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Effect of Kuvan on Neurocognitive Function, Blood Phenylalanine Level, Safety, and Pharmacokinetics in Children With PKU (PKU-015)

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ClinicalTrials.gov Identifier: NCT00838435
Recruitment Status : Completed
First Posted : February 6, 2009
Results First Posted : December 22, 2020
Last Update Posted : December 22, 2020
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Brief Summary:
This multicenter, open label study is designed to evaluate the safety of Kuvan® and its effect on neurocognitive function, blood Phe concentration, and growth in children with PKU who are 0-6 years old.

Condition or disease Intervention/treatment Phase
Phenylketonuria Drug: sapropterin dihydrochloride Phase 3

Detailed Description:

Rigorous control of diet is typically advocated in children 4 years and under with PKU because brain sensitivity to high Phe concentrations is expected to be greatest during these years of rapid neurocognitive development.

Prolonged high blood Phe concentrations are neurotoxic and lead to impairment of intelligence and other brain functions (such as attentiveness). Reduction of blood Phe concentrations through dietary control is an important determinant of long-term neurologic outcome in PKU patients, and reduction of blood Phe concentrations in patients with PKU has been shown to decrease the long term risk of neurologic injury.

It is difficult for many patients to maintain reduced blood Phe, and many patients with PKU experience some degree of neurological impairment despite efforts to maintain dietary Phe control.

The strongest determinant of intelligence quotient (IQ) and cognitive function is compliance with blood Phe control. Several clinical studies with Kuvan have already demonstrated efficacy in reducing blood Phe in subjects older than 4 years. This study will examine whether addition of Kuvan to the standard of care at an early age in children with well controlled diets can lower blood Phe levels (ie, reach and maintain a goal of ≤ 240 micromole/L) and preserve neurocognitive functioning. In addition, this study will provide data on Kuvan exposure, rate of uptake, half life, and clearance in young children.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 95 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3b Open-Label Study to Evaluate the Effect of Kuvan® on Neurocognitive Function, Maintenance of Blood Phenylalanine Concentrations, Safety, and Population Pharmacokinetics in Young Children With Phenylketonuria
Study Start Date : February 2009
Actual Primary Completion Date : September 14, 2018
Actual Study Completion Date : September 14, 2018


Arm Intervention/treatment
Experimental: sapropterin dihydrochloride
A dose of 20 mg/kg will be administered dissolved in water or apple juice, based on subject's age and ability, and taken orally once daily with food.
Drug: sapropterin dihydrochloride
A dose of 20 mg/kg will be administered dissolved in water or apple juice, based on subject's age and ability, and taken orally once daily with food.
Other Names:
  • Kuvan
  • Phenoptin
  • BH4
  • 6R BH4




Primary Outcome Measures :
  1. Full-Scale Intelligence Quotient (FSIQ) Score [ Time Frame: Assessments through 84 months. ]

    Full Scale Intelligence Quotient (FSIQ) is a score derived through administration of selected subtests from age appropriate Wechsler Intelligence assessments. Weschler Preschool and Primary Scale of Intelligence (WPPSI)-III is used for children >30 months and ≤6 years; and Weschler Intelligence Scale for Children (WISC)-IV is used for children >6 years old. The outcome variable will be the FSIQ score from WPPSI-III and/or WISC-IV tests.

    FSIQ results can range from 40 being the lowest and 160 being the highest. Higher scores are associated with higher intelligence quotient.



Secondary Outcome Measures :
  1. Number of Subjects With Adverse Events (AEs) [ Time Frame: Up to 7 years ]

    Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, and that does not necessarily have a causal relationship with this treatment.

    Drug Related Adverse all noxious and unintended responses to a medical product related to any dose. This means that a causal relationship between a medicinal product and an AE is at least a reasonable possibility, ie, the relationship cannot be ruled out.

    A serious adverse event (SAE) is an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.


  2. Change From Baseline in Growth Measurements - Height Z-Scores [ Time Frame: Baseline and up to 84 months ]

    Z-scores of Height determined using World Health Organization(WHO) growth charts for children <24 months and Centers for Disease Control and Prevention(CDC) clinical growth charts for children 24 months and older.

    A height z-score is a standardized height measure after considering important factors like age and gender, in which higher z-scores are associated with taller children. Z-scores (or standard deviation scores) describe how far a measurement is from the median (mean). A z-score of 0 is the same as a 50th percentile; a positive value is a factor of standard deviation (SD) unit above the 50%; and a negative value is a factor of SD unit below 50%.


  3. Change From Baseline in Growth Measurements - Weight Z-Scores [ Time Frame: Baseline and up to 84 months ]

    Z-scores of Weight determined using World Health Organization(WHO) growth charts for children <24 months and Centers for Disease Control and Prevention(CDC) clinical growth charts for children 24 months or older.

    A weight z-score is a standardized weight measure after considering important factors like age and gender, in which higher z-scores are associated with heavier children. Z-scores (or standard deviation scores) describe how far a measurement is from the median (mean). A z-score of 0 is the same as a 50th percentile; a positive value is a factor of SD unit above the 50%; and a negative value is a factor of SD unit below 50%.


  4. Change From Baseline in Growth Measurements - Head Circumference Z-Scores [ Time Frame: Baseline and up to 84 months ]

    Z-scores of Head Circumference determined using World Health Organization(WHO) growth charts for children <24 months and Centers for Disease Control and Prevention(CDC) clinical growth charts for children 24 months and older.

