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    Summary
    EudraCT Number:2013-001818-14
    Sponsor's Protocol Code Number:RELATE-TRD
    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:2013-08-13
    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 number2013-001818-14
    A.3Full title of the trial
    RELATE and PREDICT TRD
    A pharmacological and neuroimaging study investigating neurobiological effects of Selective Serotonin Reuptake Inhibitors and Norepinephrine Reuptake inhibitors on dopaminergic reward-learning signals and prediction of clinical (non-) response in Major Depressive Disorder
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    RELATE-TRD
    A.3.2Name or abbreviated title of the trial where available
    RELATE & PREDICT TRD
    A.4.1Sponsor's protocol code numberRELATE-TRD
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN00014787
    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 Groningen
    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 supportZonMW
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportLundbeck BV
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUCP/UMCG
    B.5.2Functional name of contact pointProf.dr. R.A. Schoevers, head
    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.5.4Telephone number31503612065
    B.5.5Fax number31503611699
    B.5.6E-mailR.A.Schoevers@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 Escitalopram 5mg (RVG 30494) Nortriptyline 10mg (RVG 03285) and 25mg (RVG 03286)
    D.2.1.1.2Name of the Marketing Authorisation holderLundbeck 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 nameescitalopram or nortriptyline
    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 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 placeboCapsule
    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
    Major Depressive Disorder
    E.1.1.1Medical condition in easily understood language
    Depression
    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 16.0
    E.1.2Level PT
    E.1.2Classification code 10012378
    E.1.2Term Depression
    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
    The proposed study aims to examine:
    I. whether MDD-patients with a high TRD-level have diminished reward/reinforcement learning, dysfunctional dopaminergic, glutamatergic and/or GABA-ergic neurotransmission (relative to no-TRD patients/controls)
    II. how treatment with the contemporary antidepressants escitalopram and nortriptyline affect these dysfunctions in no-TRD and high-TRD patients.
    III. prediction of treatment-outcomes within the first weeks of antidepressant treatment
    E.2.2Secondary objectives of the trial
    IV. What changes in serotonine and dopamine occur in platelet poor plasma and platelets after treatment with escitalopram/nortriptyline/placebo, and are these changes mediated by the SERT-genotye and/or miR-16?
    V. Are therapeutic drug monitoring quantifications measured by venous blood sampling or the dried bloood spot method equivalent?
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients:
    - Male or female, age: 20 - 60 years
    - DSM-IV diagnosis of MDD (ascertained by structured interview for DSM-IV (SCID))
    - Hamilton Depression Rating Scale (HDRS17)>18
    - Without or with resistance to previous antidepressant treatment; described as Group I, non-TRD [who used <=1 antidepressant for the current MDD-episode and are currently drug-free] and Group II TRD [who were nonresponsive to >=2 antidepressants (SSRIs and/or SNRIs) during the current MDD-episode].

    Controls:
    - Male or female, age: 20 - 60 years
    - No DSM-IV diagnosis/abuse/dependence (SCID)
    - Inventory for Depressive Symptomatology (IDS-SR) <=14
    - Controls will be matched with participating patients on age (+/-3 years), sex and estimated intelligence with the Dutch adult reading test (DART).
    E.4Principal exclusion criteria
    Patients:
    - Psychotic or Bipolar depression
    - Comorbid current (primary) anxiety disorder
    - Comorbid current abuse/dependence of alcohol, cannabis, cocaine, amphetamine
    - Neurologic or auto-immune disease, hypothyroidism
    - Contra-indications for escitalopram or nortriptyline like earlier non-response (in the current episode)
    - Contra-indications for fMRI-scanning (metal objects in the body, claustrophobia)

    Controls:
    - First degree family history of psychiatric illnesses
    - Contra-indications for fMRI-scanning
    - Neurologic or auto-immune diseases, hypo-/hyperthyroidism
    E.5 End points
    E.5.1Primary end point(s)
    Clinical:
    - decrease in HDRS17-score (continuous scores)
    - response and remission (defined as >=50% decrease in HDRS-17 and HDRS-17<=7, respectively)
    - early improvement in week 2 will be defined as >=20% decrease in HDRS

    Neuroimaging:
    - Pavlovian learning paradigm: BOLD response of prediction errors in VTA/ventral striatum/habenula
    - PET: amphetamine challenged decrease in [11C]Raclopride binding in the striatum
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline: clinical assessment, neurocognitive tests, fMRI and when possible PET scanning
    T0: randomisation
    Week 1-Week 6: clinical visits: assessment of clinical response, adverse effects and adjustment of study drug dosages based on blood levels
    T3 (week 8): clinical assessment, neurocognitive tests, fMRI and when possible PET scanning
    E.5.2Secondary end point(s)
    Clinical:
    - decreases in IDS-SR-30 (continuous scores)
    - early improvement in IDS-SR-30 (>=20% decrease)
    - response (>=50% decrease in IDS-SR-30) and remission (IDS-SR-30<=14)
    - total patient-drop-out and specified as due to inefficacy or adverse effects
    - changes in SHAPS, SRRS, CORE and RRS-NL

    Neuroimaging:
    - voxel-based morphometry (VBM) based volumes of the pgACC, sgACC, dorsal ACC, amygdala, hippocampus and DLPFC
    - resting state scans: group maps of the DMN as determined with an independent component analysis. Seed-region based functional connectivity from a priori RoIs in the amygdala, pgACC, sgACC, ventral striatum/Nucleus accumbens, VTA and habenula
    - MRS-measurements: GABA and glutamate in basal ganglia and pgACC

    Neurocognitive:
    - Exogenous Cueing Task: The 'benefit' ratio of response times on valid emotional trials versus valid neutral trials and the 'delay' ratio of response times on invalid emotional trials compared to the neutral trials
    - Faces Emotional Recognition Task: the percentage of recognition of different facial expressions and the recognition threshold (level of emotional intensity at which participants correctly identify >=75% of the facial expressions of emotion for four consecutive intensities)
    - Emotional Categorization: the percentage correct responses and response times to self-referent items, stratified for positive/negative adjectives
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline: clinical assessment, neurocognitive tests, fMRI and when possible PET scanning
    T0: randomisation
    Week 1-Week 6: clinical visits: assessment of clinical response, adverse effects and adjustment of study drug dosages based on blood levels
    T3 (week 8): clinical assessment, neurocognitive tests, fMRI and when possible PET scanning
    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 Yes
    E.6.8Bioequivalence Yes
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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
    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 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: 165
    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 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 state165
    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)
    - In patients responsive to a study drug the drug will be continued open-label
    - In patients non-responsive to a study drug the drug will be switched to another antidepressant prescribed open-label
    - In patients receiving a placebo an antidepressant will be prescribed open-label
    - In controls drugs will be discontinued
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation RGOc / UMCG
    G.4.3.4Network Country Netherlands
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-20
    P. End of Trial
    P.End of Trial StatusOngoing
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