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The European Union Clinical Trials Register allows you to search for protocol and results information on:
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    The EU Clinical Trials Register currently displays   42771   clinical trials with a EudraCT protocol, of which   7044   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


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    Summary
    EudraCT Number:2009-015768-33
    Sponsor's Protocol Code Number:BMN162-503
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-11-04
    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 ConcernedGermany - BfArM
    A.2EudraCT number2009-015768-33
    A.3Full title of the trial
    A Phase IIIb, Multicentre, Open-Label, Randomized, Controlled Study of the Efficacy, Safety, and Population Pharmacokinetics of Sapropterin Dihydrochloride (Kuvan®) in Phenylketonuria (PKU) Patients <4 Years Old
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety Paediatric efficAcy phaRmacokinetic with Kuvan®
    A.3.2Name or abbreviated title of the trial where available
    SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®)
    A.4.1Sponsor's protocol code numberBMN162-503
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01376908
    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 pointIgnacio Alvarez, MD
    B.5.3 Address:
    B.5.3.1Street AddressShanbally, Ringaskiddy
    B.5.3.2Town/ cityCounty Cork
    B.5.3.4CountryIreland
    B.5.4Telephone number+34610174155
    B.5.6E-mailIgnacio.Alvarez@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 nameSapropterin Dihydrocholoride
    D.3.2Product code NAP
    D.3.4Pharmaceutical form Soluble tablet
    D.3.4.1Specific paediatric formulation Yes
    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 62989337
    D.3.9.3Other descriptive nametetrahydrobiopterin
    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
    Phenylketonuria
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    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
    1.Evaluate the efficacy after 26 weeks of Kuvan® treatment + Phe-restricted diet therapy in increasing dietary Phe tolerance, as compared to dietary therapy alone in <4 year-old infants and children with phenylketonuria (PKU). Phe tolerance will be defined as the amount of dietary Phe (mg/kg/day) ingested while maintaining blood Phe levels within the range of 120-360 μmol/L (defined as ≥120 to < 360 μmol/L).
    2.Evaluate the safety after 26 weeks of Kuvan® treatment in <4 year-old infants and children with PKU.
    3.Evaluate BH4 (tetrahydrobiopterin; sapropterin) blood levels via scheduled PopPK samplings.
    E.2.2Secondary objectives of the trial
    1.Evaluate blood Phe levels for all subjects during the 26-week Study Period.
    2.Evaluate the effectiveness of Kuvan® treatment in increasing dietary Phe tolerance, as compared to pre-Kuvan® treatment during the 26-week Study Period in <4 year-old infants and children with PKU.
    3.Assess neurodevelopmental function during Kuvan® treatment, as compared to dietary treatment alone, during the 26-week Study Period in <4 year-old infants and children with PKU.
    4.Assess potential effects on blood pressure during the 26-weeks Study Period and the 3-year Extension Period.
    5.Assess potential effects on growth during the 26-weeks Study Period and the 3-year Extension Period.
    6.Evaluate long-term safety, neurodevelopmental outcomes, dietary Phe tolerance, and blood Phe levels in the 3-year Extension Period.
    7.Investigate in BH4-responsive individuals the predictive value of the phenylalanine hydroxylase (PAH) genotype.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Male or female PKU infants and young children <4 years of age at the scheduled Day 1 visit of the 26-week Study Period (taking into consideration the maximum of 42 days in the Screening Period).
    2.At least two previous blood Phe levels ≥ 400 μmol/L obtained on 2 separate occasions.
    3.Previously responded, as assessed by the Investigator, to a BH4 test, if all 3 of the following criteria are satisfied:
    a.The BH4 dose was 20 mg/kg/day;
    b.The duration of the test was at least for 24 hours; and
    c.A 30% decrease in blood Phe levels.
    NOTE: If a patient has not undergone a BH4 test prior to Screening, such a test must be performed, (Please refer to the note , section 7.1.1 bullet point #7).
    4.Defined level of dietary Phe tolerance consistent with the diagnosis of PKU;
    5.Good adherence to dietary treatment, including prescribed dietary Phe restriction and prescribed amounts of Phe-free protein supplements and low-Phe foods.
