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

Phenylketonuria Clinical Trial

— KOGNITO  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01965912
• Other study ID #: EMR 700773-002
• Secondary ID: 2009-015844-41
• Status: Completed
• Phase: Phase 4
• Start date: October 2013
• Est. completion date: January 4, 2023

Study information

• Verified date: March 2023
• Source: BioMarin Pharmaceutical
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: January 4, 2023
• Est. primary completion date: January 4, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years to 5 Years

Eligibility

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

Related Conditions & MeSH terms

• Phenylketonuria
• Phenylketonurias

Intervention

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).

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
BioMarin Pharmaceutical

Countries where clinical trial is conducted

Germany,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Full Scale Intelligence Quotient (FSIQ) Score of the Wechsler Intelligence Scale for Children (WISC)-IV		Year 7
Secondary	Height compared to the World Health Organization (WHO) Growth Standards		up to 7 years
Secondary	Weight compared to the World Health Organization (WHO) Growth Standards		up to 7 years
Secondary	Blood levels of tyrosine, tryptophan, pre-albumin and methylmalonic acid		up to 7 years
Secondary	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
Secondary	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
Secondary	Change from Baseline in FSIQ score at 2, 4 and 7 years		Baseline, and Year 2, 4 and 7
Secondary	Dietary Phenylalanine tolerance		up to 7 years
Secondary	Phenylalanine levels		up to 7 years
Secondary	Index of Dietary Control (IDC)		up to 7 years
Secondary	Percentage of tablets taken to assess treatment compliance		up to 7 years
Secondary	Distribution of phenylalanine hydroxylase (PAH) genotype		Baseline
Secondary	Number of subjects with Adverse Events and Serious Adverse Events		up to 7 years