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    EudraCT Number:2013-005558-31
    Sponsor's Protocol Code Number:I10E-1306
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-05-20
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-005558-31
    A.3Full title of the trial
    International, multicentre, efficacy and safety study of I10E in the maintenance treatment of patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy: Extension of PRISM study
    Studio internazionale, multicentrico, per valutare l’efficacia e la sicurezza di I10E nel trattamento di mantenimento dei pazienti affetti da poliradiculoneuropatia demielinizzante infiammatoria cronica: estensione dello studio PRISM I10E-1302
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Extension of the international study on efficacy and safety of I10E in CIDP patients
    Estensione dello studio internazionale sull’ l’efficacia e la sicurezza di I10E in pazienti con CIDP
    A.3.2Name or abbreviated title of the trial where available
    PRISM 2
    PRISM 2
    A.4.1Sponsor's protocol code numberI10E-1306
    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 SponsorLFB BIOTECHNOLOGIES
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAzienda Farmaceutica: LFB Biotechnologies
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLFB BIOTECHNOLOGIES
    B.5.2Functional name of contact pointClinical trial information desk
    B.5.3 Address:
    B.5.3.1Street Address3, avenue des Tropiques, BP 40305 – LES ULIS
    B.5.3.2Town/ cityCOURTABOEUF CEDEX
    B.5.3.3Post code91958
    B.5.4Telephone number+33 1 69 82 70 10
    B.5.5Fax number+33 1 69 82 72 72
    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.2.1.2Country which granted the Marketing AuthorisationItaly
    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: immunoglobulina umana normale 10% per somministrazione endovenosa
    D.3.2Product code I10E
    D.3.4Pharmaceutical form Solution for infusion
    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 INNimmunoglobulina umana normale per somministrazione endovenosa
    D.3.9.2Current sponsor code I10E
    D.3.9.3Other descriptive nameIMMUNOGLOBULINA UMANA NORMALE per somministrazione endovenosa
    D.3.9.4EV Substance CodeSUB12041MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 Yes
    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
    Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
    poliradiculoneuropatia demielinizzante infiammatoria cronica (CIDP)
    E.1.1.1Medical condition in easily understood language
    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is
    an acquired paralytic illness affecting peripheral nerves and caused by a
    demyelinating process.
    La poliradiculoneuropatia demielinizzante infiammatoria cronica è una condizione di paralisi acquisita dovuta a un processo di demielinizzazione dei nervi periferici
    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 18.0
    E.1.2Level PT
    E.1.2Classification code 10057645
    E.1.2Term Chronic inflammatory demyelinating polyradiculoneuropathy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    he study is descriptive. The primary objective is to assess the efficacy
    of I10E administered at a reduced maintenance dose in sustaining CIDP response after an initial 6-month treatment in PRISM study
    Lo studio è descrittivo. L’obiettivo primario è valutare l’efficacia di I10E somministrato alla dose ridotta di mantenimento nel sostenere la risposta della CIDP dopo un trattamento iniziale di 6 mesi nell'ambito dello studio PRISM
    E.2.2Secondary objectives of the trial
    The secondary objective is to assess the safety of I10E in this patient population.
    L'obiettivo secondario è valutare la sicurezza di I10E in questa popolazione di pazienti
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    only in the Italian sites an Ancillary sub study will be conducted to evaluate :
    • Change from baseline to EOS visit in nerve conduction velocities, distal latencies, amplitude of the negative phase of compound muscle action potentials and F wave for the following peripheral nerves: median nerve, ulnar nerve and deep fibular nerve (F wave assessed on ulnar nerve only).
    • Change from baseline to EOS visit in nerve maximal/minimal cross section area (CSA), intra-nerve and inter-nerve variability assessed by ultrasonography (US) and US immune-related classification (see section 1.4.4. peripheral nerve ultrasonography), in the following peripheral nerves: median nerve, ulnar nerve, fibular nerve and sural nerve.
    Solo nei centri Italiani sarà condotto uno studio ancillare atto a valutare :
    - la variazioni dal basale alla visita di EOS nelle velocità di conduzione nervosa, latenze distali, ampiezza della fase negativa del potenziale d’azione muscolare composto e onda F per i seguenti nervi periferici: nervo mediano, nervo ulnare e nervo fibulare profondo (onda F valutata solo sul nervo ulnare);
    - la variazioni dal basale alla visita di EOS nell’area della massima/minima sezione trasversale del nervo (Cross Section Area, CSA), variabilità intra-nervo e inter-nervo e classificazione US immunocorrelata (vedere sezione 1.4.4. Esame elettrofisiologico e ultrasonografia del nervo periferico), nei seguenti nervi periferici: nervo mediano, nervo ulnare, nervo fibulare e nervo surale.
    E.3Principal inclusion criteria
    . Male or female patient aged 18 years or more.
    2. Responder patient who have completed the last visit of PRISM I10E-
    1302 study defined as a patient with a decrease ≥1 point in the adjusted INCAT disability score between baseline and the end-of-study (EOS) visit of PRISM I10E-1302 study.
