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

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ClinicalTrials.gov Identifier: NCT01274026
Recruitment Status : Completed
First Posted : January 11, 2011
Last Update Posted : September 17, 2018
Sponsor:
Collaborator:
BioMarin Pharmaceutical
Information provided by (Responsible Party):
Hans C Andersson, Tulane University School of Medicine

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.


Condition or disease Intervention/treatment
Phenylketonuria Behavior and Behavior Mechanisms PAH Gene Expression Drug: sapropterin dihydrochloride

  Show Detailed Description

Study Type : Observational
Actual Enrollment : 21 participants
Observational Model: Other
Time Perspective: Prospective
Official Title: Evaluation of Behavior, Executive Function, Neurotransmitter Function and Genomic Expression in PKU "Nonresponders" to Kuvan® (Sapropterin Dihydrochloride)
Study Start Date : January 2011
Actual Primary Completion Date : December 2013
Actual Study Completion Date : December 2013


Group/Cohort Intervention/treatment
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.
Drug: sapropterin dihydrochloride

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.

Other Name: Kuvan




Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. change in neurotransmitter synthesis [ Time Frame: assessment during a 4 week trial of Kuvan administration ]

    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.




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Ages Eligible for Study:   2 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
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.
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 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.

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 attention deficit hyperactivity disorder (ADHD),
  • received sapropterin therapy in the 2 months prior to the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01274026


Locations
United States, Louisiana
Tulane University Health Science Center
New Orleans, Louisiana, United States, 70112
Sponsors and Collaborators
Tulane University School of Medicine
BioMarin Pharmaceutical
Investigators
Principal Investigator: Hans C Andersson, MD Tulane University School of Medicine

Responsible Party: Hans C Andersson, Director, Hayward Genetics Center, Tulane University School of Medicine
ClinicalTrials.gov Identifier: NCT01274026     History of Changes
Other Study ID Numbers: 183590-1
First Posted: January 11, 2011    Key Record Dates
Last Update Posted: September 17, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Hans C Andersson, Tulane University School of Medicine:
phenylketonuria
PKU
phenylalanine
neurotransmitters
gene
Kuvan
sapropterin

Additional relevant MeSH terms:
Phenylketonurias
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Verapamil
Neurotransmitter Agents
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Physiological Effects of Drugs