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    Summary
    EudraCT Number:2012-000632-26
    Sponsor's Protocol Code Number:TMC-BIV-11-02
    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:2012-10-16
    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 number2012-000632-26
    A.3Full title of the trial
    Effect of BivaliRudin on Aortic Valve Intervention Outcomes 2/3 (BRAVO 2/3)
    Effetto di bivalirudina sugli esiti di intervento di sostituzione della valvola aortica 2/3 (BRAVO 2/3)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of BivaliRudin on Aortic Valve Intervention Outcomes 2/3 (BRAVO 2/3)
    Effetto di bivalirudina sugli esiti di intervento di sostituzione della valvola aortica 2/3 (BRAVO 2/3)
    A.3.2Name or abbreviated title of the trial where available
    BRAVO 2/3
    BRAVO 2/3
    A.4.1Sponsor's protocol code numberTMC-BIV-11-02
    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 SponsorTHE MEDICINES COMPANY UK
    B.1.3.4CountryUnited Kingdom
    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 supportThe Medicines Company
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThe Medicines Company
    B.5.2Functional name of contact pointGlobal Health Science Center
    B.5.3 Address:
    B.5.3.1Street AddressBalsberg 8058
    B.5.3.2Town/ cityZurich-Flughafen
    B.5.3.3Post code8058
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number0041448281084
    B.5.5Fax number0041448281082
    B.5.6E-mailmedicalinformation@themedco.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 Angiox
    D.2.1.1.2Name of the Marketing Authorisation holderThe Medicines Company
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBIVALIRUDIN
    D.3.9.1CAS number 128270-60-0
    D.3.9.2Current sponsor codeB01AE06
    D.3.9.4EV Substance CodeSUB05862MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients undergoing transcatheter aortic valve replacement (TAVR) procedures performed via the transfemoral approach
    Pazienti sottoposti a sostituzione transcatetere della valvola aortica eseguita con l'approccio transfemorale
    E.1.1.1Medical condition in easily understood language
    Patients undergoing transcatheter aortic valve replacement (TAVR) procedures performed through a large artery in the thigh (transfemoral)
    Pazienti sottoposti a sostituzione transcatetere della valvola aortica eseguita attraverso una larga arteria nella coscia (transfemorale)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level SOC
    E.1.2Classification code 10042613
    E.1.2Term Surgical and medical procedures
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level SOC
    E.1.2Classification code 10007541
    E.1.2Term Cardiac disorders
    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 objective of this study is to assess the safety and efficacy of using bivalirudin instead of unfractionated heparin (UFH) in transcatheter aortic valve replacements (TAVR). The hypothesis is that bivalirudin will reduce bleeding rates compared to UFH, and will improve the overall clinical outcomes of TAVR patients.
    L’obiettivo di questo studio è di valutare la sicurezza e l’efficacia dell’uso di bivalirudina al posto di eparina non-frazionata (UFH) in interventi di sostituzione transcatetere della valvola aortica (TAVR). L’ipotesi è che la bivalirudina riduca i tassi di sanguinamento rispetto all’eparina non-frazionata e che migliori gli esiti clinici complessivi dei pazienti sottoposti a sostituzione transcatetere della valvola aortica.
