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    EudraCT Number:2012-002299-15
    Sponsor's Protocol Code Number:FIO11-05
    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:2012-07-04
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2012-002299-15
    A.3Full title of the trial
    The effect of glycopyrroniumbromide on nocturnal clozapine induced sialorrhea in psychiatric patients: a randomized, cross-over, double blind, placebo controlled trial with an extended open label phase (QUITSPIT study)
    Het effect van glycopyrroniumbromide op nachtelijk clozapine geïnduceerd speekselverlies (CIS) bij psychiatrische patiënten: een gerandomiseerd, cross-over, dubbelblind, placebo gecontroleerd onderzoek met verlengde fase (QUITSPIT-studie)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The effect of glycopyrroniumbromide oral solution for nocturnal drooling due to the use of clozapine
    Het effect van glycopyrroniumbromide drank op nachtelijk speekselverlies door clozapine
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberFIO11-05
    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 SponsorUniversitair Medisch Centrum Utrecht
    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 supportForeest Medical School, Medisch Centrum Alkmaar
    B.4.1Name of organisation providing supportZiekenhuisapotheek UMC Utrecht
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitair Medisch Centrum Utrecht
    B.5.2Functional name of contact pointZiekenhuisapotheek UMC Utrecht
    B.5.3 Address:
    B.5.3.1Street AddressHeidelberglaan 100
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3584 CX
    B.5.4Telephone number0031887557218
    B.5.5Fax number0031302516756
    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 No
    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 nameGlycopyrroniumbromide
    D.3.4Pharmaceutical form Oral solution
    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.3.9.1CAS number 596-51-0
    D.3.9.4EV Substance CodeSUB07951MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.2
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 placeboOral solution
    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
    Nocturnal sialorrhea caused by the use of clozapine
    Overmatig nachtelijk speekselverlies veroorzaakt door het gebruik van clozapine
    E.1.1.1Medical condition in easily understood language
    drooling during the night caused by the use of clozapine
    kwijlen tijdens de slaap veroorzaakt door het gebruik van clozapine
    E.1.1.2Therapeutic area Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]
    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
    To determine the effect of oral glycopyrroniumbromide in comparison with placebo on the severity of nocturnal sialorrhea in psychiatric patients treated with clozapine
    Het bepalen van het effect van oraal glycopyrroniumbromide ten opzichte van placebo op de ernst van de klachten van nachtelijk speekselverlies bij patiënten met een psychiatrische aandoening die clozapine gebruiken.
    E.2.2Secondary objectives of the trial
    1) to determine patient's satisfaction with oral glycopyrroniumbromide compared to placebo regarding nocturnal sialorrhea
    2) to determine the effect of oral glycopyrroniumbromide compared to placebo on patient's opinion to clozapine
    3) to determine the effect of oral glycopyrroniumbromide compared to placebo on the occurence of side effects
    4) previously mentioned primary and secundary objectives in a subset of patients receiving a double dose of oral glycopyrroniumbromide in an open label extension compared to single dose oral glycopyrroniumbromide treatment in the randomized, double-blind phase
    1) het meten van de tevredenheid over oraal glycopyrroniumbromide ten opzichte van placebo op de mate van nachtelijk speekselverlies bij patiënten met een psychiatrische aandoening die clozapine gebruiken.
    2) het meten van het effect van oraal glycopyrroniumbromide ten opzichte van placebo op de houding van de patiënt ten aanzien van clozapine.
    3) het meten van het effect van oraal glycopyrroniumbromide op het optreden van bijwerkingen ten opzichte van placebo.
    4) hierboven genoemde primaire en secundaire onderzoeksdoelen in een subset van patiënten die in een open-label extensie van de studie een hogere dosis oraal glycopyrroniumbromide gebruiken ten opzichte van de lage dosering glycopyrroniumbromide uit de dubbelblinde fase.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -patients using clozapine who are diagnosed with schizophrenia, a schizoaffective disorder or other psychiatric condition meeting DSM-IV criteria;
    -a clozapine dosage that remained unchanged for three months prior to inclusion;
    -age between 18 and 65 years;
    -nocturnal sialorrhea defined as a score ≥ 2 on the PGI-S (Patient Global Impression of Severity Questionnaire)
    -no change in dosages of specific comedication (clonidine, sulpride, moclobemide) that potentially reduces salivary flow for 1 month prior to inclusion
    -the patients is able to answer questionnaires during a weekly consultation (by telephone) with the researcher
    -the patient is willing and according to the treating physician, able to give informed consent
    -patiënten die clozapine gebruiken en gediagnosticeerd zijn met schizofrenie, een schizo-affectieve stoornis of een andere psychiatrische aandoening volgens DSM-IV criteria;
    -dosering clozapine onveranderd gedurende minimaal 3 maanden voorafgaand aan de start van het onderzoek;
    -leeftijd tussen 18 en 65 jaar;
    -nachtelijk overmatig speekselverlies, met een score ≥ 2 op de PGI-S (Patient Global Impression of Severity Questionnaire)
    -dosering van comedicatie (clonidine, sulpride, moclobemide) die de speekselproductie zou kunnen verminderen onveranderd gedurende 1 maand voorafgaand aan de start van het onderzoek
    - de patiënt is in staat om de score op de meetinstrumenten wekelijks vast te stellen in een (telefonisch) consult met een onderzoeker
    -de patiënt is bereid en volgens de behandelend arts in staat om informed consent te tekenen voor deelname aan de studie.
