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    Summary
    EudraCT Number:2009-015844-41
    Sponsor's Protocol Code Number:BMN162-502
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-06-13
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2009-015844-41
    A.3Full title of the trial
    A Phase IV 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.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of the Long-term Effects on Mental Abilities of 4 to 5 Year-old Children with a Disease Caused by an Enzyme Defect (Phenylketonuria) that Have Been Treated with Kuvan® (a Medicinal Product aimed at Restoring the Defect) for 7 Years.
    A.3.2Name or abbreviated title of the trial where available
    KOGNITO (Kuvan®’s effect on the cOGNITion of children with phenylketOnuria)
    A.4.1Sponsor's protocol code numberBMN162-502
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBioMarin International Ltd.
    B.1.3.4CountryIreland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBioMarin International Ltd.
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBioMarin International Ltd.
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street AddressShanbally, Ringaskiddy
    B.5.3.2Town/ cityCounty Cork
    B.5.3.4CountryIreland
    B.5.6E-mailKOGNITO@bmrn.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Kuvan
    D.2.1.1.2Name of the Marketing Authorisation holderBioMarin International Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/04/199
    D.3 Description of the IMP
    D.3.1Product nameKuvan
    D.3.4Pharmaceutical form Soluble tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSAPROPTERIN
    D.3.9.1CAS number 62989-33-7
    D.3.9.3Other descriptive nametetrahydrobiopterin
    D.3.9.4EV Substance CodeSUB10445MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Phenylketonuria
    E.1.1.1Medical condition in easily understood language
    Disease, where a genetic defect leads to non-functional enzyme, causing accumulation of an amino acid (phenylalanine) in the body and the presence of a related substance in urine (phenylketonuria)
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10034873
    E.1.2Term Phenylketonuria (PKU)
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this trial is to evaluate the long-term neurocognitive (NC) outcomes in children with hyperphenylalaninemia (HPA) due to phenylketonuria (PKU) treated with Kuvan® and a phenylalanine (Phe)-restricted diet for 7 years.
    E.2.2Secondary objectives of the trial
    The main secondary objectives of this trial are to evaluate the growth and safety in children with HPA due to PKU treated with Kuvan® and a Phe-restricted diet and followed for a period of 7 years.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The target population for this trial is children with confirmed diagnosis of PKU.

    Inclusion criteria:
    • Male or female outpatients, 4 to 5 years of age (≥4 and <6) at the time of ICF signature by parent(s) or guardian(s).
    • Confirmed clinical and biochemical diagnosis of PKU, including at least two separate blood Phe levels ≥400 μmol/L.
    • Defined pre-Kuvan®/-tetrahydrobiopterin (BH4) dietary Phe 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 Phe levels and/or Phe tolerance.
    - For subjects not treated with Kuvan®/BH4 at Screening: a response test has been performed during Screening or is available from the patient’s medical records and satisfies the 3 following criteria: a decrease in blood Phe levels of at least 30% was observed after at least 24 hours with a dose of at least 10 mg/kg/day.
    • IQ ≥70, as assessed with the WPPSI™-III 2nd part.
    Note: If a subject has undertaken the same test up to 3 months before Screening as part of his/her clinical follow-up, the score can be recorded and the test doesn’t need to be repeated.
    • Good adherence with dietary treatment (including prescribed dietary Phe restriction and prescribed amounts of Phe-free protein supplements and low-Phe foods), as assessed by the Investigator.
    • Well-controlled Phe levels, as assessed by a minimum of 75% of Phe levels within the target recommended in each centre during the previous 3 months.
    • Low Phe 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.
    E.4Principal exclusion criteria
    • Known hypersensitivity to Kuvan® or its excipients.
    • Known hypersensitivity to other approved or non-approved formulations of tetrahydrobiopterin.
    • 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.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be the mean IQ score of PKU children on diet and treated with Kuvan® after 7 years of treatment in the study.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 7 years of treatment with Kuvan® in the study.
    E.5.2Secondary end point(s)
    • Height and weight compared to the World Health Organization (WHO) Growth Standards at each time point.
    • Blood levels of tyrosine (Tyr), tryptophan, pre-albumin, and methylmalonic acid compared to age-related norms.
    • IQ score and subscores at each time-point:
    - the Verbal IQ, the Performance IQ and the Full Scale IQ (FSIQ) of the WPPSI™-III at baseline;
    - the Verbal Comprehension, the Perceptual Reasoning, the Working Memory, the Processing Speed Indexes and the FSIQ of the WISC®-IV at post-baseline time-points.
    • Change from baseline in FSIQ score at 2, 4 and 7 years.
    • Dietary Phe tolerance over the 7 year period, as represented by mean Phe prescription (in mg/day and mg/kg/day) quarterly and mean Phe intake (in mg/day) bi-annually.
    • Monthly Phe levels and Phe levels on the day of the IQ test.
    • IDC (Index of Dietary Control = half-year Phe level medians averaged from baseline to 2, 4 and 7 years).
    • Adherence to treatment (diet+Kuvan®) as assessed by the percentage of monthly Phe levels within target blood Phe concentration during Study Period and adherence to Kuvan® treatment as assessed by percentage of tablets taken.
    • Frequencies and distributions of phenylalanine hydroxylase (PAH) genotype and relationships with response to Kuvan®/BH4.
    • Safety (extent of exposure to Kuvan®; nature, incidence, and severity of adverse events (AEs)/serious adverse events (SAEs), including relationship to trial treatment, AEs/SAEs leading to dose modification or discontinuation of trial treatment; changes and abnormalities in vital signs and safety laboratory parameters; physical examination; use of concomitant medications).
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 7 years of treatment with Kuvan® in the study.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    This trial will be completed after:
    • All enrolled subjects who have received at least one dose of study drug have completed all scheduled visits or have prematurely discontinued
    • Follow-up of all subjects with ongoing AEs at the conclusion of treatment has been addressed
    • Site monitoring visits to resolve any outstanding data discrepancy issues have been completed
    • The database has been locked
    • All sites have undergone a final site closure termination visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 30
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 30
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    paediatric patients
    F.4 Planned number of subjects to be included
    F.4.1In the member state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 30
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After a subject has completed the trial or has withdrawn prematurely, standard treatment for PKU should be continued in accordance with the trial site’s standard-of-care and generally-accepted medical practices and depending on the subject’s individual medical needs. Subjects may continue to receive Kuvan® treatment post-study if prescribed by a physician in a country where the drug has marketing authorization and is commercially available.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-07-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-01-26
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