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    Summary
    EudraCT Number:2013-004313-41
    Sponsor's Protocol Code Number:47659
    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:2014-02-24
    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 number2013-004313-41
    A.3Full title of the trial
    Effect of pre-operative pain treatment by means of duloxetine on postoperative outcome after total hip or knee arthroplasty
    Effecten van pre-operatieve pijnbehandeling, middels duloxetine, op postoperatieve uitkomsten na totale heup- of knie arthroplastiek.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of pre-operative pain treatment on postoperative outcome after total hip or knee replacement surgery
    Effecten van pre-operatieve pijnbehandeling op postoperatieve uitkomsten na totale heup- of knievervanging
    A.3.2Name or abbreviated title of the trial where available
    Duloxetine In OsteoArthritis study (DOA-study)
    Duloxetine in Artrose studie
    A.4.1Sponsor's protocol code number47659
    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 SponsorUMCG
    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 supportStichting ARGON (reumafonds "Dutch Arthritis Foundation")
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUMCG
    B.5.2Functional name of contact pointDepartment of Orthopaedics
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9700 RB
    B.5.3.4CountryNetherlands
    B.5.6E-mailm.stevens@umcg.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 Cymbalta
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland 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 Gastro-resistant capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Osteoarthritis (knee or hip)
    Artrose (knie of heup)
    E.1.1.1Medical condition in easily understood language
    degenerative joint disease (knee or hip)
    gewrichtsslijtage (knie of heup)
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10031161
    E.1.2Term Osteoarthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10023476
    E.1.2Term Knee osteoarthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10020108
    E.1.2Term Hips osteoarthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    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 degree pain relief 6 months after THA/TKA when screened pre-operative for centralized pain and subsequent treated accordingly for a period of 10 weeks with Duloxetine compared to usual care (no Duloxetine)
    Het bepalen van de mate van pijnverlichting 6 maanden na THA / TKA, wanneer pre-operatief is gescreend op centrale pijn en aansluitend is behandeld, voor een periode van 10 weken, met duloxetine vergeleken met standaard behandeling (geen duloxetine)
    E.2.2Secondary objectives of the trial
    To determine the effect at different follow-up time points when screened pre-operative for centralized pain and subsequent treated accordingly for a period of ten weeks with Duloxetine compared to treated as usual (no Duloxetine) on:
    * The degree of pain relief and neuropathic pain symptoms;
    * The degree of sensitisation/sensitivity (measured by QST);
    * The degree of functional improvement
    and physical activity;
    * Quality of life and perceived
    satisfaction//expectation level (at the
    time on waiting list);
    * Depressive and anxiety symptoms.
    * The degree of Pain Catastrophizing
    Het bepalen van het effect , op verschillende tijdspunten, wanneer pre-operatief is gescreend op centrale pijn en aansluitend is behandeld, voor een periode van 10 weken, met duloxetine , vergeleken met standaard behandeling (geen duloxetine) op:
    * De mate van pijnverlichting en
    neuropatische pijnsymptomen;
    * De mate van sensitisatie/gevoeligheid (gemeter met QST);
    * De mate van functionele verbetering en
    fysieke activiteit;
    * Kwaliteit van leven en ervaren
    tevredenheid / verwachtingsniveau;
    * Depressieve symptomen en
    angstklachten.
    * De mate van Pijn Catastroferen
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Primary Osteoarthritis (based on clinical and radiological ACR-criteria)
    2. Age >18 years
    3. A neuropathic or at least a mixed neuropathic / noiciceptive pain phenotype (m-painDETECT-score >12)
    1. Primaire artrose (gebaseerd op de klinische en radiologische ACR-criteria)
    2. leeftijd > 18 jaar
    3. Een neuropatisch of ten minste een gemengd nociceptief / neuropatisch pijntype (m-painDETECT-score>12)
    E.4Principal exclusion criteria
    General exclusion criteria:
    1. Surgical hip or knee joint procedures less than 1 year previously
    2. Cognitive and/or neurological disorders that could interfere strongly with questionnaire surveys (e.g. Dementia)
    3. Serious or unstable medical condition that could likely lead to hospitalization during the course of the study or compromise study participation.
    4. Planned or intended to perform THA or TKA within the study duration (present planned arthroplasty not included)
    5. A history of peripheral nerve injury
    6. Previous exposure to Duloxetine

