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

BioMarin Pharmaceutical95 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Phenylketonuria

Interventions

sapropterin dihydrochlorideDRUG

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.

Eligibility

Sex: ALLMax age: 6 Years

Medical Language ↔ Plain English

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.

Locations (19)

Unnamed facility

La Jolla, California, United States

Unnamed facility

Orange, California, United States

Unnamed facility

Tampa, Florida, United States

Outcomes

Primary Outcomes

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.

Time frame: Assessments through 84 months.

Secondary Outcomes

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.

Time frame: Up to 7 years

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%.

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.