Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   36118   clinical trials with a EudraCT protocol, of which   5940   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).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2012-003626-24
    Sponsor's Protocol Code Number:MK-3102-011
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-11-23
    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 number2012-003626-24
    A.3Full title of the trial
    A Multicenter, Phase III, Randomized, Placebo-Controlled Trial to Assess the Safety and Efficacy of MK-3102 Monotherapy in Subjects with Type 2 Diabetes Mellitus and Inadequate Glycemic Control
    Egy multicentrikus, III. fázisú, randomizált, placebokontrollos vizsgálat az MK-3102 monoterápia biztonságosságának és hatékonyságának értékelésére 2-es típusú diabetes mellitusban és elégtelen glikémiás kontrollban szenvedő betegek esetében
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 study in Patients with Type 2 Diabetes Mellitus
    III-as fázisú vizsgálat 2-es típusú diabetes mellitusban szenvedő betegek esetében
    A.4.1Sponsor's protocol code numberMK-3102-011
    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 SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., 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 supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.5.2Functional name of contact pointGlobal Clinical Trials Operations
    B.5.3 Address:
    B.5.3.1Street AddressOne Merck Drive
    B.5.3.2Town/ cityWhitehouse Station, NJ
    B.5.3.3Post code08889-0100
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1732 594 2622
    B.5.5Fax number+1732-594-3560
    B.5.6E-mailira_gantz@merck.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 nameMK-3102
    D.3.2Product code MK-3102
    D.3.4Pharmaceutical form Capsule
    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 INNOmarigliptin
    D.3.9.2Current sponsor codeMK-3102
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 Metformin
    D.2.1.1.2Name of the Marketing Authorisation holderAurobindo Pharma USA, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameMetformin
    D.3.4Pharmaceutical form 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 INNMETFORMIN
    D.3.9.1CAS number 657-24-9
    D.3.9.4EV Substance CodeSUB08831MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 placeboCapsule
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    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
    Type 2 Diabetes Mellitus
    E.1.1.1Medical condition in easily understood language
    Type 2 Diabetes Mellitus is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency
    A 2-es típusú diabetes mellitus egy anyagcsere-rendellenesség, amelyet magas vércukorszint jellemez, melynek oka az inzulin rezisztencia és relatív inzulin hiány.
    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 16.1
    E.1.2Level PT
    E.1.2Classification code 10067585
    E.1.2Term Type 2 diabetes mellitus
    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
    After 24 weeks, to assess the effect of treatment with MK-3102 compared with placebo on A1C.

    To assess the safety and tolerability of MK-3102.
    E.2.2Secondary objectives of the trial
    (1) Objective: After 24 weeks, to assess the effect of treatment with MK-3102 compared with placebo on FPG.
    (2) Objective: After 24 weeks, to assess the effect of treatment with MK-3102 on proportion of subjects achieving an A1C goal of <7.0% (53 mmol/mol).
    (3) Objective: After 54 weeks, to assess the effect of treatment with MK-3102 on proportion of subjects achieving an A1C goal of <7.0% (53 mmol/mol).
    (4) Objective: After 24 weeks, and after 54 weeks, to assess the effect of treatment with MK-3102 compared with placebo on 2-hour Post-Meal Glucose (PMG).
    (5) Objective: After 54 weeks, to assess the effect of treatment with MK-3102 on A1C and FPG.
    (6) Objective: After 24 weeks, and after 54 weeks, to assess the effect of treatment with MK-3102 on proportion of subjects achieving an A1C goal of <6.5% (48 mmol/mol).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject has T2DM and must be ≥18 years of age (for India: ≥18 and ≤65 years of age) on the day of signing the informed consent form.
