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

NCT ID: NCT01274026

Last Updated: 2023-08-14

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 21 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2011-01-31
• Study Completion Date: 2013-12-31

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.

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.

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 patient's 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 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.

Conditions

Phenylketonuria; Behavior and Behavior Mechanisms; PAH Gene Expression

Study Design

• Observational Model Type: OTHER
• Study Time Perspective: PROSPECTIVE

Study Groups

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.

sapropterin dihydrochloride

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Kuvan

Eligibility Criteria

Inclusion Criteria

• established Hayward Genetics Center patients:
• confirmed diagnosis of PKU,
• aged 2-21 years,

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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

BioMarin Pharmaceutical

INDUSTRY

Sponsor Role: collaborator

Tulane University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hans C Andersson, MD

Role: PRINCIPAL_INVESTIGATOR

Tulane University School of Medicine

Locations

Tulane University Health Science Center

New Orleans, Louisiana, United States

Countries

United States

Other Identifiers

183590-1

Identifier Type: -

Identifier Source: org_study_id