Kuvan®'s Effect on the Cognition of Children With Phenylketonuria

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 4 Open-Label, Single-Cohort Study of the Long-Term Neurocognitive Outcomes in 4 to 5 Year-Old Children With Phenylketonuria Treated With Sapropterin Dihydrochloride (Kuvan®) for 7 Years

Conditions
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Phenylketonuria

Intervention / Treatment
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* Drug: Kuvan®


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Kuvan®<br> | Drug: Kuvan®<br>* 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).<br>* Other names: Sapropterin dihydrochloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Full Scale Intelligence Quotient (FSIQ) Score of the Wechsler Intelligence Scale for Children (WISC)-IV |  | Year 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Height compared to the World Health Organization (WHO) Growth Standards |  | up to 7 years | 
| 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 | 
| Dietary Phenylalanine tolerance |  | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phenylketonuria, Kuvan, Sapropterin dihydrochloride