    A head circumference z-score is a standardized head circumference measure after considering important factors like age and gender, in which higher z-scores are associated with children with larger heads. Z-scores (or standard deviation scores) describe how far a measurement is from the median (mean). A z-score of 0 is the same as a 50th percentile; a positive value is a factor of SD unit above the 50%; and a negative value is a factor of SD unit below 50%.


  5. Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results [ Time Frame: At Month 6, 12, 18 and 24 ]
    The Bayley-III is a tool for assessing all facets of development in infants within an age range of 12 to 30 months, with normative data available for infants as young as 16 days. Composite scores are derived for cognitive, language, and motor development and scaled to a metric, with a range of 40 to 160. Higher scores are a better outcome.

  6. Baseline Concentration of Tetrahydrobiopterin (BH4)(C0) [ Time Frame: At predose and postdose - 0.22, 3.2 and 7 hours ]
    Baseline concentration of BH4(C0) with associated inter-individual variability.

  7. Absorption Rate Constant (Ka) of Kuvan [ Time Frame: At predose and postdose - 0.22, 3.2 and 7 hours ]
    Population pharmacokinetic parameter, Absorption Rate Constant (Ka)

  8. Apparent Volume of Distribution (V/F) of Kuvan [ Time Frame: At predose and postdose - 0.22, 3.2 and 7 hours ]
    Population pharmacokinetic parameter apparent volume of distribution (V/F)

  9. Apparent Clearance (CL/F) of Kuvan [ Time Frame: At predose and postdose - 0.22, 3.2 and 7 hours ]
    Population pharmacokinetic parameter apparent clearance (CL/F)



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 6 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Established diagnosis of PKU with hyperphenylalaninemia (HPA) documented in the medical record by at least 2 blood Phe concentrations greater than or equal to 360 micromole/L (6 mg/dL) taken at least 3 days apart
  • Documented blood Phe control (defined by the standard used at each treatment center) prior to study enrollment, if applicable (eg, the subject is old enough for these data to be collected); blood Phe concentrations for subjects < 6 months old at Screening must be considered controlled and stable by the Investigator
  • Willing to adhere to a prescribed Phe restricted diet in order to maintain blood Phe concentrations within the recommended ranges established at the subject's study site
  • Age 0 to 6 years old, inclusive, at Screening
  • Parent(s) or guardian(s) willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures
  • Parent(s) or guardian(s) willing and able to comply with all study procedures
  • Female subjects of childbearing potential (as determined by the investigator) and sexually mature male subjects willing to use a medically accepted method of contraception throughout the study. Female subjects of childbearing potential willing to undergo periodic pregnancy tests during the course of the study

Exclusion Criteria:

  • Established diagnosis of primary tetrahydrobiopterin (BH4) deficiency
  • Known hypersensitivity to Kuvan or its excipients
  • History of organ transplantation
  • Perceived to be unreliable or unavailable for study participation or to have parents or legal guardians who are perceived to be unreliable or unavailable
  • Use of methotrexate or other medications that inhibit folate metabolism
  • Serious neuropsychiatric illness (eg, major depression) not currently under medical control
  • Use of Kuvan or any investigational agent within 30 days prior to Screening, or known requirement for any investigational agent prior to completion of all scheduled study assessments
  • Concurrent disease or condition that would interfere with study participation or safety (eg, seizure disorder, oral steroid-dependent asthma or other condition requiring oral or parenteral corticosteroid administration, or insulin dependent diabetes)
  • Any condition that, in the view of the Principal Investigator (PI), renders the subject at high risk for failure to comply with treatment or to complete the study
  • Use of phosphodiesterase type 5 (PDE5) inhibitor.

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): NCT00838435


Locations
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United States, California
La Jolla, California, United States
Orange, California, United States
United States, Florida
Tampa, Florida, United States
United States, Illinois
Chicago, Illinois, United States
United States, Massachusetts
Boston, Massachusetts, United States
United States, Missouri
Kansas City, Missouri, United States
United States, Ohio
Cleveland, Ohio, United States
Columbus, Ohio, United States
United States, Pennsylvania
Hershey, Pennsylvania, United States
United States, Tennessee
Nashville, Tennessee, United States
United States, Utah
Salt Lake City, Utah, United States
United States, Wisconsin
Milwaukee, Wisconsin, United States
Canada, Alberta
Edmonton, Alberta, Canada
Canada, British Columbia
Vancouver, British Columbia, Canada
Canada, Manitoba
Winnipeg, Manitoba, Canada
Canada, Ontario
Hamilton, Ontario, Canada
Toronto, Ontario, Canada
Canada, Quebec
Montreal, Quebec, Canada
Sainte-Foy, Quebec, Canada
Sponsors and Collaborators
BioMarin Pharmaceutical
Investigators
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Study Director: Joshua Lilienstein, M.D. BioMarin Pharmaceutical
  Study Documents (Full-Text)

Documents provided by BioMarin Pharmaceutical:
Study Protocol  [PDF] November 30, 2010
Statistical Analysis Plan  [PDF] April 26, 2019

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Responsible Party: BioMarin Pharmaceutical
ClinicalTrials.gov Identifier: NCT00838435    
Other Study ID Numbers: PKU-015
First Posted: February 6, 2009    Key Record Dates
Results First Posted: December 22, 2020
Last Update Posted: December 22, 2020
Last Verified: December 2020
Keywords provided by BioMarin Pharmaceutical:
Phenylketonuria
PKU
Kuvan
Phenoptin
Biopten
Neurocognitive Function
Phenylalanine
Additional relevant MeSH terms:
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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
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Vasodilator Agents