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

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
BioMarin Pharmaceutical
ClinicalTrials.gov Identifier:
First received: October 16, 2013
Last updated: May 10, 2016
Last verified: May 2016
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 Intervention Phase
Drug: Kuvan®
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:

Further study details as provided by BioMarin Pharmaceutical:

Primary Outcome Measures:
  • Mean Full Scale Intelligence Quotient (FSIQ) Score of the Wechsler Intelligence Scale for Children (WISC)-IV [ Time Frame: Year 7 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Height compared to the World Health Organization (WHO) Growth Standards [ Time Frame: up to 7 years ] [ Designated as safety issue: No ]
  • Weight compared to the World Health Organization (WHO) Growth Standards [ Time Frame: up to 7 years ] [ Designated as safety issue: No ]
  • Blood levels of tyrosine, tryptophan, pre-albumin and methylmalonic acid [ Time Frame: up to 7 years ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Change from Baseline in FSIQ score at 2, 4 and 7 years [ Time Frame: Baseline, and Year 2, 4 and 7 ] [ Designated as safety issue: No ]
  • Dietary Phenylalanine tolerance [ Time Frame: up to 7 years ] [ Designated as safety issue: No ]
  • Phenylalanine levels [ Time Frame: up to 7 years ] [ Designated as safety issue: No ]
  • Index of Dietary Control (IDC) [ Time Frame: up to 7 years ] [ Designated as safety issue: No ]
  • Percentage of tablets taken to assess treatment compliance [ Time Frame: up to 7 years ] [ Designated as safety issue: No ]
  • Distribution of phenylalanine hydroxylase (PAH) genotype [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • Number of subjects with Adverse Events and Serious Adverse Events [ Time Frame: up to 7 years ] [ Designated as safety issue: Yes ]

Enrollment: 34
Study Start Date: October 2013
Estimated Study Completion Date: December 2022
Estimated Primary Completion Date: November 2022 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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


Ages Eligible for Study:   4 Years to 5 Years
Genders Eligible for Study:   Both
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01965912

Research Site
Düsseldorf, Germany
Research site
Munich, Germany
Research site
Münster, Germany
Research site
Bologna, Italy
Research site
Milano, Italy
Research site
Padova, Italy
Research site
Rome, Italy
Research site
Baracaldo Bilbao, Spain
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
London, United Kingdom
Sponsors and Collaborators
BioMarin Pharmaceutical
Study Director: Medical Responsible BioMarin Pharmaceutical
  More Information

Responsible Party: BioMarin Pharmaceutical
ClinicalTrials.gov Identifier: NCT01965912     History of Changes
Other Study ID Numbers: EMR 700773-002  2009-015844-41 
Study First Received: October 16, 2013
Last Updated: May 10, 2016
Health Authority: European Union: European Medicines Agency
Germany: Federal Institute for Drugs and Medical Devices
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Italy: Ethics Committee
Italy: The Italian Medicines Agency
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Spain: Ethics Committee

Keywords provided by BioMarin Pharmaceutical:
Sapropterin dihydrochloride

Additional relevant MeSH terms:
Amino Acid Metabolism, Inborn Errors
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Genetic Diseases, Inborn
Metabolic Diseases
Metabolism, Inborn Errors
Nervous System Diseases
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents

ClinicalTrials.gov processed this record on May 26, 2016