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    Summary
    EudraCT Number:2016-002885-30
    Sponsor's Protocol Code Number:ARES
    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:2020-11-04
    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 number2016-002885-30
    A.3Full title of the trial
    Novel strategies of antithrombotic prophylaxis in patients with Essential Thrombocythemia (ET) at high risk of cardiovascular events: comparison of different dosing regimens of administration of
    low-dose acetylsalicylic acid
    Nuove strategie di profilassi antitrombotica in pazienti con Trombocitemia Essenziale (TE): valutazione di differenti regimi posologici di acido acetilsalicilico a basse dosi.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    ND
    ND
    A.3.2Name or abbreviated title of the trial where available
    ARES-Aspirin Regimens in ESsential thrombocythemia
    ARES
    A.4.1Sponsor's protocol code numberARES
    A.5.4Other Identifiers
    Name:FARM12Y8HHNumber:ARES
    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 SponsorFONDAZIONE POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI IRCCS UNIVERSITA' CATTOLICA DEL SACRO CUORE
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAIFA - Italian Medicines Agency
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFONDAZIONE POLICLINICO GEMELLI
    B.5.2Functional name of contact pointArea di ematologia
    B.5.3 Address:
    B.5.3.1Street AddressL.go Gemelli 8
    B.5.3.2Town/ cityRoma
    B.5.3.3Post code00168
    B.5.3.4CountryItaly
    B.5.4Telephone number0630154968
    B.5.5Fax number0630155209
    B.5.6E-mailvalerio.destefano@policlinicogemelli.it
    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 CARDIOASPIRIN - 100 MG COMPRESSE GASTRORESISTENTI30 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderBAYER S.P.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 namecardioaspirina
    D.3.2Product code [nd]
    D.3.4Pharmaceutical form Gastro-resistant 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 INNACIDO ACETILSALICILICO
    D.3.9.2Current sponsor codend
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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 CARDIOASPIRIN - 100 MG COMPRESSE GASTRORESISTENTI30 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderBAYER S.P.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 namecardioaspirina
    D.3.2Product code [nd]
    D.3.4Pharmaceutical form Gastro-resistant 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 INNACIDO ACETILSALICILICO
    D.3.9.2Current sponsor codend
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 placeboGastro-resistant 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
    Essential thrombocytemia
    Trombocitemia essenziale
    E.1.1.1Medical condition in easily understood language
    nd
    nd
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10015493
    E.1.2Term Essential thrombocythaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1- To investigate whether aspirin regimens based on twice or three times daily derived TXA2, without significantly affecting in vivo PGI2 biosynthesis, as compared to the standard, once daily 100 mg regimen. The comparison between aspirin 100 mg twice or 3 times daily vs. 100 mg od will test a superiority hypothesis in terms of serum TXB2 levels associated with each new regimen vs. standard treatment. PGIM comparisons will assess the non-inferiority of any multiple daily dosing vs standard od regimen.
    2- To evaluate the long-term persistence of superior biochemical efficacy of an optimized, multiple daily dosing regimen of aspirin, as compared to the standard 100 mg od regimen.
    Parte A Determinare se somministrazioni ripetute di 100 mg di aspirina nelle 24 ore (100 mg x 2 e 100 mg x 3) siano superiori al trattamento standard di 100 mg una volta al giorno nell’inibire il trombossano (TX) A2 piastrinico senza modificare significativamente la produzione di prostaciclina (PGI2) vascolare (= 30%)
    Parte B: valutare la persistenza della superiore efficacia biochimica a lungo termine di somministrazioni ripetute giornaliere di 100 mg di aspirina (la migliore posologia rilevata nella Parte A nel rapporto inibizione TXA2/inibizione PGI2) vs. una posologia standard di una volta al giorno mediante misurazioni ripetute di TXB2 sierico.
    E.2.2Secondary objectives of the trial
    1. Safety. The safety of the multiple daily aspirin regimen will be assessed in an exploratory fashion by recording major bleeding and clinically relevant non-major bleeding.
    Any thrombotic complication (major and minor) will also be recorded.
    These objectives will be explored in part B of the study, over 20-month treatment, with descriptive statistics.
    2. Tolerability. The tolerability will be assessed in an exploratory fashion by recording: a. the gastrointestinal symptoms; b. the MPN symptom burden as scored by the MPN-SAF questionnaire modified to capture all microvascular symptoms and a pain numeric rating scale (NRS) for erythromelalgia
    3. Stability over time of in vivo platelet activation, as assessed by the urinary biomarker TXM, will be e
    Sicurezza a lungo termine della posologia con somministrazioni ripetute giornaliere, rispetto alla posologia standard di una volta al giorno valutata come:
    - Eventi emorragici maggiori o clinicamente rilevanti
    - Eventi avversi gastrointestinali maggiori non emorragici
    - Eventi trombotici
    - Tollerabilità a lungo termine della posologia a somministrazioni ripetute giornaliere rispetto alla posologia standard di una volta al giorno valutata come:
    - Sintomi gastrointestinali
    - Effetto sulla sintomatologia generale legata alla TE
    - Effetto sui disturbi del microcircolo associati alla TE
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A patient will be eligible if all of the following criteria apply:
    - age between 18 and 75 years;
    - an ET diagnosis according to WHO 2008 criteria;2
    - ongoing aspirin 100 mg daily since at least 1 month, according to the judgement of the referring Hematologist;
    - the patient understands and voluntarily signs an informed consent.
