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    Summary
    EudraCT Number:2013-003519-23
    Sponsor's Protocol Code Number:D513BC00001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-12-20
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-003519-23
    A.3Full title of the trial
    A Multinational, Randomised, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Ticagrelor 90 mg twice daily on the Incidence of Cardiovascular Death, Myocardial Infarction or Stroke in Patients with Type 2 Diabetes Mellitus
    Studio multinazionale, randomizzato, in doppio cieco, controllato verso placebo per valutare l’effetto di Ticagrelor 90 mg assunto due volte al giorno sull’incidenza di morte per cause cardiovascolari, infarto del miocardio e ictus in pazienti con diabete mellito di tipo 2.
    [THEMIS - effect of Ticagrelor on Health outcomes in diabEtes Mellitus patients Intervention Study]
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study Comparing Cardiovascular Effects of Ticagrelor versus Placebo in Patients with Type 2 Diabetes Mellitus
    Studio Per Confrontare Effetti Cardiovascolari Di Ticagrelor Versus Placebo In Pazienti Con Diabete Mellito Di Tipo 2
    A.3.2Name or abbreviated title of the trial where available
    THEMIS
    THEMIS
    A.4.1Sponsor's protocol code numberD513BC00001
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1149-3152
    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.1.3.4CountrySweden
    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.4.2CountrySweden
    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 Address1800 Concord Pike, PO Box 15437
    B.5.3.2Town/ cityWilmington, DE
    B.5.3.3Post code19850-5437
    B.5.3.4CountryUnited States
    B.5.4Telephone number001800336 9933
    B.5.6E-mailinformation.center@astrazeneca.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 Yes
    D.2.1.1.1Trade name BRILIQUE
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameTicagrelor 90mg film-coated tablets
    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 INNticagrelor
    D.3.9.1CAS number 274693-27-5
    D.3.9.2Current sponsor codeAZD6140
    D.3.9.3Other descriptive nameTICAGRELOR
    D.3.9.4EV Substance CodeSUB30898
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number90
    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
    major cardiovascular events in type 2 diabetes mellitus patients
    eventi cardiovascolari maggiori in pazienti con diabete mellito di tipo 2
    E.1.1.1Medical condition in easily understood language
    cardiovascular death, myocardial infarction and stroke
    morte per cause cardiovascolari, infarto del miocardio e ictus
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10042244
    E.1.2Term Stroke
    E.1.2System Organ Class 100000004852
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10028596
    E.1.2Term Myocardial infarction
    E.1.2System Organ Class 10007541 - Cardiac disorders
    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 of the study is to compare the effect of long-term treatment with ticagrelor 90 mg twice daily (bd) vs. placebo for the prevention of major cardiovascular (CV) events (composite of CV death, myocardial infarction [MI] or stroke) in patients with Type 2 Diabetes Mellitus (T2DM) at high risk for CV events, but without a previous medical history of MI or stroke.
    The primary efficacy variable is time from randomisation to first occurrence of any event from the composite of CV death, MI or stroke (ischaemic, haemorrhagic or unknown etiology).
    L’obiettivo primario dello studio è comparare l’effetto del trattamento a lungo termine con ticagrelor 90 mg assunto due volte al giorno (bd) verso placebo per la prevenzione di eventi cardiovascolari maggiori (evento composito di morte per cause cardiovascolari [CV], infarto del miocardio [IM] o ictus) in pazienti con diabete mellito di tipo 2 (T2DM) ad alto rischio di eventi CV, ma senza una storia clinica di precedenti IM o ictus.
    La variabile primaria di efficacia è il tempo dalla randomizzazione alla prima occorrenza di uno degli eventi compositi di morte per cause CV, IM o ictus (ischemico, emorragico o di eziologia sconosciuta).
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study (presented in hierarchical order) are to compare the effect of long-term treatment with ticagrelor vs. placebo for:
    1. Prevention of the composite of all-cause death, MI or stroke. The efficacy variable is time from randomisation to first occurrence of any event from the composite of all-cause death, MI or stroke
    2. Prevention of CV death. The efficacy variable is time from randomisation to death of CV cause
    3. Prevention of all-cause death. The efficacy variable is time from randomisation to death of any cause
    Gli obiettivi secondari dello studio (presentati in ordine gerarchico) sono quelli di comparare gli effetti a lungo termine del trattamento con ticagrelor verso placebo per:
    1. Prevenzione degli eventi compositi di morte per qualunque causa, IM o ictus. La variabile di efficacia è il tempo dalla randomizzazione alla prima occorrenza di uno degli eventi compositi di morte per qualunque causa, IM, ictus.
    2. Prevenzione della morte per cause CV. La variabile di efficacia è il tempo dalla randomizzazione al momento di morte per cause CV.
    3. Prevenzione di morte per tutte le cause. La variabile di efficacia è il tempo dalla randomizzazione al momento di morte per qualunque causa.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Men or women ≥50 years of age
    Diagnosed with T2DM defined by ongoing glucose lowering drug treatment prescribed by a physician for treatment of T2DM since at least 6 months prior to Visit 1
    At high risk of CV events, defined as history of percutaneous coronary intervention or coronary artery bypass graft or angiographic evidence of ≥ 50% lumen stenosis of at least 1 coronary artery
    Maschi e femmine di età ≥ 50 anni
    Diabete mellito di tipo 2 (T2DM) diagnosticato in trattamento con un farmaco che abbassa i livelli di glucosio prescritto da un medico per il trattamento del T2DM da almeno 6 mesi prima di visita 1
    Alto rischio di eventi cardiovascolari CV, definito come storia di intervento coronarico percutaneo o bypass arterioso coronarico o evidenza angiografica di stenosi luminare ≥ 50% di almeno una arteria coronarica
    E.4Principal exclusion criteria
    1. Previous MI (with the exception of definite secondary MI [e.g., due to coronary revascularization procedure, profound hypotension, hypertensive emergency, tachycardia, or profound anaemia])
    2. Previous stroke (transient ischaemic attacks [TIA] is not included in the stroke definition)
    3. Planned use of ADP receptor antagonists (e.g., clopidogrel, ticlopidine, prasugrel), dipyridamole, or cilostazol. Planned use of ASA treatment at doses >150 mg od.