    2. Subject meets one of the following criteria:
    a. Subject is currently not on an AHA (off AHA therapies for ≥12 weeks) and has a Visit 1/Screening Visit A1C ≥7.0 (53 mmol/mol) and ≤10.0%.% (86 mmol/mol).
    b. Subject is currently on a stable dose for > 12 weeks of a single AHA or low-dose dual oral AHA combination therapy (i.e., ≤50% maximum labeled dose of each agent [except thiazolidinediones (TZDs)]) and has a Visit 1/ Screening Visit A1C ≥6.5 (48 mmol/mol) and ≤9.0% (75 mmol/mol) AND based upon review of the subject's current diet, medical regimen, and Visit 1 A1C, subject is considered by the investigator to be likely to meet Visit 3/Week -2 inclusion criterion of A1C ≥7.0 (53 mmol/mol) and ≤10.0% (86 mmol/mol) AFTER the 8-week wash-off period prior to Visit 3/Week-2 (Visit 2/Week -10 to Visit 3/ Week -2).
    3. Subject meets one of the following criteria:
    a. Subject is a male
    b. Subject is a female not of reproductive potential defined as one who has either
    • reached natural menopause (defined as ≥12 months of spontaneous amenorrhea in women >45 years of age, or ≥6 months of spontaneous amenorrhea with serum follicular stimulating hormone [FSH] levels in the postmenopausal range as determined by the laboratory), or
    • had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation or occlusion at least 6 weeks prior to screening
    c. Subject is a female of reproductive potential and agrees to:
    • remain abstinent from heterosexual activity (if this form of birth control is accepted by local
    regulatory agencies and ethics review committees as the sole method of birth control), or
    • agrees to use (or have their partner use) acceptable contraception to prevent pregnancy within the projected duration of the trial and for 21 days after the last dose of blinded study medication. Two methods of contraception will be used to avoid pregnancy. Acceptable combinations of methods include:
    - use of one of the following double-barrier methods: diaphragm with spermicide and a condom, cervical cap and a condom, contraceptive sponge and a condom
    - Use of hormonal contraception (any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent [including oral, subcutaneous, intrauterine and intramuscular agents, and cutaneous patch]) with one of the following: diaphragm with spermicide; cervical cap; contraceptive sponge; condom; vasectomy; or intrauterine device (IUD).
    - Use of an IUD with one of the following: condom; diaphragm with spermicide; contraceptive sponge; vasectomy; or hormonal contraception (see above).
    - Vasectomy with one of the following: diaphragm with spermicide; cervical cap; contraceptive sponge; condom; IUD; or hormonal contraception (see above).
    4. Subject understands the trial procedures, alternative treatments available, and risks involved with the trial, and voluntarily agrees to participate by giving written informed consent. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
    5. Subject has an A1C of ≥7.0% (53 mmol/mol) and ≤10.0% (86 mmol/mol) within 2 weeks of Visit 3/Week -2.
    6. Subject has 100% compliance with MK-3102 placebo treatment during the single-blind run-in period (as determined by site-performed capsule count).


    E.4Principal exclusion criteria
    1.Subject has a history of type 1 diabetes mellitus or a history of ketoacidosis or is assessed by the investigator as possibly having type 1 diabetes confirmed with a C-peptide <0.7 ng/mL (0.23 nmol/L)
    2.has been treated with:
    a.thiazolidinedione (TZD) within 4 months of signing informed consent, or
    b.GLP-1 receptor mimetic or agonist or DPP-4 inhibitors within 6 months of signing informed consent, or
    c.insulin or sodium-glucose cotransporter (SGLT2) inhibitor within 12 weeks prior to signing informed consent
    d.MK-3102 at any time prior to signing informed consent
    3.has a history of hypersensitivity to a DPP-4 inhibitor
    4.is currently participating in/has participated in another trial with an investigational compound or device within the prior 12 weeks of signing the informed consent and does not agree to refrain from participating in any other trial
    5.has a history of intolerance,hypersensitivity or any contraindication to metformin (in Phase A),glimepiride or other sulfonyurea (in Phase B) based upon the label in the country of the investigational site
    6.is on a weight loss program and is not in the maintenance phase;has been on a weight loss medication in the past 6 months;or has undergone bariatric surgery within 12 months prior to signing the informed consent.
