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    Summary
    EudraCT Number:2015-001202-34
    Sponsor's Protocol Code Number:PK-NAF-RMN
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-08
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-001202-34
    A.3Full title of the trial
    A preliminary, multicenter study on the relationship between cortical damage and blood brain barrier damage in Multiple Sclerosis patients with high cortical disease activity. Correlation between [11C]-PK-11195 or [18F]-NAF PET (Positron Emission Tomography) and high field MRI (Magnetic Resonance Imaging): a synergistic effect by using a double-technique approach.
    STUDIO ESPLORATIVO, PILOTA, MULTICENTRICO SULLA RELAZIONE TRA DANNO CORTICALE E DINAMICA DEL DANNO DELLA BARRIERA EMATO-ENCEFALICA IN PAZIENTI AFFETTI DA SCLEROSI MULTIPLA E CON ALTA ATTIVIT¿ CORTICALE DI MALATTIA. CORRELAZIONE TRA [11C]-PK-11195 O [18F]-NAF PET (TOMOGRAFIA AD EMISSIONE DI POSITRONI) E RM (RISONANZA MAGNETICA) AD ALTO CAMPO: EFFETTO SINERGICO DI DUE METODICHE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A preliminary, multicenter study on the relationship between cortical damage and blood brain barrier damage in Multiple Sclerosis patients with high cortical disease activity,
    STUDIO ESPLORATIVO MULTICENTRICO DI CONFRONTO TRA RISONANZA MAGNETICA E TOMOGRAFIA AD EMISSIONE DI POSITRONI (MEDIANTE UTILIZZO DEL TRACCIANTE, [11C]-PK-11195 E DEL TRACCIANTE [18F]-NAF, UTILIZZATI PER INDIVIDUARE RISPETTIVAMENTE DANNO CORTICALE E DANNO ALLA BARRIERA EMATO- ENCEFALICA) VOLTO A VALUTARE SE LE DUE TECNICHE UTILIZZATE POSSANO MIGLIORARE QUALITATIVAMENTE L¿IMAGING CEREBRALE
    A.3.2Name or abbreviated title of the trial where available
    A preliminary, multicenter study on the relationship between cortical damage and blood brain barrier
    STUDIO ESPLORATIVO, PILOTA, MULTICENTRICO SULLA RELAZIONE TRA DANNO CORTICALE E DINAMICA DEL DANNO D
    A.4.1Sponsor's protocol code numberPK-NAF-RMN
    A.5.4Other Identifiers
    Name:PK-NAF-RMN Number:PK-NAF-RMN
    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 SponsorAZIENDA OSPEDALIERA UNIVERSITARIA INTEGRATA VERONA
    B.1.3.4CountryItaly
    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 supportOspedale Sacro Cuore Don Calabria Negrar
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAzienda Ospedaliera Universitaria Integrata Verona- UOC di Neurologia
    B.5.2Functional name of contact pointUOC di Neurologia B
    B.5.3 Address:
    B.5.3.1Street AddressP.le L. A. Scuro, 10
    B.5.3.2Town/ cityVerona
    B.5.3.3Post code37134
    B.5.3.4CountryItaly
    B.5.4Telephone number0458124768
    B.5.5Fax number0458027492
    B.5.6E-mailsupporto.noprofit@ospedaleuniverona.it
    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 nameNa18F
    D.3.2Product code Na18F
    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.3.9.2Current sponsor codeNaF
    D.3.10 Strength
    D.3.10.1Concentration unit Ci/kg curie(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 No
    D.IMP: 2
    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]-PK-11195
    D.3.2Product code [11C]-PK-11195
    D.3.4Pharmaceutical form Suspension 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.3.9.2Current sponsor code[11C]-PK-11195
    D.3.10 Strength
    D.3.10.1Concentration unit Ci/kg curie(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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
    Multiple Sclerosis
    Sclerosi Multipla
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis
    Sclerosi Multipla
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10039720
    E.1.2Term Sclerosis multiple
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objectives of this study are:
    - to verify the usefulness of PET imaging in Multiple Sclerosis and to confirm its sensitivity in demonstrating grey matter damage, even improving or integrating MRI imaging, from qualitative (by showing the presence of damaged grey matter, not detected by MRI) and quantitative (by grading the grey matter lesion activity) point of view;
    - to evaluate the PK11195 or NaF ability to show micro-structural changes within the Normal Appearing Grey Matter, thus improving the spatial and functional resolution of MRI.
    Obiettivo primario dello studio ¿ verificare l¿applicabilit¿ della PET nella Sclerosi Multipla confermando che essa risulta sensibile nei confronti del danno a carico della sostanza grigia visibile alla RM eventualmente migliorando od integrando il risultato della RM sia sotto l¿aspetto quantitativo (evidenza di tessuto danneggiato non visibile alla RM) sia sotto quello qualitativo (evidenziando importanti aspetti aggiuntivi come lo stato di attivit¿ delle lesioni in sostanza grigia). Valutare inoltre la capacit¿ dei traccianti [11C]-PK11195 e [18F]-NaF di evidenziare alterazioni microstrutturali della GM, non visualizzabili con la RM (sostanza grigia apparentemente normale), migliorando, cos¿, la risoluzione dell¿attuale imaging cerebrale.
    E.2.2Secondary objectives of the trial
    - To verify, by using [11C]-PK11195-PET, the degree of microglial activation within cortical lesions and the normal appearing grey matter, aiming at clarifying the origin of cortical damage and at grading those cortical lesions already detected by MRI;
    - to verify, by using [18F]-NaF-PET, the presence of blood brain barrier damage in cortical lesions, aiming at identifying and differentiate hyper-acute/acute cortical lesions from sub-acute/chronic cortical lesions.
    -Verificare, per mezzo del tracciante [11C]-PK11195, il grado di attivazione microgliale all¿interno delle lesioni corticali e nella sostanza grigia apparentemente normale al fine di chiarire la patogenesi del danno corticale e tipizzare, se possibile, le lesioni corticali visibili alla RM aprendo la strada per un pi¿ esteso studio sulle relative variabili cliniche (diagnostiche e prognostiche);
    - Verificare, per mezzo del tracciante [18F]-NaF, la possibile presenza di segni di danno di barriera all¿interno delle lesioni corticali evidenziate, identificando, cos¿, lesioni corticali in fase iperattiva, che potrebbero beneficiare di una terapia a forte potere antiinfiammatorio (steroidi ad alte dosi), esattamente come si fa oggi per le lesioni attive a carico della sostanza bianca. Inoltre, l¿evidenza di minimi danni di barriera, potrebbe suggerire la presenza di infiammazione subpiale, un tipo di danno corticale difficilmente evidenziabile per mezzo della RM.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Sex: Female and Male
    - Age: = 18 years old
    - Diagnosis of Multiple Sclerosis according to McDonald criteria, 2010 rev.
    - EDSS 0-5.5
    - Cerebral MRI with Gadolinium within two weeks the PET scanning
    - High cortical disease activity (presence of at least 10 cortical lesions and/or epilepsy/seizures not secondary to non-MS pathology) and/or severe mnestic or executive impairment in neuropsychological tests.
