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    EudraCT Number:2014-001069-28
    Sponsor's Protocol Code Number:D5881C00004
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-11-14
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-001069-28
    A.3Full title of the trial
    A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction with EpaNova in HiGh Cardiovascular Risk PatienTs with Hypertriglyceridemia (STRENGTH)
    Studio sugli esiti a lungo termine per valutare la riduzione del rischio residuo da statine con Epanova nei/nelle pazienti ad alto rischio cardiovascolare con ipertrigliceridemia (STRENGTH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction with EpaNova in HiGh Cardiovascular Risk PatienTs with Hypertriglyceridemia (STRENGTH)
    Studio sugli esiti a lungo termine per valutare la riduzione del rischio residuo da statine con Epanova nei/nelle pazienti ad alto rischio cardiovascolare con ipertrigliceridemia (STRENGTH)
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberD5881C00004
    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 SponsorAstraZeneca AB
    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 supportAstraZeneca AB
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    B.5.2Functional name of contact pointInformation Center
    B.5.3 Address:
    B.5.3.1Street AddressPepparedsleden 1
    B.5.3.2Town/ cityMölndal
    B.5.3.3Post code43183
    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 nameEpanova
    D.3.2Product code Epanova
    D.3.4Pharmaceutical form Capsule, soft
    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 INNNA
    D.3.9.2Current sponsor codeOmefas
    D.3.9.3Other descriptive nameOMEGA-3 FATTY ACIDS
    D.3.9.4EV Substance CodeSUB32453
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number800
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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, soft
    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
    Severe persistent Hypertriglyceridemia in High Cardiovascular Risk

    Ipertrigliceridemia persistente grave in pazienti ad alto rischio cardiovascolare
    E.1.1.1Medical condition in easily understood language
    High triglyceride levels in the blood in patients with high cardiovascular
    Livelli elevati di trigliceridi nel sangue in pazienti ad alto rischio cardiovascolare
    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 17.1
    E.1.2Level LLT
    E.1.2Classification code 10020870
    E.1.2Term Hypertriglyceridemia
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the effectiveness of adding Epanova to statin therapy (with or without ezetimibe) for lowering MACE (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, emergent/elective coronary revascularization, or hospitalization for unstable angina) in patients with persistent hypertriglyceridemia and low HDL-cholesterol (HDL-C)
    L'obiettivo primario è valutare l'efficacia dell'aggiunta di Epanova alla terapia statinica (con o senza ezetimibe) per la riduzione dei MACE (morte cardiovascolare, infarto miocardico non fatale, ictus non fatale, rivascolarizzazione coronarica emergente/elettiva o ricovero per angina instabile) in pazienti con ipertrigliceridemia persistente e bassi livelli di colesterolo HDL (HDL-C).
    E.2.2Secondary objectives of the trial
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men or women, ≥18 years of age.
    2. Patient must be on a stable diet and statin* therapy at least 4 weeks prior to randomization (Visit 2) and meet the following criteria where the qualifying lipid parameters should be obtained from the same visit:
    a. LDL-C <100 mg/dL (<2.59 mmol/L). Patient will also qualify if LDL-C ≥100 mg/dL (≥2.59 mmol/L) and if on a high-intensity or maximum tolerated moderate- or lowintensity statin dose, with or without ezetimibe therapy, for at least 4 weeks (see Appendix D). The maximum tolerated dosage of a statin is defined as the approved dose
    per local label that the patient can tolerate without unacceptable adverse effects such as muscle aches/pain/weakness or elevations in liver enzymes or creatine kinase (CK) that are determined by the investigator to be clinically relevant and due to statin therapy.
    b. TG level ≥200 and <500 mg/dL (≥2.26 and <5.65 mmol/L) and HDL-C <40 mg/dL (1.03 mmol/L) for men or HDL-C <45 mg/dL (1.16 mmol/L) for women. *co-administration with ezetimibe or fixed-dose ezetimibe/simvastatin 10/10, 10/20, 10/40 mg (see restrictions regarding 80 mg simvastatin in Section 7.4) or fixed-dose
    ezetimibe/atorvastatin 10/10, 10/20, 10/40, or 10/80 mg is allowed.
