Evaluation of Behavior, Executive Function, Neurotransmitter Function and Genomic Expression Kuvan Nonresponders

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Brief Title † Evaluation of Behavior, Executive Function, Neurotransmitter Function and Genomic Expression Kuvan Nonresponders
Official Title † Evaluation of Behavior, Executive Function, Neurotransmitter Function and Genomic Expression in PKU "Nonresponders" to Kuvan® (Sapropterin Dihydrochloride)
Brief Summary This study seeks to establish evidence: 1. that physiologic changes, unrelated to effect on the PAH enzyme, occur in PKU patients who are treated with Kuvan® therapy, 2. that these changes may be caused by enhanced neurotransmitter synthesis in the brain or an upregulation of gene expression (increasing the ability of genes to produce functional enzymes), 3. and that beneficial changes in behavior and cognition, especially executive functioning skills may result. The objective of this study is to correlate any change in behavior and executive function skills of PKU patients who are non-responsive to sapropterin effect on the PAH enzyme, as defined by lowered blood PHE levels, with urine neurotransmitter levels and broad gene expression prior to and after sapropterin administration. Expected outcomes would include evidence of sapropterin effects on upregulation of enzymes other than PAH that control neurotransmitter synthesis, and any resulting correlation with behavioral and cognitive changes. The investigators hope this study will inform further detailed investigations into the biochemical and molecular actions of sapropterin (Kuvan®) that lead to increased understanding of possible treatment effects beyond a lowered blood PHE response.
Detailed Description The study participant population will include approximately 30 established PKU patients receiving care from Hayward Genetics Center, who were found previously to exhibit no decrease in blood PHE levels (nonresponders) with administration of sapropterin. Subjects will act as their own controls. Primary endpoints will be measurement of behavioral and cognitive function, neurotransmitter levels, and gene expression of enzyme activity after 4 weeks on treatment compared to baseline levels. At study baseline each patient will attend an approximately 1 hour clinic visit at their usual genetics clinic location. Study purpose, design, and requirements will be discussed, and consents/assents reviewed and signed. Rating inventories of executive function performance and behavior (BASC-2 and BRIEF tools) will be administered to patients and parents by the PI and/or the Study Coordinator. Urine samples will be collected non-invasively for measurement of neurotransmitter levels. Blood will be collected by venipuncture (3-5 ml) for microarray expression analysis and analysis of plasma amino acids. 3-day food records previously provided to participants for completion will be collected. Participants will be provided with a 4 week supply of Kuvan® and instructions on how to take the medication during the study period. The importance of maintaining usual dietary intake (food choices and metabolic formula) to minimize any research effect not attributable to sapropterin administration will be emphasized. Sapropterin will be discontinued at the end of the 4 week study period. All of these measures will be repeated at the same sites with study participants at the end of week 4 of the study period. At the ends of weeks 1 and 2 additional blood samples will be sent to Hayward Genetics Center for measurement of PHE and TYR levels to ascertain no significant changes have occurred in a patient's usuual dietary intake. These samples will be drawn at each patient's local state health unit, as is done for usual monitoring. Nutrient analysis of the 3-day food diaries will be conducted at Hayward Genetics Center. 1. Behavior and executive function will be assessed using published validated inventories for ages 2-21 years, completed as patient self-reports and as parent (or guardian) reports when appropriate. Instruments used will be the Behavioral Assessment System for Children (BASC-2) parental Rating Scale and Self-Reporting Personality Rating Scale, and the Behavioral Rating Inventory of Executive Function (BRIEF) Parent Form Instruments of Executive Function. Completed inventories will be scored using electronic evaluation instruments by the Study Coordinator and PI, with consultation from Harvard Medical Center experts as needed. 2. Urine samples will be non-invasively collected and sent for analysis of catechols and neurotransmitters to an NIH laboratory specializing in this technique. Samples will be blinded to prevent bias. 3. Microarray analysis of blood samples will be conducted at Hayward Genetics Molecular Laboratory to determine any effect on gene expression, and thus enzyme activity, as a result of sapropterin administration. 4. Plasma amino acids will be analyzed at Hayward Genetics Biochemical Laboratory to document that patients are "nonresponsive" to sapropterin (no resultant lowering of blood PHE); and to monitor any changes in plasma amino acids that could indicate a patient's failure to maintain usual dietary restrictions 5. 3-day food diaries completed by patients (or parent/guardians) at home will document any substantive changes in usual dietary intake during the study period. These will be analyzed at Hayward Genetics Center using the MetabolicPro web-based analysis program.
Study Phase N/A
Study Type † Interventional
Study Design † Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary Outcome Measure † change in behavior and/or executive function as a result of Kuvan administration
Secondary Outcome Measure † change in neurotransmitter synthesis
Condition † Phenylketonuria Behavior and Behavior Mechanisms PAH Gene Expression
Intervention † Drugsapropterin dihydrochloride
Study Arms / Comparison Groups
Publications *

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information
Recruitment Status † Drug
Estimated Enrollment † 30
Start Date † January 2011
Completion Date January 2012
Primary Completion Date August 2011
Eligibility Criteria † Inclusion Criteria: - established Hayward Genetics Center patients: - confirmed diagnosis of PKU, - aged 2-21 years, - not responsive to sapropterin with decreased blood PHE levels Exclusion Criteria: - pregnancy - preexisting cognitive disorder or concurrent disease that would interfere with participation, - documented equal to or greater than 20% decrease in blood PHE levels as a response to sapropterin administration, - receiving neurotransmitter supplementation or medication for ADHD, - received sapropterin therapy in the 2 months prior to the study
Gender Both
Ages 2 Years - 21 Years
Accepts Healthy Volunteers Accepts Healthy Volunteers
Contacts †† Amy Cunningham, MS, 504-988-2989,
Location Countries † United States
Administrative Information
NCT ID † NCT01274026
Organization ID 183590-1
Secondary IDs ††
Responsible Party
Study Sponsor † Tulane University School of Medicine
Collaborators ††
Investigators † : ,
Information Provided By
Verification Date January 2011
First Received Date † January 10, 2011
Last Updated Date January 10, 2011
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists.
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