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    Summary
    EudraCT Number:2018-000637-12
    Sponsor's Protocol Code Number:P170909J
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-01-31
    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 number2018-000637-12
    A.3Full title of the trial
    Efficacy and safety of rituximab in the treatment of good prognosis microscopic polyangiitis
    Efficacité et tolérance du rituximab dans le traitement de la polyangéite microscopique de bon pronostic
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of rituximab in the treatment of good prognosis microscopic polyangiitis
    Efficacité et tolérance du rituximab dans le traitement de la polyangéite microscopique de bon pronostic
    A.3.2Name or abbreviated title of the trial where available
    RITUXGOPRO
    A.4.1Sponsor's protocol code numberP170909J
    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 SponsorASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
    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 supportMinistry of Health
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
    B.5.2Functional name of contact pointDRCI Hôpital St Louis
    B.5.3 Address:
    B.5.3.1Street Address1 av. Claude Vellefaux
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number330144841738
    B.5.5Fax number330144841701
    B.5.6E-mailjosephine.braun@aphp.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 Yes
    D.2.1.1.1Trade name RIXATHON 500mg
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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.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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with newly diagnosed or relapsing MPA, without any poor prognosis marker (FFS=0).
    Stratification will be made according to peripheral nerve involvement.
    Patients avec une PAM nouvellement diagnostiquée ou en rechute, sans marqueur de mauvais pronostic (FFS modifié = 0).
    La stratification sera faite en fonction de l'atteinte nerveuse périphérique.
    E.1.1.1Medical condition in easily understood language
    Patients with newly diagnosed or relapsing MPA, without any poor prognosis marker (FFS=0)
    Patients avec une PAM nouvellement diagnostiquée ou en rechute, sans marqueur de mauvais pronostic (FFS modifié = 0)
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10063344
    E.1.2Term Microscopic polyangiitis
    E.1.2System Organ Class 10047065 - Vascular disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective: To demonstrate the superiority of a rituximab-based treatment compared to standard therapy in patients with microscopic polyangiitis without any bad prognosis marker.
    Objectif principal : Démontrer la supériorité de l’association du rituximab au traitement de référence comparativement aux glucocorticoïdes seuls (traitement de référence) chez les patients ayant une PAM sans facteur de mauvais pronostic.
    E.2.2Secondary objectives of the trial
    1. Demonstrate a glucocorticoids sparing effect of the rituximab-based regimen by measuring the cumulative dose of glucocorticoids in each group from M0 to M18.
    2. Compare the number of patients who achieve a complete remission. Remission is defined by the absence of sign attributable to vasculitis and a BVAS=0 at M3
    3. Among patients who enter remission, compare proportion of patients who relapse and time to first relapse.
    4. Compare proportion of major and minor relapses between arms.
    5. Compare overall survival rate in each arm at M18
    6. Compare the quality of life and handicap of patients and compare between groups. Quality of life and handicap is evaluated with scores HAQ, SF36 and EQ-5D
    7. Compare the sequelae of patients at the end of follow-up with the Vasculitis Damage Index (VDI)
    8. Compare the proportion of patients who are still on glucocorticoids for their vasculitis at the end of the follow-up (M18)
    9. Evaluate the number and severity of side effect.
    1. Démontrer un effet d'épargne corticoïde du bras recevant le rituximab en mesurant la dose cumulée de GC dans chaque groupe de M0 à M18.
    2. Comparer le nombre de patients en rémission complète définie par l'absence de signe d’activité attribuable à la vascularite et un BVAS = 0 à M3
    3. Parmi les patients en rémission, comparer la proportion de patients en rechute et le délai de survenue de la première rechute..
    4. Comparer la proportion de rechutes majeures et mineures entre les bras.
    5. Comparer le taux de survie global dans chaque bras à M18
    6. Comparer la qualité de vie et le handicap des patients et comparer entre les groupes. La qualité de vie et le handicap sont évalués avec les scores HAQ, SF36 et EQ-5D
    7. Comparer les séquelles des patients à la fin du suivi avec le score (VDI)
    8. Comparer la proportion de patients qui sont encore sous glucocorticoïdes pour leur vascularite à la fin du suivi (M18)
    9. Évaluer le nombre et la gravité des effets secondaires.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient (male or female) aged 18 years old and over
    2. Patient agreement to participate in the study and signed written informed consent
    3. Patient with MPA according to the CHCC established in 2012
    4. Absence of any poor prognosis factor (modified five factor score (FFS) 1996=0)
    5. Patient with recent onset or relapse of the disease (<1 month) defined by BVAS≥3, who did not receive any other treatment than glucocorticoids over the last month. One to 3 initial glucocorticoids pulse(s) are allowed.
