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    Summary
    EudraCT Number:2017-004823-66
    Sponsor's Protocol Code Number:ELTCAN1
    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:2019-03-19
    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 number2017-004823-66
    A.3Full title of the trial
    Early-life stress, the endocannabinoid system, and fear memory extinction
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Early-life stress, the endocannabinoid system, and fear memory extinction
    A.4.1Sponsor's protocol code numberELTCAN1
    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 SponsorRadboudumc
    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 supportRadboudumc
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRadboudumc
    B.5.2Functional name of contact pointDept Psychiatry Radboudumc
    B.5.3 Address:
    B.5.3.1Street AddressReinier Postlaan 10
    B.5.3.2Town/ cityNijmegen
    B.5.3.3Post code6500HB
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31243613490
    B.5.5Fax number+3124361
    B.5.6E-mailrobbert-jan.verkes@radboudumc.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 No
    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 nameNamisol
    D.3.2Product code ECP002A
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNamisol
    D.3.9.1CAS number 1972-08-03
    D.3.9.3Other descriptive nameDELTA-9-TETRAHYDROCANNABINOL
    D.3.9.4EV Substance CodeSUB27785
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number7.5
    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.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 Hydrocortison CF
    D.2.1.1.2Name of the Marketing Authorisation holderCentrafarm 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.3.1Product nameHydrocortison CF
    D.3.2Product code RVG 50730
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHydrocortison CF
    D.3.9.3Other descriptive nameHYDROCORTISONE
    D.3.9.4EV Substance CodeSUB08065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 placeboTablet
    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
    healthy volunteers
    gezonde vrijwilligers
    E.1.1.1Medical condition in easily understood language
    intended indication: posttraumatic stress disorder (PTSD)
    beoogde indicatie: posttraumatic stress disorder (PTSD)
    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 LLT
    E.1.2Classification code 10036876
    E.1.2Term Prolonged posttraumatic stress disorder
    E.1.2System Organ Class 100000004873
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective: Our key objective is to determine if a cannabinoid manipulation is more effective than a glucocorticoid manipulation to facilitate fear memory extinction retention in an experimental model of exposure therapy in healthy individuals with early life stress.
    Het primaire doel van dit onderzoek is nagaan of het toedienen van een cannabinoïd effectiever is dan dat van een corticosteroïd om het uitdoven (extinctie) van angst-herinneringen makkelijker te maken. Wij zullen dat doen in een experimenteel model van exposure therapie in gezonde individuen met stress in de vroege kindertijd.
    E.2.2Secondary objectives of the trial
    Secondary objectives:

    1) To investigate the diverging effects of THC and hydrocortisone on the activation of relevant brain structures (e.g., hippocampus, amygdala and left anterior temporal lobe) during autobiographic memory retrieval in groups with and without ELS.

    2) To investigate the diverging effects of THC and hydrocortisone on the activation of the amygdala during processing of biologically salient stimuli in groups with and without ELS.

    3) To compare the structural morphology (grey matter, white matter) between groups with and without ELS.

    4) To detect the influence of ELS on biological markers of endocannabinoid function
    (e.g., the endocannabinoids 2-AG and AEA, CB1 gene DNA-methylation and CB1 receptor expression).
    Secundaire doelen:
    1) Het onderzoeken van de uiteenlopende effecten van THC en hydrocortison op de activiteit van relevante hersenstructuren (bijv. hippocampus, amygdala en linker anterieure temporaal lob) tijdens het ophalen van autobiographische herinneringen in groepen met en zonder ELS.

    2) Het onderzoeken van de uiteenlopende effecten van THC en hydrocortison op de activiteit van de amygdala tijdens het verwerken van biologisch belangrijke prikkels in groepen met en zonder ELS.

    3) Het vergelijken van de structurele morfologie (grijze stof, witte stof) tussen groepen met en zonder ELS.

    4) Het vast stellen van het effect van ELS op biologische ‘markers’ van het functioneren van het (bijv. endocannabinoïden (AEA en 2-AG), CB1 gen DNA-methylatie en CB1 receptor expressie)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    There will be two groups of healthy volunteers, with and without early life stress experiences (ELS)

    Inclusssion criteria:
    For both groups:

    -Healthy volunteers between 18 and 45 years of age
    -Predominant right-handedness.
    -History of taking cannabis.

