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    Summary
    EudraCT Number:2013-000324-34
    Sponsor's Protocol Code Number:APD356-G000-401
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-07-07
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2013-000324-34
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Effect of Long-Term Treatment with BELVIQ (lorcaserin HCl) on the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects with Cardiovascular Disease or Multiple Cardiovascular Risk Factors
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A research study to assess whether lorcaserin HCl affects the risk of developing cardiovascular diseases in obese or overweight men and women at higher risk of developing these diseases
    A.3.2Name or abbreviated title of the trial where available
    CAMELLIA
    A.4.1Sponsor's protocol code numberAPD356-G000-401
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation PlanP/243/2011
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEisai Limited
    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 supportEisai Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEisai Limited
    B.5.2Functional name of contact pointEisai Medical Information
    B.5.3 Address:
    B.5.3.1Street AddressEuropean Knowledge Centre, Mosquito Way
    B.5.3.2Town/ cityHatfield
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44845676 1400
    B.5.5Fax number+44845676 1401
    B.5.6E-mailEUMed_info@eisai.net
    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 nameLorcaserin hydrochloride (BELVIQ)
    D.3.2Product code APD356
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLorcaserin
    D.3.9.1CAS number 856681-05-5
    D.3.9.2Current sponsor codeAPD356
    D.3.9.3Other descriptive namelorcaserin hydrochloride hemihydrate (lorcaserin hydrochloride HH; lorcaserin HCl hemihydrate; lorcaserin HCl HH) ; IUPAC: (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine hydrochloride hemihydrate; Other chemical names: (1R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine hydrochloride hemihydrate (1R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3- benzo[d]azepinium chloride hemihydrate; Laboratory code names: APD356 Hemihydrate (APD356HH) AR226173 hydrochloride hemihydrate
    D.3.9.4EV Substance CodeSUB34935
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Obese and overweight patients with cardiovascular (CV) disease and/or multiple CV risk factors
    E.1.1.1Medical condition in easily understood language
    Obese and overweight patients with cardiovascular disease and/or at higher risk of developing this diesease
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029883
    E.1.2Term Obesity
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10033307
    E.1.2Term Overweight
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    -To demonstrate that, in obese and overweight subjects with cardiovascular (CV) disease and/or multiple CV risk factors, lorcaserin HCl 10 mg administered twice daily (BID) does not increase the incidence of major adverse cardiovascular events (MACE = myocardial infarction [MI], or stroke, or CV death) compared to placebo, with a noninferiority margin for the hazard ratio of 1.4

    -To demonstrate that, in obese and overweight subjects with CV disease and/or multiple CV risk factors, lorcaserin HCl 10 mg BID reduces the incidence of MACE+ (MACE or hospitalization for unstable angina or heart failure (HF), or any coronary revascularization) compared to placebo
    E.2.2Secondary objectives of the trial
    Key secondary objective: To confirm that, in subjects with prediabetes at Baseline based on the 2013 ADA guideline, lorcaserin HCl 10 mg BID reduces the incidence of conversion to type 2 diabetes mellitus (T2DM) compared to placebo.
    For other Secondary Objectives: MACE and MACE+, Prediabetes, Renal, Safety and exploratory related please refer to the protocol amendment 2 pages 3 and 4.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    For correction of the previous Sub-studies included, the correct Sub-Study is:

    Echo Sub Study
    Echocardiograms will be obtained on a subset of approximately 3600 subjects at selected sites as designated on the Schedule of
    Procedures/Assessments (Table 4Table 4). Acquisition of new ECHO data in all subjects will cease when at least 1000 subjects have completed the Month 36 echocardiographic assessment.

