Clinical trial NCT01965912: Kuvan®'s Effect on the Cognition of Children With Phenylketonuria
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Phenylketonuria
Keywords: Phenylketonuria
Kuvan
Sapropterin dihydrochloride
Lead sponsor: BioMarin Pharmaceutical
Sponsor class: INDUSTRY
First posted: 2013-10-18
Enrollment: 34
Sex: ALL
Minimum age (years): 4
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Mean Full Scale Intelligence Quotient (FSIQ) Score of the Wechsler Intelligence Scale for Children (WISC)-IV
timeFrame: Year 7
Secondary outcomes:
measure: Height compared to the World Health Organization (WHO) Growth Standards
timeFrame: up to 7 years
measure: Weight compared to the World Health Organization (WHO) Growth Standards
timeFrame: up to 7 years
measure: Blood levels of tyrosine, tryptophan, pre-albumin and methylmalonic acid
timeFrame: up to 7 years
measure: 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
timeFrame: Baseline
measure: 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
timeFrame: up to 7 years
measure: Change from Baseline in FSIQ score at 2, 4 and 7 years
timeFrame: Baseline, and Year 2, 4 and 7
measure: Dietary Phenylalanine tolerance
timeFrame: up to 7 years
measure: Phenylalanine levels
timeFrame: up to 7 years
measure: Index of Dietary Control (IDC)
timeFrame: up to 7 years
measure: Percentage of tablets taken to assess treatment compliance
timeFrame: up to 7 years
measure: Distribution of phenylalanine hydroxylase (PAH) genotype
timeFrame: Baseline
measure: Number of subjects with Adverse Events and Serious Adverse Events
timeFrame: up to 7 years
Other outcomes:
Locations:
city: Munich
country: Germany
facility: Research site
city: Münster
country: Germany
facility: Research site
city: Bologna
country: Italy
facility: Research site
city: Roma
country: Italy
facility: Research site - Bambino Gesu
city: Roma
country: Italy
facility: Research site - La Sapienza
city: Barcelona
country: Spain
facility: Research Site
city: Murcia
country: Spain
facility: Research site
city: Santiago de Compostela
country: Spain
facility: Research site
city: Birmingham
country: United Kingdom
facility: Research site
city: Bristol
country: United Kingdom
facility: Research site
city: London
country: United Kingdom
facility: Research Site - Evelina
city: London
country: United Kingdom
facility: Research site - GOSH
Study officials:
affiliation: BioMarin Pharmaceutical
name: Ece Kucuksayrac, MD
role: STUDY_DIRECTOR
References: