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    Summary
    EudraCT Number:2020-005954-78
    Sponsor's Protocol Code Number:100-059
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-04-30
    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 ConcernedFrance - ANSM
    A.2EudraCT number2020-005954-78
    A.3Full title of the trial
    Exploring P-glycoprotein-mediated efflux transport at the blood-brain barrier as a biomarker of drug-resistance in focal epilepsy
    Etude du transport d’efflux par la P-glycoprotéine au niveau de la barrière hémato-encéphalique de patients atteints d’épilepsie focale
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    To study the potential of P-glycoprotein-mediated efflux transport of [11C]metoclopramide as a biomarker of drug-resistance in epilepsy
    Étudier le potentiel du transport du [11C]métoclopramide par efflux médié par la glycoprotéine P comme biomarqueur de la résistance aux médicaments dans l'épilepsie
    A.3.2Name or abbreviated title of the trial where available
    EPIFLUX
    A.4.1Sponsor's protocol code number100-059
    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 SponsorCEA
    B.1.3.4CountryFrance
    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 supportANR
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCEA
    B.5.2Functional name of contact pointClinicaltrials vigilance
    B.5.3 Address:
    B.5.3.1Street AddressCEA Saclay
    B.5.3.2Town/ cityGif sur Yvette
    B.5.3.3Post code91190
    B.5.3.4CountryFrance
    B.5.4Telephone number33169087460
    B.5.5Fax number33169087125
    B.5.6E-mailclinicaltrialsvigilance.shfj@cea.fr
    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]metoclopramide
    D.3.4Pharmaceutical form 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 INNMETOCLOPRAMIDE
    D.3.9.1CAS number 364-62-5
    D.3.9.4EV Substance CodeSUB08902MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number100
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Investigation in healthy volunteers and epilepsy patients
    E.1.1.1Medical condition in easily understood language
    Investigation in healthy volunteers and epilepsy patients
    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
    To assess via 11C-metoclopramide PET the P-gp function at the blood brain barrier of patients with epilepsy
    Etudier les propriétés d'efflux par la P-gp au niveau de la barrière hémato-encéphalique grâce à l'imagerie TEP au 11C-metoclopramide chez des patients atteints d'épilepsie.
    E.2.2Secondary objectives of the trial
    •To evaluate the sensitivity of 11C-metoclopramide to localize epileptogenic foci in DRE
    •To study the brain kinetics of 11C-metoclopramide in focal lesions of patients with DRE and healthy controls
    •To address the hypothesis of heterogeneity of P-gp function between seizure onset zones in patients with multiregional epilepsy (investigate the possible presence of individual drug-resistant foci).
    •To assess the feasibility to discriminate drug resistant from drug sensitive epileptogenic foci
    •To test a compartmental model for quantification of 11Cmetoclopramide brain PET in epilepsy patients as well as the implementation of an image derived input function (IDIF)
    •To assess radiolabeled metabolites of 11C-metoclopramide in plasma as and measure therapeutic drug levels
    •To retrospectively correlate the impact of ABCB1single nucleotide polymorphisms (SNPs) on brain distribution of 11C-metoclopramide
    •To measure the plasma free fraction (fP) of 11C-metoclopramide
    •Evaluer la sensibilité du 11C-metoclopramide pour détecter et localiser les FE chez des patients atteints d'EPR sans lésion structurelle
    •Etudier la cinétique cérébrale du 11C-metoclopramide au niveau des foyers épileptogènes de patients PR
    •Tester l'hypothèse d'une hétérogénéité fonctionnelle de la P-gp entre les FE chez les patients atteints d'épilepsie multifocale. Evaluer la possibilité pour un foyer d'être intrinsèquement PR.
    •Etudier la possibilité de distinguer un foyer PR d'un foyer PS par l'imagerie.
    •Mettre au point et évaluer une méthode de quantification des données d'imagerie cérébrales obtenues avec le 11C-metoclopramide qui ne nécessite pas de prélèvement artériel.
    •Etudier le métabolisme du 11C-metoclopramide et sa fixation aux protéines plasmatiques (fP).
    •Mesurer les concentrations sanguines des médicaments antiépileptiques
    •Corréler les données cinétiques cérébrales du 11C-metoclopramide avec le polymorphisme génétique du gène de la P-gp (SNP ABCB)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Age: ≥18 years old<65
    •Ability to comprehend the full nature and purpose of the study, including possible risks.
    •Diagnosis:
    oGroup 1: patients with drug-resistant epilepsy without structural lesions the suspected epileptogenic outbreak will be delineated based on the results of phase 1 of the pre-surgical work-up.
    oGroup 2: patients with epileptogenic structural lesionals and drugresistant epilepsy with the exception of patients whose epilepsy is linked to the presence of a tumor such as a grade 2 glioma); the suspected epileptogenic focus will be delineated based on the results of the phase 1 pre-surgical workup.
    oGroup 3: patients with medically controlled focal epilepsy not having had a crisis for at least 1 year.
    oGroup 4: Patients with multifocal epilepsy, which may or may not include subjects with lesional epilepsy.
    oGroup 5: Patients with idiopathic generalized epilepsy phamacoresistant well-characterised on EEG
    oGroup 6: Healthy volunteers
    •Physical examination and laboratory analysis (standard biochemistry, blood count, coagulation test): no presence of clinically relevant abnormal findings or values which the investigator considers may interfere with the objectives of the present study
    •No additional neurological or other diseases, which the investigator considers may affect the outcome of the study
    •Age: ≥18 ans<65
    •Aptitude à comprendre la nature et les objectifs de l'étude et d'en apprécier les risques.
    •Diagnostic:
    oGroupe 1: Patients atteints d'épilepsie pharmaco-résistante (EPR) non-lésionnelle ; le foyer épileptogène suspecté sera délimité à partir des résultats de la phase 1 du bilan pré-chirurgical.
    oGroupe 2: Patients atteints d'épilepsie pharmaco-résistante (EPR) lésionnelle (à l'exception de patients dont l'épilepsie est liée à la présence d'une tumeur comme un gliome de grade 2) ; le foyer épileptogène suspecté sera délimité à partir des résultats de la phase 1 du bilan pré-chirurgical.
    oGroupe 3: Patients atteints d'épilepsie focale contrôlée, n'ayant pas fait de crise depuis au moins 1 an.
    oGroupe 4: Patients atteints d'épilepsie multifocale pouvant inclure des sujets atteints d'épilepsie lésionnelle ou non.
    oGroupe 5: Patients atteints d'épilepsie généralisée idiopathique pharmaco-résistante bien caractérisée sur l'EEG
    oGroupe 6: Sujets sains (sujets contrôle)
    •Examen médical physique et biologique (bilan coagulation(volontaire seulement)). Absence d'anomalie clinique ou de résultat biologique pouvant interférer avec les objectifs de l'étude à l'appréciation des investigateurs.
    •Absence de trouble neurologique ou de pathologie autre que l'épilepsie pouvant compromettre les objectifs de l'étude selon les
    investigateurs.
    E.4Principal exclusion criteria
    • Unwillingness to sign the informed consent
    • Any abnormality found as part of the pre-treatment screening or in any of the performed laboratory tests that the investigator considers to interfere with the objectives of the study
    • Intake of medication during two weeks before the start of the study, which the investigator considers may affect the validity of the study. Furthermore, intake of any drugs which may cause potential harm to the subject (e.g. anticoagulation for subjects undergoing arterial cannulation) is forbidden.
    • Changes in medication within 2 weeks before the scan, which the investigator considers may affect the validity of the study
    • Any disease or condition (e.g. pregnancy, breastfeeding, evolutive tumor) which the investigator considers may affect the subject’s safety or outcome of the study
    • Exposure to radiation exceeding the allowed maximum foreseen by the current guidelines
    • History of ethanol dependence and currently abstinent
    • Inability to comprehend the full nature and purpose of the study
    • Contraindication for PET or MR imaging e.g. claustrophobia, metallic endoprosthesis, non-MR safe implants
    • Subject participating in a parallel drug study/ radiotraceur <1year
    • Vulnerable person (person under guardianship, curatorship)
    • Refus de signer le consentement
    • Toute anomalie de l’examen Clinique ou des résultats biologiques (bilan coagulation pour les volontaires) observée lors du bilan d’inclusion qui pourrait, selon les investigateurs, interférer avec les objectifs de l’étude.
    • Prise de médicaments dans les 2 semaines précédant l’étude qui pourraient, selon les investigateurs, compromettre la validité des résultats. La prise de médicament qui pourrait mettre en danger les sujets est formellement interdite (ex. Prise d’anticoagulants chez les sujets pour lesquels la pose d’un cathéter artériel est prévue).
    • Changement de traitement dans les deux semaines avant l’étude qui pourrait, selon les investigateurs, compromettre la validité des résultats.
    • Toute pathologie ou tout état (ex. Tumeur évolutive, grossesse, allaitement) que les investigateurs considèrent comme pouvant compromettre la sécurité du sujet ou les objectifs de l’étude.
    • Exposition aux rayonnements supérieure aux limites fixées par la réglementation.
    • Historique d’addiction à l’alcool.
    • Contre-indication à la réalisation d’examens d’imagerie TEP ou IRM (ex. claustrophobie, prothèse métallique, implants dont la compatibilité avec l’IRM n’a pas été démontrée).
    • Participation en parallèle à une étude sur un médicament / radiopharmaceutique <1an
    • Personnes protégées (tutelle, curatelle
    E.5 End points
    E.5.1Primary end point(s)
    kE,brain = elimination slope for radioactivity washout from the brain
    kE,brain = pente d'élimination pour le lavage de la radioactivité du cerveau
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of study
    E.5.2Secondary end point(s)
    • kE,brain map = Parametric approach: radioactivity washout from the brain efflux clearance calculated for each pixel and expressed as map.
    • 11C-metoclopramide pharmacokinetics in the blood over time
    • 11C-metoclopramide parent fraction = 11C-metoclopramide metabolism in epilepsy patients (and the influence of co-medication and antiepileptic drug levels on it)
    • K1, k2 and VT = compartmental modeling outcome parameters influx rate constant from plasma into brain/epileptic focus (K1), efflux rate constant from brain/epileptic focus into plasma (k2) and volume of distribution (VT) calculated from image derived input function (IDIF) (IDIF results will be validated with arterial blood sampling from a subgroup of patients)
    • ABCB1 single nucleotide polymorphisms
    • (fP) free fraction of 11C-metoclopramide fraction in plasma
    • kE,brain = pente d’élimination de la radioactivité du cerveau obtenue à partir de cartes paramétriques
    • Pharmacocinétique sanguine (veineuse, ou veineuse/artérielle chez les sujets sains, du 11C-metoclopramide
    • Proportion du 11C-metoclopramide inchangé (non-métabolisé) dans le sang au cours du temps (et influence des co-médications et de leurs concentrations sanguines sur celle-ci)
    • K1, k2 et VT = Paramètres pharmacocinétiques issus de la modélisation compartimentale comme le volume de distribution (VT), la constante d’influx du sang vers le cerveau (K1) et la constante d’efflux du cerveau vers le sang (k2). Ces paramètres sont estimés à partir des données issues des prélèvements de sang artériel chez les volontaires sains afin de valider une méthode permettant de s’en affranchir chez les patients (fonction d’entrée dérivée de l’image).
    • Polymorphisme génétique (SNP) du gène ABCB1
    • Fraction libre (non liée aux protéines plasmatique) du 11C-metoclopramide fP)
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    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 Yes
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    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 years4
    E.8.9.1In the Member State concerned months3
    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: 100
    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 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 state100
    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
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-08-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-13
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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