    In this study, echocardiographic images will be acquired in a subset of subjects to establish the cardiac safety of lorcaserin HCl. Standardized training will be provided for all echocardiographers, and will implement centralized procedures for collecting, analyzing, and reporting echocardiographic data. All echocardiograms will be over-read by 2 blinded central readers (primary and secondary). Baseline echocardiograms will be performed in between Visits 1 and 2, after the results of screening assessments have been obtained but prior to randomization, and subject eligibility is confirmed.
    E.3Principal inclusion criteria
    1. Body mass index (BMI) ≥27kg/m2
    2. Subjects able and willing to comply with a reduced-calorie diet and an increased physical activity program
    3. Age ≥40 years with established CV disease as defined by one of the following:
    a. History of documented MI or ischemic stroke >1 month before randomization
    b. History of peripheral artery disease as manifested by symptomatic claudication with an ankle-brachial pressure index of <0.85
    c. History of revascularization (coronary, carotid, or peripheral artery)
    d. Significant unrevascularized coronary arterial stenosis defined as ≥50% in two or more coronary arteries
    OR
    Age ≥55 years for women or ≥50 years for men who have T2DM without established CV disease plus at least one of the following CV risk factors:
    a. Hypertension, defined as systolic blood pressure (SBP) >140 or diastolic blood pressure (DBP) >90, or currently receiving therapy for documented hypertension
    b. Dyslipidemia, defined as low density lipoprotein-cholesterol (LDL-C) >130 mg/dL, or high density lipoprotein-cholesterol (HDL-C) <40 mg/dL, or currently taking prescription lipid-lowering therapy for documented dyslipidemia
    c. c. Estimated glomerular filtration rate (eGFR) ≥30 to ≤60 mL/min/1.73 m2 per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
    d. High sensitivity C-reactive protein (hsCRP) > 3 mg/L detected by the central laboratory in the absence of known acute or chronic inflammatory conditions (eg, infection, rheumatologic disease)
    e. Urinary albumin-to-creatinine ratio (ACR) ≥30 μg/mg in spot urine
    Subjects with T2DM may have a pre-existing or new diagnosis of T2DM. Subjects with pre-existing T2DM should have prior documentation consistent with the diagnosis and/or be on active pharmacotherapy for T2DM. A new diagnosis of T2DM (ie, discovered at Screening) should be based on the 2013 American Diabetes Association (ADA) guidelines. The diagnostic criteria are met if a subject has unequivocal hyperglycemia (random plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic symptoms of hyperglycemia or hyperglycemic crisis) OR any of the following criteria are observed and confirmed:
    o HbA1c ≥6.5%
    o fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L)
    o 2-hour plasma glucose ≥200 mg/dL (11.1mmol/L) by an oral glucose tolerance test (OGTT)
    All T2DM subjects must have an HbA1c <10% at Screening. If subjects are being treated, or upon diagnosis need to be treated with antidiabetic agents, the T2DM treatment regimen must be stable for at least 3 months prior to randomization. A single rescreen is allowed following stabilization. Stable control refers to minimal dose changes to existing medications for glycemic control and no medications being initiated for glycemic control in the 3 months before randomization. Minimal changes are defined as a change in insulin dose < 10% of daily dose, without any change in dose frequency, no add-on or discontinuation of other antidiabetic agents, and the subject has not been hospitalized due to hypo- or hyperglycemic events.
    4. Provide written informed consent
    5. Willing and able to comply with all aspects of the protocol
    E.4Principal exclusion criteria
    1.Current moderate or greater symptoms of congestive cardiac failure (New York Heart Association [NYHA] class III or IV)
    2. Known left ventricular (LV) ejection fraction <20%
    3. Current moderate or greater symptoms of pulmonary hypertension (PH) (World Health Organization [WHO] functional Class III and IV)
    4. Known severe valvular disease defined by clinical diagnosis and/or most recent echocardiography. History of severe valvular disease is allowed if it has been corrected by valve replacement or repair
    5. Severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2 per the CKD-EPI equation based on ideal body weight), or end-stage renal disease (ESRD)
    6. Severe hepatic impairment (Child-Pugh score 10 to 15)
    7. Use of other products intended for weight loss including prescription drugs, over-the-counter (OTC) drugs, and herbal preparations within 1 month prior to Screening
    8. Use of more than 1 serotonergic drug, within 1 month before Screening, or during the screening window, but not limited to:
    a. selective serotonin reuptake inhibitors (SSRIs)
    b. serotonin norepinephrine reuptake inhibitors (SNRIs)
    c. tricyclic antidepressants (TCAs)
    d. bupropion
    e. triptans
    f. St. John’s Wort and tryptophan
    g. Monoamine oxidase inhibitors [MAOIs]
    h.linezolid
    i.dextromethorphan
    j.lithium
    k.tramadol
    l.antipsychotics or other dopamine antagonists

