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    Summary
    EudraCT Number:2013-005395-18
    Sponsor's Protocol Code Number:U1111-1144-0576
    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:2014-09-10
    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 number2013-005395-18
    A.3Full title of the trial
    Effects of GLP1 agonist liraglutide in patients with antipsychotic-drugs-associated diabetes mellitus
    Effecten van GLP1-agonist Liraglutide bij patienten met diabetes mellitus ten gevolge van anti-psychotica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Assessing the efficacy and safety of the GLP1-agonist liraglutide in patients who developed diabetes as a consequence of the use of anti-psychotic drugs
    Onderzoek naar de effecten van het medicijn liraglutide bij patiënten met een type suikerziekte (diabetes) die veroorzaakt is door het gebruik van antipsychotische medicijnen.
    A.3.2Name or abbreviated title of the trial where available
    GRADUATE
    GRADUATE
    A.4.1Sponsor's protocol code numberU1111-1144-0576
    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 SponsorUniversity Medical Center 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 supportUniversity Medical Center
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center
    B.5.2Functional name of contact pointB. Silvius
    B.5.3 Address:
    B.5.3.1Street AddressF02.126 Heidelberglaan 100
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3584 CX
    B.5.3.4CountryNetherlands
    B.5.6E-mailbsilvius@umcutrecht.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 Liraglutide
    D.2.1.1.2Name of the Marketing Authorisation holderNovoNordisk
    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.3.1Product nameLiraglutide
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    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 placeboInjection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    antipsychotic-drugs-associated diabetes mellitus
    diabetes mellitus veroorzaakt door het gebruik van anti-psychotica
    E.1.1.1Medical condition in easily understood language
    diabetes caused by the use of antipsychotic drugs
    type suikerziekte die veroorzaakt is door het gebruik van antipsychotische medicijnen
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10029505
    E.1.2Term Non-insulin-dependent diabetes mellitus
    E.1.2System Organ Class 100000004861
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10012612
    E.1.2Term Diabetes mellitus non insulin-dep
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To explore the efficacy of liraglutide in terms of glycaemic control assessed by HbA1c.
    Effect onderzoeken van liraglutide op de glychemische huishouding op basis van het Hab1c
    E.2.2Secondary objectives of the trial
    • To explore the effect of liraglutide on cardiovascular risk factors, body weight and intra-abdominal fat content using CT-scans in obese patients with antipsychotics-associated diabetes mellitus
    • To explore feasibility of liraglutide in the treatment of antipsychotic drugs- associated diabetes and obesity in patients suffering from severe mental illness in terms of compliance with the treatment regimen
    • To explore possible change in psychiatric symptoms during treatment with liraglutide in severe mental illness using questionnaires.
    Effect onderzoeken van liraglutide op cardiovasculaire riscofactoren zoals gewicht, intra-abdominaal vet (gemeten door CT scan) bij obese patienten met diabetes veroorzaakt door het gebruik van antipsychotica
    Onderzoeken of deze groep patienten compliance heeft bij het gebruik van dit middel
    Onderzoeken van de mogelijke psychiatrische veranderingen
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Informed consent obtained before any trial related activities
    • Males or females aged 18 years or older
    • Diabetes mellitus developed while on anti-psychotic drugs for at least six months
    • Use of metformin for the treatment of diabetes
    • HbA1c >7.0% - ≤ 10.0 mmol/l (53 – 86 mmol/mol)
    • BMI 30 – 45 kg/m2
    • Regarded capable to understand and follow the protocol
    Getekend toestemmingsformulier voordat er een studiehandeling heeft plaats gevonden
    Mannen of vrouwen van 18 jaar of ouder
    Diabetes ontwikkeld door het gebruik van anti-psychotica voor op zijn minst 6 maanden
    Gebruik van metformine voor de behandeling van diabetes
    HbA1c >7.0% - ≤ 10.0 mmol/l (53 – 86 mmol/mol)
    BMI 30 – 45 kg/m2
    In staat zijn om het protocol te kunnen begrijpen en te volgen
    E.4Principal exclusion criteria
    • Any type of diabetes present before the use of anti-psychotic drugs
