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

12 de mayo de 2015 actualizado por: Children's Hospital of Philadelphia

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

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.

Descripción general del estudio

Estado

Terminado

Condiciones

Intervención / Tratamiento

Descripción detallada

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.

Tipo de estudio

Intervencionista

Inscripción (Actual)

6

Fase

  • No aplica

Contactos y Ubicaciones

Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.

Ubicaciones de estudio

  • Estados Unidos
    • Pennsylvania
      • Philadelphia, Pennsylvania, Estados Unidos, 19106
        • Children's Hospital of Philadelphia, Section of Metabolism,PKU program

Criterios de participación

Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.

Criterio de elegibilidad

Edades elegibles para estudiar

18 años a 50 años (Adulto)

Acepta Voluntarios Saludables

No

Géneros elegibles para el estudio

Todos

Descripción

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

Plan de estudios

Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.

¿Cómo está diseñado el estudio?

Detalles de diseño

  • Propósito principal: Tratamiento
  • Asignación: N / A
  • Modelo Intervencionista: Asignación de un solo grupo
  • Enmascaramiento: Único

Armas e Intervenciones

Grupo de participantes/brazo
Intervención / Tratamiento
Experimental: Sapropterin (KUVAN)
All subjects will receive Sapropterin (KUVAN) therapy at a dose of 20/mk/kg/day for four months.
Droga: 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.
Otros nombres:
  • BH4
  • KUVAN

¿Qué mide el estudio?

Medidas de resultado primarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Plasma Phenylalanine Level (mg/dl)
Periodo de tiempo: Measurements were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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.
Measurements were obtained at the beginning and conclusion of each study period (baseline and 4 months)

Medidas de resultado secundarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Hopkins Verbal Learning Test (HVLT) Total Recall
Periodo de tiempo: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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.
Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
Hopkins Verbal Learning Test (HVLT) Delayed Recall
Periodo de tiempo: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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.
Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
Paced Auditory Serial Addition Task (PASAT)
Periodo de tiempo: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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.
Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
Symbol-Digit Modalities Test (SMTD)
Periodo de tiempo: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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.
Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
Wechsler Adult Intelligence Scale (WAIS-IV)-Digit Span
Periodo de tiempo: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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.
Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
Delis-Kaplan Executive Function System Verbal Fluency Subtest (D-KEFS)
Periodo de tiempo: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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.
Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)

Colaboradores e Investigadores

Aquí es donde encontrará personas y organizaciones involucradas en este estudio.

Patrocinador

Children's Hospital of Philadelphia

Investigadores

  • Investigador principal: Can Ficicioglu, MD, PhD, Children's Hospital of Philadelphia,University of Pennsylvania

Fechas de registro del estudio

Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados ​​por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.

Fechas importantes del estudio

Inicio del estudio

1 de marzo de 2010

Finalización primaria (Actual)

1 de julio de 2011

Finalización del estudio (Actual)

1 de septiembre de 2011

Fechas de registro del estudio

Enviado por primera vez

28 de septiembre de 2009

Primero enviado que cumplió con los criterios de control de calidad

29 de septiembre de 2009

Publicado por primera vez (Estimar)

30 de septiembre de 2009

Actualizaciones de registros de estudio

Última actualización publicada (Estimar)

8 de junio de 2015

Última actualización enviada que cumplió con los criterios de control de calidad

12 de mayo de 2015

Última verificación

1 de mayo de 2015

Más información

Términos relacionados con este estudio

Palabras clave

Términos MeSH relevantes adicionales

Otros números de identificación del estudio

  • IRB 09-007154

Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .

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