained within the WAIS is an assessment of digit-coding which consists of nine digit-symbol pairs followed by a list of digits. Under each digit the subject should write down the corresponding symbol as fast as possible. The number of correct symbols within the allowed time (e.g. 90 or 120 sec) is measured, with a higher score representative of a higher performance component of IQ/intelligence.

Delis-Kaplan Executive Function System Verbal Fluency Subtest (D-KEFS)

The Delis-Kaplan Executive Function System (D-KEFS) is a neuropsychological test is used to measure a variety of verbal and nonverbal executive functions for both children and adults. Among the 9 subtests is the Verbal Fluency Test which measures letter fluency, category fluency, and category switching. Verbal Fluency Test. This subtest requires an individual to randomly generate words based upon given parameters (ex., as words beginning with the letter F) and the believed areas of executive function assessed are cognitive flexibility, response inhibition, and verbal fluency. Raw scores are calculated based on the number of correct answers, which are then converted to scaled scores with a mean of 10 and standard deviation of 3. Higher scaled score represents a higher level of executive verbal and nonverbal function.

Full Information

NCT ID

NCT00986973

First Posted

September 28, 2009

Last Updated

May 12, 2015

Sponsor

Children's Hospital of Philadelphia

1. Study Identification

Unique Protocol Identification Number

NCT00986973

Brief Title

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

Acronym

PKU

Official Title

A Pilot Study of FDG PET Findings in Patients With Phenylketonuria Before and After BH4 Supplementation

Study Type

Interventional

2. Study Status

Record Verification Date

May 2015

Overall Recruitment Status

Completed

Study Start Date

March 2010 (undefined)

Primary Completion Date

July 2011 (Actual)

Study Completion Date

September 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Children's Hospital of Philadelphia

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Phenylketonuria

Keywords

PKU, BH4, KUVAN, PET scan, Neurodevelopment

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

Outcomes Assessor

Allocation

N/A

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sapropterin (KUVAN)

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Sapropterin

Other Intervention Name(s)

KUVAN, BH4

Intervention Description

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.

Primary Outcome Measure Information:

Title

Plasma Phenylalanine Level (mg/dl)

Description

Time Frame

Measurements were obtained at the beginning and conclusion of each study period (baseline and 4 months)

Secondary Outcome Measure Information:

Title

Hopkins Verbal Learning Test (HVLT) Total Recall

Description

Time Frame