PhenylketonuriaISTNCT01274026
Evaluation of Behavior, Executive Function, Neurotransmitter Function and Genomic Expression Kuvan Nonresponders
An observational study of Phenylketonuria and Behavior and Behavior Mechanisms, run by Tulane University School of Medicine at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 to 21 yearsHealthy volunteers can take part
- Conditions the study is for
- Phenylketonuria, Behavior and Behavior Mechanisms, PAH Gene Expression
- What is being tested?
- sapropterin dihydrochloride
- How many people
- 21 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2011to Dec 2013
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 21 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Study population: Study participants were solicited from treated patients diagnosed with PKU who are followed by our clinic. Participants were initially limited to those who had undergone a trial with sapropterin (FDA approved drug available for treatment) as part of their clinical care and been found to be non-responsive. Subsequently, with IRB approval, some patients diagnosed with PKU from our clinic population who were naive to sapropterin were added to the study.
Who may be able to join
- established Hayward Genetics Center patients:
- confirmed diagnosis of PKU,
- aged 2-21 years,
- not responsive to sapropterin with decreased blood PHE levels Subsequent to the start of the study inclusion criteria were amended: the upper limit of age was omitted, and a limited number of patients who were naive to sapropterin were recruited.
Who cannot join
- 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 attention deficit hyperactivity disorder (ADHD),
- received sapropterin therapy in the 2 months prior to the study
Trial locations and contacts
1 site in 1 country.
United States1 site
Tulane University Health Science Center
New Orleans, Louisiana, 70112
About this study
Official title: Evaluation of Behavior, Executive Function, Neurotransmitter Function and Genomic Expression in PKU "Nonresponders" to Kuvan® (Sapropterin Dihydrochloride)
This observational study seeks to establish evidence:
- that physiologic changes, unrelated to effect on the Phenylalanine Hydroxylase (PAH) enzyme, occur in Phenylketonuria (PKU) patients who are treated with sapropterin (Kuvan®) therapy,
- 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),
- and that beneficial changes in behavior and cognition, especially executive functioning skills may result.
Read more
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.
Read the 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 consents/assents 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) and/or 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 patient's usual dietary intake. These samples were drawn at each patient's local state health unit, as is done for usual monitoring. Nutrient analysis of the 3-day food diaries was conducted at Hayward Genetics Center.
- 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.
- 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.
- 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.
- 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 patient's failure to maintain usual dietary restrictions. Patients naive to Kuvan who responded were noted and function as comparators.
- 3-day food diaries completed by patients (or parent/guardians) 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.
- Being tested
- sapropterin dihydrochloride
- Keywords
- phenylketonuria, PKU, phenylalanine, neurotransmitters, gene, Kuvan, sapropterin
- Medical subject headings
- Phenylketonurias, Behavior
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
sapropterin dihydrochlorideDrug
Also called Kuvan
In 30 PKU patients found previously to exhibit no decrease in blood PHE levels behavioral and cognitive function, neurotransmitter levels, and gene expression of enzyme activity will be measured at baseline and after 4 weeks of Kuvan administration. Rating inventories of executive function performance and behavior will be administered to patients and parents.
Urine neurotransmitters, blood microarray expression, and plasma amino acids will be measured (plasma PHE and TYR levels will also be measured at weeks 1 and 2). Nutrient analysis of 3 day food diaries will be conducted.
| Study group | Role | What they receive |
|---|---|---|
| evaluation of benefit of sapropterin | Intervention 'sapropterin dihydrochloride': 20 individuals, either known to be non-responsive, or naive to sapropterin, are given a 4 week administration of sapropterin. Pre-, and Post- evaluation of behavior, executive function, neurotransmitter function, and genomic expression are assessed and evaluated for change. Receives: Drug: sapropterin dihydrochloride |
What is being measured
The primary outcome is the main question the study is designed to answer.
change in behavior as a result of Kuvan administration
This study seeks to establish evidence that behavioral changes, unrelated to blood phenylalanine levels, occur in PKU patients who are treated with Kuvan therapy, and that beneficial changes in behavior as measured by validated measurement questionnaires may result.
Measured: assessment during a 4 week trial of Kuvan
change in executive function as a result of Kuvan administration
This study seeks to establish evidence: that cognitive changes unrelated to blood phenylalanine levels occur in PKU patients who are treated with Kuvan therapy, and that beneficial changes in cognition, especially executive functioning skills as measured by validated measurement questionnaires may result.
Measured: assessment during a 4 week trial of Kuvan
Secondary outcomes (1)
change in neurotransmitter synthesis
This study seeks to establish evidence:
that physiologic changes, unrelated to effect on the PAH enzyme, occur in PKU patients who are treated with Kuvan® therapy,and 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), 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.