    3. Patient is at high risk for a future cardiovascular event if at least one of the following criteria (3a, 3b or 3c)* is present via patient history, physical exam, or medical records at the time of screening:
    a. Any atherosclerotic CVD as defined by one or more of the following:
    - previous clinical myocardial infarction (MI) ≥30 days prior to randomization
    - percutaneous coronary intervention (PCI) including balloon angioplasty and coronary stenting ≥ 6 months prior to randomization
    - coronary artery bypass grafting (CABG) ≥30 days prior to randomization
    - coronary angiogram including computed tomography angiogram (CTA) demonstrating more than or equal to a 50% stenosis in at least one native or graft vessel
    - anginal symptoms with a defect documented by stress testing with nuclear perfusion imaging or a wall motion abnormality determined by stress echocardiogram
    - asymptomatic coronary ischemia documented by stress testing with nuclear perfusion imaging or by stress echocardiogram
    - peripheral vascular disease with symptoms of claudication and ankle brachial index <0.9 performed by a vascular lab or angiogram (including CTA) showing more than or equal to 50% stenosis)
    - history of peripheral arterial revascularization (surgical or percutaneous) ≥30 days prior to randomization
    - carotid endarterectomy or more than or equal to 50% stenosis in a carotid artery determined by carotid ultrasound or angiogram ≥30 days prior to randomization
    - history of abdominal aortic aneurysm diagnosed ≥30 days prior to randomization
    - ischemic stroke ≥30 days prior to randomization
    b. History of diabetes mellitus (type 1 or 2) and ≥40 years of age for men and ≥50 years of age for women, plus one of the following risk factors:
    - chronic cigarette smoking at screening (at least 1 cigarette per day for > 1 month)
    - history of hypertension (blood pressure >140/90 mm Hg) or taking antihypertensive medication
    - high-sensitivity C-reactive protein (hs-CRP) > 2.0 mg/L (19.05 nmol/L) determined at Visit 1
    - history of albuminuria (urinary albumin:creatinine ratio [ACR] >30 mg/g).
    c. Male patients >50 years of age or females >60 years of age, with at least one of the following risk factors:
    - family history of premature coronary heart disease (father <55 years of age, mother <65 years of age)
    - chronic cigarette smoking at screening (at least 1 cigarette per day for > 1 month)
    - hs-CRP >2.0 mg/L (19.05 nmol/L) determined at Visit 1
    - impaired renal function as estimated using the Chronic Kidney Disease Epidemiology Collaboration formula for glomerular filtration rate (eGFR) <45 mL/min per 1.73 m2 (patients on dialysis are excluded).
    - coronary calcium score >300 Agatston units (AU).
    4. Patient must have been on a stable diet prior to randomization and willing to follow the NCEP TLC diet, or equivalent diet, throughout the study.
    1.Uomini o donne di età ≥18 anni.2.I/Le pazienti devono seguire una dieta stabile e una terapia statinica* da almeno 4 settimane prima della randomizzazione (Visita 2) e soddisfare i seguenti criteri, dove i parametri lipidici di qualifica devono essere ottenuti alla stessa visita:a.LDL-C <100 mg/dl (<2,59 mmol/l). Il/La paziente sarà ritenuto/a idoneo/a anche se l'LDL-C ≥100 mg/dl (≥2,59 mmol/l) e se riceve statine ad alta intensità (atorvastatina 40 o 80 mg e rosuvastatina 20 o 40 mg) o una dose di statina di intensità moderata o bassa massimamente tollerata, con o senza terapia a base di ezetimibe, per almeno 4 settimane (vedi Allegato D). Il dosaggio massimo tollerato di una statina è definito come la dose approvata in base al foglio informativo locale che il/la paziente è in grado di tollerare senza effetti avversi inaccettabili come dolori muscolari/dolori/debolezza o aumentidegli enzimi epatici o della creatinchinasi (Creatine Kinase, CK) che lo sperimentatore ritiene clinicamente rilevanti e dovuti alla terapia statinica.b.Livello di TG ≥200 e <500 mg/dl (≥2,26 e <5,65 mmol/l) e HDL-C <40 mg/dl (1,03 mmol/l) per gli uomini o HDL-C <45 mg/dl (1,16 mmol/l) per le donne.*è consentita la co-somministrazione con ezetimibe o una dose fissa di ezetimibe/simvastatina 10/10, 10/20, 10/40 mg (vedere limitazioni riguardanti simvastatina 80 mg alla Sezione 7.4) o una dose fissa di ezetimibe/atorvastatina 10/10, 10/20, 10/40 o 10/80 mg.
