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

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ClinicalTrials.gov Identifier: NCT01965912
Recruitment Status : Active, not recruiting
First Posted : October 18, 2013
Last Update Posted : October 12, 2022
Information provided by (Responsible Party):
BioMarin Pharmaceutical

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.

Condition or disease Intervention/treatment Phase
Phenylketonuria Drug: Kuvan® Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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 Start Date : October 2013
Estimated Primary Completion Date : December 30, 2022
Estimated Study Completion Date : December 30, 2022

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 Name: Sapropterin dihydrochloride

Primary Outcome Measures :
  1. Mean Full Scale Intelligence Quotient (FSIQ) Score of the Wechsler Intelligence Scale for Children (WISC)-IV [ Time Frame: Year 7 ]

Secondary Outcome Measures :
  1. Height compared to the World Health Organization (WHO) Growth Standards [ Time Frame: up to 7 years ]
  2. Weight compared to the World Health Organization (WHO) Growth Standards [ Time Frame: up to 7 years ]
  3. Blood levels of tyrosine, tryptophan, pre-albumin and methylmalonic acid [ Time Frame: up to 7 years ]
  4. 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 ]
  5. 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 ]
  6. Change from Baseline in FSIQ score at 2, 4 and 7 years [ Time Frame: Baseline, and Year 2, 4 and 7 ]
  7. Dietary Phenylalanine tolerance [ Time Frame: up to 7 years ]
  8. Phenylalanine levels [ Time Frame: up to 7 years ]
  9. Index of Dietary Control (IDC) [ Time Frame: up to 7 years ]
  10. Percentage of tablets taken to assess treatment compliance [ Time Frame: up to 7 years ]
  11. Distribution of phenylalanine hydroxylase (PAH) genotype [ Time Frame: Baseline ]
  12. Number of subjects with Adverse Events and Serious Adverse Events [ Time Frame: up to 7 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years to 5 Years   (Child)
Sexes Eligible for Study:   All
Accepts 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01965912

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Research site
Munich, Germany
Research site
Münster, Germany
Research site
Bologna, Italy
Research site - Bambino Gesu
Roma, Italy
Research site - La Sapienza
Roma, Italy
Research Site
Barcelona, Spain
Research site
Murcia, Spain
Research site
Santiago de Compostela, Spain
United Kingdom
Research site
Birmingham, United Kingdom
Research site
Bristol, United Kingdom
Research Site - Evelina
London, United Kingdom
Research site - GOSH
London, United Kingdom
Sponsors and Collaborators
BioMarin Pharmaceutical
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Study Director: Ece Kucuksayrac, MD BioMarin Pharmaceutical
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Responsible Party: BioMarin Pharmaceutical
ClinicalTrials.gov Identifier: NCT01965912    
Other Study ID Numbers: EMR 700773-002
2009-015844-41 ( EudraCT Number )
First Posted: October 18, 2013    Key Record Dates
Last Update Posted: October 12, 2022
Last Verified: September 2022
Keywords provided by BioMarin Pharmaceutical:
Sapropterin dihydrochloride
Additional relevant MeSH terms:
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Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases