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    EudraCT Number:2020-000647-30
    Sponsor's Protocol Code Number:EFC16645
    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:2021-06-15
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2020-000647-30
    A.3Full title of the trial
    A Phase 3, randomized, double-blind, efficacy and safety study comparing SAR442168 to placebo in participants with nonrelapsing secondary progressive multiple sclerosis
    Studio di Fase 3, randomizzato, in doppio cieco, di efficacia e sicurezza, che confronta SAR442168 verso placebo in pazienti affetti da sclerosi multipla progressiva secondaria non recidivante (HERCULES)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    nonrelapsing secondary progressive multiple sclerosis (NRSPMS) study of Bruton tyrosine kinase (BTK) inhibitor SAR442168 (HERCULES)
    Studio sull’inibitore della Tirosin-chinasi di Bruton (BTK) SAR442168 nella nrSMSP (HERCULES)
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberEFC16645
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1246-7768
    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 SponsorGENZYME CORPORATION
    B.1.3.4CountryUnited States
    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 supportGENZYME CORPORATION
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSANOFI S.r.l.
    B.5.2Functional name of contact pointCONTACT POINT
    B.5.3 Address:
    B.5.3.1Street AddressVIALE BODIO, 37/B
    B.5.3.2Town/ cityMILANO
    B.5.3.3Post code20158
    B.5.4Telephone number800226343
    B.5.5Fax number0239394168
    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-
    D.3.2Product code [SAR442168]
    D.3.4Pharmaceutical form Film-coated 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.3.9.1CAS number 1971920-73-6
    D.3.9.2Current sponsor codeSAR442168
    D.3.9.3Other descriptive namePRN2246
    D.3.9.4EV Substance CodeSUB195428
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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. cell therapy medicinal product Information not present in EudraCT
    D. therapy medical product Information not present in EudraCT
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. 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 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 placeboFilm-coated tablet
    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
    Non-relapsing Secondary Progressive Multiple Sclerosis
    Sclerosi multipla progressiva secondaria non recidivante
    E.1.1.1Medical condition in easily understood language
    Non-relapsing Secondary Progressive Multiple Sclerosis
    Sclerosi multipla progressiva secondaria non recidivante
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10063400
    E.1.2Term Secondary progressive multiple sclerosis
    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
    To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in NRSPMS
    Determinare l’efficacia di SAR442168 verso placebo nel ritardare la progressione della disabilità nella NRSMSP
    E.2.2Secondary objectives of the trial
    - To evaluate efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic resonance imaging (MRI) lesions, cognitive performance, physical function, and quality of life
    - To evaluate safety and tolerability of SAR442168
    - To evaluate population pharmacokinetics (PK) of SAR442168 and relevant metabolites in NRSPMS and its relationship to efficacy and safety
    - To evaluate pharmacodynamics (PD) of SAR442168
    - Valutare l’efficacia di SAR442168 rispetto al placebo in termini di endpoint clinici, lesioni alla RM, capacità cognitive, funzione fisica e qualità della vita
    - Valutare la sicurezza e la tollerabilità di SAR442168
    - Valutare la farmacocinetica (PK) di popolazione di SAR442168 ed il rispettivo/i metabolita/i rilevante/i nella sclerosi multipla secondariamente progressiva non recidivante (SMSPnr) e il suo rapporto con efficacia e sicurezza
    - Valutare la farmacodinamica (Pharmacodynamics,[PD]) di SAR442168
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - 18 to 60 years of age inclusive
    - Diagnosis of nonrelapsing secondary progressive multiple sclerosis according to the 2017 McDonald criteria
    - Expanded disability status scale (EDSS) between 3.0 to 6.5 points inclusive, at screening
    - The participant must have documented evidence of disability progression observed during the 12 months before screening
    - Absence of clinical relapses for at least 24 months
    - Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
    - Participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    - Is not a woman of child bearing potential (WOCBP) OR
    - Is a WOCBP and agrees to use an acceptable contraceptive method
    - Il/la partecipante deve avere un’età compresa tra 18 e 60 anni
    - Diagnosi pregressa di RRSM in conformità ai criteri di Mcdonald modificati del 2017
    - Punteggio EDSS allo screening da 3,0 a 6,5 punti, inclusi.
    - Il/la partecipante deve presentare evidenza documentata di progressione della disabilità osservata nei 12 mesi precedenti lo screening.
    - Assenza di recidive cliniche per almeno 24 mesi.
    - L’utilizzo di contraccettivi da parte di maschi e femmine deve essere in linea con le normative locali riguardanti i metodi di contraccezione per coloro che partecipano agli studi clinici.
    • Una partecipante è idonea a partecipare se non è incinta e non sta allattando e se presenta almeno una delle seguenti condizioni:
    - non è una donna in età fertile (WOCBP)
    - È una donna in età fertile (Woman of Childbearing Potential, [WOCBP]) e accetta di utilizzare un metodo contraccettivo accettabile
    E.4Principal exclusion criteria
    - The participant has conditions that would adversely affect study participation such as short life expectancy.
