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    Summary
    EudraCT Number:2018-002637-37
    Sponsor's Protocol Code Number:NL66693.058.18
    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:2018-12-20
    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 number2018-002637-37
    A.3Full title of the trial
    Manipulating NMDA-dependent learning to alter nocebo effects: A pharmacological fMRI study on pain and itch.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Manipulating learning mechanisms to alter nocebo effects: A pharmacological neuroimaging study on pain and itch.
    A.3.2Name or abbreviated title of the trial where available
    Nocebo and Learning
    A.4.1Sponsor's protocol code numberNL66693.058.18
    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 SponsorLeiden University
    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 supportLeiden University, Institute of Psychology
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden University
    B.5.2Functional name of contact pointInstitute of Psychology
    B.5.3 Address:
    B.5.3.1Street AddressWassenaarsweg 52
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 AK
    B.5.3.4CountryNetherlands
    B.5.6E-maila.evers@fsw.leidenuniv.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 D-cycloserine
    D.2.1.1.2Name of the Marketing Authorisation holderAcademisch Ziekenhuis Leiden
    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 nameD-cycloserine
    D.3.4Pharmaceutical form Capsule
    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 Yes
    D.3.11.13.1Other medicinal product typeAntibiotic
    D.IMP: 2
    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 Ketanest-S
    D.2.1.1.2Name of the Marketing Authorisation holderEurocept BV
    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 nameEsketamine
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous 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 Yes
    D.3.11.13.1Other medicinal product typeAnesthetic
    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 placeboCapsule
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Nocebo effects on pain and itch
    E.1.1.1Medical condition in easily understood language
    Nocebo effects on pain and itch (i.e., expectancy effects that contribute to the persistence or aggravation of pain and itch symptoms).
    E.1.1.2Therapeutic area Body processes [G] - Physical Phenomena [G01]
    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
    The primary objective is to test the role of NMDA receptor-dependent learning in an experimental model of conditioned nocebo effects on self-reported pain (sub-study 1) and itch (sub-study 2). Secondary objectives are to examine the role of NMDA manipulations and related neural correlates during the induction, evocation, and attenuation of nocebo effects using statistical learning models. We also aim to explore neural differences between control stimulations and nocebo-augmented pain and itch. Lastly, the moderating effects of psychological variables measured with questionnaires on the nocebo effect will also be explored.
    E.2.2Secondary objectives of the trial
    Secondary objectives for both sub-studies are:
    1. To examine neural activations during the induction of nocebo effects on pain or itch. Multivariate pattern analysis will be used to investigate differences in BOLD responses during the induction of nocebo effects and thereby classify participants into pharmacological treatment groups.
    2. To examine neural activations during the evocation of nocebo effects on pain or itch.
    3. To explore neural activations between the experience of pain and itch.
    4. To explore neural activations between the experience of nocebo-augmented sensations and the experience of control sensory stimulations.
    5. To predict the magnitude of induced nocebo effects on pain or itch, based on patterns of BOLD responses during the induction of nocebo effects.
    6. To explore whether psychological characteristics of catastrophizing, anxiety, body vigilance, or attitudes towards medication influence the magnitude of conditioned nocebo effects on pain and itch.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    This study is comprised of two parallel sub-studies:
    Sub-study 1, on pain: "Manipulating NMDA-dependent learning to alter nocebo effects on PAIN: A pharmacological fMRI study". In this sub-study we aim to additionally investigate neural correlates and the effect of NMDA receptor manipulations on the counterconditioning of nocebo effects on pain through counterconditioning.
    Sub-study 2, on itch: "Manipulating NMDA-dependent learning to alter nocebo effects on ITCH: A pharmacological fMRI study". In this sub-study we aim to additionally investigate neural correlates and the effect of NMDA receptor manipulations on the extinction of nocebo effects on itch.