    6. Patient with anti-MPO antibody measured by ELISA
    7. Negative pregnancy test (serum β-hCG) for women of child-bearing potential and a willingness to use contraceptive measures adequate to prevent the subject or the subject’s partner from becoming pregnant during the study and 12 months after stopping therapy
    1. Patient (homme ou femme) de plus de 18 ans
    2. Patient acceptant de participer à l'étude et ayant signé le consentement éclairé
    3. Patient ayant une PAM selon la classification CHCC établie en 2012
    4. Absence de facteur de mauvais pronostic (FFS 1996 modifié = 0)
    5. Patient présentant une maladie récemment active (<1 mois) au diagnostic ou en rechute définie par un BVAS≥3, qui n'a reçu aucun autre traitement que les glucocorticoïdes au cours du mois dernier. Une à trois perfusion(s) initiale(s) de glucocorticoïdes est (sont) autorisées.
    6. Patient ayant des anticorps anti-MPO mesurés par ELISA
    7. Test de grossesse négatif (β-hCG sérique) pour les femmes en âge de procréer et mode de contraception efficace pendant toute la durée de l'étude et durant 12 mois après la fin de l’étude
    E.4Principal exclusion criteria
    1. Small-sized vessels vasculitis not associated with anti-MPO antibody or associated with anti-PR3 positivity.
    2. Patients with either GPA or EGPA vasculitis according to ACR criteria.
    3. Patient with a modified FFS 1996 ≥ 1.
    4. Patient with alveolar haemorrhage requiring mechanical ventilation.
    5. Patient with previous glucocorticoids treatment >1 month and >10mg/day either for vasculitis or for any other reason.
    6. Patient already receiving immunosuppressant or biological agent.
    Prior treatment with any of the following:
    - azathioprine, methotrexate, mycophenolate mophetil, mycophenolic acid within 4 weeks before inclusion
    - alkylant agent such as cyclophosphamide within 6 months before inclusion
    - anti-TNF inhibitors : infliximab within 8 weeks, adalimumab and etanercept within 2 weeks before inclusion
    -anti-CD20 therapy within one year before inclusion.
    7. Patient with a previous diagnosis of cancer < 5 years (except for in situ cervical cancer and skin carcinoma with R0 resection)
    8. Patient with acute infections or chronic active infections (including HIV, hepatitis B or C).
    9. Breast feeding woman or woman refusing the use of a contraceptive method for the 18 months’ duration of the study.
    10. Contraindication to treatment (glucocorticoids or rituximab).
    11. Unable to receive written informed consent of patient. Patient unable to understand the protocol.
    12. Patient already in another therapeutic protocol.
    13. Patient without social security.
    14. Patient with severe cardiac failure defined as class IV according to New York Heart Association classification.
    15. Patients with hypersensitivity to a monoclonal antibody or biological agent.
    1. Vascularite des vaisseaux de petit calibre non associée à un anticorps anti-MPO ou associée à une positivité des anti-PR3.
    2. Patients atteints de GPA ou EGPA selon les critères ACR
    3. Patient avec un FFS modifié 1996 ≥ 1
    4. Patient présentant une hémorragie alvéolaire nécessitant une ventilation mécanique
    5. Patient ayant reçu un traitement par glucocorticoïdes durant plus d’1 mois à une dose > 10 mg / jour pour sa vascularite ou pour toute autre raison.
    6. Patient recevant déjà un immunosuppresseur ou une biothérapie.
    Traitement préalable avec l'une des molécules suivantes :
    - azathioprine, méthotrexate, mycophénolate mofétil, acide mycophénolique dans les 4 semaines précédant l'inclusion
    - agent alkylant tel que le cyclophosphamide dans les 6 mois précédant l'inclusion
    - anti-TNFα : infliximab dans les 8 semaines, adalimumab et étanercept dans les 2 semaines précédant l'inclusion
    - Traitement anti-CD20 un an avant l'inclusion.
    7. Patient avec un diagnostic préalable de cancer <5 ans (sauf pour le cancer cervical in situ et le carcinome cutané avec résection R0)
    8. Patiente ayant une infection aiguë ou chronique active (VIH, hépatite B ou C)
    9. Femme allaitante ou refusant l'utilisation d'une méthode contraceptive durant les 18 mois de l’étude
    10. Contre-indication au traitement (glucocorticoïdes ou rituximab)
    11. Impossibilité de recevoir le consentement éclairé écrit du patient. Patient incapable de comprendre le protocole
    12. Patient déjà dans un autre protocole thérapeutique
    13. Patient sans sécurité sociale
    14. Patient avec une insuffisance cardiaque sévère (Classe IV de la New York Heart Association)
    15. Patient avec une hypersensibilité à un anticorps monoclonal ou un agent biologique.
    E.5 End points
    E.5.1Primary end point(s)
    Assessment criterion: Disease free survival from month 3 to month 18 in patients with microscopic polyangiitis treated with rituximab and glucocorticoids compared to glucocorticoids alone.
    Primary failure: Vasculitis requiring a modification of immunosuppressive treatment or prednisone tapering protocol before M3
    Remission is defined by the absence of sign attributable to vasculitis and a Birmingham Vasculitis Activity Score (BVAS)=0 at M3
    Relapse is defined after visit M3 by a BVAS>0 or the impossibility to decrease glucocorticoids according to the predefined protocol.
