Effects of Kuvan on Brain and Cognition in Individuals With Phenylketonuria
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Purpose
Investigators at Washington University will examine the effects of sapropterin (Kuvan) on brain and cognition in individuals with phenylketonuria (PKU) using neuropsychological and neuroimaging procedures. Sapropterin is a medication developed by BioMarin Pharmaceutical, Inc. that is approved by the FDA for treatment of patients with PKU to reduce phenylalanine (Phe) levels. Patients beginning treatment with sapropterin as standard clinical care will be enrolled in the study. As a first step, patients with PKU will receive baseline neuropsychological and neuroimaging evaluations 1 day prior to beginning treatment with sapropterin. Screening for response to sapropterin will occur over 4 weeks. At the end of 4 weeks, response to sapropterin will be reviewed, and patients with a reduction of ≥ 20% in blood Phe will continue in the study. Follow-up neuropsychological and neuroimaging evaluations will occur at the end of 6 months of treatment with sapropterin.
The focus of neuropsychological testing will be executive abilities, as these abilities are particularly susceptible to disruption in individuals with PKU. We hypothesize that improvements in these abilities will occur following treatment with sapropterin. For neuroimaging assessments, structural magnetic resonance imaging (MRI) will permit evaluation of changes in the structure and volume of the gray and white matter of the brain, whereas diffusion tensor imaging (DTI)will permit evaluation of the functional integrity of the white matter of the brain.
| Condition | Intervention |
|---|---|
|
Phenylketonuria |
Drug: Sapropterin (Kuvan) |
| Study Type: | Observational |
| Study Design: | Observational Model: Case Control Time Perspective: Prospective |
| Official Title: | Effects of Sapropterin on Brain and Cognition in Individuals With Phenylketonuria |
- Wechsler Abbreviated Scale of Intelligence [ Time Frame: baseline & 6 month follow-up ] [ Designated as safety issue: No ]
- diffusion tensor imaging of the brain [ Time Frame: baseline & 6 month follow-up ] [ Designated as safety issue: No ]
- working memory n-back task [ Time Frame: baseline & 6 month follow-up ] [ Designated as safety issue: No ]
- working memory recognition span task [ Time Frame: baseline & 6 month follow-up ] [ Designated as safety issue: No ]
- strategic processing list learning task [ Time Frame: baseline & 6 month follow-up ] [ Designated as safety issue: No ]
- strategic processing verbal fluency task [ Time Frame: baseline & 6 month follow-up ] [ Designated as safety issue: No ]
- inhibitory control go/no-go task [ Time Frame: baseline & 6 month follow-up ] [ Designated as safety issue: No ]
- inhibitory control stimulus-response compatibility task [ Time Frame: baseline & 6 month follow-up ] [ Designated as safety issue: No ]
- structural magnetic resonance imaging of the brain [ Time Frame: baseline & 6 month follow-up ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 35 |
| Study Start Date: | July 2008 |
| Estimated Study Completion Date: | July 2009 |
| Estimated Primary Completion Date: | July 2009 (Final data collection date for primary outcome measure) |
| Groups/Cohorts | Assigned Interventions |
|---|---|
|
Phenylketonuria
Individuals with phenylketonuria (PKU) who are beginning treatment with sapropterin.
|
Drug: Sapropterin (Kuvan)
20mg/kg/day taken once daily or as otherwise prescribed by physician as standard care.
Other Name: Kuvan
|
|
Control
Healthy individuals without phenylketonuria (PKU).
|
Detailed Description:
Investigators at Washington University will examine the effects of sapropterin (Kuvan) on brain and cognition in individuals with phenylketonuria (PKU) using neuropsychological and neuroimaging procedures. Sapropterin is a medication developed by BioMarin Pharmaceutical, Inc. that was recently approved by the FDA for treatment of patients with PKU to reduce phenylalanine (Phe) levels. Patients beginning treatment with sapropterin as standard clinical care will be enrolled. As a first step, 25 patients with PKU who are ≥ 6 years of age will receive baseline neuropsychological and neuroimaging evaluations 1 day prior to beginning their treatment with sapropterin. Screening for response to sapropterin (20mg/kg/day) will then occur over 4 weeks as standard care for enrolled patients. At the end of 4 weeks, response to sapropterin will be reviewed. Fifteen patients with a reduction of ≥ 20% in blood phenylalanine (Phe) will continue in the study and receive follow-up neuropsychological and neuroimaging evaluations at the end of 6 months of treatment with sapropterin.