    For ELS group:

    -Comply the inclusion standard with questionnaires: “Maltreatment and Abuse Chronology of Exposure Scale (MACE-X)”. There are 10 subscales in MACE-X, the criterion for each subscale is listed here, all types of exposure of trauma should be before ten years old. There are six subscales which are very relevant to severe childhood maltreatment: Emotional Neglect, Parental Nonverbal Emotional Abuse, Parental Physical Maltreatment, Parental Verbal Abuse, Sexual Abuse, or Witnessing Interparental Violence. Participant should reach at least one criterion of those six subscales to be included for certain types of childhood maltreatment:
    In emotional neglect subscale, ( the cut-off is 2 items out of 5 ).
    In non-verbal emotional abuse subscale, ( the cut-off is 4 out of 6).
    In parental physical maltreatment subscale, ( the cut-off is 4 items).
    In parental verbal abuse subscale, ( the cut-off is 3 items out of 4).
    In sexual abuse subscale, ( the cut-off is 2 items out of 7).
    In witnessing interparental violence subscale, ( the cut-off is 2 items out of 5).
    There are four subscales which are less relevant to severe childhood maltreatment, the criterion of each subscale are listed here below, if participants only fulfil the criteria of any one or more of those four subscales, they will not be included in ELS group:
    In peer emotional abuse subscale, ( the cut-off is 4 items out of 5 ).
    In peer physical bullying subscale, ( the cut-off is 2 items out of 5 ).
    In physical neglect, ( the cut-off is 2 items out of 5 ).
    In witnessing violence to siblings subscale, ( the cut-off is 1 items out of 4 ).

    For Non-ELS group: Since we need to recruit participants in control group with no experiences of early-life stress, thus we will include people who score 0 on six very relevant to severe childhood maltreatment (SCM) subscales and also below threshold of other four less relevant to severe childhood maltreatment (LSCM) subscales in “Maltreatment and Abuse Chronology of Exposure Scale (MACE-X)”.
    Er zullen twee groepen zijn: gezonde vrijwilligers met en zonder 'early life stress experiences' (ELS)

    Inclusie criteria:
    Voor beide groepen:

    - Gezonde vrijwilligers, tussen 18 en 45 jaar oud
    - Rechtshandig
    - Voorgeschiedenis van cannabisgebruik.

    Voor de ELS groep:

    Voldoen aan het inclusiecriterium van het instrument: “Maltreatment and Abuse Chronology of Exposure Scale (MACE-X)”. Er zijn 10 subschalen in MACE-X. Het criterium voor elke subschaal is hieronder gegeven, all typen van blootstelling aan trauma moeten voor het tiende jaar zijn geweest. Er zijn zes subschalen die zeer relevant zijn voor ernstige mishandeling in de kindertijd: ‘Emotional Neglect’, ’Parental Nonverbal Emotional Abuse’, ‘Parental Physical Maltreatment’, ‘Parental Verbal Abuse’, ‘Sexual Abuse’, en ‘Witnessing Interparental Violence’. Deelnemers dienen tenminste te scoren io een van deze zes subschalen:
    In de cemotional neglect subschaal ( de cut-off is 2 items van de of 5 ).
    In de non-verbal emotional abuse subschaal, (de cut-off is 4 van de 6).
    In de parental physical maltreatment subschaal, (de cut-off is 4 items).
    In de parental verbal abuse subschaal, ( de cut-off is 3 items van de 4).
    In de sexual abuse subschaal, ( de cut-off is 2 items van de 7).
    In de witnessing interparental violence subschaal, ( de cut-off is 2 items van de 5).
    Er zijn vier subschalen die minder belangrijk zijn voor ernstige mishandeling in de kindertijd: het criterium voor elke subschaal is hieronder gegeven. Als personen enkel de aan criteria voldoen voor een of meer van deze vier subschalen, zullen niet ingedeeld worden in de ELS groep:
    In de peer emotional abuse subschaal, (de cut-off is 4 items van de 5 ).
    In de peer physical bullying subschaal, (de cut-off is 2 items van de 5 ).
    In de physical neglect, (de cut-off is 2 items van de 5 ).
    In de witnessing violence to siblings subschaal, (de cut-off is 1 items van de 4).