    Duloxetine related exclusion criteria:
    7. Allergy to study medication or compounds of the Duloxetine capsule (or another SNRI);
    8. History of peptic ulcer disease or bleeding disorder (or other substantial risk factor for bleeding)
    9. Psychiatric disorders, other than depression;
    10. Severe depression (HADS score >15 on depression subscale);
    11. A history of alcohol or other substance abuse (excluding nicotine and caffeine) or dependence within the five years prior to enrollment;
    12. Currently pregnant or lactating, our planned to become pregnant within the study period
    13. History of cardiac arrhythmias, cardiac failure, myocardial infarct;
    14. impaired function of the liver, or known cirrhosis or liver transplantation;
    15. severe renal impairment, or had renal transplantation or receiving renal dialysis;
    16. Hyponatraemia, or a history of frequent hyponatremias;
    17. History of uncontrolled hypertension, history of glaucoma (or with increased intraocular pressure) ,uncontrolled thyroid disease and a history of uncontrolled seizures;
    18. Usage of non selective monoamine oxidase (MAO) inhibitors, TCA’s , SSRIs, SNRIs in the last year;
    19. Usage of strong CYP1A2-inhibitors
    Algemene exclusiecriteria:
    1. Chirurgische heup- of knie interventies korter dan 1 jaar geleden
    2. Cognitieve en/of neurologische aandoeningen die sterk kunnen interfereren met vragenlijstonderzoek (bv. dementie)
    3. Ernstige of instabiele medische aandoeningen die gedurende de studiedeelname waarschijnlijk zullen leiden tot hospitalisatie, of sterk compromitteren met studieparticipatie.
    4. Geplande of voornemens uit te voeren THA of TKA binnen de studieduur (anders dan de huidige voorgenomen THA/TKA)
    5. Perifeer zenuwletsel in voorgeschiedenis
    6. Een voorgeschiedenis van duloxetine gebruik.

    Duloxetine gerelateerde exclusiecriteria:
    7. Allergie voor de studiemedicatie, of onderdelen van de duloxetine capsule (of een andere SNRI)
    8 Maagzweer of andere bloedstollingsstoornis (of een andere substantiële risicofactor voor bloedingen)
    9 Psychiatrische aandoening, anders dan depressie
    10. Ernstige depressie (HADS score >15 op depressie subschaal)
    11. Alcohol of middelenmisbruik/verslaving in voorgeschiedenis ( anders dan nicotine en cafeïne) korter dan 5 jaar geleden.
    12. Zwanger of lacterend, of plannen voor een zwangerschap binnen de studieperiode.
    13. Hartritmestoornis, hartfalen of hartinfarct in voorgeschiedenis
    14. Leverfunctiestoornis , cirrose of lever transplantatie in voorgeschiedenis
    15. Ernstige nierfunctiestoornis of niertransplantatie in voorgeschiedenis of ondergaat nierdialyse
    16. Hyponatraemie of regelmatig hyponatriëmien in voorgeschiedenis
    17. Oncontroleerbare hypertensie, glaucoom (of verhoogde intraoculaire druk), oncontroleerbare schildklieraandoening of oncontroleerbare toevallen in voorgeschiedenis
    18. Gebruik van MAO-remmers, TCAs, SSRIs of SNRIs in het voorgaande jaar
    19. Gebruik van sterke CYP1A2-remmers in voorgeschiedenis
    E.5 End points
    E.5.1Primary end point(s)
    The degree of postoperative pain, assessed with the pain subscales of the Knee injury and Osteoarthritis Outcome Score (KOOS) or the Hip disability and Osteoarthritis Outcome Score (HOOS).
    De mate van postoperatieve pijn, bepaalde met de pijn subschalen van de "Knee injury and Osteoarthritis Outcome Score (KOOS) of de "Hip disability and Osteoarthritis Outcome Score" (HOOS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months after THA/TKA
    6 maanden na THA/TKA
    E.5.2Secondary end point(s)
    Pain
    Secondary endpoints that will be used to asses the change of perceived pain are the Visual Analogue Scale (VAS) and the pain subscales of the KOOS/HOOS. Neuropathic pain will be assessed by means of the modified-painDETECT (m-PDQ) questionnaire (knee m-PDQ, hip m-PDQ).

    Sensitisation/sensitivity measurements (QST)
    A multimodel assessment of pain responses will be performed to assess characteristics associated with neuropathic pain and/or (central) sensitization. Two QST-measurements will be assessed, namely; Mechanical Temporal Summation (MTS) and Blunt Pressure Pain Thresholds (PPT).