Measured: assessment during a 4 week trial of Kuvan administration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jan 2011 (estimated)
- Study startJan 2011
- Primary completionDec 2013
- Study completionDec 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for PhenylketonuriaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Prospective
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Tulane University School of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- BioMarin Pharmaceutical
- Responsible party
- Sponsor
- Investigators
- Hans C Andersson, MD, Principal investigator, Tulane University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01274026
- Sponsor's protocol ID
- 183590-1
- Acronym
- IST
- Status last verified
- Aug 2023
- First submitted
- 10 Jan 2011
- Last updated
- 14 Aug 2023
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Aug 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of Behavior, Executive Function, Neurotransmitter Function and Genomic Expression in PKU "Nonresponders" to Kuvan® (Sapropterin Dihydrochloride)
- ClinicalTrials.gov ID
- NCT01274026
- Acronym / sponsor ID
- IST / 183590-1
- Keywords
- phenylketonuria, PKU, phenylalanine, neurotransmitters, gene, Kuvan, sapropterin
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- Tulane University School of MedicineUniversity, hospital or other
- Collaborators
- BioMarin Pharmaceutical
- Study start
- Jan 2011
- Primary completion
- Dec 2013 (actual)
- Study completion
- Dec 2013 (actual)
- First posted
- 11 Jan 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This observational study seeks to establish evidence:
- that physiologic changes, unrelated to effect on the Phenylalanine Hydroxylase (PAH) enzyme, occur in Phenylketonuria (PKU) patients who are treated with sapropterin (Kuvan®) therapy,
- 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),
- 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 consents/assents 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) and/or 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 patient's usual dietary intake. These samples were drawn at each patient's local state health unit, as is done for usual monitoring. Nutrient analysis of the 3-day food diaries was conducted at Hayward Genetics Center.
- 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.
- 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.
- 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.
- 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 patient's failure to maintain usual dietary restrictions. Patients naive to Kuvan who responded were noted and function as comparators.
- 3-day food diaries completed by patients (or parent/guardians) 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 design
- Observational model
- Other
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| evaluation of benefit of sapropterin | – | Drug: sapropterin dihydrochlorideIntervention 'sapropterin dihydrochloride': 20 individuals, either known to be non-responsive, or naive to sapropterin, are given a 4 week administration of sapropterin. Pre-, and Post- evaluation of behavior, executive function, neurotransmitter function, and genomic expression are assessed and evaluated for change. |
Who may qualify
- Ages
- 2 to 21 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
- Study population
- Study participants were solicited from treated patients diagnosed with PKU who are followed by our clinic. Participants were initially limited to those who had undergone a trial with sapropterin (FDA approved drug available for treatment) as part of their clinical care and been found to be non-responsive. Subsequently, with IRB approval, some patients diagnosed with PKU from our clinic population who were naive to sapropterin were added to the study.
Key inclusion criteria (4 listed)
- established Hayward Genetics Center patients:
- confirmed diagnosis of PKU,
- aged 2-21 years,
- not responsive to sapropterin with decreased blood PHE levels Subsequent to the start of the study inclusion criteria were amended: the upper limit of age was omitted, and a limited number of patients who were naive to sapropterin were recruited.
Key exclusion criteria (5 listed)
- 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 attention deficit hyperactivity disorder (ADHD),
- received sapropterin therapy in the 2 months prior to the study
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| sapropterin dihydrochlorideAlso: KuvanIn 30 PKU patients found previously to exhibit no decrease in blood PHE levels behavioral and cognitive function, neurotransmitter levels, and gene expression of enzyme activity will be measured at baseline and after 4 weeks of Kuvan administration. Rating inventories of executive function performance and behavior will be administered to patients and parents. Urine neurotransmitters, blood microarray expression, and plasma amino acids will be measured (plasma PHE and TYR levels will also be measured at weeks 1 and 2). Nutrient analysis of 3 day food diaries will be conducted. | Drug | evaluation of benefit of sapropterin |
Primary outcome
change in behavior as a result of Kuvan administration
Time frame: assessment during a 4 week trial of Kuvan
This study seeks to establish evidence that behavioral changes, unrelated to blood phenylalanine levels, occur in PKU patients who are treated with Kuvan therapy, and that beneficial changes in behavior as measured by validated measurement questionnaires may result.
change in executive function as a result of Kuvan administration
Time frame: assessment during a 4 week trial of Kuvan
This study seeks to establish evidence: that cognitive changes unrelated to blood phenylalanine levels occur in PKU patients who are treated with Kuvan therapy, and that beneficial changes in cognition, especially executive functioning skills as measured by validated measurement questionnaires may result.
1 secondary outcome
change in neurotransmitter synthesis
Time frame: assessment during a 4 week trial of Kuvan administration
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Aug 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hans C Andersson, MD principal investigator
Tulane University School of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Phenylketonuria and Behavior and Behavior Mechanisms, run by Tulane University School of Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Aug 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
change in behavior as a result of Kuvan administration (time frame: assessment during a 4 week trial of Kuvan). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Aug 2023.