Phenylketonuria
Conditions
Keywords
Phenylketonuria, Kuvan, Sapropterin dihydrochloride
Brief summary
The study is a single-cohort, interventional, open-label trial to evaluate long-term neurocognitive (NC) outcomes in children aged 4 to 5 years with phenylketonuria (PKU) treated with Kuvan® and Phenylalanine-restricted diet over a period of 7 years.
Interventions
DRUGKuvan®
Kuvan® oral soluble tablet will be administered once daily along with Phenylalanine-restricted diet for a period of 7 years. Dosage of Kuvan® could range from 5 to 20 milligram per kilogram per day (mg/kg/day), as per Summary of Product Characteristics (SPC).
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 5 Years
Healthy volunteers
No
Inclusion criteria
* Male or female outpatients, 4 to 5 years of age (greater than or equal to 4 and less than 6) at the time of informed consent form signature by parent(s) or guardian(s) * Confirmed clinical and biochemical diagnosis of PKU, including at least two separate blood phenylalanine levels greater than or equal to 400 micromole per liter (mcmol/L) * Defined pre-Kuvan®/-tetrahydrobiopterin (BH4) dietary phenylalanine tolerance consistent with the diagnosis of PKU * Responsive to Kuvan®/BH4: * For subjects currently treated with Kuvan®/BH4 at Screening: subject is a responder as per Investigator judgment based on documented effect of Kuvan®/BH4 on phenylalanine levels and/or phenylalanine tolerance * For subjects not treated with Kuvan®/BH4 at Screening: a response test has been performed during Screening or is available from the subject's medical records and satisfies the 3 following criteria: a decrease in blood phenylalanine levels of at least 30 percent was observed after at least 24 hours with a dose of at least 10 mg/kg/day * Intelligence Quotient (IQ) greater than or equal to 70, as assessed with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-III, 2nd part * Good adherence with dietary treatment (including prescribed dietary phenylalanine restriction and prescribed amounts of phenylalanine-free protein supplements and low-phenylalanine foods), as assessed by the Investigator * Well-controlled phenylalanine levels, as assessed by a minimum of 75 percent of phenylalanine levels within the target recommended in each centre during the previous 3 months * Low phenylalanine diet started within the first 3 weeks of life * Parent(s) or guardian(s) willing to comply with all study procedures, maintain strict adherence with the diet, and willing and able to provide written, signed informed consent before any trial-related activities are carried out, as well as ability of child to comply with trial procedures
Exclusion criteria
* Known hypersensitivity to Kuvan® or its excipients * Known hypersensitivity to other approved or non-approved formulations of BH4 * Previous diagnosis of BH4 deficiency * Current use of methotrexate, trimethoprim or other dihydrofolate reductase inhibitors * Current use of medications that are known to affect nitric oxide synthesis, metabolism or action * Current use of experimental or unregistered drugs (other than sapropterin/BH4) that may affect the study outcomes or use of such agents within 30 days prior to Screening * Concurrent use of levodopa * Concurrent disease or condition that would induce repeatedly catabolic situations, or interfere with the trial participation, diet, or NC development, as assessed by the Investigator * Any condition that, in the view of the Investigator, renders the subject at high risk for failure to comply with treatment or to complete the trial * Participation in a clinical trial investigating any other agent than Kuvan® within the past 30 days
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Mean Full Scale Intelligence Quotient (FSIQ) Score of the Wechsler Intelligence Scale for Children (WISC)-IV | Year 7 |
Secondary
| Measure | Time frame |
|---|---|
| Weight compared to the World Health Organization (WHO) Growth Standards | up to 7 years |
| Blood levels of tyrosine, tryptophan, pre-albumin and methylmalonic acid | up to 7 years |
| Intelligence Quotient (IQ) score and sub-scores such as, verbal IQ, performance IQ, Full Scale Intelligence Quotient (FSIQ) of Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-III | Baseline |
| Intelligence Quotient (IQ) score and sub-scores such as verbal comprehension, perceptual reasoning, working memory, and processing speed indexes and Full Scale Intelligence Quotient (FSIQ) of the Wechsler Intelligence Scale for Children (WISC)-IV | up to 7 years |
| Change from Baseline in FSIQ score at 2, 4 and 7 years | Baseline, and Year 2, 4 and 7 |
| Height compared to the World Health Organization (WHO) Growth Standards | up to 7 years |
| Phenylalanine levels | up to 7 years |
| Index of Dietary Control (IDC) | up to 7 years |
| Percentage of tablets taken to assess treatment compliance | up to 7 years |
| Distribution of phenylalanine hydroxylase (PAH) genotype | Baseline |
| Number of subjects with Adverse Events and Serious Adverse Events | up to 7 years |
| Dietary Phenylalanine tolerance | up to 7 years |
Countries
Germany, Italy, Spain, United Kingdom
Outcome results
None listed