effect of kuvan on neurocognitive function, blood phenylalanine level, safety, and pharmacokinetics in children with pku

Conditions: Phenylketonuria

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.

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.

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.

Keywords: phenylketonuria pku kuvan phenoptin biopten neurocognitive function phenylalanine