A matched control group of 10 healthy individuals without PKU will receive baseline neuropsychological and neuroimaging evaluations. The 10 control participants will receive follow-up neuropsychological (but not neuroimaging) evaluations for comparison purposes and to control for possible practice effects in repeated neuropsychological testing.
The focus of neuropsychological testing will be executive abilities, as these abilities are particularly susceptible to disruption in individuals with PKU. Specifically, the focus of neuropsychological assessment will be working memory, strategic processing, and inhibitory control, as our research group has shown that each of these executive abilities is impaired in individuals with PKU. (White, D. 2001 Neuropsychol.)(White, D. 2002 J. Int. Neuropsychol. Soc.)(Christ, S. 2006 Dev. Neuropsychol.) We hypothesize that improvements in these abilities will occur following treatment with sapropterin.
For neuroimaging assessments, both structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI; mean diffusivity and anisotropy) will be used. Structural MRI will permit evaluation of changes in the structure and volume of the gray and white matter of the brain. DTI will permit evaluation of the functional integrity of the white matter of the brain. Brain abnormalities have been noted in individuals with PKU, and using DTI our research group recently identified abnormalities in the integrity of white matter in early and continuously treated individuals with PKU.
The primary objectives of the proposed study are two-fold. First, we will determine if cognition (particularly executive abilities) improves in patients with PKU who have been treated with sapropterin for a period of 6 months. Second, we will determine if the structure and functional integrity of the brain improves in patients with PKU who have been treated with sapropterin for a period of 6 months. In addition, the interrelationships between changes in cognition and brain will be examined.
Eligibility| Ages Eligible for Study: | 6 Years to 50 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
| Sampling Method: | Non-Probability Sample |
Primary care clinic for phenylketonuria. St. Louis community for control.
Inclusion Criteria:
- Willing and able to provide informed consent or assent.
- Willing and able to comply with study procedures.
- Greater than or equal to 6 years of age.
- For phenylketonuria,intention of physician to prescribe sapropoterin.
- For phenylketonuria,phenylalanine level greater than or equal to 450μmol/L.
- For phenylketonuria, negative pregnancy test if of childbearing potential.
- For phenylketonuria, willing to use contraception if sexually active.
Exclusion Criteria:
- Pregnant, breastfeeding, or planning to become pregnant during study.
- Use of investigational product less than 30 days prior to or during study.
- Concurrent condition that could interfere with participation or safety.
- Any condition creating high risk of poor compliance with study.
- Perceived to be unreliable or unavailable for study.
- Use of L-Dopa, methotrexate, or other drugs that inhibit folate metabolism.
- For phenylketonuria, known hypersensitivity to sapropterin or excipients.
Contacts and Locations| United States, Missouri | |
| Washington University | |
| St. Louis, Missouri, United States, 63130 | |
| Principal Investigator: | Desiree White, Ph.D. | Washington University School of Medicine |
| Principal Investigator: | Dorothy K. Grange, M.D. | Washington University School of Medicine |
More Information
Publications:
| Responsible Party: | Desiree A. White, Ph.D., Associate Professor of Psychology, Washington University |
| ClinicalTrials.gov Identifier: | NCT00730080 History of Changes |
| Other Study ID Numbers: | PKU/Kuvan/White |
| Study First Received: | August 1, 2008 |
| Last Updated: | August 1, 2008 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by Washington University School of Medicine:
|
phenylketonuria sapropterin Kuvan |
cognition executive abilities brain |
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 |
ClinicalTrials.gov processed this record on June 18, 2013