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    Summary
    EudraCT Number:2020-000784-23
    Sponsor's Protocol Code Number:KKS-276
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-07-22
    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 ConcernedGermany - BfArM
    A.2EudraCT number2020-000784-23
    A.3Full title of the trial
    The effects of esketamine and treatment expectation in acute major depressive disorder: a pharmacological fMRI-study (Expect)
    Die Effekte von Behandlungserwartung an Esketamin vs. Placebo bei akuter majorer Depression: eine pharmakologische fMRT-Studie (Expect)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The effects of esketamine and treatment expectation in acute major depressive disorder
    Die Effekte von Behandlungserwartung an Esketamin vs. Placebo bei akuter majorer Depression
    A.4.1Sponsor's protocol code numberKKS-276
    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 SponsorPhilipps-Universität Marburg
    B.1.3.4CountryGermany
    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 supportDeutsche Forschungsgemeinschaft (DFG)
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKoordinierungszentrum für Klinische Studien (KKS)
    B.5.2Functional name of contact pointKKS Marburg
    B.5.3 Address:
    B.5.3.1Street AddressKarl-von-Frisch-Str. 4
    B.5.3.2Town/ cityMarburg
    B.5.3.3Post code35043
    B.5.3.4CountryGermany
    B.5.4Telephone number+4964212826618
    B.5.5Fax number+4964212866517
    B.5.6E-mailyasmin.moran@kks.uni-marburg.de
    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 Ketanest S
    D.2.1.1.2Name of the Marketing Authorisation holderPFIZER PHARMA PFE GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameKetanest S
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEsketamin-Hydrochlorid
    D.3.9.1CAS number 6740-88-1
    D.3.9.4EV Substance CodeSUB08365MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 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
    To unravel the neural correlates of the interaction between positive expectation (high/low) and single dose antidepressant treatment (verum/placebo) with esketamine in patients with major depressive disorder
    E.1.1.1Medical condition in easily understood language
    To unravel the interaction between positive expectation and single dose antidepressant treatment with esketamine in patients with major depressive disorder

    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 20.0
    E.1.2Level SOC
    E.1.2Classification code 10037175
    E.1.2Term Psychiatric disorders
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10081270
    E.1.2Term Major depressive disorder
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10057840
    E.1.2Term Major 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
    Major depressive disorder (MDD) is highly prevalent (8-15%), severely disabling and associated with enormous socioeconomic impact. Antidepressant medication for the treatment of MDD has proven effective in randomized controlled trials (RCTs), however, placebo response is substantial and has been increasing over the last 3 decades.
    In this double-blind, randomized, controlled parallel-group, 4-arm, monocenter trial project we will employ the factors ‘treatment’ (intravenous esketamine / placebo, single application) and verbally induced ‘expectation’ (high / low) combined with functional magnetic resonance imaging (fMRI, resting state, emotion and reward processing paradigms, on the same day as the esketamine/placebo treatment) to investigate the psychological and neural mechanisms underlying the antidepressant effects of expectation, and how these interact with the pharmacological effects of esketamine.
    E.2.2Secondary objectives of the trial
    Not appicable
    See secondery endpoints below
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. a current depressive episode lasting at least four weeks
    2. an initial score of at least 7 (corresponding to a mild degree of depression) on the Montgomery Åsberg Depression Rating Scale (MADRS)
    3. Negative serum pregnancy test in women of childbearing potential.
    4. Patients with reproductive potential must agree to maintain highly effective methods of contraception by practicing abstinence or by using at least two methods of birth control from the date of consent through the end of the study. If abstinence could not be practiced, a combination of hormonal contraceptive (oral, injectable, or implants) and a barrier method (condom, diaphragm with a vaginal spermicidal agent) has to be used.
    E.4Principal exclusion criteria
    1. psychotic symptoms (ascertained using SCID-5 Interview measured by module A-E)
    2. acute suicidality (clinical assessment by study physician)
    3. hypertension > 180/100 mmHg (according to resting blood pressure, as assessed by study physician using blood pressure measurement)
    4. hyperthyroidism that has not been sufficiently treated (clinical history by study physician and current thyroid parameters will have to be within the following ranges: TSH 0,34-5,6 mU/l, fT3 3,2-6,9 pmol/l, fT4 7,5-21 pmol/l)
    5. severe hepatic impairment (clinical history by study physician and current liver parameters will have to be within the following ranges: serum albumin < 2,8 g/dl serum bilirubin > 3,0mg/dl, prothrombin time < 40 % or INR > 2,3)
    6. hypersensitivity to the active substance of esketamine or to any of the excipients listed in section 6.1 of the SmPC (clinical history by study physician)
    7. unstable angina or myocardial infarction in the last 6 months (clinical history by study physician)
    8. Myocardial failure (clinical history and physical examination by study physician)
    9. Glaucoma or perforating eye injuries (clinical history by study physician)
    10. patients will be excluded if they have any drug or alcohol dependency/abuse within the previous three months or if they are under acute influence of alcohol (clinical assessment by study physician and alcohol breath test)
    11. any contraindications for MRI, i.e. non-removable medical devices (such as pacemakers, insulin pumps, implantable drug infusion pumps etc) or metal devices /foreign bodies (such as aneurysm clips, metal splinters in the eye , intrauterine devices etc) and pregnancy (clinical assessment by study physician and serum pregnancy test)
    12. medical conditions likely to affect brain anatomy or physiology (clinical assessment by study physician)
    13. age <18 or > 65 years
    14. inability to provide written informed consent
    15. Breastfeeding (clinical history by study physician)
    16. simultaneous participation in other clinical trials if not permitted by the Principal Investigator
    17. Patients for whom an elevated blood pressure or an increased intracranial pressure represents a serious risk will be excluded (clinical history and blood pressure measurement by study physician)
    18. Patients with manifest ischemic heart diseases will be excluded (clinical history by study physician)
    19. Increased intracranial pressure (clinical history by study physician)
    20. Severe psychological disorders other than depression (Structured Clinical Interview for DSM-5 (SCID-5) measured by module A-E)
    21. Concomitant therapy with Xanthin-derivates and ergometrin (clinical history by study physician)
    22. Treatment with strong inhibitors or inducers of CYP3A4 (for example, but not exclusively, HIV protease inhibitors, Macrolide antibiotics, Azole antifungals, Carbamazepine, Phenobarbital; clinical history by study physician)
    23. Diazepam treatment (clinical history by study physician)
    E.5 End points
    E.5.1Primary end point(s)
    Brain activation in networks implicated in (i) reward and (ii) emotion processing, (iii) placebo and (iv) antidepressant treatment response in MDD and (v) the pathophysiology of MDD (in particular the ventromedial prefrontal cortex [VMPFC], rostral anterior cingulate cortex (rACC), amygdala and hippocampus).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The evaluation will performed during one single day (visit 1)
    E.5.2Secondary end point(s)
    • Behavioural reaction times and hit rates in the Monetary Incentive Delay task.
    •Changes in depressive symptoms (self-rating beck depression inventory [BDI-II], expert rating Montgomery Åsberg Depression Rating Scale [MADRS]) in response to high vs. low expectation and placebo vs. esketamine.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The evaluation will performed 4 hours, 2, 3 and 6 days after visit 1
    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 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 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 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 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 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
    End of the study is defined as "Last patient Out" and database closure.
    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 months39
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months39
    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: 176
    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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state176
    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
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-11-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-05
    P. End of Trial
    P.End of Trial StatusCompleted
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