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    Summary
    EudraCT Number:2011-003466-33
    Sponsor's Protocol Code Number:1103-011
    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:2013-01-29
    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 number2011-003466-33
    A.3Full title of the trial
    Memantine Add-On Therapy to Clozapine
    Memantine als additietherapie bij clozapine
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Memantine as an adjunctive therapy to ongoing clozapine treatment: a proof-of-concept study
    Memantine toevoeging bij voortgezette behandeling met clozapine: een studie om het concept te bewijzen
    A.3.2Name or abbreviated title of the trial where available
    MAOTC
    MAC
    A.4.1Sponsor's protocol code number1103-011
    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 SponsorMental Health Services North Holland North
    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 supportMental Health Services North Holland North
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMental Health Services North Holland North
    B.5.2Functional name of contact pointSelene Veerman, MD
    B.5.3 Address:
    B.5.3.1Street AddressRhijnvis Feithlaan 150C
    B.5.3.2Town/ cityAlkmaar
    B.5.3.3Post code1813 KV
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31725357560
    B.5.5Fax number+31725408471
    B.5.6E-mails.veerman@ggz-nhn.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 Ebixa
    D.2.1.1.2Name of the Marketing Authorisation holderH. Lundbeck A/S
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMemantine hydrochloride
    D.3.2Product code EU/1/02/219/023
    D.3.4Pharmaceutical form Film-coated 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 INNMemantine hydrochloride
    D.3.9.1CAS number S 10102-43-9
    D.3.9.2Current sponsor codeUnknown
    D.3.9.3Other descriptive nameEbixa
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Cognitive functioning, severity of psychopathology and treatment response (positive symptoms and negative symptoms of schizophrenia), depressive symptoms, social cognition, obsessive-compulsive symptoms, psychosocial functioning, quality of life and adverse effects in outpatients with refractory schizophrenia and a nonsatisfactory response to clozapine (duration of adequate clozapine treatment at least six months).
    Cognitief functioneren, ernst van psychopathologie en behandelrespons (positieve symptomen en negatieve symptomen van schizofrenie), depressieve symptomen, sociale cognitie, obsessief-compulsieve symptomen, psychosociaal functioneren, kwaliteit van leven en bijwerkingen bij ambulante patiënten met therapieresistente schizofrenie en onvoldoende respons na minimaal 6 maanden adquate behandeling met clozapine.
    E.1.1.1Medical condition in easily understood language
    Cognitive function, severity of psychopathology, depressive symptoms, obsessive-compulsive symptoms, social outcome and adverse effects in ambulatory patients with clozapine-resistant schizophrenia.
    Cognitieve functie, ernst van psychopathologie, depressieve symptomen, obsessief-compulsieve symptomen, sociale uitkomst en bijwerkingen bij ambulante patiënten met clozapineresistente 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 17.1
    E.1.2Level PT
    E.1.2Classification code 10039626
    E.1.2Term Schizophrenia
    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
    1. Is memantine efficacious as an adjunctive treatment to clozapine in patients with refractory schizophrenia to improve cognitive impairment?
    2. Does memantine in combination with clozapine diminish the severity of psychopathology, positive and negative symptoms?
    1.Is memantine een effectieve clozapine augmentatiestrategie bij therapieresistente schizofrenie om cognitieve disfuncties te verbeteren?
    2. Heeft de combinatiebehandeling van memantine en clozapine een gunstig effect op de ernst van de psychopathologie, negatieve en positieve symptomen van schizofrenie?
    E.2.2Secondary objectives of the trial
    1. Does memantine have a beneficial effect on depressive symptoms?
    2. Does memantine add-on therapy to clozapine have a beneficial effect on social cognition?
    3. Does memantine improve obsessive-compulsive symptoms?
    4. Are there differences in efficacy and tolerability of clozapine treatment combined with memantine compared to clozapine treatment in combination with placebo in other areas of clinical outcome: psychosocial functioning, quality of life and dropout rate?
    1. Heeft memantine een gunstig effect op depressieve symptomen?
    2. Heeft de additie van memantine aan clozapine een gunstig effect op sociale cognitie?
    3. Verbetert memantine obsessief-compulsieve symptomen?
    4. Bestaan verschillen in de werkzaamheid en verdraagbaarheid van clozapinebehandeling gecombineerd met memantine, vergeleken met clozapinebehandeling met placebo, betreffende andere klinische uitkomstmaten, zoals psychosociaal functioneren, kwaliteit van leven en uitvalspercentage uit de studie?