    • Use of glucose-lowering medication other than metformin
    • cardiovascular event in the last 6 months
    • Reduced cardiac function (LVEF < 30%)
    • evidence of active retinopathy
    • controlled or uncontrolled hypertension (systolic pressure > 180 mm Hg and/or diastolic pressure > 100 mm Hg
    • Renal failure (MDRD < 30 ml/min)
    • Liver function abnormalities (ALT and/or AST > 3 times the upper limit of normal)
    • History of chronic pancreatitis or previous acute pancreatitis
    • Known or suspected hypersensitivity to trial product(s) or related product(s)
    • Female of child-bearing potential who is pregnant, breast-feeding or intend to become pregnant or is not using adequate contraceptive methods
    • Participation in another trial or receipt of any investigational medicinal product within 90 days prior to screening
    • Subjects who are considered incapable for inclusion by their physicians
    • Subjects who are considered inadequate for liraglutide administration themselves or lack network of support
    • Subjects who are actively suicidal
    • Recurrent use of corticosteroids
    • Personal or family history of medullary thyroid carcinoma and patients with multiple endocrine neoplasia type 2 (MEN2)
    • Known or suspected abuse of alcohol or narcotics
    Type diabetes ontstaan voor het gebruik van anti-psychotica
    Gebruik van glucoseverlagende middelen anders dan Metformine
    Doorgemaakt cardiovasculair event in de afgelopen 6 maanden
    Verminderde hartfunctie (LVEF < 30%)
    Bewijs van actieve retinopathie
    Gecontrolleerde of ongecontrolleerde hypertensie (systolic pressure > 180 mm Hg and/or diastolic pressure > 100 mm Hg
    Nierfunctiestoornis (MDRD < 30 ml/min)
    Leverfunctiestoornissen (ALT en/of AST > 3 keer hoger dan normaalgrens)
    Voorgeschiedenis met chronische pancreatitis of aanwezige acute pancreatitis
    Bekende gevoeligheid voor het te onderzoeken middel of onderdelen daarvan
    Vrouwen die zwanger zijn, zwanger willen worden of borstvoeding geven en geen adequate voorbehoedsmiddelen gebruiken
    Indien er deelgenomen is aan een andere studie met medicatie die korter dan 90 dagen geleden
    Indien psychaiter concludeert dat patient niet capabel is voor deelname
    Patienten waarbij vanuit kan worden gegaan dat ze niet therapietrouw zullen zijn
    Actieve doodswens
    Gebruik van cortocosteroiden
    Persoonlijke of familiegeschiedenis met MEN2
    Bekende alcohol- of narcotic abuses
    E.5 End points
    E.5.1Primary end point(s)
    The primary end point of this study is the change in HbA1c from baseline to ‘end of trial’
    Verandering van HbA1c van de baseline tot het einde van de studie.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of the study
    Aan het einde van de studie
    E.5.2Secondary end point(s)
    Efficacy
    o Change in fasting glucose
    o Change in body weight and BMI
    o Change in waist and hip circumferences and waist hip ratio
    o Change in blood pressure
    o Change in lipid levels
    o Change in abdominal fat content ( abdominal CT-scan)

    Safety/ Feasibility
    o Compliance with use of drug liraglutide (number of injection vials used)
    o (Serious) Adverse events during liraglutide use

    Change in psychiatric symptoms
    o CAPE-score
    o CGI- score
    o PANS-score

    Patient-reported outcomes
    o PAID (problem areas in diabetes)
    o SF-12
    o DTSQ
    o EQ5D

    Effect wordt gemeten door de veranderingen te meten in nuchtere glucose, gewicht, BMI, heup- en buikomtrek, bloeddruk, lipiden, abdominaal vet
    Veiligheid wordt gemeten door compliance te meten, SAE/AE 's meten
    Veranderingen in psyche worden gemeten d.m.v. CAPE, CGI en PANS score
    Patientenervaringen worden gemeten d.m.v. vragenlijsten PAID, SF-12, DTSQ, EQ5D
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of this study and meanwhile
    Aan het einde van de studie en tussendoor
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 Yes
    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 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 the study is 24 weeks after the last patient was randomised
    Het einde van de studie is 24 weken nadat de laatste patient is gerandomiseerd
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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)
    not different from the expected normal treatment
    niet anders dan voor de studie
    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 Decision2014-09-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-02-06
    P. End of Trial
    P.End of Trial StatusOngoing
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