Fluorodeoxyglucose Positron Emission Tomography (FDG PET) Findings in Patients With Phenylketonuria Before and After KUVAN Therapy (PKU)
tiistai 12. toukokuuta 2015 päivittänyt: 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.
Tutkimuksen yleiskatsaus
Yksityiskohtainen kuvaus
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.
Opintotyyppi
Interventio
Ilmoittautuminen (Todellinen)
6
Vaihe
- Ei sovellettavissa
Yhteystiedot ja paikat
Tässä osiossa on tutkimuksen suorittajien yhteystiedot ja tiedot siitä, missä tämä tutkimus suoritetaan.
Opiskelupaikat
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Pennsylvania
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Philadelphia, Pennsylvania, Yhdysvallat, 19106
- Children's Hospital of Philadelphia, Section of Metabolism,PKU program
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Osallistumiskriteerit
Tutkijat etsivät ihmisiä, jotka sopivat tiettyyn kuvaukseen, jota kutsutaan kelpoisuuskriteereiksi. Joitakin esimerkkejä näistä kriteereistä ovat henkilön yleinen terveydentila tai aiemmat hoidot.
Kelpoisuusvaatimukset
Opintokelpoiset iät
18 vuotta - 50 vuotta (Aikuinen)
Hyväksyy terveitä vapaaehtoisia
Ei
Sukupuolet, jotka voivat opiskella
Kaikki
Kuvaus
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
Opintosuunnitelma
Tässä osiossa on tietoja tutkimussuunnitelmasta, mukaan lukien kuinka tutkimus on suunniteltu ja mitä tutkimuksella mitataan.
Miten tutkimus on suunniteltu?
Suunnittelun yksityiskohdat
- Ensisijainen käyttötarkoitus: Hoito
- Jako: Ei käytössä
- Inventiomalli: Yksittäinen ryhmätehtävä
- Naamiointi: Yksittäinen
Aseet ja interventiot
Osallistujaryhmä / Arm |
Interventio / Hoito |
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Kokeellinen: Sapropterin (KUVAN)
All subjects will receive Sapropterin (KUVAN) therapy at a dose of 20/mk/kg/day for four months.
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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.
Muut nimet:
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Mitä tutkimuksessa mitataan?
Ensisijaiset tulostoimenpiteet
Tulosmittaus |
Toimenpiteen kuvaus |
Aikaikkuna |
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Plasma Phenylalanine Level (mg/dl)
Aikaikkuna: Measurements were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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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.
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Measurements were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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Toissijaiset tulostoimenpiteet
Tulosmittaus |
Toimenpiteen kuvaus |
Aikaikkuna |
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Hopkins Verbal Learning Test (HVLT) Total Recall
Aikaikkuna: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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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.
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Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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Hopkins Verbal Learning Test (HVLT) Delayed Recall
Aikaikkuna: 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.
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Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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Paced Auditory Serial Addition Task (PASAT)
Aikaikkuna: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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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.
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Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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Symbol-Digit Modalities Test (SMTD)
Aikaikkuna: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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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.
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Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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Wechsler Adult Intelligence Scale (WAIS-IV)-Digit Span
Aikaikkuna: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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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.
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Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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Delis-Kaplan Executive Function System Verbal Fluency Subtest (D-KEFS)
Aikaikkuna: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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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.
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Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)
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Yhteistyökumppanit ja tutkijat
Täältä löydät tähän tutkimukseen osallistuvat ihmiset ja organisaatiot.
Sponsori
Tutkijat
- Päätutkija: Can Ficicioglu, MD, PhD, Children's Hospital of Philadelphia,University of Pennsylvania
Opintojen ennätyspäivät
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Opi tärkeimmät päivämäärät
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Opintoihin ilmoittautumispäivät
Ensimmäinen lähetetty
Maanantai 28. syyskuuta 2009
Ensimmäinen toimitettu, joka täytti QC-kriteerit
Tiistai 29. syyskuuta 2009
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Keskiviikko 30. syyskuuta 2009
Tutkimustietojen päivitykset
Viimeisin päivitys julkaistu (Arvio)
Maanantai 8. kesäkuuta 2015
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Tiistai 12. toukokuuta 2015
Viimeksi vahvistettu
Perjantai 1. toukokuuta 2015
Lisää tietoa
Tähän tutkimukseen liittyvät termit
Avainsanat
Muita asiaankuuluvia MeSH-ehtoja
Muut tutkimustunnusnumerot
- IRB 09-007154
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