    3. Covered by national healthcare insurance system as required by local regulations.
    4. Written informed consent obtained prior to any study-related procedures.
    1. Paziente di sesso maschile o femminile di età pari o superiore a 18 anni.
    2. Paziente rispondente che abbia completato l’ultima visita dello studio PRISM I10E-1302 definito come paziente con una diminuzione di 1 punto nel punteggio di disabilità secondo la scala rettificata correlata al trattamento e alla causa della neuropatia infiammatoria (Inflammatory Neuropathy Cause And Treatment, INCAT) tra la visita al basale e la visita di fine dello studio (End of Study, EOS) dello studio PRISM I10E-1302.
    3. Coperto dal sistema di assicurazione sanitaria nazionale, come richiesto dalle normative locali.
    4. Consenso informato scritto ottenuto prima di effettuare qualsiasi procedura correlata allo studio.
    E.4Principal exclusion criteria
    Based on follow-up and results of analyses performed in PRISM I10E-1302 study, a patient may be eligible in PRISM 2 I10E-1306 study if none of the following criteria is met:
    1. History of severe allergic reaction or serious adverse reaction to any Ig.
    2. Known hypersensitivity to human Ig or to any of the excipients of I10E (glycine and polysorbate 80).
    3. History of cardiac insufficiency (New York Heart Association (NYHA) III/IV), uncontrolled cardiac arrhythmia, unstable ischemic heart disease, or uncontrolled hypertension.
    4. History of venous thromboembolic disease, myocardial infarction or cerebrovascular accident.
    5. Risk factor for blood hyperviscosity such as cryoglobulinemia or haematological malignancy with monoclonal gammopathy.
    6. History of personal or familial congenital thrombophilia or acquired thrombophilia.
    7. Factors contributing to venous stasis such as long-term bed confinement.
    8. Body mass index (BMI) ≥40 kg/m².
    9. Protein-losing enteropathy characterised by serum protein levels <60 g/L and serum albumin levels <30 g/L or nephrotic syndrome characterised by proteinuria ≥3.5 g/24 hours, serum protein levels <60 g/L and serum albumin levels <30 g/L.
    10. Glomerular filtration rate <80 mL/min/1.73m² measured according to the Modified Diet Renal Disease (MDRD) calculation.
    11. Serum levels of Alanine aminotransferase (AST) or Aspartate aminotransferase (ALT) >2 times upper limit of normal range.
    12. Any other ongoing disease that may cause chronic peripheral neuropathy, such as toxin exposure, dietary deficiency, uncontrolled diabetes, hyperthyroidism, cancer, systemic lupus
    erythematosus or other connective tissue diseases, infection with HIV, Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV), Lyme disease, multiple myeloma, Waldenström's macroglobulinaemia, amyloidosis, and hereditary neuropathy 13. Woman with positive results on a urine pregnancy test or
    breastfeeding woman or woman of childbearing potential without an effective contraception. Effective contraceptives are injectable, patch or combined oestro-progestative or progestative contraceptives, Copper T or levonorgest releasing intra-uterine devices, depot intramuscular medroxyprogesterone, subcutaneous progestative contraceptive implants, condoms or occlusive caps (diaphragm or
    cervical/vault caps) with spermicide, true abstinence (when this is in line with the preferred and usual lifestyle of the patient).
    Sulla base del follow-up e dei risultati delle analisi effettuate nello studio PRISM I10E-1302, un paziente può essere ritenuto idoneo allo studio PRISM 2 I10E-1306 se nessuno dei seguenti criteri è soddisfatto:

    1. Anamnesi di grave reazione allergica o reazione avversa grave a qualsiasi Ig.
    2. Ipersensibilità nota alle Ig umane o a uno qualsiasi degli eccipienti di I10E (glicina e polisorbato 80).
    3. Anamnesi di insufficienza cardiaca (New York Heart Association [NYHA] III/IV), aritmia cardiaca non controllata, cardiopatia ischemica instabile o ipertensione non controllata.
    4. Anamnesi di malattia tromboembolica venosa, infarto del miocardio o incidente cerebrovascolare.
    5. Fattore di rischio per iperviscosità ematica, tra cui crioglobulinemia o malignità ematologiche con gammopatia monoclonale.
    6. Anamnesi personale o familiare di trombofilia congenita o trombofilia acquisita.
    7. Fattori che contribuiscono alla stasi venosa, quali il confinamento a letto a lungo termine.
    8. Indice di massa corporea (IMC) ≥ 40 kg/m².
    9. Enteropatia proteino-disperdente caratterizzata da livelli sierici di proteine < 60 g/l e livelli sierici di albumina < 30 g/l o sindrome nefrosica caratterizzata da proteinuria ≥ 3,5 g/24 ore, livelli sierici di proteine < 60 g/l e livelli sierici di albumina < 30 g/l.

    10. Velocità di filtrazione glomerulare < 80 ml/min/1,73 m², misurata secondo il calcolo dell’equazione della Dieta modificata per la malattia renale (Modified Diet in Renal Disease, MDRD).
