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    Summary
    EudraCT Number:2020-005995-37
    Sponsor's Protocol Code Number:COAV101A12306
    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:2021-06-21
    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 number2020-005995-37
    A.3Full title of the trial
    A Phase lllb, open-label, single-arm, single-dose, multicenter study to evaluate the safety, tolerability and efficacy of gene replacement therapy with intravenous OAV101 (AVXS-101) in pediatric patients with spinal muscular atrophy (SMA)
    Etude de phase IIIb, multicentrique, en ouvert, à un seul bras, évaluant la sécurité d’emploi, la tolérance, et l’efficacité d’une dose unique de thérapie génique par OAV101 (AVXS-101), administrée par voie intraveineuse, chez des patients pédiatriques atteints d’amyotrophie spinale
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and Efficacy of Intravenous OAV101 (AVXS-101) in Pediatric Patients With Spinal Muscular Atrophy (SMA) (SMART)
    Sécurité et efficacité d'OAV101 (AVXS-101) administrée par voie intraveineuse, chez des patients pédiatriques atteints d’amyotrophie spinale (SMART)
    A.3.2Name or abbreviated title of the trial where available
    SMART
    A.4.1Sponsor's protocol code numberCOAV101A12306
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04851873
    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 SponsorNovartis Pharma AG
    B.1.3.4CountrySwitzerland
    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 supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma SAS
    B.5.2Functional name of contact pointInformation&Communication Médicales
    B.5.3 Address:
    B.5.3.1Street Address8/10 rue Henri Sainte-Claire Deville
    B.5.3.2Town/ cityRueil Malmaison Cedex
    B.5.3.3Post code92500
    B.5.3.4CountryFrance
    B.5.4Telephone number+33 1 5547 6600
    B.5.5Fax number+33 15547 6100
    B.5.6E-mailicm.phfr@novartis.com
    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 Zolgensma
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Gene Therapies EU Limited
    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 Yes
    D.2.5.1Orphan drug designation numberEMA/OD/028/15
    D.3 Description of the IMP
    D.3.1Product nameOAV101
    D.3.2Product code AVXS-101
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Yes
    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 INNONASEMNOGENE ABEPARVOVEC
    D.3.9.1CAS number 1922968-73-7
    D.3.9.2Current sponsor codeOAV101
    D.3.9.3Other descriptive namepreviously termed sc.AAV9.CB.SMN and AVXS-101
    D.3.9.4EV Substance CodeSUB193254
    D.3.10 Strength
    D.3.10.1Concentration unit vector genomes (vg)/mL
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number20000000000000
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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
    Spinal Muscular Atrophy
    Amyotrophie spinale
    E.1.1.1Medical condition in easily understood language
    Spinal Muscular Atrophy
    Amyotrophie spinale
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10041582
    E.1.2Term Spinal muscular atrophy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety and tolerability of IV OAV101 over a 12-month period in participants with SMA weighing ≥ 8.5 kg and ≤ 21 kg
    Evaluer pendant une période de 12 mois la sécurité d’emploi et la tolérance d’OAV101 administré par voie IV chez des patients atteints d’amyotrophie spinale pesant entre ≥ 8,5 kg et ≤ 21 kg
    E.2.2Secondary objectives of the trial
    To determine the efficacy of IV OAV101 at 6 and 12 months post dose in participants with SMA weighing ≥ 8.5 kg and ≤ 21 kg as measured by change from baseline in:
    · Developmental motor milestone achievement as assessed by World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) and Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) criteria
    · Hammersmith Functional Motor Scale - Expanded (HFMSE)
    · Revised Upper Limb Module (RULM), as appropriate according to participant age
    Evaluer l’efficacité d’OAV101, 6 et 12 mois après son administration chez des patients atteints d’amyotrophie spinale pesant entre ≥ 8,5 kg et ≤ 21 kg
    · Atteinte des étapes de développement moteur selon les critères MGRS de l’Organisation mondiale de la Santé [OMS] (WHO-MGRS, World Health Organization-Multicentre Growth Reference Study) et les critères de la troisième édition de l’échelle de Bayley pour le développement des nourrissons et des enfants (Bayley-III)
    • Variation par rapport à la Baseline de l’échelle étendue de la fonction motrice d’Hammersmith (HFMSE, Hammersmith Functional Motor Scale-Expanded)
    • Variation par rapport à la Baseline du score du module révisé des membres supérieurs (RULM, Revised Upper Limb Module), le cas échéant, en fonction de l’âge des patients
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Symptomatic SMA diagnosis based on gene mutation analysis with bi-allelic survival motor neuron 1 (SMN1) mutations (deletion or point mutations) and any copy of the survival motor neuron 2 (SMN2) gene.
    Weight ≥ 8.5 kg and ≤ 21 kg at the time of Screening Visit 2
    Naive to treatment or have discontinued an approved drug/therapy

    other protocol-defined inclusion criteria may apply
    Patient atteint d’amyotrophie spinale symptomatique diagnostiquée par l’analyse de mutations génétiques : les deux allèles du gène SMN1 doivent être porteurs de mutations (ponctuelles ou délétions), quel que soit le nombre de copies du gène SMN2
    Patient ayant un poids compris entre ≥ 8,5 kg et ≤ 21 kg au moment de la Visite de Sélection
    Patient naïf de tout traitement de l’amyotrophie spinale ou ayant arrêté un médicament/traitement autorisé

    d'autres critères d'inclusion définis par le protocole peuvent s'appliquer
    E.4Principal exclusion criteria
    Previous OAV101 use or previous use of any AAV9 gene therapy
    Body Mass Index (BMI) < 3rd percentile based on World Health Organization (WHO) Child Growth Standard
    Participant with history of aspiration pneumonia or signs of aspiration (eg, coughing or sputtering of food) within 4 weeks prior to screening
    Anti-Adeno-associated virus serotype 9 (AAV9) antibody titer > 1:50 as determined by ligand binding immunoassay at the time of screening
    History of gene therapy, hematopoietic transplantation, or solid organ transplantation

    other protocol-defined exclusion criteria may apply
    Utilisation antérieure d’OAV101 ou de toute autre thérapie génique basée sur AAV9
    Indice de masse corporelle < 3ème percentile selon les normes de croissance de l’enfant de l’Organisation mondiale de la Santé
    Antécédents de pneumonie d’inhalation ou signes d’inhalation (par ex. toux ou crachats de nourriture) au cours des 4 semaines précédant la Sélection
    Titre d’anticorps anti-AAV9 > 1:50, déterminé au moment de la Sélection à l’aide d’un test immunologique de liaison de ligand
    Antécédent de thérapie génique, de greffe de moelle osseuse ou de transplantation d’organe

    d'autres critères d'exclusion définis par le protocole peuvent s'appliquer
    E.5 End points
    E.5.1Primary end point(s)
    Number of participants with treatment emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.

    Number of participants with important identified and important potential risks (Adverse Events of Special Interest (AESI)) The following are important identified and important potential risks (AESI) associated with OAV101: Hepatotoxicity, Thrombocytopenia, Cardiac adverse events, Sensory abnormalities suggestive of ganglionopathy, and Thrombotic microangiopathy. These will be assessed by the investigator.

    Change from baseline in vital signs measurements - systolic and diastolic blood pressure (mmHg)

    Change from baseline in vital signs measurements - respiratory rate (breaths per minute)

    Change from baseline in vital signs measurements - pulse (beats per minute)

    Change from baseline in vital signs measurements - temperature (degrees Celsius)

    Change from baseline in vital signs measurements - oxygen saturation level (%)
    Nombre de participants ayant un évènements indésirables graves et non graves survenant sous traitement. Un évènements indésirables est tout événement médical (par exemple, tout signe défavorable et involontaire [y compris les résultats de laboratoire anormaux], symptôme ou maladie) chez un participant à un essai clinique après avoir fourni un consentement éclairé écrit pour la participation à l'étude.

    Nombre de participants présentant des risques importants identifiés et potentiels importants (Evénements indésirables d'intérêt particulier (AESI)). Les éléments suivants sont des risques importants identifiés et potentiels importants (AESI) avec OAV101:
    Hépatotoxicité, thrombocytopénie, événement indésirable cardiaques, anomalies sensorielles évocatrices d'une ganglionopathie et microangiopathie thrombotique. Ils seront évalués par l'investigateur.

    Changement dans les mesures des signes vitaux - pression artérielle systolique et diastolique (mmHg)

    Changement par rapport à la ligne de base dans les mesures des signes vitaux - fréquence respiratoire (respirations par minute)

    Changement dans les mesures des signes vitaux - pouls (battements par minute)

    Changement dans les mesures des signes vitaux - température (degrés Celsius)

    Changement dans les mesures des signes vitaux - niveau de saturation en oxygène (%)
    E.5.1.1Timepoint(s) of evaluation of this end point
    up to 12 months
    jusqu'à 12 mois
    E.5.2Secondary end point(s)
    Achievement of development motor milestones according to the Bayley Scale of Infant and Toddler Development.
    Developmental motor milestones are assessed via the developmental milestone checklist, formed of 10 yes/no questions with optional video documentation. The developmental milestones are: head control, sitting with support, sitting without support, sitting without support for 30 seconds, hands-and-knees crawling, pulls to stand, standing with assistance, walking with assistance, standing alone and walking alone. A yes response indicates that the patient reached a particular development milestone.

    Change from baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE), as appropriate according to participant age
    The HFMSE was devised for use in children with SMA to give objective information on motor ability and clinical progression. The HFMSE is formed of 33 assessments rated from 0 (unable to perform functional task) to 2 (able to perform functional task unassisted). Higher scores indicated higher levels of motor ability.

    Change from baseline in Revised Upper Limb Module (RULM), as appropriate according to participant age.
    The RULM assesses motor performance in the upper limbs from childhood through adulthood in ambulatory and non-ambulatory individuals with SMA. 'The scale consists of an entry item to establish functional levels and 19 items covering distal to proximal movements. The entry item is a modified version of the Brooke scale, including activities ranging from no functional use of hands (score 0) to full bilateral shoulder abduction (score 6). The entry item does not contribute to the total score but serves as a functional classification of overall upper limb functional ability. Of the remaining 19 items, 18 are scored on a 3 point scoring system and 1 item is scored on a 2 point scoring system. The test is performed unilaterally using the limb preferred by the participant. The total score ranges from 0, if all the items cannot be performed, to 37, if all the activities are achieved fully without any compensation. ' Higher scores indicate higher levels of motor ability.
    Atteinte des jalons du développement moteur selon l'échelle de Bayley pour le développement du nourrisson et du tout-petit. Les jalons moteurs du développement sont évalués via une liste composée de 10 questions oui/non avec une documentation vidéo facultative. Les jalons du développement sont : tenir la tête droite, s’asseoir avec un léger soutien, se tenir assis sans soutien, s’asseoir sans soutien 30 secondes, se déplacer à quatre pattes, se mettre debout, se tenir debout avec l’aide de quelqu’un, marcher avec l’aide de quelqu’un, se tenir debout seul et marcher seul(e). Une réponse oui indique que le patient a atteint une étape de développement particulière.

    Changement de l'échelle de motricité fonctionnelle Hammersmith - Étendue (HFMSE), selon l'âge des participants. Le HFMSE a été conçu pour être utilisé chez les enfants atteints d’amyotrophie spinale afin de fournir des informations objectives sur la capacité motrice et la progression clinique. Le HFMSE est composé de 33 évaluations notées de 0 (incapable d'effectuer une tâche fonctionnelle) à 2 (capable d'effectuer une tâche fonctionnelle sans assistance). Des scores plus élevés indiquent des niveaux plus élevés de capacité motrice.

    Changement dans le module révisé des membres supérieurs (RULM), le cas échéant en fonction de l'âge des participants.
    Le RULM évalue les performances motrices des membres supérieurs de l'enfance à l'âge adulte chez les personnes ambulatoires et non ambulatoires atteintes d'amyotrophie spinale. «L'échelle se compose d'un élément d'entrée pour établir les niveaux fonctionnels et de 19 éléments couvrant les mouvements distaux à proximaux. L'item d'entrée est une version modifiée de l'échelle de Brooke, comprenant des activités allant de l'absence d'utilisation fonctionnelle des mains (score 0) à l'abduction bilatérale complète de l'épaule (score 6). L'élément d'entrée ne contribue pas au score total mais sert de classification fonctionnelle de la capacité fonctionnelle globale des membres supérieurs. Sur les 19 éléments restants, 18 sont notés sur un système de notation à 3 points et 1 élément est noté sur un système de notation à 2 points. Le test est effectué unilatéralement en utilisant le membre préféré du participant. Le score total va de 0, si tous les éléments ne peuvent pas être exécutés, à 37, si toutes les activités sont réalisées pleinement sans aucune compensation. Des scores plus élevés indiquent des niveaux plus élevés de capacité motrice
    E.5.2.1Timepoint(s) of evaluation of this end point
    up to 12 months
    jusqu'à 12 mois
    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 Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    Tolérance
    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 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 Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Canada
    France
    Germany
    Italy
    Portugal
    Spain
    Switzerland
    Taiwan
    United Kingdom
    United States
    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
    Study completion is defined as when the last participant finishes their Study Completion visit and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision.
    La fin de l'étude est atteinte lorsque le dernier participant termine sa dernière visite de l'étude et que toutes les évaluations associées à cette visite ont été documentées et suivies de manière appropriée par l'investigateur ou dans le cas d'une décision d'arrêt précoce de l'étude, la date de cette décision .
    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 months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    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 Yes
    F.1.1Number of subjects for this age range: 24
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 15
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 8
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 1
    F.1.2Adults (18-64 years) No
    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 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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 14
    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)
    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 Decision2021-08-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-07-01
    P. End of Trial
    P.End of Trial StatusOngoing
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