    9. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months prior to Screening including, but not limited to: pergolide, ergotamine, methysergide or cabergoline
    10. History or evidence of clinically significant disease (e.g., malignancy, cardiac, respiratory, gastrointestinal, renal, or psychiatric disease) that in the opinion of the investigator(s) could affect the subject’s safety, interfere with the study assessments, or result in a life expectancy of less than 1 year
    11. Use of lorcaserin HCl within 6 months prior to Screening or hypersensitivity to lorcaserin HCl or any of the excipients
    12. History of alcohol dependence or abuse within 2 years prior to Visit 1 (Screening)
    13. Recreational drug use within the 2 years prior to Visit 1 (Screening)
    14. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days preceding informed consent (the exclusion criterion will not apply if the subjects are no longer in follow- up and have discontinued use of an investigational drug or device for at least 30 days. It will not apply if subjects are enrolled in registries or observational studies)
    15. Planned bariatric surgery or bariatric surgery performed within 1 year before screening
    16. Subjects considered by the investigator to have insufficient motivation to remain in a long-term clinical trial or who are considered likely to drop out for nonmedical reasons, e.g., social issues
    17. Females must not be breastfeeding or pregnant at Visit 1 (Screening) or Visit 2 (Baseline) (as documented by a negative beta-human chorionic gonadotropin [β-hCG]). A separate Baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
    18. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least 1 month before dosing). Females of childbearing potential are defined as those who:
    •Had unprotected sexual intercourse within 30 days before study entry
    •Do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 28 days after study drug discontinuation.
    •Are currently abstinent, and do not agree to use a double-barrier method (as described above) or refrain from sexual activity during the study period and for 28 days after study drug discontinuation.
    •Are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during the study and for 28 days after study drug discontinuation
    E.5 End points
    E.5.1Primary end point(s)
    -Time from randomization to first occurrence of MACE (first occurrence of any of the following events: MI, stroke, or CV death)

    -Time from randomization to first occurrence of MACE+ (first occurrence of any of the following events: MACE or hospitalization for unstable angina or HF, or any coronary revascularization)
    E.5.1.1Timepoint(s) of evaluation of this end point
    -Potential MACE/MACE+ events will be recorded throughout the study

    E.5.2Secondary end point(s)
    Key secondary endpoint:
    Time from randomization to conversion to T2DM, defined as first occurrence of any component of the 2013 ADA diagnostic criteria in subjects with prediabetes at Baseline. The diagnostic criteria are met if a subject has unequivocal hyperglycemia (random plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic symptoms of hyperglycemia or hyperglycemic crisis) OR any of the following criteria are observed and subsequently confirmed on repeat laboratory testing
    o HbA1c ≥6.5%
    o FPG≥126 mg/dL (7.0 mmol/L)
    o 2-hour plasma glucose ≥200mg/dL (11.1 mmol/L) by an OGTT
    Investigators should make every effort to obtain central lab confirmatory testing no later than 6 weeks after meeting any of the above criteria. Abnormalities of any 1 of the above 3 criteria on repeat testing constitutes diagnostic confirmation of diabetes. Subjects who have been started on anti-diabetic medications following abnormalities in preliminary testing do not require confirmatory testing.

    Other secondary endpoints:
    Other secondary endpoints are detailed on pages 12, 13 and 14 of the protocol amendment 2.
    E.5.2.1Timepoint(s) of evaluation of this end point
    -Potential MACE/MACE+ events recorded throughout the study
    -HbA1c, random plasma glucose and fasting plasma glucose will be measured in blood samples collected at Screening, Baseline, and specified timepoints throughout the study
    -Glycemic and end-organ benefits in subjects with T2DM at Baseline: HbA1c, random plasma glucose and fasting plasma glucose (FPG) will be measured in blood samples collected at Screening, Baseline, and specified timepoints throughout the study
    -Cardiac valve function and pulmonary arterial pressure: Baseline and 1 year
    - Exploratory Endpoints: cv risk factors, eGFR,ACR and LFTs baseline, 1 year and yearly thereafter; OAD use at baseline and 6 months;FDAdefined valvulopathy and estimated pulmonary artery systolic pressure baseline, 2 years and yearly thereafter
    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 No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.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) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned35
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA145
    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
    Bahamas
    Canada
    Chile
    Mexico
    New Zealand
    Poland
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days15
    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: 7200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4800
    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 state1400
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 2320
    F.4.2.2In the whole clinical trial 12000
    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 Decision2014-09-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-05-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-04-23
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