    6.Maintenance of blood Phe levels within the therapeutic target range of 120-360 μmol/L (defined as ≥120 to <360 μmol/L) over a 4-month period prior to Screening, as assessed by the Investigator. At least, the last 4 values of phenylalanine (either from venous blood or dry blood spot) should be assessed, out of which 75% should be within the above therapeutic range.
    7.Parent(s) and/or guardian(s) willing to comply with all study procedures, maintain strict adherence to the diet, and willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any study procedures.
    E.4Principal exclusion criteria
    1.Use of Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin within the previous 30 days, unless for the purposes of a BH4 responsiveness test.
    2.Previous exposure to Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin for >30 days.
    3.Known hypersensitivity to Kuvan® or its excipients.
    4.Known hypersensitivity to other approved or non-approved formulations of tetrahydrobiopterin.
    5.Previous diagnosis of BH4 deficiency.
    6.Current use of methotrexate, trimethoprim, or other dihydrofolate reductase inhibitors.
    7.Current use of medications that are known to affect nitric oxide synthesis, metabolism or action.
    8.Current use of levodopa.
    9.Current use of experimental or unregistered drugs that may affect the study outcomes.
    10.Inability to comply with study procedures.
    11.Inability to tolerate oral intake.
    12.History of organ transplantation.
    13.Concurrent disease or condition that would interfere with study participation or increase the risk for adverse events, including seizure disorders, corticosteroid administration, active malignancy, diabetes mellitus, severe congenital heart disease, renal or hepatic failure.
    14.Other significant disease that in the Investigator’s opinion would exclude the subject from the trial.
    15.Any condition that, in the view of the Principal Investigator renders the subject at high risk for failure to comply with treatment or to complete the study.
    E.5 End points
    E.5.1Primary end point(s)
    Dietary Phe tolerance after 26 weeks (6 months) of treatment with Kuvan® + a Phe-restricted diet, as compared to just a Phe-restricted diet alone.
    E.5.1.1Timepoint(s) of evaluation of this end point
    26 weeks (6 months)
    E.5.2Secondary end point(s)
    -Levels of blood Phe during the 26-week Study Period and the 3-year Extension Period.
    -Change from Baseline (prior to enrolment) in dietary Phe tolerance after 26 weeks (6 months)
    -treatment with Kuvan® + a Phe-restricted diet vs. just a Phe-restricted diet.
    -Dietary Phe tolerance during the 3-year Extension Period.
    -Blood pressure during the 26-week Study Period and the 3-year Extension Period.
    -Growth parameters (length or height, weight, and maximum occipital-frontal head
    circumference) during the 26-week Study Period and the 3-year Extension Period.
    -Neuromotor developmental milestones and standardized neurodevelopment test results during the 26-week Study Period and the 3-year Extension Period.
    -Safety, including attention to age group-specific safety concerns:
    -Nature, incidence, and severity of adverse events;
    -Long-term safety for patients enrolled into the Extension Period.
    -Incidence of hypophenylalaninemia (blood Phe <120 μmol/L);
    -Changes from baseline in vital signs and clinical laboratory parameters.
    Population PK endpoints will include:
    -CL/f (apparent clearance);
    -V/f (apparent volume of distribution);
    -AUC0-∞ (area under the plasma concentration curve, time 0 to infinity);
    -Cmax (maximum observed plasma concentration);
    -Tmax (time to maximum plasma concentration); and
    -t1/2 (terminal elimination half-life).
    -PAH genotype.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of study part (26 weeks) or at the end of the extension period
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3.1Comparator description
    diet only
    E.8.2.4Number of treatment arms in the trial2
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Turkey
    E.8.7Trial has a data monitoring committee Yes
    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
    •all enrolled subjects who have received at least one dose of study drug have completed all scheduled visits
    •follow-up of all subjects with ongoing adverse events at the conclusion of treatment has been addressed
    •site monitoring visits to resolve any outstanding data discrepancy issues have been completed for all participating centres
    •the database has been locked
    •all sites have undergone a final site closure/study termination visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days8
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    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: 56
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 33
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 23
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 less than four years of age
    F.4 Planned number of subjects to be included
    F.4.1In the member state17
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 51
    F.4.2.2In the whole clinical trial 56
    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)
    The investigator is responsible to plan the treatment of care for the subject after they have ended their participation in the trial
    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 Decision2011-04-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-05-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-02-17
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