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Eligible for the study are outpatients, both sexes, age 18 to 60, meeting DSM-IV criteria for schizophrenia, based on the definitions in the Mini International Neuropsychiatric Interview Plus (MINI-Plus) with persistent residual psychopathology, failing to achieve the remission criteria, after adequate treatment with clozapine for at least 6 months. Before the start of the study clozapine plasma concentration has been at least 350 ng/ml for 12 weeks or has not reached 350 ng/ml due to intolerability. Remission defined as simultaneous ratings of mild or less (≤ 3 points) on 8 of the PANSS items evaluating the core symptoms of schizophrenia (P1 delusions, G9 unusual thought content, P3 hallucinatory behaviour, P2 conceptual disorganisation, G5 mannerisms and posturing, N1 blunted affect, N4 passive or apathetic social withdrawal, N6 lack of spontaneity and flow of conversation) (Os van and Kahn, 2007). Patients should be able to understand the study information and procedures and give informed consent. All participants fulfilling the inclusion and not fulfilling the exclusion criteria may, after a detailed description by a doctor and the written declaration of informed consent on an according form, participate in the study.
    Voor de studie komen in aanmerking ambulante patiënten, zowel mannen als vrouwen, die voldoen aan de criteria voor schizofrenie volgens de MINI-Plus met persistende pathologie, terwijl niet wordt voldaan aan de remissie criteria, waarbij gelijktijdig met drie of lager wordt gescoord op 8 items van de PANSS, die de kernsymptomen beschrijven van schizofrenie (P1 waanvoorstellingen, G9 ongewone gedachte-inhoud, P3 hallucinatoir gedrag, P 2 conceptuele desorganisatie, G5 maniërisme en poses, N1 afgestompt gevoel, N4 passieve/apathische sociale teruggetrokkenheid, N6 gebrek aan spontaneïteit en conversabiliteit) (Os van and Kahn, 2007). Voor de studie komt in aanmerking een patiënt, die onvoldoende effect heeft van clozapine (duur van clozapine behandeling minimaal 6 maanden, voorafgaande aan de start van de studie is de clozapine plasma spiegel 350 ng/ml gedurende minimaal 12 weken geweest of onder deze grenswaarde gebleven vanwege onverdraagbaarheid). De patiënt dient de informatie en procedures omtrent de studie te begrijpen en informed consent te geven. Alle participanten, die voldoen aan de inclusiecriteria en niet aan de exclusiecriteria mogen, na een gedetailleerde omschrijving door een arts en een schriftelijke verklaring van informed consent, deelnemen aan de studie.
    E.4Principal exclusion criteria
    - Pregnancy.
    - Lactating women.
    - Female subjects without adequate contraception.
    - Known hypersensitivity to memantine or ingredients used in this tablet.
    - Uncontrolled epilepsy.
    - Recent myocardial infarction.
    - Uncontrolled hypertension.
    - Renal insufficiency (GFR < 30 ml/min).
    - Severe liver failure (ASAT 175 U/l and/or ALAT 225 U/l in men and 175 U/l in women).
    - Lactose intolerance.
    - Co-medication with NMDA-antagonists such as amantadine, ketamine, dextromethorphan.
    - Co-medication with glutamate antagonists such as lamotrigine and topiramate.
    - Extremely ill patients (Global Assessment of Functioning [GAF] ≤ 20), who are not reliably able to give their informed consent.
    - Moderate or severe Alzheimer’s disease.
    - Zwangerschap.
    - Lacterende vrouwen.
    - Vrouwen zonder adequate anticonceptie.
    - Bekende hypersensitiveit voor memantine of ingrediënten van deze tablet.
    - Ongecontroleerde epilepsie.
    - Recent myocard infarct.
    - Ongecontroleerde hypertensie.
    - Nierinsufficiëntie (GFR < 30 ml/min).
    - Ernstige leverfunctiestoornissen (ASAT 175 U/l en/of ALAT 225 U/l bij mannen en 175 U/l bij vrouwen).
    - Comedicatie met NMDA-antagonisten zoals amantadine, ketamine, dextromethorphan.
    - Comedicatie met glutamaatantagonisten zoals lamotrigine en topiramaat.
    - Ernstig zieke patienten (GAF ≤ 20), die niet wilsbekwaam zijn en geen informed consent kunnen geven op betrouwbare wijze.
    - Matige tot ernstige ziekte van Alzheimer.
    E.5 End points
    E.5.1Primary end point(s)
    a. Cognitive functioning will be assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB), an outstandingly sensitive and extensively validated cognitive testing battery. The tests are computerized, non-linguistic and culturally blind, consisting of 9 tests:
    1. Motor screening (MOT) (3 minutes);
    2. Verbal Recognition Memory (VRM)-immediate (20 minutes);
    3. Rapid Visual Information Processing (RVP) (7 minutes);
    4. Intra/ Extradimensional Set Shifting (IED) (7 minutes);
    5. Reaction Time: Simple and 5 Choice (RTI) (5 minutes);
    6. Verbal Recognition Memory (VRM)-delayed;
    7. One Touch Stockings of Cambridge (OTS) (10 minutes);
    8. Paired Associates Learning (PAL) (7 minutes);
    9. Spatial Working Memory (SWM) (8 minutes).

