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    Summary
    EudraCT Number:2009-018168-81
    Sponsor's Protocol Code Number:EMR-700773-503
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-03-03
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2009-018168-81
    A.3Full title of the trial
    ENDURE: A Phase IV, prospective, open-label, uncontrolled, multi-centre cohort trial to assess the responsiveness of subjects with phenylketonuria (PKU) to treatment with Kuvan® 20 mg/kg/day for 28 days
    A.3.2Name or abbreviated title of the trial where available
    ENDURE
    A.4.1Sponsor's protocol code numberEMR-700773-503
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck Serono Norway
    B.1.3.4CountryNorway
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 holderMerck Serono Europe Limited, London
    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 number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Soluble tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNSapropterindihydrochloride
    D.3.9.1CAS number 69056-38-8
    D.3.9.3Other descriptive nameSAPROPTERIN HYDROCHLORIDE
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typeA synthetic formulation of tetrahydrobiopterin (BH4), a natural cofactor essential for the hydroxylation of the amino acid phenylalanine (Phe) into tyrosine.
    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
    Subjects diagnosed with Phenylketonuria (PKU) (classic or mild PKU, or mild hyperphenylalaninaemia (HPA)).
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10034873
    E.1.2Term Phenylketonuria (PKU)
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    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 the study is to evaluate the proportion of responders (≥30% reduction from baseline in blood Phe level) to 20 mg/kg/day Sapropterin dihydrochloride treatment at several time points during 28 +/- 1 days.
    E.2.2Secondary objectives of the trial
    The secondary endpoints include:
     To assess the overall safety of a 4 weeks testing period of Kuvan® 20mg/kg/day in patients not responding early
     To evaluate the proportion of early, late, partial responders and non-responders
     To evaluate genetic PAH mutations associated with certain traits, i.e. response, adverse events,
     To identify subtypes of patients (disease severity, age) associated with the types of response (early/late/partial/non responder)
     To assess the blood phenylalanine-to-tyrosine ratio during a 4 weeks testing period of Kuvan® 20mg/kg/day
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •aged 4 years or older at the time the informed consent is obtained
    •diagnosed with PKU (subgroups defined as: classic PKU [blood Phe >1200 µmol/L], mild PKU [blood Phe 600–1200 µmol/L] or mild HPA [blood Phe 300–600 µmol/L]
    •have received no previous treatment with sapropterin dihydrochloride (either Kuvan® or any other formulations of tetrahydrobiopterin)
    •adherent to their normal diet and willing to adhere to the given diet for the 4 week study period
    •Provide a signed (by parent if below 18 years) written informed consent.
    •Documented genotyping for both PAH mutations (PKU genotype)
    •PKU diagnosis should be documented with at least two historical blood Phe levels above 400 µmol/L
    E.4Principal exclusion criteria
    •have documented BH4 deficiency
    •have any contraindications to receive Kuvan® as outlined in the SmPC not willing or able to comply with the study procedures
    •be pregnant, planning pregnancy or breastfeeding
    •have been exposed to any investigational medicinal drugs or treatments within 30 days or 5 half lives, whichever is longer, prior to the screening visit
    •using concomitant treatment with folate synthesis inhibiting drugs
    •concurrent use of Levodopa
    •concurrent use of inhibitors of dihydrofolate reductase (e.g. methotrexate, trimethoprim)
    •concurrent use of agents that cause vasodilation, including those administered topically, by affecting nitric oxide (NO) metabolism or action including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomin), phosphodistrerase type 5 (PDE-5) inhibitors and monoxidil
    •have a concurrent disease potentially interfering safety (e.g. seizure disorder, oral steroid dependent asthma, other conditions requiring systemic corticosteroids, or insulin-dependent diabetes mellitus)
    •have inadequate liver function, defined by alanine aminotransferase (ALT)  2 x upper limit of normal (ULN)
    •have clinically significant renal dysfunction, defined by serum creatinine > 250 µmol/l
    •Have any medical condition that, in the judgment of the investigator, would jeopardize the patient’s safety following exposure to study drug or would significantly interfere with the patient’s ability to comply with the provisions of this protocol
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this trial is the proportion of subjects with at least 30% reduction from baseline in blood Phe level (responders) in any blood sample during the 28 +/- 1 days treatment with 20 mg/kg/day Kuvan®.
    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 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 Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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 Information not present in EudraCT
    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
    For administrative and safety reporting purposes the end of the trial will be defined as the date of the follow-up visit of the last subject.
    (See section 10.1.6 in the protocol).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Yes
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 Yes
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients from 4 years can be included in the study.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 70
    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 Decision2010-04-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-03-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-05-02
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