    4. Planned coronary, cerebrovascular, or peripheral arterial revascularization.
    5. Anticipated concomitant oral or intravenous therapy with strong cytochrome P450 3A4 (CYP3A4) inhibitors or CYP3A4 substrates with narrow therapeutic indices that cannot be stopped for the course of the study:
     Strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin (but not erythromycin or azithromycin), nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir.
     CYP3A4 substrates with narrow therapeutic index: quinidine, simvastatin at doses >40 mg daily or lovastatin at doses >40 mg daily
    6. Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin (at venous thrombosis treatment not prophylaxis doses)
    7. Patients with known bleeding diathesis or coagulation disorder, or with uncontrolled hypertension (defined as a systolic BP ≥180 mmHg and/or diastolic BP ≥100 mmHg)
    8. History of previous intracerebral bleed at any time, gastrointestinal (GI) bleed within the past 6 months, or major surgery within 30 days
    9. Increased risk of bradycardic events (e.g., known sick sinus syndrome, second or third degree AV block or previous documented syncope suspected to be due to bradycardia) unless treated with a pacemaker
    10. Known severe liver disease (e.g., ascites and/or clinical signs of coagulopathy)
    11. Renal failure requiring dialysis
    1. Precedente infarto del miocardio IM (ad eccezione di IM secondario definito [ad es. dovuto alla procedura di rivascolarizzazione coronarica, ipotensione profonda, emergenza ipertensiva, tachicardia o profonda anemia])
    2. Precedente ictus (l’attacco ischemico transitorio TIA non è compreso nella definizione di ictus)
    3. Uso pianificato di antagonisti del recettore ADP (es. clopidogrel, ticlopidina, prasugrel), dipiridamolo o cilostazolo. Uso pianificato di ASA a dosi di trattamento > 150 mg al giorno.
    4. Rivascolarizzazione coronarica, cerebrovascolare o arteriosa periferica pianficata
    5. Necessità di uso concomitante di terapia orale o intravenosa con inibitori potenti del citocromo P450 3A4 (CYP3A4) o che hanno per substrato CYP3A4 con ristretto indice terapeutico che non può essere interrotto durante il corso dello studio
    - Inibitori forti: ketoconazolo, itroconazolo, voriconazolo, telitromicina, claritromicina (ma non eritromicina o azitromicina), nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir
    - Farmaci che hanno per substrato CYP3A4 con ristretto indice terapeutico:quinidina, simvastatina o lovastatina a dosi > 40 mg al giorno
    6. Necessità d’uso di terapia cronica anticoagulante orale o uso cronico di eparina a basso peso molecolare (trattamento per trombosi venosa non a dosi di profilassi)
    7. Pazienti con diatesi sanguinante nota o disordini della coagulazione o con ipertensione non controllata (definita come pressione sistolica ≥180 mmHg e/o diastolica ≥100 mmHg)8. Storia di precedente sanguinamento intracerebrale in ogni momento, sanguinamento gastrointestinale (GI) nei precedenti 6 mesi alla randomizzazione, o intervento chirurgico importante nei 30 giorni precedenti la randomizzazione
    9. Rischio aumentato di eventi bradicardici (es. sindrome della malattia del seno nota, blocco AV di secondo o terzo grado o precedente sincope documentata di sospetta origine bradicardica) a meno di trattamento con pacemaker.
    10. Malattia epatica severa nota (es. Ascite e/o segni clinici di coagulopatia)
    11. Insufficienza renale che richiede dialisi
    E.5 End points
    E.5.1Primary end point(s)
    Time from randomisation to first occurrence of any event from the composite of CV death, MI or stroke (ischaemic, haemorrhagic or unknown etiology).
    Tempo dalla randomizzazione alla prima occorrenza di uno degli eventi compositi di morte per cause CV, IM o ictus (ischemico, emorragico o di eziologia sconosciuta).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to approximately 35 months.
    Fino a circa 35 mesi.
    E.5.2Secondary end point(s)
    Time from randomisation to first occurrence of any event from the composite of all-cause death, MI or stroke.
    Time from randomisation to death of CV cause.
    Time from randomisation to death of any cause.
    Tempo dalla randomizzazione alla prima comparsa di uno qualsiasi uno degli eventi compositi di tutte le cause di morte, infarto miocardico o ictus.
    Tempo dalla randomizzazione alla morte per cause CV.
    Tempo dalla randomizzazione alla morte per qualsiasi causa.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to approximately 35 months.
    Fino a circa 35 mesi.
    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 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 concerned20
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA300
    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
    Canada
    China
    France
    Italy
    Japan
    Netherlands
    Romania
    Slovakia
    Sweden
    Argentina
    Australia
    Brazil
    Chile
    Czech Republic
    Germany
    Hong Kong
    Hungary
    India
    Korea, Republic of
    Spain
    Thailand
    Israel
    Mexico
    Peru
    Philippines
    Poland
    Russian Federation
    South Africa
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    United States
    Vietnam
    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
    Last subject last visit
    LSLV
    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 months32
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months35
    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: 8500
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8500
    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 state230
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 5000
    F.4.2.2In the whole clinical trial 17000
    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)
    Standard of care
    Standard di cura
    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 Decision2014-02-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-08
    P. End of Trial
    P.End of Trial StatusCompleted
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