    E.4Principal exclusion criteria
    -known hypersensitivity to glycopyroniumbromide, sorbic acid or saccharine sodium;
    -a comorbidity associated with sialorrhea (Parkinsons disease, cerebral palsy);
    -one of the following comorbidities: inadequately treated constipation, urine retention, bladder obstruction
    -concurrent use of anticholinergic agents: tricyclic antidepressants or anticholinergics (atropine, ipratropiumbromide, trihexyfenidyl,
    biperiden, scopolamine, oxybutinine);
    -concurrent use of medications that potentially interact with glycopyrroniumbromide
    (potassium chloride retard tablets, digoxine, corticosteroids)
    -pregnancy or lactation
    -a history of myasthenia gravis, cardiac arrhythmia, symptomatic coronary insufficiency, glaucoma, pyloris stenosis, paralytic ileus, prostate hypertrophy, renal failure
    -unable to autonomic medication intake
    -gebleken overgevoeligheid voor glycopyrroniumbromide, sorbinezuur of natrium saccharine;
    -patiënten met een comorbiditeit geassocieerd met overmatig speekselverlies (ziekte van Parkinson, cerebrale verlamming)
    -patiënten met één van de volgende actuele comorbiditeiten: niet adequaat behandelde obstipatie, urineretentie, obstructie van de blaas.
    -patiënten die gelijktijdig anticholinerg werkende middelen gebruiken: tricyclische antidepressiva; anticholinergica (atropine, ipratropiumbromide, trihexyfenidyl, biperideen, scopolamine, oxybutinine);
    -patiënten die gelijktijdig de volgende medicatie gebruiken, waardoor er een interactie kan
    optreden: kaliumchloride in wasmatrix (bv Slow-K), digoxine, corticosteroïden
    -zwangerschap of lactatie
    -patiënten met één van de volgende aandoeningen in de voorgeschiedenis: myasthenia gravis, hartritmestoornissen, symptomatische coronaire insufficiëntie, glaucoom samenhangend met een nauwe oogkamerhoek, pylorusstenose, paralytische ileus,
    prostaathypertrofie, ernstige nierfunctiestoornissen
    -patiënten die niet in staat zijn om zelfstandig de medicatie in te nemen.
    E.5 End points
    E.5.1Primary end point(s)
    The percentage of patients showing a clinically significant improvement in nocturnal sialorrhea severity. A clinically significant improvement is defined as a reduction of at least 1 point on the PGI-I (Patient Global Impression of improvement questionnaire).
    Het percentage patiënten dat een klinisch relevante verbetering laat zien op de ernst van het nachtelijk speekselverlies. Een klinisch relevante verbetering wordt gedefinieerd als 1 punt vermindering op de PGI-I (Patient Global Impression of improvement questionnaire).
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 6 days of treatment
    na 6 dagen behandelen
    E.5.2Secondary end point(s)
    The mean score on the PGI-I, PGI-S, NHRS (Nocturnal Hypersalivation Rating Scale) and MSQ (Medication Satisfaction Questionnaire), the occurence of side effects and patients satisfaction with oral glycopyrroniumbromide
    De gemiddelde score op de PGI-I, PGI-S, NHRS (Nocturnal Hypersalivation Rating Scale) en MSQ (Medication Satisfaction Questionnaire), het optreden van bijwerkingen en de tevredenheid ten aanzien van oraal glycopyrroniumbromide
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 6 days of treatment
    na 6 dagen behandelen
    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Patient satisfaction
    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. 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other Yes
    E. trial design description
    met verlengde fase (open-label extensie)
    with extended phase (open label extension)
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other Yes
    E. description
    dubbele dosis glycopyrroniumbromide (verlengde fase,open label) wordt vergeleken met de enkele dosis
    double dose glycopyrroniumbromide (extended phase, open label) is compared to the single dose
    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 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
    de laatste visite van de laatste patiënt in het onderzoek (LVLS = last visit, last subject)
    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 months6
    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 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 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: 33
    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 Yes
    F. of other specific vulnerable populations
    psychiatric patients
    psychiatrische patiënten
    F.4 Planned number of subjects to be included
    F.4.1In the member state33
    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 treating physician (psychiatrist) will discuss the opportunity to continue the use of glycopyrroniumbromide oral solution with the patient. It is taken into account if there was any benefit from the glycopyrroniumbromide oral solution and if the patient well tolerated the oral solution during the study.
    de behandelend psychiater zal met de patiënt bespreken of het mogelijk is om door te gaan met het gebruik van glycopyrroniumbromide drank. Hierin wordt meegenomen of glycopyrroniumbromide drank tijdens het onderzoek goed verdragen is en of de patiënt er baat bij heeft gehad.
    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 Decision2012-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-10-03
    P. End of Trial
    P.End of Trial StatusCompleted
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