Effects of Kuvan on Brain and Cognition in Individuals With Phenylketonuria

This study is enrolling participants by invitation only.
Sponsor:
Collaborators:
BioMarin Pharmaceutical
University of Missouri-Columbia
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT00730080
First received: August 1, 2008
Last updated: December 3, 2013
Last verified: December 2013
  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. Patients with a reduction of ≥ 20% in blood Phe (i.e., responders) will receive follow-up neuropsychological and neuroimaging evaluations after 6 months of treatment with sapropterin. Patients (both responders and nonresponders) will receive long-term follow-up neuropsychological and neuroimaging evaluations 3 to 5 years after initial enrollment in the study.

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

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Wechsler Abbreviated Scale of Intelligence [ Time Frame: baseline & follow-ups ] [ Designated as safety issue: No ]
    assesses general intellectual ability

  • diffusion tensor imaging of the brain [ Time Frame: baseline & follow-ups ] [ Designated as safety issue: No ]
    assesses functional white matter integrity


Secondary Outcome Measures:
  • n-back task [ Time Frame: baseline & follow-ups ] [ Designated as safety issue: No ]
    assesses working memory

  • recognition span task [ Time Frame: baseline & follow-ups ] [ Designated as safety issue: No ]
    assesses working memory

  • list learning task [ Time Frame: baseline & follow-ups ] [ Designated as safety issue: No ]
    assesses strategic processing

  • verbal fluency task [ Time Frame: baseline & follow-ups ] [ Designated as safety issue: No ]
    assesses strategic processing

  • go/no-go task [ Time Frame: baseline & follow-ups ] [ Designated as safety issue: No ]
    assesses inhibitory control

  • stimulus-response compatibility task [ Time Frame: baseline & follow-ups ] [ Designated as safety issue: No ]
    assesses inhibitory control

  • structural magnetic resonance imaging of the brain [ Time Frame: baseline & follow-ups ] [ Designated as safety issue: No ]
    assesses structural brain integrity


Enrollment: 44
Study Start Date: July 2008
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: March 2015 (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 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. As a first step, 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. Patients with a reduction of ≥ 20% in blood Phe (i.e., responders) will receive follow-up neuropsychological and neuroimaging evaluations after 6 months of treatment with sapropterin. Patients (both responders and nonresponders) will receive long-term follow-up neuropsychological and neuroimaging evaluations 3 to 5 years after initial enrollment in the study.

A matched control group of healthy individuals without PKU will receive baseline and follow-up neuropsychological and 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 whether cognition (particularly executive abilities) improves in patients with PKU who have been treated with sapropterin. Second, we will determine whether the structure and functional integrity of the brain improves in patients with PKU who have been treated with sapropterin. 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
Study Population

Primary care clinic for phenylketonuria. St. Louis community for control.

Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00730080

Locations
United States, Missouri
Washington University
St. Louis, Missouri, United States, 63130
Sponsors and Collaborators
Washington University School of Medicine
BioMarin Pharmaceutical
University of Missouri-Columbia
Investigators
Principal Investigator: Desiree White, Ph.D. Washington University Early Recognition Center
Principal Investigator: Dorothy K. Grange, M.D. Washington University Early Recognition Center
  More Information

Publications:

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00730080     History of Changes
Other Study ID Numbers: PKU/Kuvan/White
Study First Received: August 1, 2008
Last Updated: December 3, 2013
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 July 26, 2014