    3.Il/La paziente è ad alto rischio di un futuro evento cardiovascolare se almeno uno dei seguenti criteri (3a, 3b o 3c)* è presente nell'anamnesi del/della paziente, nell'esame obiettivo o nelle cartelle cliniche al momento dello screening: a.Qualsiasi MCV aterosclerotica definita da uno o più dei seguenti:
    •infarto miocardico (IM) clinico pregresso ≥30 giorni prima della randomizzazione;
    •intervento coronarico percutaneo (ICP), incluse angioplastica con palloncino e stent coronarico ≥ 6 mesi prima della randomizzazione; •bypass aorto-coronarico (Coronary Artery Bypass Grafting, CABG) ≥30 giorni prima della randomizzazione;
    •angiografia coronarica inclusa l'angiografia con tomografia computerizzata (Computed Tomography Angiogram, CTA) che dimostri una stenosi pari o superiore al 50% in almeno un vaso nativo o innesto; •sintomi di angina con un difetto documentato da esame da sforzo con imaging di perfusione nucleare o un'anomalia nel movimento delle pareti determinata da ecocardiogramma da sforzo; •ischemia coronarica asintomatica documentata da esame da sforzo con imaging di perfusione nucleare o ecocardiogramma da sforzo; •malattia vascolare periferica con sintomi di claudicazione e indice caviglia-brachiale <0,9 effettuato tramite analisi vascolare o angiografia (inclusa CTA) che presenti una stenosi superiore o pari al 50%; •anamnesi di rivascolarizzazione arteriosa periferica (chirurgica o percutanea) ≥30 giorni prima della randomizzazione; •endoarteriectomia carotidea o stenosi superiore o pari al 50% in un'arteria carotidea determinata mediante ecografia o angiografia carotidea ≥30 giorni prima della randomizzazione; •anamnesi di aneurisma aortico addominale diagnosticato ≥30 giorni prima della randomizzazione; •ictus ischemico ≥30 giorni prima della randomizzazione. b.Anamnesi di diabete mellito (tipo 1 o 2) ed età ≥40 anni per uomini ed età ≥50 anni per donne, oltre a uno dei seguenti fattori di rischio: •tabagismo cronico allo screening (almeno 1 sigaretta al giorno per >1 mese); •anamnesi di ipertensione (pressione sanguigna >140/90 mmHg) o assunzione di farmaci antipertensivi; •proteina C reattiva ad alta sensibilità (high-sensitivity C-Reactive Protein, hs-CRP) > 2,0 mg/l (19,05 mmol/l) determinata alla Visita 1; •anamnesi di albuminuria (rapporto albumina urinaria:creatinina [Albumin:Creatinine Ratio, ACR] >30 mg/g). c.Pazienti di sesso maschile di età >50 anni o di sesso femminile di età >60 anni, con almeno uno dei seguenti fattori di rischio: •anamnesi familiare di coronaropatia prematura (padre <55 anni di età, madre <65 anni di età); •tabagismo cronico allo screening (almeno 1 sigaretta al giorno per >1 mese); •hs-CRP >2,0 mg/l (19,05 nmol/l) determinata alla Visita 1; •insufficienza renale valutata usando la formula di Collaborazione epidemiologica sulla malattia renale cronica (Chronic Kidney Disease Epidemiology Collaboration, CKD-EPI) per il tasso di filtrazione glomerulare (Glomerular Filtration Rate, eGFR) <45 ml/min per 1,73 m2 (i/le pazienti in dialisi sono esclusi); •punteggio di calcio coronarico >300 unità Agatston (Agatston Units, AU). 4.Il/La paziente deve aver seguito una dieta stabile prima della randomizzazione ed essere disposto/a a seguire la dieta TLC NCEP, o una dieta equivalente, durante l'intero studio.