    - informed consent
    - for [18F]-NaF-PET study, a sub-group of patients who presented seizures in the past 2 months will be chosen
    - Pazienti di sesso maschile e femminile
    - Età = 18 anni
    - Diagnosi di Sclerosi Multipla secondo McDonald, revisione 2010
    - EDSS: 0-5,5
    - RM encefalo (di routine) con gadolinio effettuata nelle due settimane precedenti la visita basale
    - Alta attività corticale di malattia indicata dalla presenza di almeno 10 lesioni corticali e/o epilessia/crisi epilettiche non secondarie ad altre patologie del SNC e/o grave compromissione della funzione mnesica o esecutiva ai test Neuropsicologici
    - Consenso informato consapevole della diagnosi
    - Per lo studio [18F]-NaF-PET si selezioneranno, tra i pazienti rispondenti ai criteri di inclusione, quelli che hanno presentato episodi epilettici negli ultimi 2 mesi e che mostrino, quindi, la maggiore probabilità di danno corticale recente
    E.4Principal exclusion criteria
    - Co-occurring of other illness that can alter PET imaging (neoplasms, infectious disease, etc)
    - previous brain surgery
    - pregnancy (for women in reproductive age, a b-HCG test will be performed) or breast feeding
    - allergy or intolerance to one or more of the drugs employed in this study
    - Positività ad altre patologie che possano alterare l’indagine PET (neoplasie, malattie infettive, etc)
    - Precedente chirurgia sull’encefalo
    - Gravidanza (per le donne in età fertile l’assenza di gravidanza deve essere confermata da test negativo per la b-HCG) o allattamento in corso
    - Allergia o intolleranza ad uno o più farmaci utilizzati nello studio
    E.5 End points
    E.5.1Primary end point(s)
    To detect the presence of cortical lesions in PET images at timepoint t=40 minutes for 18F-Na and at timepoint t=20 minutes for PK11195 . To verify if these lesions are also detected by MRI sequences
    Rilevare la presenza di lesioni a carico della corteccia cerebrale nelle immagini PET al tempo t=40 minuti per il 18F-Na ed al tempo t=20 minuti per il PK 11195. Verificare se tali lesioni siano anche visibili alla RM o se siano lesioni non visibili alla RM
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary endpoint detection time approximately overlaps the time of acquisition of the two acquisitions (PET and MRI), imaging fusion and the reading of images. We estimate a period of one month after the acquisition of the last exam.
    Il tempo di rilevazione dell’ endpoint primario è sostanzialmente concomitante con l’esecuzione dei due esami (PET e MRI), la loro fusione (che avviene in un tempo di un’ora circa) e la loro lettura da parte dei ricercatori del gruppo. Si stima una finestra massima di un mese di tempo dopo l’esecuzione dell’ultimo esame
    E.5.2Secondary end point(s)
    1.To quantify, by using [11C]-PK11195-PET, microglial activation degree within cortical lesions and ¿MRI normal appearing grey matter¿ at t=20 minutes - To estimate the correlation of microglial activation with some demographic and clinical data (age, disease duration, disability, EDSS) 2- To quantify, by using [18F]-NaF-PET, blood brain barrier damage signs in cortical lesions at t=40 minutes - To estimate the correlation of microglial activation with some demographic and clinical data (age, disease duration, disability, EDSS)
    1. Quantificare, per mezzo del tracciante [11C]-PK11195, il grado di attivazione microgliale all¿interno delle lesioni corticali e nella sostanza grigia apparentemente normale in RM al tempo t= 20 minuti. Stimare la correlazione di tale attivazione microgliale con alcuni parametri demografici (et¿ e durata di malattia) e con i parametri clinici (grado di disabili¿, EDSS) 2. Quantificare, per mezzo del tracciante [18F]-NaF, la presenza di segni di danno di barriera all¿interno delle lesioni corticali evidenziate, confermando, cos¿, l¿esistenza di lesioni corticali in fase iperattiva al tempo t=40 minuti. Stimare la correlazione di tale danno di barriera con alcuni parametri demografici (et¿ e durata di malattia) e con i parametri clinici (grado di disabili¿, EDSS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoint detection time approximately overlaps the time of acquisition of the two acquisitions (PET and MRI), imaging fusion and the reading of images. We estimate a period of one month after the acquisition of the last exam.
    La rilevazione dell¿endpoint, ¿ conseguente alla acquisizione ed analisi delle immagini e non richiede ulteriori rivalutazioni cliniche o di imaging
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    prognostic
    prognosi
    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.8.2.4Number of treatment arms in the trial2
    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.8.5.1Number of sites anticipated in the EEA2
    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 Information not present in EudraCT
    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
    When last patient have performed PET
    Termine esecuzione PET per l'ultimo soggetto
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days69
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days69
    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: 18
    F.1.3Elderly (>=65 years) Yes
    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 No
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 18
    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)
    Patients will follow the routinely clinical, therapeutical and neuroradiological program, as normal good clinical practice.
    A seguito dell¿esecuzione dell¿esame PET, non essendo esso in alcuno modo una forma di trattamento farmacologico, i pazienti proseguono il loro normale iter clinico-terapeutico-radiologico, come da normale pratica clinica.
    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 Decision2016-02-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-04
    P. End of Trial
    P.End of Trial StatusOngoing
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