    b. Severity of psychopathology and treatment response:
    1. Clinical Global Impression Severity Scale (CGI-S), a 7-point scale that requires the clinician to rate the severity of the patient's psychiatric illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis (Guy, 1976).

    2. Subscale for positive symptoms of the Positive And Negative Syndrome Scale, based on a semi-structured interview (SCI-PANSS). The PANSS is a validated measure and it is the most widely used scale to assess the symptoms of schizophrenia. This 30-item rating scale is designed to measure severity of psychopathology, reporting five components: positive, negative, depression, agitation-excitement and disorganisation (Kay et al 1987). The administration time of the SCI-PANSS is approximately 30 to 40 minutes.
    3. Subscale for negative symptoms of the Positive And Negative Syndrome Scale, (SCI-PANSS).
    a. Cognitief functioneren zal worden onderzocht met behulp van de Cambridge Neuropsychological Test Automated Battery (CANTAB), een uitstekend sensitieve en uitvoerig gevalideerde cognitieve testbatterij. De testen zijn geautomatiseerd, Windowsgebaseerd, nonlinguiïstisch, cultureel blind en omvatten tal van non-verbale functies. Deze CANTAB bestaat uit 9 testonderdelen:
    1. Motor screening (MOT) (inductie) (3 minuten);
    2. Verbal Recognition Memory (VRM)-immediate (semantisch / verbaal geheugen) (20 minuten);
    3. Rapid Visual Information Processing (RVP) (aandacht) (7 minuten);
    4. Intra/ Extradimensional Set Shifting (IED) (executieve functie) (7 minuten);
    5. Reaction Time: Simple and 5 Choice (RTI) (aandacht) (5 minuten);
    6. Verbal Recognition Memory (VRM)- delayed (sematisch / verbaal geheugen);
    7. One Touch Stockings of Cambridge (OTS) (executieve functie) (10 minuten);
    8. Paired Associates Learning (PAL) (visueel geheugen) (7 minuten);
    9. Spatial Working Memory (SWM) (executieve functie) (8 minuten).


    b. Ernst van psychopathologie en behandelrespons:
    1. Clinical Global Impression Severity Scale (CGI-S), een 7-puntsschaal waarbij de onderzoeker de ernst van de symptomen van de psychiatrische ziekte scoort op basis van ervaring met patiënten met deze psychiatrische stoornis.