    E.2.2Secondary objectives of the trial
    None
    Nessuno
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    All patients ≥18 years of age who are deemed appropriate candidates at high surgical risk(Euroscore ≥18,or considered inoperable)undergoing TAVR via transfemoral arterial access, that have provided written informed consent before initiation of any study related procedures
    Saranno eleggibili per l’inclusione tutti i pazienti di ≥18 anni di età considerati candidati appropriati ad alto rischio chirurgico (Euroscore ≥18 o considerati inoperabili), sottoposti a intervento di TAVR via accesso arterioso tansfemorale, che abbiano firmato il consenso informato prima di iniziare le procedure dello studio
    E.4Principal exclusion criteria
    1. Contraindication to bivalirudin or UFH 2. Refusal to receive blood transfusion 3. Mechanical valve (any location) or mitral bioprosthetic valve 4. Extensive calcification of the common femoral artery, or minimal luminal diameter<6.5 mm 5. Use of elective surgical cut-down for transfemoral access 6. Concurrent performance of percutaneous coronary intervention with TAVR 7. International normalized ratio (INR) ≥ 2 on the day of TAVR procedure, or known history of bleeding diathesis 8. History of hemorrhagic stroke, intracranial hemorrhage, intracerebral mass or aneurysm, or arteriovenous malformation 9. Severe left ventricular dysfunction (left ventricular ejection fraction<15%) 10. Severe aortic regurgitation or mitral regurgitation (4+) 11. Hemodynamic instability (e.g. requiring inotropic or IABP support) within 2 hours of the procedure 12. dialysis dependent 13. Administration of thrombolytics, glycoprotein IIb/IIIa inhibitors, or warfarin in the 3 days prior to the procedure 14. Acute myocardial infarction, major surgery or any Therapeutic cardiac procedure (other than balloon aortic valvuloplasty) within 30 days 15. Percutaneous coronary intervention within 30 days 16. Upper gastrointestinal or genitourinary bleed within 30 days 17. Stroke or transient ischemic attack within 30 days 18. Any surgery or biopsy within 2 weeks 19. Administration of: a. UFH within 30 minutes of the procedure b. Enoxaparin within 8 hours of the procedure c. Fondaparinux or other LMWHs within 24 hours of the procedure d. Dabigatran, rivaroxaban or other oral anti-Xa or antithrombin agent within 48 hours of the procedure e. Thrombolytics, GPI, or warfarin within 72 hours of the procedure 20. Absolute contraindications or allergy that cannot be pre‐medicated to iodinated contrast 21. Contraindications or allergy to aspirin or clopidogrel 22. Known or suspected pregnant women, or nursing mothers. Women of child‐bearing potential will be asked if they are pregnant and will be tested for pregnancy. 23. Previous enrolment in this study 24. Treatment with other investigational drugs or devices within the 30 days preceding enrollment or planned use of other investigational drugs or devices before the primary endpoint of this study has been reached Patients excluded for any of the above reasons may be re‐screened for participation at any time if the exclusion characteristic has changed.
    1. Controindicazioni alla bivalirudina o UFH 2. Rifiuto a ricevere trasfusioni 3. Valvola meccanica (in qualsiasi posizione) o valvola mitralica bioprostetica 4. Estesa calcificazione dell’arteria femorale comune o diametro luminale minimo &lt;6.5 mm 5. Uso di incisione chirurgica elettiva per l’accesso transfemorale 6. Esecuzione concomitante di intervento coronarico percutaneo con TAVR 7. Rapporto internazionale di normalizzazione (INR) ≥ 2 nel giorno dell’esecuzione della TAVR, o storia conosciuta di diatesi sanguinante 8. Storia di evento emorragico, emorragia intracranica, massa o aneurisma intracerebrale, o malformazione arteriovenosa 9. Grave disfunzione del ventricolo sinistro (frazione di eiezione del ventricolo sinistro &lt;15%) 10. Grave rigurgito aortico o mitralico (4+) 11. Instabilità emodinamica (es. richiedente un supporto inotropico o IABP) entro 2 ore dalla procedura 12. dialisi dipendente 13. Somministrazione di trombolitici, inibitori della glicoproteina IIb/IIIa, o warfarin nei 3 giorni precedenti la procedura 14. Infarto miocardico acuto, intervento di chirurgia maggiore o qualsiasi procedura cardiaca terapeutica (tranne la valvuloplastica con palloncino) entro 30 giorni dalla procedura 15. Intervento coronarico percutaneo entro 30 giorni 16. Sanguinamento del tratto gastrointestinale superiore o genitourinario entro 30 giorni 17. Stroke o attacco ischemico transitorio entro 30 giorni 18. Qualsiasi intervento chirurgico o biopsia entro 2 settimane 19. Somministrazione di: a. UFH entro 30 minuti dalla procedura b. Enoxaparin entro 8 ore dalla procedura c. Fondaparinux o altri LMWH entro 24 ore dalla procedura d. Dabigatran, rivaroxaban o altri anti-Xa orali o agenti antitrombinici entro 48 ore dalla procedura e. Trombolitici, GPI, o warfarin entro 72 ore dalla procedura 20. Controindicazioni assolute o allergia al contrasto iodato che non possano essere pre-medicate 21. Controindicazioni o allergia all’aspirina o al clopidogrel 22. Gravidanza certa o presunta o allattamento. Alle donne fertili verrà chiesto se sono gravide e verrà eseguito un test di gravidanza. 