    E.4Principal exclusion criteria
    1. Allergy or intolerance to omega-3 carboxylic acids, omega-3 fatty acids, omega-3-acid ethyl esters, or corn oil.
    2. Known hypersensitivity to fish and/or shellfish.
    3. Use of fibrates, bile acid sequestrants, or niacin or its analogues (>250 mg/day) within 4 weeks prior to Visit 2. Patients taking these agents may be considered for inclusion in the study if these therapies have been discontinued for 4 weeks or more prior to Visit 2.
    4. Statin naïve at Visit 1.
    5. Use of simvastatin 80 mg or ezetimibe/simvastatin 10/80 mg within 4 weeks prior to Visit 2. Patients taking these agents may be considered for inclusion in the study if these therapies have been discontinued and replaced with a protocol acceptable statin treatment that is stabilized for 4 weeks or more prior to Visit 2.
    6. Use of any prescription medications containing eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), e.g. Lovaza® or Vascepa®, within 4 weeks prior to Visit 2. Patients taking these agents may be considered for inclusion in the study if these therapies have been discontinued for 4 weeks or more prior to Visit 2.
    7. More than one capsule/day (any dose) of omega-3 dietary supplements. Up to one capsule/day will be permitted if started prior to Visit 1 (new omega-3 supplements are not permitted at Visits 1, 1a, or 1b,
    8. Use of prescription or over-the-counter (OTC) weight loss drugs at any time after Visit 1.
    9. Chronic use of oral corticosteroids during screening (acute use for inflammation for example from poison ivy, or intranasal or inhaled steroids for allergies/asthma, or intraarticular injections are allowed).
    10. Use of tamoxifen, estrogens, progestins, or testosterone, that has not been stable for >4 weeks at Visit 1, or is unstable prior to Visit 2.
    11. Known lipoprotein lipase impairment or deficiency, or apolipoprotein C-II deficiency.
    12. Hemoglobin A1c (Hb A1c) >10% at Visit 1.
    13. Poorly controlled hypertension (resting blood pressure ≥180 mm Hg systolic and/or ≥100 mm Hg diastolic) at two consecutive visits prior to randomization at Visit 2.
    14. Uncontrolled hypothyroidism, or thyroid stimulating hormone (TSH) >2.0 times upper limit of normal (ULN) at Visit 1. Patients who are clinically euthyroid, on stable thyroid replacement therapy for 2 months prior to Visit 1 are allowed.
    15. History of cancer (except non-melanoma skin cancer, or carcinoma in situ of cervix) within the previous two years.
    16. Patients on dialysis.
    17. Females who are pregnant, planning to be pregnant during the study period, lactating, or women of childbearing potential who are not using an acceptable method of contraception. A woman is considered of childbearing potential if she is not surgically sterile or if her last menstrual period was <12 months prior to Visit 1. Acceptable methods of contraception for this study include use of double barrier contraception, intrauterine device, all oral, patch, etc. hormonal contraceptives as long as dose and type is stable for 3 months prior to Visit 1. In addition, true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject.
    18. Creatine kinase >5.0 times ULN; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3.0 times ULN; or total bilirubin (TBL) >2.0 times ULN (except with a confirmed diagnosis of Gilbert’s disease), at Visit 1. A diagnosis of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) with stable elevations
    of AST and/or ALT (>3.0 times ULN) is eligible for participation in the study.
    19. Excessive use of alcohol or other substance abuse that in the investigator’s opinion would jeopardize the patient’s participation in the study or interpretation of the data.
    20. Exposure to any investigational agent within 4 weeks prior to Visit 1, including previous enrollment or randomization in this study.
    21. Any other condition the investigator believes would interfere with the patient’s ability to provide informed consent, comply with study instructions, or which might confound the interpretation of the study results or put the patient at undue risk.
    1.Allergia o intolleranza ad acidi carbossilici omega-3, acidi grassi omega-3, etil esteri di acidi omega-3 o olio di mais.
    2.Ipersensibilità nota a pesce e/o crostacei.
    3.Uso di fibrati, sequestranti degli acidi biliari o niacina o suoi analoghi (>250 mg/giorno) nelle 4 settimane precedenti alla Visita 2. I/Le pazienti che assumono questi agenti possono essere considerati/e per l'inclusione nello studio se queste terapie sono state interrotte 4 settimane o più prima della Visita 2.
