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    Summary
    EudraCT Number:2017-002636-16
    Sponsor's Protocol Code Number:VUMC-ANW-MS-GG-062017
    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:2017-08-09
    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 number2017-002636-16
    A.3Full title of the trial
    Cognitive impairment and functional reorganization in multiple sclerosis: The role of GABA and glutamate
    Cognitieve achteruitgang en functionele reorganisatie in multiple sclerose: de rol van GABA en glutamaat
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Understanding problems with attention, memory and concentration in persons with multiple sclerosis
    Het begrijpen van problemen met aandacht, geheugen en concentratie bij mensen met Multiple Sclerose.
    A.3.2Name or abbreviated title of the trial where available
    GABA and glutamate in cognitive impairment in MS
    A.4.1Sponsor's protocol code numberVUMC-ANW-MS-GG-062017
    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 SponsorVU University medical center Amsterdam
    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 supportVU University medical center
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVU University medical center
    B.5.2Functional name of contact pointMarijn Huiskamp
    B.5.3 Address:
    B.5.3.1Street AddressBoelelaan 1108
    B.5.3.2Town/ cityAmsterdam
    B.5.3.4CountryNetherlands
    B.5.6E-mailm.huiskamp@vumc.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 name[11C]flumazenil
    D.3.4Pharmaceutical form Solution for injection in administration system
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    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 Yes
    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 typeTo specify the radiopharmaceutical product, it is a radiolabeled tracer to be used in PET research.
    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
    Multiple Sclerosis (MS). And specifically cognitive problems in MS.
    Multiple Sclerose (MS). En in het bijzonder cognitieve problemen geassocieerd met MS.
    E.1.1.1Medical condition in easily understood language
    MS is a disease of the brain and the spinal cord. It causes 'scars' in the white matter. Persons with MS often have difficulties moving and feeling, but also with thinking.
    MS is een ziekte van de hersenen en het ruggemerg. Het veroorzaakt daar 'littekens' in de witte stof. Mensen met MS hebben vaak moeite met bewegen en voelen, maar ook met het denkvermogen.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    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 main objective of this study is to investigate if the occurrence of cognitive impairment and functional reorganization in MS can be explained by changes in GABA and glutamate concentration and GABAA receptor binding. The levels of GABA and glutamate will be measured with Magnetic Resonance Spectroscopy and the binding of GABAA receptors will be assessed with Positron Emission Tomography.
    Het doel van dit onderzoek is te onderzoeken of MS gerelateerde cognitieve achteruitgang en functionele reorganisatie verklaard kan worden door veranderingen in de concentraties van GABA, glutamaat en GABAA receptoren.
    E.2.2Secondary objectives of the trial
    2a. To investigate whether cognitively preserved (CP) and impaired (CI) MS patients differ on levels of glutamate (as measured with MRS).

    2b. To investigate whether the MS patients with and without cognitive impairment differ on levels of GABA (as measured with MRS).

    2c. To investigate whether the MS patients with and without cognitive impairment differ on levels of GABAA receptor binding (as measured with [11C]-flumazenil PET).

    3. To investigate whether functional reorganization can be explained by the characteristics of the glutamate and GABA systems as described above.

    4. To investigate the relationship between the characteristics of the GABAergic and glutamatergic systems and functional connectivity.
    2a. Onderzoeken of cognitief behouden (CP) en cognitief gestoorde (CI) MS patiënten verschillen in de hoeveelheid glutamaat (gemeten met MRS).

    2b. Onderzoeken of cognitief behouden (CP) en cognitief gestoorde (CI) MS patiënten verschillen in de hoeveelheid GABA (gemeten met MRS).

    2c. Onderzoeken of cognitief behouden (CP) en cognitief gestoorde (CI) MS patiënten verschillen in de hoeveelheid GABAA receptoren (gemeten met [11C]flumazenil PET).

    3. Onderzoeken of functionele reorganisatie verklaard kan worden met de karakteristieken van het GABAerge en glutamaterge systeem zoals hierboven beschreven.

    4. Het onderzoeken van de relatie tussen de kenmerken van het GABAerge en glutamaterge systeem en functionele connectiviteit.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To participate in the MRI part of the study:
    - Clinically definite Relapsing Remitting or Secondary Progressive Multiple sclerosis
    - Sufficient visual acuity and motor performance to perform the MRI task
    - Between 18 and 60 years of age

    To participate in the PET-part of the study:
    - Minimum hemoglobin values of 8 g/dl for men and 7 g/dl for women
    Om deel te nemen aan het MRI-deel van deze studie:
    - Klinisch vastgestelde relapsing remitting of secundair progressieve Multiple Sclerose.
    - Voldoende gezichts- en motorisch vermogen om de MRI taak uit te voeren.
    - Tussen de 18 en 60 jaar oud.