    Therefore, patients who experience a primary failure or fail to enter remission or relapse will be considered as treatment failure.
    Critère d’évaluation : Survie sans maladie de M3 à M18 dans une population de patients atteints de PAM traités par rituximab et glucocorticoïdes comparativement aux glucocorticoïdes seuls.
    Echec primaire : vascularite nécessitant une modification du traitement immunosuppresseur ou du schéma de décroissance de la prednisone avant M3.
    La rémission est définie par l'absence de signe attribuable à la vascularite et un score d'activité de vascularite de Birmingham (BVAS) = 0 à un mois (M3).
    La rechute est définie après la visite M3 par un BVAS> 0 ou l'impossibilité de diminuer les glucocorticoïdes selon le protocole prédéfini.
    Par conséquent, les patients qui présentent un échec primaire ou qui ne sont pas mis en rémission ou qui rechutent seront considérés comme un échec thérapeutique.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Month 3 to month 18
    de M3 à M18
    E.5.2Secondary end point(s)
    1. Demonstrate a glucocorticoids sparing effect of the rituximab-based regimen by measuring the cumulative dose of glucocorticoids in each group from M0 to M18. GC dose will be recorded at each visit
    2. Compare the number of patients who achieve a complete remission. Remission is defined by the absence of sign attributable to vasculitis and a BVAS=0 at M3
    3. Among patients who enter remission, compare proportion of patients who relapse and time to first relapse. Relapse is defined after visit M3 by the reoccurrence of signs or symptoms attributable to vasculitis and a BVAS≥1 or the impossibility to decrease GC therapy according to the predefined protocol
    4. Compare proportion of major and minor relapses between arms. Major relapse is defined by reappearance or worsening of disease with a BVAS≥1 and involvement of at least one major organ, a life-threatening manifestation, or both
    Minor relapse is defined by reappearance or worsening of disease with a BVAS≥1, not corresponding to a major relapse
    5. Compare overall survival rate in each arm at M18
    6. Compare the quality of life and handicap of patients and compare between groups. Quality of life and handicap is evaluated with scores HAQ, SF36 and EQ-5D
    7. Compare the sequelae of patients at the end of follow-up with the Vasculitis Damage Index (VDI)
    8. Compare the proportion of patients who are still on glucocorticoids for their vasculitis at the end of the follow-up (M18)
    9. Evaluate the number and severity of side effect. Record of adverse events and serious adverse events related to vasculitis or treatment in each group at each visit. Classification is made according to the CTCAE toxicity grading scale.
    1. Démontrer un effet d'épargne corticoïde du bras recevant le rituximab en mesurant la dose cumulée de GC dans chaque groupe de M0 à M18. La dose de GC sera recueillie à chaque visite
    2. Comparer le nombre de patients en rémission complète La rémission est définie par l'absence de signe d’activité attribuable à la vascularite et un BVAS = 0 à M3
    3. Parmi les patients en rémission, comparer la proportion de patients en rechute et le délai de survenue de la première rechute. La rechute est définie après la visite M3 par la réapparition de signes ou de symptômes attribuables à la vascularite et à un BVAS≥1 ou l'impossibilité de diminuer le traitement corticoïde selon le protocole prédéfini.
    4. Comparer la proportion de rechutes majeures et mineures entre les bras. La rechute majeure est définie par la réapparition ou l’aggravation de signes attribuables à la maladie avec BVAS≥1 et l'atteinte d'au moins un organe majeur, une manifestation potentiellement mortelle, ou les deux.
    Une rechute mineure est définie par la réapparition ou l’aggravation de signes attribuables à la maladie avec un BVAS≥1, ne correspondant pas à une rechute majeure.
    5. Comparer le taux de survie global dans chaque bras à M18
    6. Comparer la qualité de vie et le handicap des patients et comparer entre les groupes. La qualité de vie et le handicap sont évalués avec les scores HAQ, SF36 et EQ-5D
    7. Comparer les séquelles des patients à la fin du suivi avec le score (VDI)
    8. Comparer la proportion de patients qui sont encore sous glucocorticoïdes pour leur vascularite à la fin du suivi (M18)
    9. Évaluer le nombre et la gravité des effets secondaires par recueil des événements indésirables et des événements indésirables graves liés à la vascularite ou au traitement dans chaque groupe à chaque visite. La classification est faite selon le système de classification de la toxicité CTCAE.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At each visit from M0 to M18
    A chaque visite de M0 à M18
    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 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.7.1.3.1Other 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 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 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 concerned31
    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 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
    LVLS
    Dernière visite dernier patient
    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: 65
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 35
    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 state106
    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)
    Standard of care follow-up for this condition
    Suivi de soins habituels pour cette maladie
    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 Decision2019-03-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-13
    P. End of Trial
    P.End of Trial StatusOngoing
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