    E.3Principal inclusion criteria
    To be eligible, participants must meet all of the following criteria:
    1. Between 18 and 35 years of age
    2. Good understanding of spoken and written English
    3. Native Dutch speaker
    E.4Principal exclusion criteria
    A potential subject who meets any of the following exclusion criteria will be excluded from participation in this study:
    1. History of serious or chronic medical or psychiatric conditions
    2. History of chronic pain or itch conditions
    3. Experiencing pain or itch on the day of testing
    4. Currently using antihistamines, analgesic medication, or itch-reducing medication (in the 12 hours prior to testing)
    5. Recent use of psychotropic drugs (including recreational drugs such as cannabis and psychotropic prescription-medication; in the past month)
    6. Currently being (or intending to become) pregnant, or currently breastfeeding
    7. Colour-blindness
    8. Body Mass Index under 16 or over 30
    9. Meeting any exclusion criteria for entering the MR scanner (e.g., permanent metal parts in the body)
    10. Having a too high threshold for pain (where high pain cannot be induced with temperatures lower than 49.5 °C) or not responding to histamine (no itch response)
    E.5 End points
    E.5.1Primary end point(s)
    The main study parameter is the magnitude of induced nocebo effects on self-reported pain and itch in the first evocation phase as compared between the pharmacological groups. The magnitude of the induced nocebo effects on pain and itch is measured as the difference between self-reported pain and itch on a Numeric Rating Scales between conditioned and control evocation trials in early trials of the first evocation phase.
    E.5.1.1Timepoint(s) of evaluation of this end point
    During the single experimental session, in early trials of the first evocation phase for each sub-study.
    E.5.2Secondary end point(s)
    Secondary study endpoints for both sub-studies are:
    - The classification accuracy (into pharmacological groups), indicating that patterns of activation in the network of a priori ROIs form a model that can detect differences in neural activations during the induction of nocebo effects.
    - The classification accuracy (into pharmacological groups), indicating that patterns of activation in the network of a priori ROIs form a model that can detect differences in neural activations during the first evocation phase.
    - The classification accuracy, indicating that patterns of activation in the network of a priori ROIs form a model that can detect commonalities and differences in neural activations between the experience of pain and itch.
    - The classification accuracy, indicating that patterns of activation in the network of a priori ROIs form a model that can detect common neural activations between the experience of nocebo-augmented pain and nocebo-augmented itch, thereby indicating a signature of activations relevant to the manifestation of nocebo effects, independent from sensory input.
    - The prediction accuracy, indicating that patterns of activation in the network of a priori ROIs form a model that can predict the magnitude of induced nocebo effects based on patterns of activations during the induction of nocebo effects.
    - The moderation of the magnitude of induced nocebo effects in the first evocation phase by scores on the psychological questionnaires.

    Secondary parameters for the pain sub-study only:
    - The magnitude of nocebo effects on pain present after nocebo attenuation, between the pharmacological groups, as measured in early trials of the second evocation phase relative to early trials of the first evocation phase.
    - The classification accuracy (into pharmacological groups) indicating that patterns of activation in the network of a priori ROIs form a model that can detect differences in neural activations during the attenuation of nocebo effects.

    Secondary parameters for the itch sub-study only:
    - Differences in the time course of extinction of nocebo effects on itch, as measured during the evocation phase between the pharmacological groups.
    E.5.2.1Timepoint(s) of evaluation of this end point
    During the single experimental session.
    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 No
    E.6.5Efficacy No
    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 Yes
    E.6.13.1Other scope of the trial description
    Research into fundamental (neurobiological) mechanisms
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Double dummy
    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.8.2.3.1Comparator description
    No treatment
    E.8.2.4Number of treatment arms in the trial4
    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 Yes
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    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: 200
    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 Yes
    F.3.2Patients No
    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 state200
    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, except in the rare occasion that a subject reports feeling unwell for any reason on the day of the experimental session, in which case the responsible medical doctor will attend to the subject in the hospital until the subject feels well enough to depart.
    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 Decision2018-12-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-29
    P. End of Trial
    P.End of Trial StatusOngoing
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