    4.Naive alle statine alla Visita 1.
    5.Uso di simvastatina 80 mg o ezetimibe/simvastatina 10/80 mg nelle 4 settimane precedenti alla Visita 2. I/Le pazienti che assumono questi agenti possono essere considerati/e per l'inclusione nello studio se queste terapie sono state interrotte e sostituite con un trattamento statinico accettabile in base al protocollo, che si sia stabilizzato da 4 o più settimane prima della Visita 2.
    6.Uso di un qualsiasi farmaco prescrivibile contenente acido eicosapentaenoico (Eicosapentaenoic Acid, EPA) e/o acido docosaesaenoico (Docosahexaenoic Acid, DHA), ad es. Lovaza® o Vascepa®, nelle 4 settimane precedenti alla Visita 2. I/Le pazienti che assumono questi agenti possono essere considerati/e per l'inclusione nello studio se queste terapie sono state interrotte 4 o più settimane prima della Visita 2.
    7.Più di una capsula/giorno (qualsiasi dose) di integratori dietetici a base di omega-3. Fino a una capsula/giorno sarà consentita se la somministrazione è iniziata prima della Visita 1 (nuovi integratori a base di omega-3 non sono consentiti alle Visite 1, 1a o 1b).
    8.Uso di farmaci dimagranti prescrivibili o da banco in qualsiasi momento dopo la Visita 1.9.Uso cronico di corticosteroidi orali durante lo screening (è consentito l'uso acuto per infiammazione, per esempio da edera velenosa, di steroidi intranasali o inalati per allergie/asma oppure di iniezioni interarticolari).
    10.Uso di tamoxifene, estrogeni, progestine o testosterone che non sia stato stabile da >4 settimane alla Visita 1 o che sia instabile prima della Visita 2.
    11.Riduzione o deficit noti di lipoproteina lipasi o deficit di apolipoproteina C-II.12.Emoglobina A1c (Hb A1c) >10% alla Visita 1.13.Ipertensione scarsamente controllata (pressione sanguigna a riposo ≥180 mmHg sistolica e/o ≥100 mmHg diastolica) a due visite consecutive prima della randomizzazione alla Visita 2.14.Ipotiroidismo non controllato o ormone tireostimolante (TSH) >2,0 volte il limite superiore di normalità (Upper Limit of Normal, ULN) alla Visita 1. I/Le pazienti clinicamente eutiroidei/e, che seguono una terapia sostitutiva tiroidea stabile da 2 mesi prima della Visita 1, sono ammessi/e.
    15.Anamnesi di cancro (eccetto carcinoma cutaneo diverso da melanoma o carcinoma in situ della cervice) nei due anni precedenti.16.Pazienti in dialisi.17.Donne in gravidanza, che pianificano una gravidanza durante il periodo dello studio, in allattamento o in età fertile che non adottano un metodo contraccettivo accettabile. Una donna è considerata in età fertile se non è chirurgicamente sterile o se l'ultimo periodo mestruale è stato <12 mesi prima della Visita 1. I metodi contraccettivi accettabili per questo studio includono l'uso di metodi contraccettivi di doppia barriera, di un dispositivo intrauterino o dell'astinenza, di tutti i contraccettivi ormonali, orali, cerotti, ecc. purché la dose e il tipo siano stabili da 3 mesi prima della Visita 1. Anche l’astinenza completa è un metodo accettato, quando è in linea con lo stile di vita normale e preferito del soggetto.18.Creatinchinasi >5,0 volte l'ULN, aspartato aminotransferasi (AST) o alanina aminotransferasi (ALT) >3,0 volte l'ULN o bilirubina totale (Total Bilirubin, TBL) >2,0 volte l'ULN (eccetto con una diagnosi confermata della malattia di Gilbert) alla Visita 1. Una diagnosi di steatosi epatica non alcolica (Non-Alcoholic Fatty Liver Disease, NAFLD) o steatoepatite non alcolica (Non-Alcoholic Steatohepatitis, NASH) con aumenti stabili dei livelli di AST e/o ALT (>3,0 volte l'ULN) è idonea per la partecipazione allo studio.19.Il consumo eccessivo di alcol o l'abuso di altre sostanze che, secondo il parere dello sperimentatore, possa compromettere la partecipazione del/della paziente allo studio o l'interpretazione dei dati.20.Esposizione a qualsiasi agente sperimentale nelle 4 settimane precedenti alla Visita 1, ivi incluso un precedente arruolamento o randomizzazione a questo studio.21.Qualsiasi altra condizione che, a giudizio dello sperimentatore, possa interferire con la capacità del/della paziente di firmare il consenso informato, rispettare le istruzioni dello studio o che possa interferire con l'interpretazione dei risultati dello studio o esporre il/la paziente a un rischio eccessivo.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is the time to first occurrence of any component of the composite of MACE. Patients will remain in the study until the required number of patients with MACE has occurred. We anticipate that patients will be in the study for 3-5 years. Patients who discontinue investigational product (IP) will continue to be assessed as specified per the protocol.