    7.has undergone a surgical procedure within 4 weeks prior to signing informed consent or has planned major surgery during the trial
    8.Subject is on or likely to require treatment for ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids
    9.is currently being treated for hyperthyroidism or subject is on thyroid hormone therapy and has not been on a stable dose for at least 6 weeks
    10.is currently on or likely to require treatment with a prohibited medication
    11.is expecting to undergo hormonal therapy in preparation to donate eggs during the period of the trial,including 21 days following the last dose of blinded study medication
    12.has a medical history of active liver disease,including chronic active hepatitis B or C,primary biliary cirrhosis, or symptomatic gallbladder disease
    13.has HIV as assessed by medical history
    14.has had new or worsening signs or symptoms of coronary heart disease or congestive heart failure within the past 3 months,or has any of the following disorders within the past 3 months:
    a.Acute coronary syndrome
    b.Coronary artery intervention
    c.Stroke or transient ischemic neurological disorder
    15.has poorly controlled hypertension defined as systolic blood pressure of ≥160 mm Hg or diastolic blood pressure of ≥90 mm Hg
    16.has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer,or in situ cervical cancer
    17.has a clinically important hematological disorder
    18.has exclusionary laboratory values (as per protocol)
    19.has a positive urine pregnancy test
    20.is pregnant or breast-feeding,or is expecting to conceive during the trial,including 21 days following the last dose of blinded study medication
    21.is a user of recreational or illicit drugs or has had a recent history of drug abuse
    22.routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week,or engages in binge drinking
    23.has a history or current evidence of any condition that makes participation not in the subject’s best interest
    24.has donated blood products or has had phlebotomy of >300 mL within 8 weeks of signing informed consent, or intends to donate blood products within the projected duration of the trial OR subject has received, or is anticipated to receive,blood products within 12 weeks of signing informed consent or within duration of the trial
    25.is unlikely to adhere to the trial procedures or is planning to relocate during the trial
    26.has symptomatic hyperglycemia that requires immediate initiation,adjustment,or addition of antihyperglycemic therapy or has a fasting plasma glucose consistently
    27.has a clinically significant ECG abnormality which exposes the subject to risk by enrolling in the trial
    28.has a fasting plasma glucose consistently
    29.has poorly controlled hypertension defined as systolic blood pressure of ≥160 mm Hg or diastolic blood pressure of ≥90 mm Hg
    30.is on lipid-lowering medication or thyroid replacement therapy,and has not been on a stable regimen for the 4 weeks (lipid-lowering medication),or 6 weeks (thyroid replacement therapy) prior to Visit 4/Day 1
    31.has a positive urine pregnancy test
    32.has a site-fasting-fingerstick glucose (FFSG) >260 mg/dL (>14.4 mmol/L)
    33.has developed a new medical condition/change in status of an established medical condition,developed a laboratory or ECG abnormality,or required a new treatment or medication during the pre-randomization period which meets any previously described trial exclusion criteria or which,in the opinion of the investigator,exposes the subject to risk by enrolling in the trial
    E.5 End points
    E.5.1Primary end point(s)
    A1C – Change from baseline at Week 24
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 weeks
    E.5.2Secondary end point(s)
    - Change from baseline in fasting plasma glucose (FPG) at week 24
    - Proportion of subjects attaining A1C glycemic goals of < 7% (53 mmol/ mol) after 24 weeks of treatment
    - Proportion of subjects attaining A1C glycemic goals of < 7% (53 mmol/ mol) after 54 weeks of treatment
    - Change from baseline in 2-hour post meal glucose (PMG) at week 24
    E.5.2.1Timepoint(s) of evaluation of this end point
    24 weeks (54 weeks for the third secondary end point)
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group 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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA44
    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
    Bulgaria
    Germany
    Hungary
    India
    Italy
    Korea, Republic of
    Philippines
    Romania
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    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 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: 285
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 165
    F.4.2.2In the whole clinical trial 300
    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)
    Subjects will return to their normal standard of care therapy
    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 Decision2013-01-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-01-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-06-19
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2019 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA