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    Summary
    EudraCT Number:2010-022240-21
    Sponsor's Protocol Code Number:ISIS183750-CS4
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2011-05-31
    Trial results View 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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2010-022240-21
    A.3Full title of the trial
    A Phase 1b/2 Study of Carboplatin-Paclitaxel, with or without ISIS 183750 (an eIF4E Inhibitor), in Patients with Stage IV Non-Small Cell Lung Cancer
    IV stádiumú, nem kissejtes tüdőrákos, carboplatin-paclitaxellel kezelt betegek Fázis Ib/II vizsgálata (eIF4E gátló) ISIS 183750-nel, illetve anélkül
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Carboplatin-Paclitaxel, with or without ISIS 183750 (an eIF4E Inhibitor), in Patients with Stage IV Non-Small Cell Lung Cancer, Phase 1b/2
    Fázis Ib/II vizsgálat (eIF4E gátló) ISIS 183750-nel, illetve anélkül, IV stádiumú, nem kissejtes tüdőrákos, carboplatin-paclitaxellel kezelt betegek
    A.4.1Sponsor's protocol code numberISIS183750-CS4
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01234038
    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 SponsorIsis Pharmaceuticals Inc.
    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 supportIsis Pharmaceuticals Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPSI CRO Hungary Pharma Support LLC
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressSzabadság tér 7, 3 em.
    B.5.3.2Town/ cityBudapest
    B.5.3.3Post code1054
    B.5.3.4CountryHungary
    B.5.4Telephone number+3615556755
    B.5.5Fax number+3615556750
    B.5.6E-mailRAbudapest@psi-cro.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 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 nameeIF-4E Antisense Oligonucleotide
    D.3.2Product code ISIS 183750
    D.3.4Pharmaceutical form 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 codeISIS 183750
    D.3.9.3Other descriptive nameLY2275796
    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 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 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) 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 Yes
    D.3.11.13.1Other medicinal product typeAntisense Oligonucleotide
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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.2.5The 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 namepaclitaxel
    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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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 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) 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: 3
    D.1.2 and D.1.3IMP RoleComparator
    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.2.5The 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 namecarboplatin
    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.3.9.1CAS number 41575-94-4
    D.3.9.3Other descriptive nameCARBOPLATIN
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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) 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
    Stage IV Non-Small Cell Lung Cancer (NSCLC; including patients with pleural effusion who were previously classified as Stage IIIB)
    IV stádiumú , nem kissejtes tüdőrákos (NSCLC) betegek, (beleértve azokat az előzőleg IIIB stádiumba sorolt betegeket is, akiknél pleurális folyadékgyülem van).
    E.1.1.1Medical condition in easily understood language
    Stage IV Non-Small Cell Lung Cancer
    IV stádiumú , nem kissejtes tüdőrákos betegek.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10029522
    E.1.2Term Non-small cell lung cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    In Part 1, the primary objective is to examine the safety and tolerability of ISIS 183750 in combination with carboplatin and paclitaxel and to determine the ISIS 183750 dose for evaluation in Part 2.

    In Part 2, the primary objective is to estimate the overall survival of patients with Stage IV NSCLC treated with ISIS 183750 in combination with carboplatin and paclitaxel.
    E.2.2Secondary objectives of the trial
    In Part 1,
    To characterize the plasma and urine PK parameters
    To explore anticancer effects of ISIS 183750 in combination with carboplatin and paclitaxel

    In Part 2,
    To determine the percent changes of tumor size from baseline to the end of the 2nd treatment cycle and from
    baseline to the end of the 4th treatment cycle
    To determine the objective tumor response rate (RECIST 1.1)
    To explore the time-to-event efficacy measures
    To determine the 7-day plasma trough levels of ISIS 183750
    To determine the safety and tolerability of ISIS 183750 in combination with carboplatin and paclitaxel.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients with Stage IV NSCLC are eligible to be included in the study only if they meet all of the following
    criteria:
    1. Provide written informed consent prior to screening.
    2. Male or female patients, age ≥ 18 years.
    3. Histologically or cytologically confirmed diagnosis of NSCLC.
    4. Stage IV disease (including patients with pleural effusion who were previously classified as Stage IIIB).
    5. All of the following if patient has had prior radiation therapy:
    a. Lesion(s) used for determination of response were not previously irradiated or have increased in size since the
    completion of radiotherapy
    b. The patient has recovered from any acute effects of the radiotherapy
    c. Radiotherapy was completed at least 4 weeks prior to Screening.
    6. Part 1: Have at least non-measurable evaluable disease (e.g., lesions which are smaller than the minimum size
    required for measurability; other non-measurable lesions such as bone metastases, malignant pleural effusion)
    Part 2: Have measurable disease, defined as at least 1 lesion that can be accurately measured in at least 1
    dimension (longest diameter to be recorded) as ≥ 10 mm on cross-sectional imaging (where the CT slice
    thickness is no greater than 5 mm) or at least 20 mm by standard techniques; positron emissions tomography
    [PET] and ultrasound are not permitted methods for tumor measurements under this protocol. Consult RECIST
    1.1 guidance for additional information (Appendix 5 and Eisenhauer et al., 2009)
    7. Performance status of 0 or 1 on the ECOG Performance Status Scale.
    8. Have an estimated life expectancy of at least 12 weeks.
    9. Adequate organ function within 14 days prior to first study dose (ISIS 183750 or carboplatin/paclitaxel,
    whichever occurs first) including the following:
    a. Absolute neutrophil count (ANC)≥ 1.5 x 109/L
    b. Platelet count ≥100 x 109/L
    c. Hemoglobin ≥9 g/dL (≥5.6 mmol/L). Patients may receive packed RBC transfusion to achieve this level at the discretion of the investigator.
    d. Total bilirubin < 1.5 x upper limit of normal (ULN) unless elevated secondary to conditions such as Gilbert’s
    Disease
    e. Aspartate aminotransferase (AST) < 3 x ULN (< 5 x ULN in the presence of hepatic metastases)
    f. Alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN in the presence of hepatic metastases)
    g. Alkaline phosphatase < 3.0 x ULN
    h. Calculated creatinine clearance ≥ 60 mL/min per Cockcroft and Gault formula (see Appendix 7)
    i.Serum albumin ≥3.0 g/dL
    10. Satisfy one of the following:
    a. Females: non-pregnant and non-lactating; surgically sterile, post-menopausal, or patient or partner compliant
    with a reliable contraceptive regimen, as determined by Investigator, for 4 weeks prior to Screening. Patients of
    reproductive potential must test negative for pregnancy at Screen and must agree to use a reliable method of birth control during the study and for the 10 weeks following the last dose of ISIS 183750.
    b. Males: surgically sterile or patient or partner must agree to use a reliable contraceptive method, as determined by the Investigator during the study and for the 10 weeks following the last dose of ISIS 183750.
    11. The patient is willing and able to comply with the study visit schedule and procedures, and has geographical proximity (Investigator’s discretion) that allows follow-up specified by the protocol.
    12. For Part 1: have discontinued all prior chemotherapies, biological therapies, and other investigational
    therapies for cancer for at least 4 weeks (6 weeks for mitomycin-C or nitrosoureas) prior to study treatment and
    recovered from the acute effects of therapy.
    E.4Principal exclusion criteria
    Patients will be excluded from the study if they meet any of the following criteria:
    1. Part 1: More than 2 prior chemotherapy or biological therapy regimens (approved or experimental) for
    NSCLC, not counting adjuvant and neoadjuvant treatment. A regimen is defined as two or more consecutive
    cycles of treatment.
    Part 2: Any prior chemotherapy or biological therapy (approved or experimental) for NSCLC including adjuvant
    and neoadjuvant treatments
    2. Treatment with another investigational drug, biological agent, or device within 4 weeks (6 weeks for biological
    agents) before Screening or 5 half-lives of study agent, whichever is longer
    3. Patients with treated or untreated parenchymal brain metastases or leptomeningeal disease. Brain imaging is
    required for symptomatic patients to rule out brain metastases, but is not required in asymptomatic patients.
    4. Patients with known pericardial effusion
    5. Have active infection or serious concomitant systemic disorder (for example, heart failure) incompatible with
    the study (at the discretion of the Investigator)
    6. Presence or history of malignancy other than NSCLC, carcinoma in situ of the cervix, or non-melanoma skin
    cancer. In the case of other malignancies, patients may be considered for participation if the prior malignancies
    were diagnosed and definitively treated at least five years previously with no subsequent evidence of recurrence.
    7. Presence of an underlying disease state associated with active bleeding
    8. Ongoing therapy with oral or parenteral anticoagulants (e.g., heparin, warfarin/coumadin). Low-dose
    anticoagulants for maintenance of catheter patency and low dose aspirin (≤ 325 mg/day) and nonsteroidal
    antiinflammatory
    agents are not exclusionary.
    9. Concurrent treatment with other anticancer drugs
    10. Pre-existing peripheral neuropathy Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE)
    Grade 2
    10. Known history of HIV, HCV, or chronic HBV infection
    11. Previous treatment with a therapeutic antisense oligonucleotide or siRNA
    12. Planned concomitant participation in another clinical trial of an experimental agent, vaccine, or device
    13. Have any other medical conditions that in the opinion of the Investigator, would make the patient unsuitable for enrollment, or could interfere with the patient participating in or completing the study.
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival
    E.5.1.1Timepoint(s) of evaluation of this end point
    The time-to-event endpoints (overall survival, progression free survival, time to tumor progression, time to and duration of objective tumor response) will be estimated using Kaplan-Meier method.
    E.5.2Secondary end point(s)
    •Progression-free survival
    •Percent survival at 1-year
    •Time to objective tumor progression
    •Duration of objective tumor response for responding patients (measured from the time measurement criteria are first met for CR/PR until the first date that recurrent or progressive disease is objectively documented)
    •Time to objective tumor response
    •Percent objective tumor response (i.e., partial + complete response + stable disease) as best response
    •Percent changes of tumor size from baseline to the end of the 2nd and from baseline to the end of the 4th treatment cycle
    E.5.2.1Timepoint(s) of evaluation of this end point
    The time-to-event endpoints (overall survival, progression free survival, time to tumor progression, time to and duration of objective tumor response) will be estimated using Kaplan-Meier method. Objective tumor response rate will be analyzed using chi-square tests or the Fisher’s
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase IB
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Part2: carboplatin and paclitaxel compared to carboplatin and paclitaxel plus ISIS 183750
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days18
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days18
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 28
    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 Yes
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 66
    F.4.2.2In the whole clinical trial 118
    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)
    As per protocol
    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 Decision2011-04-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-04-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2012-12-14
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