    2. Subschalen van positieve symptomen van de Positive And Negative Syndrome Scale, gebaseerd op een semigestructureerd interview (SCI-PANSS) met een afname duur van circa 30 tot 40 minuten. De PANSS is een gevalideerd meetinstrument en is wereldwijd de meest toegepaste methode voor het inventariseren van de symptomen van schizofrenie.

    3. Subschaal van negatieve symptomen van SCI-PANSS.

    E.5.1.1Timepoint(s) of evaluation of this end point
    Assessment will take place at baseline, 12 weeks (phase 1), 14 weeks (after wash-out), 26 weeks (phase 2) or at withdrawal of study.
    Evaluatie vindt plaats bij aanvang van de studie (t=0), na 12 weken (fase 1), na 14 weken (na wash-out periode), na 26 weken (fase 2) of na uitval uit de studie.
    E.5.2Secondary end point(s)
    a. Severity of depressive symptoms:
    1. Calgary Depression Scale for Schizophrenia (CDSS); a semi-structured goal directed interview with an administration time of approximately 10 to 15 minutes, especially designed to distinguish depressive symptoms from negative symptoms and extrapiramidal
    symptoms in patients with schizophrenia (Addington et al, 1990).

    b. Social cognition will be assessed by 2 computerized tests:
    1. Reading the Mind in the Eyes test (theory of mind) (10 minutes);
    2. Emotion Recognition Task of the CANTAB (facial emotion recognition) (15 minutes).

    c. Obsessive-compulsive symptoms:
    1. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), based on information collected in a semi-structured interview of 10 items with an administration time of approximately 10 to 15 minutes (Goodman et al, 1989).

    d. Psychosocial functioning:
    1. Health of the National Outcome Scales (HoNOS), the most widely used routine clinical outcome measure used by English mental health services. The test is simple, reliable and valid to measure the health and social functioning of people with severe mental illness (Wing et al, 1999). The HoNOS consists of 12 items with 4 subscales: behavioral problems, impairments, symptoms and sociale problems. All items are assessed on a 5-point Likert scale. The administration time amounts to approximately 5 to 15 minutes.

    e. Quality of life:
    1. Manchester Short Assessment of Quality of Life (MANSA) a reliable, valid questionnaire for registration of subjective quality of life (Priebe et al, 1999). The MANSA consists of 16 items. The administration time amounts to approximately 5 minutes.

    f. Safety measures:
    1. Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS) is a 51-item self-rating scale for measuring neuroleptic induced side-effects (Day et al., 1995). The administration time amounts to approximately 15 minutes.
    2. Possible side effects of memantine, which are not mentioned in the LUNSERS (thrombosis, dyspnea and mycosis) are specifically noted in Likert ratings.
    3. Laboratory tests (fasting plasma glucose, triglycerides, LDL, HDL and total cholesterol, liverenzymes, renal function, white blood cell count and differentiation, because of the risk of clozapine-induced agranulocytosis and plasma clozapine level) (10 minutes).
    4. Blood pressure and waist circumference (10 minutes).

    g. Drop-out rate.

    a. Ernst van depressieve symptomen:
    1. Calgary Depression Scale for Schizophrenia (CDSS); een semigestructureerd interview, speciaal ontworpen om onderscheid te maken tussen depressieve symptomen, negatieve symptomen en extrapiramidale symptomen bij patiënten met schizofrenie. De afname duur is ongeveer 10 tot 15 minuten.

    b. Sociale cognitie zal worden onderzicht met behulp van 2 verschillende geautomatiseerde testen:
    1. Lees-de-ogen test (LOT) (theory of mind ontwikkeling) (10 minuten);
    2. Emotion Recognition Task van de CANTAB (herkenning gezichtsemoties) (15 minuten).

    c. Obsessief-compulsieve symptomen:
    1. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), gebaseerd op informatie, verkregen in een semigestructureerd interview van 10 items. De afname duur is ongeveer 10 tot 15 minuten.

