Ignite Creation Date:
2024-05-05 @ 11:12 PM
Last Modification Date:
2024-10-26 @ 10:30 AM
Study NCT ID:
NCT01274026
Status:
COMPLETED
Last Update Posted:
2023-08-14
First Post:
2011-01-10
Brief Title:
Evaluation of Behavior Executive Function Neurotransmitter Function and Genomic Expression Kuvan Nonresponders
Sponsor:
Tulane University School of Medicine
Organization:
Tulane University
Study Overview
Official Title:
Evaluation of Behavior Executive Function Neurotransmitter Function and Genomic Expression in PKU Nonresponders to Kuvan Sapropterin Dihydrochloride
Status:
COMPLETED
Status Verified Date:
2023-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
IST
Brief Summary:
This observational study seeks to establish evidence
1 that physiologic changes unrelated to effect on the Phenylalanine Hydroxylase PAH enzyme occur in Phenylketonuria PKU patients who are treated with sapropterin 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
1 that physiologic changes unrelated to effect on the Phenylalanine Hydroxylase PAH enzyme occur in Phenylketonuria PKU patients who are treated with sapropterin 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 anticipated study participant population was approximately 30 established PKU patients receiving care from Hayward Genetics Center who were found previously to exhibit no decrease in blood phenylalanine PHE levels nonresponders with administration of sapropterin Subjects acted as their own controls An additional number of patients naive to sapropterin were subsequently added to the study and the age exclusion of over 21 years of age was omitted per IRB approval Primary endpoints were designed to 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 attended an approximately 1 hour clinic visit at their usual genetics clinic location Study purpose design and requirements were discussed and consentsassents reviewed and signed
Rating inventories of executive function performance and behavior BASC-2 and BRIEF tools were administered to patients and parents by the Principal Investigator PI andor the Study Coordinator
Urine samples were collected non-invasively for measurement of neurotransmitter levels Blood as 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 were collected
Participants were 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 was emphasized Sapropterin was discontinued at the end of the 4 week study period The exception to this was for the naive patients who were found to be responsive to sapropterin
All of these measures were 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 were sent to Hayward Genetics Center for measurement of PHE and tyrosine TYR levels to ascertain no significant changes have occurred in a patients usual dietary intake These samples were drawn at each patients local state health unit as is done for usual monitoring Nutrient analysis of the 3-day food diaries was conducted at Hayward Genetics Center
1 Behavior and executive function were assessed using published validated inventories completed as patient self-reports and as parent or guardian reports when appropriate Instruments used were 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 were scored using electronic evaluation instruments by the Study Coordinator and PI with consultation from Harvard Medical Center experts as needed
2 Urine samples were non-invasively collected and sent for analysis of catechols and neurotransmitters to an NIH laboratory specializing in this technique Samples were blinded to this laboratory to prevent bias
3 Microarray analysis of blood samples was 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 were 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 patients failure to maintain usual dietary restrictions Patients naive to Kuvan who responded were noted and function as comparators
5 3-day food diaries completed by patients or parentguardians at home documented any substantive changes in usual dietary intake during the study period These were analyzed at Hayward Genetics Center using the MetabolicPro web-based analysis program
At study baseline each patient attended an approximately 1 hour clinic visit at their usual genetics clinic location Study purpose design and requirements were discussed and consentsassents reviewed and signed
Rating inventories of executive function performance and behavior BASC-2 and BRIEF tools were administered to patients and parents by the Principal Investigator PI andor the Study Coordinator
Urine samples were collected non-invasively for measurement of neurotransmitter levels Blood as 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 were collected
Participants were 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 was emphasized Sapropterin was discontinued at the end of the 4 week study period The exception to this was for the naive patients who were found to be responsive to sapropterin
All of these measures were 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 were sent to Hayward Genetics Center for measurement of PHE and tyrosine TYR levels to ascertain no significant changes have occurred in a patients usual dietary intake These samples were drawn at each patients local state health unit as is done for usual monitoring Nutrient analysis of the 3-day food diaries was conducted at Hayward Genetics Center
1 Behavior and executive function were assessed using published validated inventories completed as patient self-reports and as parent or guardian reports when appropriate Instruments used were 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 were scored using electronic evaluation instruments by the Study Coordinator and PI with consultation from Harvard Medical Center experts as needed
2 Urine samples were non-invasively collected and sent for analysis of catechols and neurotransmitters to an NIH laboratory specializing in this technique Samples were blinded to this laboratory to prevent bias
3 Microarray analysis of blood samples was 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 were 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 patients failure to maintain usual dietary restrictions Patients naive to Kuvan who responded were noted and function as comparators
5 3-day food diaries completed by patients or parentguardians at home documented any substantive changes in usual dietary intake during the study period These were analyzed at Hayward Genetics Center using the MetabolicPro web-based analysis program
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None