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    Summary
    EudraCT Number:2017-004834-26
    Sponsor's Protocol Code Number:2017-12
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-03-29
    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 number2017-004834-26
    A.3Full title of the trial
    Influence of dose interval on the pharmacokinetics of both unbound and
    total fractions of clozapine and norclozapine in psychiatric patients in the
    Netherlands
    Wat is de invloed van de doseerfrequentie op de farmacokinetiek van zowel
    vrije als totale concentraties clozapine en norclozapine in psychiatrische
    patienten in Nederland.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    What is the influence on the amount of clozapine in a patient's blood when
    clozapine is used once daily instead of twice daily?
    Wat is het effect op de hoeveelheid clozapine in het bloed als clozapine één
    keer per dag wordt gebruikt in plaats van twee keer per dag?
    A.3.2Name or abbreviated title of the trial where available
    INPUT study
    INPUT studie
    A.4.1Sponsor's protocol code number2017-12
    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 SponsorAlbert Schweitzer hospital
    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 supportScientific committee of the Albert Schweitzer hospital
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlbert Schweitzer hospital
    B.5.2Functional name of contact pointM.M. Beex-Oosterhuis, PharmD
    B.5.3 Address:
    B.5.3.1Street AddressAlbert Schweitzerplaats 25
    B.5.3.2Town/ cityDordrecht
    B.5.3.3Post code3318 AT
    B.5.3.4CountryNetherlands
    B.5.6E-mailm.oosterhuis@asz.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 clozapine
    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
    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 INNclozapine
    D.3.9.1CAS number 5786-21-0
    D.3.9.3Other descriptive nameCLOZAPINE
    D.3.9.4EV Substance CodeSUB06787MIG
    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
    Schizophrenia
    Schizofrenie
    E.1.1.1Medical condition in easily understood language
    Schizophrenia
    Schizofrenie
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Mental Disorders [F03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLGT
    E.1.2Classification code 10039628
    E.1.2Term Schizophrenia and other psychotic disorders
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aim of this study is to assess the differences in the pharmacokinetic properties of clozapine and norclozapine when clozapine is used OID or BID in psychiatric patients, examining both clozapine and norclozapine concentrations and its unbound fractions and total concentrations. Ultimately, the knowledge of the full pharmacokinetic profile will facilitate in developing an evidence based therapeutic window for clozapine when used OID.
    Het doel van dit onderzoek is om de farmacokinetiek van vrije en totale concentraties van clozapine en norclozapine te vergelijken bij eenmaaldaags en tweemaaldaags gebruik door psychiatrische patienten in Nederland. Kennis van het farmacokinetisch profiel bij beide doseerregimes ondersteunt het opstellen van een evidence based therapeutisch venster voor patienten die clozapine eenmaaldaags gebruiken.
    E.2.2Secondary objectives of the trial
    We will explore the influence of dose frequency on the frequency or discomfort of clozapine’s side effects using the self-rating version of the Udvalg for Kliniske Undersøgelser Side Effects Rating Scale (UKU-SERS-Pat).
    Aan de hand van een vragenlijst (patiëntversie van de Udvalg for Kliniske Undersøgelser Side Effects Rating Scale (UKUS-SERS-Pat)) wordt de frequentie en last van bijwerkingen bij eenmaaldaags gebruik van clozapine vergeleken met tweemaaldaags gebruik.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
     Age ≥18 – 65 years
     Clozapine use BID or OID
     Capacity to speak and read the Dutch language.
     Mental competency and decisional capacity with regard to participation in the current study
     Absence of active suicidality
     Clozapine use in ‘steady state’ (i.e. same dose and frequency for ≥7 days)
     Signed Informed consent
    Leeftijd ≥18 – 65 jaar
    Clozapinegebruik eenmaaldaags of tweemaaldaags
    Vermogen om de Nederlandse taal te spreken en te lezen
    Wilsbekwaamheid met betrekking tot gedegen afweging om wel of niet deel te nemen aan de studie
    Geen actieve suicidaliteit / doodswens
    Clozapine gebruik in ‘steady state’ (i.e. patient gebruikt huidige dosering en doseerfrequentie gedurende minimaal 7 dagen)
    Informed consent getekend
    E.4Principal exclusion criteria
     ‘inbewaringstelling’ (IBS)
     ‘rechterlijke machtiging’ (RM)
     Pregnancy (if known)
     Initiation, cessation or dose change of the following co-medication within 7 days prior to blood sampling:
    o Fluvoxamine
    o Hormonal anti-conceptive,
    o Ciprofloxacin,
    o Phenytoin,
    o Valproic acid,
    o Carbamazepine
    o Rifampicin.