    d. Psychosociaal functioneren:
    1. Health of the National Outcome Scales (HoNOS), een eenvoudig, betrouwbaar en valide meetinstrument, waarbij de geestelijke gezondheidstoestand en het sociaal functioneren van psychiatrische patiënten routinematig in kaart worden gebracht. De HoNOS bestaat uit 12 items met vier subschalen, te weten gedragsproblemen, beperkingen, symptomatologie en sociale problemen. Alle items worden op een vijfpunts Likertschaal door de onderzoeker ingevuld. De afname duur bedraagt ongeveer 5 tot 15 minuten.

    e. Kwaliteit van leven:
    1. Manchester Short Assessment of Quality of Life (MANSA), een betrouwbare, valide vragenlijst, waarbij de tevredenheid van de patiënt met verschillende levensdomeinen wordt geïnventariseerd. Naast een aantal demografische kenmerken bestaat de MANSA uit 16 items, waarvan 4 objectieve vragen en 12 subjectieve vragen met een 7-puntsschaal. De afname duur bedraagt ongeveer 5 minuten.

    f. Parameters in het kader van veiligheid:
    1. Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS) is een zelfinvulvragenlijst met 51 items om bijwerkingen, geïnduceerd door antipsychotica te meten (Day et al., 1995). De afname duur bedraagt ongeveer 15 minuten.
    2. Mogelijke bijwerkingen van memantine, die niet worden vermeld in de LUNSERS (trombose, kortademigheid en schimmelinfecties) worden specifiek in informatieve bepalingen vermeld.
    3. Bloedbepaling (nuchter glucose, triglyceriden, LDL, HDL en totaal cholesterol, leverenzymen, nierfunctie, leucocyten en differentiatie vanwege het risico op clozapine geïnduceerde agranulocytose en clozapinespiegel).
    4. Bloeddruk en middelomtrek.

    g. Uitval percentage.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Assessment will take place at baseline, 12 weeks (phase 1), 14 weeks (after wash-out), 26 weeks (phase 2) or at withdrawal of study. All assessments will take place on one day, starting with a venipuncture (measurements a metabolic screening, plasma clozapine level), measurements of blood pressure and waist circumference, followed by the CANTAB, the Reading the Mind in the Eyes Test, the PANSS and other questionnaires.
    Evaluatie vindt plaats bij aanvang van de studie (t=0), na 12 weken (fase 1), na 14 weken (na wash-out periode), na 26 weken (fase 2) of na uitval uit de studie. De resultaten zal worden geïnventariseerd op een dag, beginnend met een venapunctie (metabole screening en clozapinespiegel), meting van de bloeddruk en buikomtrek, gevolgd door de CANTAB, de Lees-de-ogen-test, PANSS en overige vragenlijsten.
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Na de eerste behandelfase volgt een enkel-blinde placebo wash-out fase van 2 weken.
    After the first treatment phase, a single-blind placebo wash-out phase of 2 weeks will follow.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 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
    The end of trial is reached when at least 42 of 52 included patients have received randomly the verum in maximum dosage for 11 weeks and placebo for 12 weeks. The duration of the trial for the participant is 26 weeks. The estimated duration of the trial is 12 months.
    Het einde van de studie is bereikt, wanneer minimaal 42 van de 52 geïncludeerde patiënten in willekeurige volgorde de maximale dosering van het verum gedurende 11 weken en de placebotabletten gedurende 12 weken hebben ontvangen. De duur van de studie voor de deelnemer is 26 weken. De geschatte duur van de studie is 12 maanden.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months12
    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 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: 52
    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 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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state52
    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)
    If this study shows relevant clinical improvement in patients with clozapine-refractory schizophrenia, further clinical investigation will follow to promote evidence-based care. Prior to the trial participants will be informed of the possibility to continue memantine add-on therapy to clozapine, if this combination therapy proves to have beneficial effects.
    Wanneer deze studie relevante klinische verbetering aantoont bij patiënten met clozapineresistente schizofrenie, zal verder klinisch onderzoek volgen om evidence based behandeling te bevorderen. Voorafgaande aan de studie zullen deelnemers geïnformeerd worden omtrent de mogelijkheid om memantine additie bij clozapine te continueren, mits deze combinatietherapie gunstige effecten blijkt te hebben.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-01-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-05-17
    P. End of Trial
    P.End of Trial StatusCompleted
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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