    La misura primaria del risultato è il tempo alla prima manifestazione di uno qualsiasi dei MACE. I/le pazienti rimarranno nello studio finché non si sarà verificato il numero richiesto di pazienti con MACE. Si prevede che i pazienti rimangano nello studio per 3-5 anni. I/le pazienti che interrompono il prodotto sperimentale (Investigational Product, IP) continueranno ad essere valutati/e come specificato nel protocollo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Visit 3-14, Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    Visite 3-14, Mesi 3, 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    E.5.2Secondary end point(s)
    KEY secondary outcome measures include:
    -The composite measure of CV events that include the first occurrence of cardiovascular death, non-fatal MI, and non-fatal stroke.
    - The composite measure of coronary events that include the first occurrence of cardiovascular death, non-fatal MI, emergent/elective coronary revascularization, or hospitalization for unstable angina.
    - Time to CV Death

    Other secondary outcome measures include:
    a) Emergent/elective coronary revascularization
    b) Hospitalization for unstable angina
    c) Fatal or non-fatal MI
    d) Non-fatal MI
    e) Fatal or non-fatal stroke
    f) Non-fatal stroke
    g) All-cause death

    Tertiary outcome measures will include:
    - The first occurrence of new onset atrial fibrillation (AF)
    - The composite measure of total thrombotic events that include the first occurrence of documented coronary stent thrombosis, any systemic thromboembolism including arterial stent (except coronary) thrombosis or venous thromboembolism (VTE), i.e. deep vein thrombosis (DVT) and/or pulmonary embolism (PE)
    - First occurrence of a heart failure event.

    Le misure CHIAVE di esito secondarie includono:
    • La misura composita di eventi cardiovascolari che includono la prima manifestazione di morte cardiovascolare, IM non fatale o ictus non fatale.
    • La misura composita di eventi coronarici che include la prima manifestazione di morte cardiovascolare, IM non fatale, rivascolarizzazione coronarica emergente/elettiva o ricovero per angina instabile.
    • Tempo al decesso CV

    Altre misure di esito secondarie includono:
    a) rivascolarizzazione coronarica emergente/elettiva
    b) ricovero per angina instabile
    c) IM fatale o non fatale
    d) IM non fatale
    e) ictus fatale o non fatale
    f) ictus non fatale
    g) mortalità per qualsiasi causa.

    Le misure di esito terziarie includeranno:
    • La prima manifestazione di una nuova insorgenza di fibrillazione atriale (FA).
    • La misura composita di eventi trombotici totali che includono la prima manifestazione di trombosi coronarica da stent documentata, tromboembolia sistemica incluse la trombosi arteriosa da stent (eccetto coronarica) o tromboembolia venosa (TEV), ovvero trombosi venosa profonda (TVP) e/o embolia polmonare (EP).
    • La prima manifestazione di un evento di insufficienza cardiaca.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Visit 3-14, Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    Visite 3-14, Mesi 3, 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic 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. 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 concerned20
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA190
    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
    Czech Republic
    Korea, Republic of
    New Zealand
    Russian Federation
    South Africa
    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
    When 1600 primary efficacy endpoints have been identified
    Al raggiungimento di 1600 obiettivi primari di efficacia
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    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: 5200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 7800
    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 state513
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 6500
    F.4.2.2In the whole clinical trial 13000
    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)
    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 Decision2015-01-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-30
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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