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

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

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.

Study Overview

• Status: Completed
• Conditions: Phenylketonuria
• Intervention / Treatment: Drug: Kuvan®

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Munich, Germany
    • Research Site
  • Münster, Germany
    • Research Site
• Italy
  • Bologna, Italy
    • Research Site
  • Roma, Italy
    • Research site - Bambino Gesu
  • Roma, Italy
    • Research site - La Sapienza
• Spain
  • Barcelona, Spain
    • Research Site
  • Murcia, Spain
    • Research Site
  • Santiago de Compostela, Spain
    • Research Site
• United Kingdom
  • Birmingham, United Kingdom
    • Research Site
  • Bristol, United Kingdom
    • Research Site
  • London, United Kingdom
    • Research Site - Evelina
  • London, United Kingdom
    • Research site - GOSH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 5 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Kuvan®	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).; Other Names: Sapropterin dihydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical
• Investigators: Study Director: Ece Kucuksayrac, MD, BioMarin Pharmaceutical

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): January 4, 2023
• Study Completion (Actual): January 4, 2023

Study Registration Dates

• First Submitted: October 16, 2013
• First Submitted That Met QC Criteria: October 16, 2013
• First Posted (Estimate): October 18, 2013

Study Record Updates

• Last Update Posted (Actual): April 24, 2023
• Last Update Submitted That Met QC Criteria: April 21, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Phenylketonuria; Kuvan; Sapropterin dihydrochloride
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Phenylketonurias
• Other Study ID Numbers: EMR 700773-002; 2009-015844-41 (EudraCT Number)