    - età di 18-75 anni
    - diagnosi di TE secondo i criteri WHO 2008;
    - trattamento con aspirina 100 mg/die da almeno 1 mese, prescritto dall’Ematologo di riferimento
    - capacità di comprendere e firmare volontariamente il consenso informato
    E.4Principal exclusion criteria
    A patient is not eligible if any of the following criteria apply:
    - platelet count >1,000,000/µL on three occasions over the 2 months before enrolment;
    - creatinine level >1.5 x upper limit of normal;
    - liver disease defined as AST and/or ALT values >3 x upper limit of normal;
    - BMI >35 kg/m2;
    - history of major bleeding that in the referring Hematologist's judgement may expose the patient to increased risk of bleeding recurrence
    - active cancer or cancer in complete remission from less than one year, except for treated early-stage squamous or basal cell skin carcinomas;
    - pregnancy or lactation;
    - use of non-steroidal anti-inflammatory drugs (NSAIDs) >3 times/week;
    - use of antiplatelet agents other than aspirin 100 mg od;
    - use of oral anticoagulants including vitamin K antagonists, anti-Xa or -IIa agents;
    - use of heparins or fondaparinux
    - chronic use of steroids (prednisone >5 mg/die or equivalent)
    Uno qualsiasi dei criteri di seguito elencati:
    - conta piastrinica >1,000,000/µL in almeno 3 determinazioni nei 2 mesi precedenti l’arruolamento
    - creatinina >1.5 x il limite superiore della norma;
    - valori di AST e/o ALT >3 x il limite superiore della norma;
    - BMI >35 kg/m2;
    -storia di pregresso evento emorragico che, a giudizio dell’Ematologo di riferimento, potrebbe esporre il paziente ad un aumentato rischio di recidiva di emorragia se arruolato nello studio;
    - patologia oncologica attiva o in remissione completa da < 1 anno, eccetto i carcinomi cutanei squamosi o basaliomi in stadio iniziale;
    - gravidanza o allattamento;
    - uso di FANS >3 giorni/settimana;
    - uso di antiaggreganti diversi dall’aspirina;
    - uso di anticoagulanti orali (anti-vitamina K, anticoagulanti diretti);
    - uso di eparine o fondaparinux
    - uso cronico di steroidi (prednisone >5 mg/die o equivalente)
    E.5 End points
    E.5.1Primary end point(s)
    Part A:
    Primary endpoints:
    - platelet thromboxane (TX)A2 production ex vivo, as reflected by serum TXB2 measured in samples collected in a fasting state, in the morning, before the next aspirin intake
    - vascular PGI2 biosynthesis in vivo, as reflected by urinary 2,3-dinor-6-keto-PGF1alfa (PGIM) excretion in a urine sample collected in the morning before the next aspirin intake.
    Both biomarkers will be measured at 14±2 days after randomization.
    Part B
    Primary endpoint:
    - long-term persistence of superior biochemical efficacy of the optimized vs standard aspirin regimen, as measured by repeated serum TXB2 levels in samples collected in a fasting state, in the morning, before the next aspirin intake
    Parte A
    Endpoint primario
    Miglior rapporto calcolato in relazione alla posologia dei bracci di randomizzazione tra:
    - inibizione della biosintesi di TXA2 piastrinico ex vivo, misurato come TXB2 sierico misurato a digiuno prima dell’assunzione della dose successiva di aspirina
    e
    - inibizione della biosintesi di PGI2 vascolare in vivo, misurata come 2,3-dinor-6-keto-PGF1alfa urinario in un campione raccolto a digiuno prima dell’assunzione della dose successiva di aspirina
    Entrambi i biomarcatori verranno misurati dopo 14±2 giorni dalla randomizzazione

    Parte B:
    Endpoint primario
    Persistenza a lungo termine della superiore efficacia biochimica del regime posologico sperimentale rispetto a quello standard, misurata come determinazioni ripetute nel tempo di TXB2 sierico misurato a digiuno prima dell’assunzione della dose successiva di aspirina
    E.5.1.1Timepoint(s) of evaluation of this end point
    A: 14 DAYS
    B: UP TO 21 MONTHS
    A: 14 GIORNI
    B: FINO A 21 MESI
    E.5.2Secondary end point(s)
    A. Secondary endpoints:
    - urinary TXM measured at 14±2 days after randomization
    B. Secondary endpoints:
    - major bleeding and CRNMB and/or NB-UGI AE > grade 1 attributable to aspirin and/or major thrombotic complications (Appendices 1-3)
    - tolerability: gastrointestinal and microvascular symptoms (Appendices 4-6)
    - stability over time of in vivo biosynthesis of TXA2 and PGI2 as assesses by urinary TXM and PGIM excretion, respectively (measured in patients from Units 1, 2, 9), and of plasma von Willebrand Factor (vWF). These urinary metabolites will be assessed 3 times during part B.
    PARTE A: Endpoint secondario
    - metabolita urinario del TXA2 (TXM) all’arruolamento e a 14±2 giorni dalla randomizzazione

    PARTE B: Endpoints secondari:
    - Emorragie maggiori o non-maggiori clinicamente rilevanti, eventi avversi gastrointestinali sintomatici grado >1 attribuibili all’aspirina, complicanze trombotiche maggiori (Appendici 1-3)
    - Sintomi gastrointestinali e microvascolari (Appendici 4-6)
    - Stabilità nel tempo della biosintesi in vivo di TXA2 e PGI2, misurate come TXM e PGIM in pazienti afferenti alle Unità 1, 2, 9.
    E.5.2.1Timepoint(s) of evaluation of this end point
    A. 14 DAYS
    B. UP TO 21 MOUNTHS
    A. 14 GIORNI
    B. FINO A 21 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 Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    E.8.1.7.1Other trial design description
    disegno applicabile solo alla parte A (14 giorni); la parte B è randomizzata in aperto
    nd
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned11
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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: 240
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-11-04. Yes
    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 state300
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    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)
    standard of care
    normale pratica clinica
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-09-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-27
    P. End of Trial
    P.End of Trial StatusCompleted
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