     Acute inflammation / infection (derived from having fever (i.e. body temperature >38.0 degrees Celsius and/or using an antibiotic at time of blood sampling).
     Smoking (of tobacco containing products) initiation or cessation < 7 days before participation
     inbewaringstelling (IBS)
     rechterlijke machtiging (RM)
     zwangerschap (indien bekend)
     Start, stop of doseringswijziging van de volgende co-medicatie binnen 7 dagen voor bloedafname:
    o Fluvoxamine
    o Hormonale anti-conceptie,
    o Ciprofloxacine,
    o Fenytoine,
    o Valproinezuur
    o Carbamazepine
    o Rifampicine.
     Acute ontsteking / infectie (afgeleid van temp >38 graden Celsius of gebruik van antiibiotica t.t.v. de studiedag)
     Stoppen met roken < 7 days voor aanvang van de studiedag
    E.5 End points
    E.5.1Primary end point(s)
    The main study parameters are the total and unbound clozapine and norclozapine plasma concentrations at specified time points. With these concentrations characterised pharmacokinetic profiles as well as metabolic ratio and protein binding of clozapine and norclozapine in OID and BID dosing regimens, will be determined.
    De onderzochte eindpunten zijn de totale en vrije plasma concentraties van clozapine en norclozapine op verschillende tijdstippen na inname van clozapine. Aan de hand van deze concentraties kunnen zowel de farmacokinetische profielen van clozapine en norclozapine in kaart gebracht worden bij eenmaaldaags gebruik, vergeleken met tweemaaldaags gebruik, als ook de metabole ratio en eiwitbinding.
    E.5.1.1Timepoint(s) of evaluation of this end point
    • T = 0 hours (just before clozapine intake) = trough concentration
    • T = 30 minutes = absorption phase begins
    • T = 2 hours and 4 hours = maximum concentration (Cmax) is expected to be reached after 1-3 hours
    • T = 8 hours = for BID dosing, this time point will be on the slope between the Cmax and the trough concentration
    • T = 12 hours = for OID dosing, this time point will be halfway the concentration time curve; for BID dosing, the concentration at t=12 hours is expected to be equal to the concentration at t= 0 hours (trough concentration).
    • T = 0 uur (vlak voor inname van clozapine) = 'dalspiegel'
    • T = 30 minuten = absorptie fase begint
    • T = 2 uur en 4 uur = maximum concentratie (Cmax) wordt verwacht na 1-3 uur na inname
    • T = 8 uur = voor 2 maal daags doseren bevindt dit tijdstip zich halverwege de dalende helling van de concentratietijdcurve, tussen de Cmax en de dalspiegel
    • T = 12 uur = voor 1 maal daags doseren bevindt dit tijdstip zich halverwege de dalende helling van de concentratietijdcurve, tussen de Cmax en de dalspiegel
    E.5.2Secondary end point(s)
    The frequency or discomfort of clozapine’s side effects using the self-rating version of the Udvalg for Kliniske Undersøgelser Side Effects Rating Scale (UKU-SERS-Pat) will also be assembled.
    De frequentie en mate van discomfort van bijwerkingen door clozapine worden eenmalig in kaart gebracht tijdens de onderzoeksdag door gebruik te maken van de patientversie van de Udvalg for Kliniske Undersøgelser Side Effects Rating Scale (UKU-SERS-Pat)
    E.5.2.1Timepoint(s) of evaluation of this end point
    The frequency or discomfort of clozapine’s side effects using the self-rating version of the Udvalg for Kliniske Undersøgelser Side Effects Rating Scale (UKU-SERS-Pat) will be assembled once during the study day.
    De frequentie en mate van discomfort van bijwerkingen door clozapine worden eenmalig in kaart gebracht tijdens de onderzoeksdag door gebruik te maken van de patientversie van de Udvalg for Kliniske Undersøgelser Side Effects Rating Scale (UKU-SERS-Pat)
    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 Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    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 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 concerned2
    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 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
    last visit of the last subject
    laatste studiedag van de 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 months0
    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 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    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 No
    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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    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)
    None
    Geen
    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 Decision2018-03-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-05
    P. End of Trial
    P.End of Trial StatusOngoing
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