    Function and physical activity
    Change of function will be assessed by means of the following KOOS/HOOS subscales: symptoms, ADL and sport/recreation. Change of physical activity will be assessed by means of the International Physical Activity Questionnaire (IPAQ)

    Quality of life and satisfaction
    Change of quality of life will be assessed by means of the QOL subscale of the KOOS/HOOS and the SF-36 questionnaire. Patients perceived level of expectation at the time on the waiting list (in relation to postoperative outcomes) will be assed by means of the Hospital for Special Surgery Knee Replacement Expectations survey (HSSKR) and with the Hospital for Special Surgery Hip Replacement Expectations survey (HSSHR). Furthermore, the Patient Global Impression of Improvement (PGI-I) scale will be obtained to measure a change in the level of satisfaction.

    Depression and anxiety
    Change in depression and anxiety will be assessed by means of the Hospital Anxiety and Depression Scale (HADS).

    Pain catastrophizing
    Pain catastrophizing will be assessed by means of the pain catastrophizing questionnaire (PCS).
    Pijn
    Secundaire eindpunten die gebruikt zullen worden om de ervaren pijnverandering te objectiveren zijn de “Visual Analogue Scale” (VAS), sensitisati en de pijnsubschalen van de KOOS/HOOS. Neuropatische pijn zal worden bepaald door middel van de gemodificeerde-painDETECT (m-PDQ) vragenlijst (knie m-PDQ, heup m-PDQ)

    Sensitisatie/gevoeligheid
    Twee QST-methoden zullen worden gebruikt om de eigenschappen welke geassocieerd worden met neuropatische pijn en/of (centrale) sensitisatie te objectiveren, namelijk; Mechanical Temporal Summation (MTS) en Blunt Pressure Pain Thresholds (PPT).

    Functie en fysieke activiteit
    Verandering in functie zal worden geobjectiveerd door middel van de volgende KOOS/HOOS subschalen: symptomen, ADL en sport/recreatie. Verandering van fysieke activiteit zal worden gemeten met de “International Physical Activity Questionnaire”(IPAQ)

    Kwaliteit van leven en tevredenheid
    Verandering in kwaliteit van leven zal worden bepaald door middel van de “QOL” subschaal van de KOOS/HOOS en de SF-36 vragenlijst. De ervaren mate van verwachting (in relatie tot de postoperatieve uitkomsten) zal worden bepaald middels de “Hospital for Special Surgery Knee Replacement Expectations survey” (HSSKR) of met de “Hospital for Special Surgery Hip Replacement Expectations survey” (HSSHR). Verder zal de “Patient Global Impression of Improvement” (PGI-I) schaal worden afgenomen om een verandering in de ervaren tevredenheid te objectiveren.

    Depressie en angst
    Verandering in depressie en angst zal worden bepaald middels de “Hospital Anxiety and Depression Scale” (HADS).

    Pijn catastroferen
    Pijn catastroferen zal worden bepaald middels de "pain catastrophizing questionnaire" (PCS).

    E.5.2.1Timepoint(s) of evaluation of this end point
    Pain-related time-points:
    *T1 (2 weeks after duloxetine initiation/baseline)
    *T2 (8 weeks after duloxetine initiation/baseline)
    *T4 (2 days postoperative)
    *T5 (6 weeks postoperative)

    All time-point / general time-points
    *T0 = baseline
    *T3 (10 weeks after duloxetine initiation/baseline)
    *T6 (6 months postoperative)
    * T7 (12 months postoperative)
    Pijn-gerelateerde tijdspunten:
    *T1 (2 weken na duloxetine initiatie/baseline)
    *T2 (8 weken na duloxetine initiatie/baseline)
    *T4 (2 dagen postoperatief)
    *T5 (6 weeks postoperatief)

    Alle tijdspunten / algemene tijdspunten
    *T0 = baseline
    *T3 (10 weken na duloxetine initiatie/baseline)
    *T6 (6 maanden postoperatief)
    *T7 (12 maanden postoperatief)
    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 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) 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 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 Yes
    E.8.2.3.1Comparator description
    standaard zorg (geen duloxetine)
    Usual care (no duloxetine)
    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
    The end of the trial is reached when the last included subject completed time-point T7, 12 months after surgery.
    Het einde van deze trial is bereikt wanneer de laatst geïncludeerde patiënt tijdspunt T7 is gepasseerd, 12 maanden na operatie.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months33
    E.8.9.1In the Member State concerned days
    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: 49
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 state118
    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
    none
    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 Decision2014-02-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-05-19
    P. End of Trial
    P.End of Trial StatusOngoing
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