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    Summary
    EudraCT Number:2012-000992-18
    Sponsor's Protocol Code Number:12-016
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-01-28
    Trial 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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2012-000992-18
    A.3Full title of the trial
    Proactive versus reactive inhibition in ADHD: Genetics, neurobiology and pharmacology
    Proactieve versus reactieve inhibitie bij ADHD:
    Genetica, neurobiologie en farmacologie

    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Proactive versus reactive inhibition in ADHD
    Proactieve versus reactieve inhibitie in ADHD
    A.3.2Name or abbreviated title of the trial where available
    Proactive versus reactive inhibition in ADHD
    Proactieve versus reactieve inhibitie in ADHD
    A.4.1Sponsor's protocol code number12-016
    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 SponsorUMC Utrecht
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUtrecht University
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUMC Utrecht
    B.5.2Functional name of contact points.durston@umcutrecht.nl
    B.5.3 Address:
    B.5.3.1Street AddressHeidelberglaan 100
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3584 CX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031887558161
    B.5.5Fax number0031887555487
    B.5.6E-mails.durston@umcutrecht.nl
    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 Ritalin
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharma B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form 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 INNMETHYLPHENIDATE HYDROCHLORIDE
    D.3.9.1CAS number 298-59-9
    D.3.9.4EV Substance CodeSUB03254MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 60
    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
    Attention-Deficit Hyperactivity Disorder (ADHD)
    Attention-Deficit Hyperactivity Disorder (ADHD)
    E.1.1.1Medical condition in easily understood language
    Children that suffer from some combination of hyperactivity, impulsivity, and/or inattention.
    ADHD is ook wel bekend als 'Alle Dagen Heel Druk'; kinderen met ADHD lijden aan een combinatie van hyperactiviteit, impulsiviteit en/of aandachtsproblemen.
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Psychological processes [F02]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main hypothesis we aim to address is that there are two mechanisms involved in behavioural control in ADHD, one
    proactive mechanism, regulated by DAT function in fronto-striatal networks, and one reactive mechanism regulated by
    COMT function in prefrontal cortex (SFG).
    Objective of the study:
    To address these research questions, this study has three primary and two secondary objectives.
    Primary Objectives:
    1.1) Investigate differences in stop-ERP between good and poor responders to methylphenidate
    1.2) Investigate differences in brain activation using fMRI between good and poor responders to methylphenidate
    1.3) Investigate differences in the prevalence of DAT1 and COMT polymorphism between good and poor responders to
    methylphenidate
    Het doel van het onderzoek is,naar aanleiding van genoemd theoretisch kader, om te onderzoeken of twee
    kandidaat-genen in combinatie met EEG en fMRI markers verschillen tussen kinderen met ADHD die wel en niet
    klinisch responderen op MPH.
    De primaire uitkomstmaten van deze studie zijn:
    1.) Stop-ERP verschillen tussen kinderen die wel en niet klinisch responderen op methylfenidaat.
    2.) Verschillen in hersenactivatie tussen kinderen die wel en niet klinisch responderen op methylfenidaat.
    3.) De prevalentie van de DAT1 en COMT polymorfismes tussen kinderen die wel en niet klinisch responderen op
    methylfenidaat.
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    2.1) Investigate differences in the coherence of brain activity from EEG signal
    2.2) Investigate differences in connectivity between striatum/IFG/SFG from resting state fMRI signal
    De secondaire uitkomstmaten van deze studie zijn:
    1) Verschillen in coherentie van hersenactiviteit in EEG signaal tussen kinderen die wel en niet klinisch responderen op
    methylfenidaat.
    2) Verschillen in connectiviteit tussen het striatum/ IFG/SFG in resting state fMRI activiteit tussen kinderen die wel en
    niet klinisch responderen op methylfenidaat.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Children diagnosed with ADHD according to DSM IV criteria
    Age between 8-16
    Willing to discontinue methylphenidate 48 hours before testing
    IQ above 75
    Kinderen met de diagnose ADHD volgens DSM IV criteria
    leeftijd tussen 8-16 jaar
    Bereid om inname medicatie Methylfenidaat te staken 48 uur voor deelname onderzoek
    IQ score hoger dan 75
    E.4Principal exclusion criteria
    History of or present neurological disorder
    One or more of the following comorbid disorders are diagnosed: generalized anxiety disorder, depression, tics,
    psychosis or autism
    IQ below 75
    Het lijden aan een neurologische stoornis, in verleden dan wel heden.
    Diagnose van een van de volgende stoornissen: gegeneraliseerde angst stoornis, depressie, tics, psychose of
    autisme
    IQ score onder 75.
    E.5 End points
    E.5.1Primary end point(s)
    (1) Stop-associated ERP measures at baseline (N1 and P3)
    (2) Stop-associated fMRI measures at baseline (activitity in IFG an SFG)
    (3) DAT1 and COMT genotype
    (1) Stop-gerelateerde ERP meting als baseline (N1 en P3)
    (2) Stop-gerelateerde fMRI meting als baseline (activiteit in IFG en SFG)
    (3) genotypering voor DAT1 en COMT.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After inclusion of enough participants to detect differences between responders and non-responders on at least one of the primary endpoints :estimated te be after inclusion of 80 subjects.
    Wanneer er genoeg deelnemers zijn geïncludeerd in de studie om een onderscheid te kunnen maken tussen responders en niet-responders, op ten minste een van de drie uitkomstmaten: dit ligt naar schatting op een aantal van 80 geïncludeerde deelnemers.
    E.5.2Secondary end point(s)
    (1) Coherence of brain activity from EEG
    (2) Connectivity between IFG and SFG from RS-MRI

    (1) Coherentie van hersenactiviteit gemeten met EEG.
    (2) connectiviteit tussen de IFG en SFG gemetenmet RS-fMRI.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At same time as evaluation of primary endpoints.
    Tegelijk met de evaluatie van de primaire uitkomstmaten.
    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 No
    E.6.4Safety No
    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 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 No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    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 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
    LVLS
    Laatste bezoek laatste deelnemer.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned 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: 80
    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: 36
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 44
    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
    minors
    kinderen jonger dan 18 jaar
    F.4 Planned number of subjects to be included
    F.4.1In the member state80
    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 the visits to the UMC Utrecht parents and subjects will receive a personal report containing results of the IQ-tests and a brain image from the MRI-scan.
    Na deelname ontvangen deelnemers en hun ouders een persoonlijk verslag met de uitkomst van de IQ test alsmede een foto van de MRI scan.
    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 Decision2014-09-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-06-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-11-04
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