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

Primary Purpose

Phenylketonuria

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
sapropterin dihydrochloride
Sponsored by
BioMarin Pharmaceutical
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Phenylketonuria focused on measuring Phenylketonuria, PKU, Kuvan, Phenoptin, Biopten, Neurocognitive Function, Phenylalanine

Eligibility Criteria

undefined - 6 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

sapropterin dihydrochloride

Arm Description

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.

Outcomes

Primary Outcome Measures

Full-Scale Intelligence Quotient (FSIQ) Score
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

Number of Subjects With Adverse Events (AEs)
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.
Change From Baseline in Growth Measurements - Height Z-Scores
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%.
Change From Baseline in Growth Measurements - Weight Z-Scores
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%.
Change From Baseline in Growth Measurements - Head Circumference Z-Scores
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%.
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
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.
Baseline Concentration of Tetrahydrobiopterin (BH4)(C0)
Baseline concentration of BH4(C0) with associated inter-individual variability.
Absorption Rate Constant (Ka) of Kuvan
Population pharmacokinetic parameter, Absorption Rate Constant (Ka)
Apparent Volume of Distribution (V/F) of Kuvan
Population pharmacokinetic parameter apparent volume of distribution (V/F)
Apparent Clearance (CL/F) of Kuvan
Population pharmacokinetic parameter apparent clearance (CL/F)

Full Information

First Posted
February 5, 2009
Last Updated
December 1, 2020
Sponsor
BioMarin Pharmaceutical
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1. Study Identification

Unique Protocol Identification Number
NCT00838435
Brief Title
Effect of Kuvan on Neurocognitive Function, Blood Phenylalanine Level, Safety, and Pharmacokinetics in Children With PKU
Acronym
PKU-015
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 Type
Interventional

2. Study Status

Record Verification Date
December 2020
Overall Recruitment Status
Completed
Study Start Date
February 2009 (undefined)
Primary Completion Date
September 14, 2018 (Actual)
Study Completion Date
September 14, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
BioMarin Pharmaceutical

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Phenylketonuria
Keywords
Phenylketonuria, PKU, Kuvan, Phenoptin, Biopten, Neurocognitive Function, Phenylalanine

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
95 (Actual)

8. Arms, Groups, and Interventions

Arm Title
sapropterin dihydrochloride
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
sapropterin dihydrochloride
Other Intervention Name(s)
Kuvan, Phenoptin, BH4, 6R BH4
Intervention Description
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.
Primary Outcome Measure Information:
Title
Full-Scale Intelligence Quotient (FSIQ) Score
Description
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.
Time Frame
Assessments through 84 months.
Secondary Outcome Measure Information:
Title
Number of Subjects With Adverse Events (AEs)
Description
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.
Time Frame
Up to 7 years
Title
Change From Baseline in Growth Measurements - Height Z-Scores
Description
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%.
Time Frame
Baseline and up to 84 months
Title
Change From Baseline in Growth Measurements - Weight Z-Scores
Description
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%.
Time Frame
Baseline and up to 84 months
Title
Change From Baseline in Growth Measurements - Head Circumference Z-Scores
Description
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%.
Time Frame
Baseline and up to 84 months
Title
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Description
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.
Time Frame
At Month 6, 12, 18 and 24
Title
Baseline Concentration of Tetrahydrobiopterin (BH4)(C0)
Description
Baseline concentration of BH4(C0) with associated inter-individual variability.
Time Frame
At predose and postdose - 0.22, 3.2 and 7 hours
Title
Absorption Rate Constant (Ka) of Kuvan
Description
Population pharmacokinetic parameter, Absorption Rate Constant (Ka)
Time Frame
At predose and postdose - 0.22, 3.2 and 7 hours
Title
Apparent Volume of Distribution (V/F) of Kuvan
Description
Population pharmacokinetic parameter apparent volume of distribution (V/F)
Time Frame
At predose and postdose - 0.22, 3.2 and 7 hours
Title
Apparent Clearance (CL/F) of Kuvan
Description
Population pharmacokinetic parameter apparent clearance (CL/F)
Time Frame
At predose and postdose - 0.22, 3.2 and 7 hours

10. Eligibility

Sex
All
Maximum Age & Unit of Time
6 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joshua Lilienstein, M.D.
Organizational Affiliation
BioMarin Pharmaceutical
Official's Role
Study Director
Facility Information:
City
La Jolla
State/Province
California
Country
United States
City
Orange
State/Province
California
Country
United States
City
Tampa
State/Province
Florida
Country
United States
City
Chicago
State/Province
Illinois
Country
United States
City
Boston
State/Province
Massachusetts
Country
United States
City
Kansas City
State/Province
Missouri
Country
United States
City
Cleveland
State/Province
Ohio
Country
United States
City
Columbus
State/Province
Ohio
Country
United States
City
Hershey
State/Province
Pennsylvania
Country
United States
City
Nashville
State/Province
Tennessee
Country
United States
City
Salt Lake City
State/Province
Utah
Country
United States
City
Milwaukee
State/Province
Wisconsin
Country
United States
City
Edmonton
State/Province
Alberta
Country
Canada
City
Vancouver
State/Province
British Columbia
Country
Canada
City
Winnipeg
State/Province
Manitoba
Country
Canada
City
Hamilton
State/Province
Ontario
Country
Canada
City
Toronto
State/Province
Ontario
Country
Canada
City
Montreal
State/Province
Quebec
Country
Canada
City
Sainte-Foy
State/Province
Quebec
Country
Canada

12. IPD Sharing Statement

Learn more about this trial

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

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