    11. Livelli sierici di alanina aminotransferasi (ALT) o aspartato aminotransferasi (AST) > 2 volte il limite superiore della norma.
    12. Qualsiasi altra malattia in corso che possa causare neuropatia periferica cronica, quale l’esposizione a tossine, i deficit dietetici, il diabete non controllato, l’ipertiroidismo, il tumore, il lupus eritematoso sistemico o altre malattie del tessuto connettivo, l’infezione da virus dell’immunodeficienza umana (Human Immunodeficiency Virus, HIV), il virus dell’epatite B (Hepatitis B Virus, HBV) o il virus dell’epatite C (Hepatitis C Virus, HCV), la malattia di Lyme, il mieloma multiplo, la macroglobulinemia di Waldenström, l’amiloidosi e la neuropatia ereditaria.
    13.Donne con test di gravidanza sulle urine positivo, donne in allattamento o in età fertile che non fanno uso di contraccettivi efficaci. I contraccettivi efficaci sono i contraccettivi estroprogestinici o progestinici iniettabili, in cerotto o combinati; i dispositivi intrauterini in rame a T o a rilascio di levonorgestrel; il medrossiprogesterone depot intramuscolare; gli impianti sottocutanei progestinici contraccettivi; i preservativi o i cappucci occlusivi (diaframma o cappuccio cervicale) con spermicida; l’astinenza effettiva (quando ciò è in linea con lo stile di vita preferito e usuale del paziente).
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint will be the responder rate at EOS visit. Responders are defined as patients with either: - No change or decrease in the adjusted INCAT disability score and without any change in CIDP treatment between baseline and EOS visit. or - An increase by 1 point in the adjusted INCAT disability score without requirement of any change in CIDP treatment between baseline and EOS visit.
    L’endpoint primario di efficacia sarà il tasso di rispondenti alla visita di EOS. I rispondenti sono definiti come pazienti con: - Nessuna variazione o diminuzione nel punteggio di disabilità INCAT rettificato e senza alcuna variazione nel trattamento della CIDP tra la visita al basale e la vista di EOS. O - Un incremento di 1 punto nel punteggio di disabilità INCAT rettificato, senza alcuna necessità di apportare alcuna variazione nel trattamento della CIDP tra la visita al basale e la visita di EOS.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the inclusion (baseline), end of study visit
    all’inclusione nello studio (basale), alla settimana 24 e alla visita di fine studio
    E.5.2Secondary end point(s)
    Main secondary efficacy endpoints: − Change from baseline to 24 weeks (Visit V9) and EOS visit in the adjusted INCAT disability score. − Responder rate at 24 weeks (visit V9). − Time to relapse. − Change from baseline to 24 weeks (Visit V9) and EOS visit in the following scores: ▪ Grip strength with the Martin Vigorimeter in both hands; ▪ Rasch-built Overall Disability Scale (R-ODS); ▪ Medical Research Council (MRC) 12 muscles sum score (0 to 5) and Rasch-modified MRC (0 to 3). Other secondary endpoints: - Percentage of patients at 24 weeks (Visit V9) and EOS visit with no requirement of change in CIDP treatment from baseline. - Change from baseline to 24 weeks (Visit V9) and EOS visit in Patient and Investigator Clinical Global Impression (CGI).
    Principali endpoint di efficacia secondari: - Variazione dal basale a 24 settimane (visita V9) e alla visita di EOS nel punteggio di disabilità INCAT rettificato. - Tasso di rispondenti a 24 settimane (visita V9). - Tempo alla recidiva. - Variazione dal basale a 24 settimane (visita V9) e alla visita di EOS nei seguenti punteggi: - forza della presa in entrambe le mani con il vigorimetro di Martin; - scala di disabilità complessiva secondo il modello di misurazione di Rasch (Rasch-Built Overall Disability Scale, R-ODS); - somma del punteggio di 12 muscoli secondo la scala del Consiglio per la ricerca medica (Medical Research Council, MRC) (da 0 a 5) e la scala MRC modificata in base al modello di misurazione di Rasch (da 0 a 3). Altri endpoint secondari: - Percentuale di pazienti a 24 settimane (visita V9) e alla visita di EOS con nessuna necessità di variazione del trattamento della CIDP rispetto al basale. - Variazione nell'impressione clinica globale (Clinical Global Impression, CGI) del paziente e dello Sperimentatore dal basale a 24 settimane (visita V9) e alla visita di EOS.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the inclusion, at week 24 and at the end of study visit
    al basale, alla settimana 24 e alla visita di fine studio
    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 Yes
    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 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. 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 No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Yes
    E. trial design description
    aperto, a singolo braccio
    aperto, a singolo braccio
    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 trial1
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United Kingdom
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial 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: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 30
    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)
    At the last visit patients will be switched to the normal standard of care for the condition
    All’ultima visita i pazienti passeranno alle normali procedure standard di cura per la loro condizione.
    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 Decision2015-01-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-16
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-07-04
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