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

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 30, 2022

Interventions

  • Drug: Kuvan®
    • 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).

Arms, Groups and Cohorts

  • Experimental: Kuvan®

Clinical Trial Outcome Measures

Primary Measures

  • Mean Full Scale Intelligence Quotient (FSIQ) Score of the Wechsler Intelligence Scale for Children (WISC)-IV
    • Time Frame: Year 7

Secondary Measures

  • Height compared to the World Health Organization (WHO) Growth Standards
    • Time Frame: up to 7 years
  • Weight compared to the World Health Organization (WHO) Growth Standards
    • Time Frame: up to 7 years
  • Blood levels of tyrosine, tryptophan, pre-albumin and methylmalonic acid
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: up to 7 years
  • Change from Baseline in FSIQ score at 2, 4 and 7 years
    • Time Frame: Baseline, and Year 2, 4 and 7
  • Dietary Phenylalanine tolerance
    • Time Frame: up to 7 years
  • Phenylalanine levels
    • Time Frame: up to 7 years
  • Index of Dietary Control (IDC)
    • Time Frame: up to 7 years
  • Percentage of tablets taken to assess treatment compliance
    • Time Frame: up to 7 years
  • Distribution of phenylalanine hydroxylase (PAH) genotype
    • Time Frame: Baseline
  • Number of subjects with Adverse Events and Serious Adverse Events
    • Time Frame: up to 7 years

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 4 Years

Maximum Age: 5 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • BioMarin Pharmaceutical
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Ece Kucuksayrac, MD, Study Director, BioMarin Pharmaceutical

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