    Voor de non-ELS groep: We willen in deze groep deelnemers recruteren die geen stressvolle gebeurtenissen hebben doorgemaakt in de kindertijd. Zij dienen niet te scoren op de zes subschlen betreffende ernstige trauma’s op de MACE-X en onder de drempel van vier op de minder belangrijke subschalen van de MACE-X.
    E.4Principal exclusion criteria
    For both groups:

    - Body mass index lower than 18.5 or higher than 30.
    - Abnormal hearing or (uncorrected) vision.
    - Average use of psychotropic medication or recreational drugs weekly or more.
    - Habitual smoking, i.e. more than a package of cigarettes per week and a self-reported
    inability or unease to cease smoking for 24 hours prior to testing.
    - Use of psychotropic medication, or of recreational drugs over a period of one week prior to each test session, and use of alcohol within the last 24 hours before each measurement.
    - Regular use of corticosteroids.
    - History of psychiatric treatment or current psychiatric treatment. (e.g., severe mood disorders, mania, anorexia nervosa, schizophrenia or borderline personality disorder)
    - History of neurological treatment or current neurological treatment.
    - History of endocrine treatment or current endocrine treatment. (e.g., pheochromocytoma, hyperthyroidism, Cushing’s syndrome)
    - History of repeated (more than once) of autonomic failure (e.g., vasovagal reflex syncope).
    - Contraindications for MRI scanning (e.g., pacemaker, implanted metal parts, deep brain stimulation, claustrophobia)
    - Use of medication that may interact with THC or hydrocortisone, for THC, taking Rifampicin, Ketoconazole, and Omeprazole at this moment; For Hydrocortisone, taking taking mifepristone at this moment.
    - Cognitive impairment (MMSE < 26)
    - Pregnancy
    - Night shift work
    Voor beide groepen:

    - Body mass index lager dan 18.5 of hoger dan 30.
    - Abnormaal gehoor of (ongecorrigeerd) abnormale visus.
    - Gebruik van psychotrope medicatie of vaker dan 1 keer per week recreationele drugs, en gebruik van alcohol binnen 24 uur voor de metingen.
    - Roken, meer dan een pak cigaretten per week en een zelf-gerapporteerd onvermogen om 24 uur voor de testdag te stoppen.
    - Regulier gebruik van corticosteroiden.
    - Voorgeschiedenis van psychiatrische behandeling of huidige psychiatrische behandeling. (bijv. ernstige stemmings stoornis, manie, anorexia nervosa, schizofrenie of borderline persoonlijkheidsstoornis)
    - Voorgeschiedenis van neurologische behandeling of huidige neurologische behandeling.
    - Voorgeschiedenis van endocrinlogische behandeling of huidige endocrinlogische behandeling (bijv. pheocromacytoma, hyperthyroidisme, Cushing’s syndroom).
    - Voorgeschiedenis van herhaalde autonome problemen (bijv. vasovagale collaps).
    - Contraindicaties voor MRI scanning (bijv. pacemaker, geimplanteerde metalen delen, deep brain stimulation, claustrofobie)
    - Gebruik van medicatie die kan interacteren met THC of hydrocortison, voor THC, bijv. rifampicin, ketoconazole, en omeprazole; voor hydrocortison, bijv. mifepristone.
    - Cognitieve beperkingen (MMSE < 26)
    -Zwangerschap
    - Nachtdiensten
    E.5 End points
    E.5.1Primary end point(s)
    Autonomic nervous system measurement (skin conductance, heart rate, and pupil dilation responses) and subjective scores on 5-point scale to rate the expectancy of the appearance of the unconditioned stimuli (USs) to fear-conditioned stimuli one day after extinction (i.e., safety learning).
    Metingen van het niveau van activiteit van het autonome zenuwstelsel (huidgeleiding, hartslagfrequentie, pupil verwijding) en subjectieve scores op een 5-punt schaal om de mate van verwachting van het optreden van de ‘unconditioned stimuli’ (USs) bij angst-geconditioneerde stimuli een dag na extinctie (d.w.z. het leren dat de stimuli veilig zijn)) te meten.
    E.5.1.1Timepoint(s) of evaluation of this end point
    One day after drug administration
    Een dag na toediening van de onderzoeksmedicatie
    E.5.2Secondary end point(s)
    Neuroimaging data (functional and structural neuro images), chemical data (in saliva, and blood),self-report questionnaires
    Neuroimaging gegevens (functionele en structurele opnames), chemische bepalingen (in speeksel en bloed), zelf-rapportage vragenlijsten
    E.5.2.1Timepoint(s) of evaluation of this end point
    Directly after drug administration
    Direct na toediening van de onderzoeksmedicatie
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.6Cross over Yes
    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 Yes
    E.8.2.3.1Comparator description
    hydrocortison
    hydrocortisone
    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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years32
    E.8.9.1In the Member State concerned months
    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: 48
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 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 state48
    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
    Geen
    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 Decision2019-04-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-12
    P. End of Trial
    P.End of Trial StatusOngoing
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