    Om deel te nemen aan het PET-deel van de studie:
    - Minimale hemoglobinewaarden van 8 g/dl voor mannen en 7 g/dl voor vrouwen.
    E.4Principal exclusion criteria
    For the MRI-part of the study:
    - MR contraindications
    - Neurological and/or psychiatric disorders (other than MS)
    - For MS patients: the use of corticosteroids in the 4 weeks prior to inclusion.

    For the PET-part of the study:
    - benzodiazepine use or other drug use that affects the benzodiazepine receptor system (e.g. antipsychotics that show strong binding to GABAA receptors) 4 weeks or less before the start of the study.
    - In the case of pregnancy or breastfeeding
    - Insufficient haemoglobin value values as discussed in the inclusion criteria.
    - (a history of) significant cardiac disease
    - exposure to previous radiation leading to an annual cumulative dose of more than 10mSv
    Voor het MRI-deel van de studie:
    - Contraindicaties voor MRI (zoals ferromagnetisch metaal of elektrische apparaten in het lichaam, claustrofobie)
    - Andere neurologische of psychiatrische ziekten dan MS
    - Voor MS patiënten: het gebruik van corticosteroiden in de 4 weken voor inclusie in de studie.

    Voor het PET-deel van de studie:
    - Het gebruik van benzodiazepinen of andere drugs die het benzodiazepine-receptor systeem beïnvloeden (bijvoorbeeld antipsychotica die sterk aan GABAA receptoren binden) 4 weken of minder voor aanvang van de studie.
    - Zwangerschap of borstvoeding
    - Het niet voldoen aan de hemoglobine waarden als hierboven gespecificeerd.
    - (een geschiedenis van) hart-en vaatziekten.
    - Blootstelling aan eerdere straling, leidend tot een jaarlijkse cumulatieve dosis van meer dan 10mSv (milliSievert).
    E.5 End points
    E.5.1Primary end point(s)
    The primary end point of this study is a significant difference in levels of GABA, glutamate and GABAA receptors between healthy controls and cognitively preserved and impaired MS patients. More specifically, we expect differences in the levels of GABA and glutamate in the thalamus and hippocampus and levels of GABAA receptors in the grey matter between the study groups.
    Het primaire eindpunt van deze studie is een significant verschil in hoeveelheid GABA en glutamaat en GABAA receptoren tussen gezonde controles en cognitief behouden en gestoorde MS patiënten. In het bijzonder verwachten we verschillen tussen de studiegroepen in de hoeveelheden GABA en glutamaat in de thalamus en hippocampus en verschillen in hoeveelheid GABAA receptoren in de grijze stof.
    E.5.1.1Timepoint(s) of evaluation of this end point
    There is only one time of measurement in this cross-sectional study. Therefore, there is no timepoint of evaluation of the end point.
    Er is slechts één meetmoment in deze cross-sectionele studie en daarom is er geen tijdspunt voor evaluatie van dit eindpunt.
    E.5.2Secondary end point(s)
    A secondary end point is a significant correlation between the characteristics of the GABAergic and glutamatergic system as described above and levels of functional activation. More specfically, we investigate hippocampal activation during a memory task (using fMRI) and expect the level of the BOLD-signal to be related to the levels of GABA, glutamate and GABAA receptors.
    Een secundair eindpunt is een significante correlatie tussen de kenmerken van het GABAerge en glutamaterge systeem zoals hierboven beschreven en functionele activatie. In het bijzonder onderzoeken we hippocampale activatie tijdens een geheugentaak (dmv fMRI) en verwachten dat de hoogte van het BOLD-signaal verband houdt met het niveau van GABA, glutamaat en GABAA receptoren.
    E.5.2.1Timepoint(s) of evaluation of this end point
    There is only one time of measurement in this cross-sectional study. Therefore, there is no timepoint of evaluation of the end point.
    Er is slechts één meetmoment in deze cross-sectionele studie en daarom is er geen tijdspunt voor evaluatie van dit eindpunt.
    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 Yes
    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
    Etiology. We attempt to understand if the occurrence of cognitive impairment in MS is related to changes in the GABAergic and glutamatergic systems.
    Etiologie. We willen begrijpen of het ontstaan van cognitieve problemen bij MS gerelateerd is aan veranderingen in het GABAerge en/of glutamaterge systeem.
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 No
    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
    LVLS
    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 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: 75
    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 state75
    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 Decision2017-08-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-10-09
    P. End of Trial
    P.End of Trial StatusOngoing
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