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    The EU Clinical Trials Register currently displays   44208   clinical trials with a EudraCT protocol, of which   7332   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2014-005530-64
    Sponsor's Protocol Code Number:ACE-CL-006
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-10-02
    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 ConcernedGermany - BfArM
    A.2EudraCT number2014-005530-64
    A.3Full title of the trial
    A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase 3 Study of ACP-196 Versus Ibrutinib in Previously Treated Subjects with High Risk Chronic Lymphocytic Leukemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase 3 Study of ACP-196 Versus Ibrutinib in Previously Treated Subjects with High Risk Chronic Lymphocytic Leukemia
    A.4.1Sponsor's protocol code numberACE-CL-006
    A.5.4Other Identifiers
    Name:INDNumber:118717
    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 SponsorAcerta Pharma B.V.
    B.1.3.4CountryNetherlands
    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 supportAcerta Pharma BV
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcerta Pharma, BV
    B.5.2Functional name of contact pointACE-CL-006 Clincial Team
    B.5.3 Address:
    B.5.3.1Street AddressKloosterstraat 9
    B.5.3.2Town/ cityOss
    B.5.3.3Post code5349 AB
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+16505912800
    B.5.6E-mailace-cl-006@acerta-pharma.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1624
    D.3 Description of the IMP
    D.3.1Product nameacalabrutinib
    D.3.2Product code ACP-196
    D.3.4Pharmaceutical form Capsule, hard
    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.3.8INN - Proposed INNacalabrutinib
    D.3.9.1CAS number 1420477-60-6
    D.3.9.2Current sponsor codeACP-196
    D.3.9.3Other descriptive nameCML-1476 (CML)
    D.3.9.4EV Substance CodeSUB166233
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 No
    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.2.1.1.1Trade name Imbruvica
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen Biotech
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/12/984
    D.3 Description of the IMP
    D.3.1Product nameibrutinib
    D.3.4Pharmaceutical form Capsule, hard
    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.3.8INN - Proposed INNibrutinib
    D.3.9.1CAS number 936563-96-1
    D.3.9.3Other descriptive nameIBRUTINIB
    D.3.9.4EV Substance CodeSUB120863
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    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
    High Risk Chronic Lymphocytic Leukemia
    E.1.1.1Medical condition in easily understood language
    Long term cancer of the blood
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10008976
    E.1.2Term Chronic lymphocytic leukemia
    E.1.2System Organ Class 100000004864
    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 whether ACP-196 is non-inferior to ibrutinib with respect to progression-free survival (PFS) based on independent review committee (IRC) assessment in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) with high-risk prognostic markers.
    E.2.2Secondary objectives of the trial
    Efficacy:
    To evaluate the benefit/risk of ACP-196 versus ibrutinib in terms of:
    •Grade ≥ 3 infections
    •Richter’s transformation
    •Atrial fibrillation
    •Overall survival (OS)
    Safety Objectives:
    •Safety and tolerability including AEs of interest and laboratory assessments
    Exploratory Objectives:
    •IRC-assessed ORR per IWCLL 2008 criteria (through protocol version 5.0)
    •Investigator-assessed PFS and ORR per IWCLL 2008 criteria
    •Improvement and/or resolution of disease-related symptoms
    •Improvement in incidence of diarrhea, major bleeding events, lymphocytosis, and second primary malignancy
    •Patient-reported outcome (PRO) by various scales will not be collected as of protocol version 6.0
    •Medical resource utilization (MRU) will not be collected as of protocol version 6.0
    •Summarized plasma concentrations of acalabrutinib at specified time points. PK parameters estimated, as appropriate
    •Potential predictive biomarkers and mechanisms of resistance for the disease
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Men and women ≥ 18 years of age.
    •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
    •Diagnosis of CLL that meets published diagnostic criteria (Hallek 2008):
    oMonoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥ 1 B-cell marker (CD19, CD20, or CD23) and CD5.
    oProlymphocytes may comprise ≤ 55% of blood lymphocytes.
    oPresence of ≥ 5 x 10^9 B lymphocytes/L (5000 μL) in the peripheral blood (at any point since diagnosis); this applies to CLL only.
    •Must have ≥ 1 of the following high-risk prognostic factors:
    oPresence of 17p del by central laboratory
    oPresence of 11q del by central laboratory
    •Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment:
    oEvidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/μL).
    oMassive (ie, ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly
    oMassive nodes (ie, ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
    oProgressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of < 30 X 10^9/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
    oAutoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
    oConstitutional symptoms documented in the subject’s chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease related symptoms or signs:
    -Unintentional weight loss ≥ 10% within the previous 6 months before Screening.
    -Significant fatigue (ie, ECOG performance status 2 or worse; inability to work or perform usual activities).
    -Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection.
    -Night sweats for > 1 month before Screening without evidence of infection.
    •Must have received ≥ 1 prior therapies for CLL.
    •Meet the following laboratory parameters:
    oAbsolute neutrophil count (ANC) ≥ 750 cells/μL (0.75 x 10^9/L) or ≥ 500 cells/μL (0.50 x 10^9/L) in subjects with documented bone marrow involvement and independent of growth factor support 7 days before assessment.
    oPlatelet count ≥ 30,000 cells/μL (30 x 10^9/L) without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded.
    oSerum aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT) ≤ 3.0 x upper limit of normal (ULN).
    oTotal bilirubin ≤ 1.5 x ULN.
    oEstimated creatinine clearance (ie, estimated glomerular filtration rate [eGFR] using Cockcroft-Gault) ≥ 30 mL/min.
    •Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic evaluations at the institution that administers study drug for the entire study.
    •Women who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after last dose of acelabrutinib or 90 days after the last dose of ibrutinib, whichever is longer.
    •Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 2 days after the last dose of acalabrutinib or 90 days after the last dose of ibrutinib, whichever is longer.
    •Men must agree to refrain from sperm donation during the study and for 2 days after the last dose of acalabrutinib or 90 days after the last dose of ibrutinib, whichever is longer.
    •Must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations). Note vulnerable subjects, as defined in the International Conference on Harmonisation (ICH) GCP, are not allowed on this protocol (eg, prisoners or institutionalized subjects).
    E.4Principal exclusion criteria
    •Known central nervous system (CNS) lymphoma or leukemia.
    •Known prolymphocytic leukemia or history of, or currently suspected, Richter’s syndrome.
    •Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (> 20 mg daily of prednisone daily or equivalent).
    •Prior exposure to ibrutinib or to a B-cell receptor (BCR) inhibitor (eg, Bruton tyrosine kinase [Btk] inhibitors or phosphoinositide-3 [PI3] kinase inhibitors or Syk inhibitors) or a BCL-2 inhibitor (eg, ABT-199).
    •Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.
    •Corticosteroid use > 20 mg within 1 week before first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or contrast. For example, subjects requiring steroids at daily doses > 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell count lowering are excluded.
    •Prior radio- or toxin-conjugated antibody therapy.
    •Prior allogeneic stem cell transplant or autologous transplant.
    •Major surgery within 4 weeks before first dose of study drug.
    •History of prior malignancy except for the following:
    oMalignancy treated with curative intent and with no evidence of active disease present for more than 3 years before Screening and felt to be at low risk for recurrence by treating physician
    oAdequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer
    oAdequately treated cervical carcinoma in situ without current evidence of disease
    •Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or QTc > 480 msec at screening.
    •Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
    •Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) or ongoing intravenous anti-infective treatment.
    •Known history of infection with human immunodeficiency virus (HIV).
    •Serologic status reflecting active hepatitis B or C infection. Subjects with hepatitis B core antibody positive who are surface antigen negative or who are hepatitis C antibody positive will need to have a negative polymerase chain reaction (PCR) result before randomization. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive and those who are hepatitis C PCR positive will be excluded.
    •History of stroke or intracranial hemorrhage within 6 months before randomization.
    •History of bleeding diathesis (eg, hemophilia, von Willebrand disease).
    •Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
    •Requires treatment with a strong cytochrome CYP3A4 inhibitor/inducer.
    •Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole)
    •Breastfeeding or pregnant.
    •Concurrent participation in another therapeutic clinical trial.
    • Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening
    E.5 End points
    E.5.1Primary end point(s)
    To assess whether ACP-196 is non-inferior to ibrutinib with respect to progression-free survival (PFS) based on independent review committee (IRC) assessment in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) with high-risk prognostic markers.
    E.5.1.1Timepoint(s) of evaluation of this end point
    48 months - estimated
    E.5.2Secondary end point(s)
    To compare between ACP-196 and ibrutinib in terms of:
    •Incidence of Grade ≥ 3 infections
    •Incidence of Richter’s transformation
    •Incidence of atrial fibrillation
    •OS
    E.5.2.1Timepoint(s) of evaluation of this end point
    estimated 48 months
    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 No
    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.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 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 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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA95
    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
    Israel
    New Zealand
    United States
    Turkey
    Belgium
    Denmark
    France
    Germany
    Hungary
    Italy
    Netherlands
    Poland
    Spain
    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
    LVLS
    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
    E.8.9.2In all countries concerned by the trial years11
    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: 400
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 500
    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)
    Treatment to continue as per normal treatment for this condition.
    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 Decision2016-01-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-07
    P. End of Trial
    P.End of Trial StatusCompleted
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