    - History of organ transplant.
    - Evidence of infection with human immunodeficiency virus (HIV), progressive multifocal leukoencephalopathy (PML), active hepatitis B or C, active or latent tuberculosis or other active infections that would adversely affect study participation.
    - History of malignancy within 5 years prior to screening.
    - History of alchohol or drug abuse within 1 year prior to screening.
    - Hospitalized for psychiatric disease within 2 years prior to screening.
    - Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at screening
    - Bleeding disorder, known platelet dysfunction or platelet count <150 000/µL at screening.
    - A history of significant bleeding event within 6 months prior to screening, according to the Investigator's judgment such as, but not limited to cerebral or gastrointestinal bleeding.
    - Lymphocyte count below the lower limit of normal at screening.
    - Recent live (attenuated) vaccine within 2 months before the first treatment visit.
    - Recent major surgery (within 4 weeks of screening) or planned major surgery during the study.
    - The participant has received medications/treatments for MS within a specified time frame.
    - Receiving strong inducers or inhibitors of cytochrome P450 3A (CYP3A) or CYP2C8 hepatic enzymes.
    - Receiving anticoagulant or antiplatelet therapy (such as aspirin, clopidogrel, warfarin).
    - Contraindications to magnetic resonance imaging (MRI).
    NOTE: Other Inclusion/Exclusion criteria may apply.
    - Il/la partecipante presenta condizioni che potrebbero influire negativamente sulla partecipazione allo studio quali la breve aspettativa di vita
    - Anamnesi di trapianto d’organo
    - Anamnesi di infezione da virus dell’immunodeficienza umana (HIV), leucoencefalopatia multifocale progressiva (PML), epatite B o C attiva, tubercolosi (TBC) attiva o latente o altre infezioni attive che influiscano negativamente sulla partecipazione allo studio
    - Anamnesi di tumore maligno nei 5 anni precedenti lo screening
    - Anamnesi di abuso di alcol e/o droghe entro 1 anno dalla visita di screening.
    - Ricovero dovuto a malattia psichiatrica nei 2 anni precedenti la visita di screening.
    - Anormalità di laboratorio clinicamente significative (ivi inclusa accertata malattia del fegato) o anormalità nell’ECG allo screening
    - Disturbo emorragico o disfunzione piastrinica nota o conta piastrinica <150 000/µL allo screening
    - Anamnesi di eventi emorragici significativi nei 6 mesi precedenti allo screening, in base al giudizio dello sperimentatore, tra cui, a titolo esemplificativo e non esaustivo, emorragia cerebrale o gastrointestinale.
    - Conta linfocitaria sotto il limite del normale allo screening
    - Vaccino vivo (attenuato) nei 2 mesi precedenti la prima visita di trattamento.
    - Intervento chirurgico maggiore nelle 4 settimane precedenti la visita di screening, o pianificazione di un intervento chirurgico maggiore durante lo studio.
    - Il/la partecipante ha ricevuto terapie/trattamenti per la sclerosi multipla in un determinato periodo di tempo
    - Il/la partecipante sta ricevendo forti induttori o inibitori degli enzimi epatici del citocromo P450 3A (CYP3A) o CYP2C8
    - ll/La partecipante sta ricevendo terapie anticoagulanti/antipiastriniche (aspirina, clopidogrel, warfarin)
    - Controindicazioni all’esecuzione di Risonanza Magnetica per immagini (MRI)

    NOTA: Altri criteri di inclusione/esclusione potrebbero essere applicati
    E.5 End points
    E.5.1Primary end point(s)
    - 6 month confirmed disability progression (CDP) ; Time to onset of 6 months CDP defined as follows:
    - Increase of >/=1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is </=5.0, or
    - Increase of >/=0.5 point when the baseline EDSS score is >5.0
    Confermata progressione di disabilità (CDP) a 6 mesi; Tempo all’insorgenza della CDP a 6 mesi definito come segue:
    - Aumento >/= 1,0 punto rispetto al punteggio EDSS basale quando il punteggio basale è </= 5,0 OPPURE
    - Aumento >/= 0,5 punti quando il punteggio EDSS basale è > 5,0
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to approximately 48 months
    Fino a circa 48 mesi
    E.5.2Secondary end point(s)
    1 - 3-months change in T25-FW and 9-HPT ; Time to onset of sustained 20% increase in the timed 25 foot walk (T25-FW) and the 9-hole peg test (9-HPT) for at least 3 months
    2 - 3-month CDP ; Time to onset of 3-month CDP as assessed by EDSS score
    3 - T2 hyperintense lesion by MRI ; Total number of new or enlarging T2 hyperintense lesions as detected by MRI
    4 - Time to confirmed disability improvement (CDI) ; Time to onset of CDI defined as >/=1.0 point decrease on the EDSS score from baseline confirmed over at least 6 months
    5 - Brain volume loss (BVL) ; Percent change in Brain volume loss (BVL) as detected by brain MRI at the EOS compared to month 6
    6 - Change in cognitive function ; Change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test
    (SDMT) and by the California Verbal Learning Test (CVLT-II)
    7 - Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) ; Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS
    8 - Safety and Tolerability ; Number of participants with adverse events (AEs), Serious AEs, AEs leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)
    9 - Population pharmacokinetics ; Plasma concentration of SAR442168 and relevant metabolites (population PK assessment) at Months 6, 9, and 12
    10 - Change in plasma neurofilament light chain (NfL) ; Change in NfL levels at the EOS compared to baseline
    11 - Changes in serum Immunoglobulin level ; Changes in serum Immunoglobulin level at the EOS compared to baseline
    12 - Change in lymphocyte phenotype subsets ; Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline
    13 - Change in serum chitinase-3 like protein 1 (Chi3L1) ; Change in serum chitinase-3 like protein 1 (Chi3L1) at the EOS compared to baseline
    - Variazione a 3 mesi nel T25 FW e 9HPT: tempo all’insorgenza di un aumento sostenuto del 20% nel T25 FW e nel 9 HPT per almeno 3 mesi
    - 3 mesi CDP; Tempo all’insorgenza di CDP a 3 mesi, valutata mediante punteggio EDSS
    - Lesioni iperintense in T2 con RMI; numero totale di lesioni iperintense in T2 nuove e/o in espansione, rilevate mediante RMI.
    - Tempo al CDI: Tempo all’insorgenza del CDI, definito come riduzione >/= 1,0 punto sul punteggio EDSS dal basale confermato per almeno 6 mesi
    - Perdita di volume cerebrale (BVL): Variazione percentuale nella perdita di volume cerebrale (Brain Volume Loss, [BVL]) rilevata mediante scansioni RMI alla visita EOS rispetto al Mese 6
    - Variazione della funzione cognitiva; Variazione della funzione cognitiva alla visita EOS rispetto al basale, valutata mediante test di associazione di simboli e numeri (Symbol Digit Modalities Test, [SDMT]) e mediante Test di apprendimento verbale dell’Università della California (CVLT-II)
    - Variazione nel punteggio del questionario a 54 item per la misurazione della qualità della vita associata alla sclerosi multipla ([MSQoL-54): Variazione nel punteggio del questionario a 54 item per la misurazione della qualità della vita associata alla sclerosi multipla (MSQoL-54) dal basale alla visita EOS
    - Sicurezza e tollerabilità: numero di partecipanti con eventi avversi (EA), EA seri, EA che portano a interruzione permanente del trattamento dello studio eventi avversi di speciale interesse (AESI)
    - Farmacocinetica di popolazione: Concentrazione plasmatica di SAR442168 e il/i rispettivo/i metabolita/i (valutazione della PK di popolazione) ai mesi 6, 9 e 12
    - Variazione dei livelli plasmatici della catena leggera dei neurofilamenti (NfL): Variazione dei livelli plasmatici della catena leggera dei neurofilamenti (NfL) alla visita EOS rispetto al basale
    - Variazione nel livello di immunoglobuline sieriche: Variazione nel livello di immunoglobuline sieriche alla visita EOS rispetto al basale
    - Variazione dei sottotipi di fenotipi linfocitari nel sangue intero: Variazione dei sottotipi di fenotipi linfocitari nel sangue intero alla visita EOS rispetto al basale
    - Variazioni nei livelli sierici di proteina chitinasi-3-simile 1 (Chitinase-3 Like Protein-1, [Chi3L1]): Variazioni nei livelli sierici di proteina chitinasi-3-simile 1 alla visita EOS rispetto al basale
    E.5.2.1Timepoint(s) of evaluation of this end point
    1, 2 : Up to approximately 48 months
    3, 4, 5, 6, 7, 10, 11, 12, 13 : From Baseline up to approximately 48 months
    8 : From Screening until end of study up to approximately 48 months
    9 : Months 6, 9 and 12
    1,2: Fino a circa 48 mesi
    3,4,5,6,7,10, 11, 12, 13: Dal basale fino a circa 48 mesi
    8: Dallo screening fino alla fine dello studio fino a circa 48 mesi
    9: Mesi 6, 9 e 12
    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 Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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 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 Yes
    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 Yes
    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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA144
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Russian Federation
    United States
    United Kingdom
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years4
    E.8.9.2In all countries concerned by the trial months0
    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: 1700
    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 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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 800
    F.4.2.2In the whole clinical trial 1700
    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)
    Participants completing the treatment period will be proposed to enroll in a separate Long term safety study.
    Ai partecipanti che completano il periodo di trattamento verrà proposto uno studio separato sulla sicurezza a lungo termine.
    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 Decision2020-09-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-10-14
    P. End of Trial
    P.End of Trial StatusOngoing
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