23. Precedente arruolamento in questo studio 24. Trattamento con altri farmaci sperimentali o dispositivi entro 30 giorni prima dell’ arruolamento o uso previsto di altri farmaci sperimentali o dispositivi prima del raggiungimento dell’endpoint primario di questo studio. I pazienti esclusi per una qualsiasi delle ragioni sopra elencate potranno essere ri-scrinati per la partecipazione in qualsiasi momento se le caratteristiche per l’esclusione verranno cambiate
    E.5 End points
    E.5.1Primary end point(s)
    Major bleeding(Bleeding Academic Research Consortium[BARC]type ≥ 3) at 48 hours or hospital discharge, whichever occurs first, and Net Adverse Clinical Events [NACE(including major bleeding, death, myocardial infarction [MI],and stroke) at 30 days.
    Sanguinamento maggiore (Bleeding Academic Research Consortium [BARC] tipo ≥ 3) a 48 ore o alla dimissione ospedaliera, a seconda di quale evento si verifichi per primo, e insieme di eventi avversi clinici (NACE - Net Adverse Clinical Events) (comprendenti sanguinamento maggiore, morte, infarto miocardico [MI] e ictus) a 30 giorni.
    E.5.1.1Timepoint(s) of evaluation of this end point
    48 hours or prior to hospital discharge (whichever occurs first). co-primary end-point: 30 days
    48 ore o prima delle dimissioni dall'ospedale (qualsiasi delle due avvenga prima) End point co-primario: 30 giorni
    E.5.2Secondary end point(s)
    (1) Major bleeding according to additional scales (VARC, TIMI, GUSTO, ACUITY/HORIZONS); (2)minor bleeding (BARC type 1 and 2 and TIMI minor); (3) major adverse cardiac events (MACE) including death, non-fatal MI, and stroke; (4) the rates of the individual components of MACE; (5) transient ischemic attack; (6) acute kidney injury; (7) VARC major vascular complications; (8) acquired thrombocytopenia; (9) rate of new post-procedural atrial fibrillation/flutter; (10) economic analysis of using bivalirudin in TAVR.
    (1) Sanguinamento maggiore secondo scale addizionali (VARC, TIMI, GUSTO, ACUITY/HORIZONS); (2) sanguinamento minore (BARC tipo 1 e 2 e TIMI minore); (3) eventi cardiaci avversi maggiori (MACE – Major Adverse Cardiac Events) inclusi morte, infarto miocardico non fatale e ictus; (4) incidenza delle singole componenti dei MACE; (5) attacco ischemico transitorio; (6) lesione renale acuta; (7) complicanze vascolari maggiori secondo i criteri VARC;(8) trombocitopenia acquisita; (9) incidenza di nuova fibrillazione/flutter atriale post-intervento; (10) analisi economica dell'uso di bivalirudina nella TAVR.
    E.5.2.1Timepoint(s) of evaluation of this end point
    48 hours or prior to hospital discharge (whichever occurs first) and at 30 days
    48 ore o prima delle dimissioni dall'ospedale (qualsiasi delle due avvenga prima) e a 30 giorni
    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 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.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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    eparina non frazionata
    unfractioned haeparin
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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 No
    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 years0
    E.8.9.1In the Member State concerned months14
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months14
    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.1.1Number of subjects for this age range: 0
    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: 186
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 434
    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 2012-10-16. 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 Yes
    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 state150
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 526
    F.4.2.2In the whole clinical trial 526
    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)
    as per protocol
    secondo protocollo
    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 Decision2012-11-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-10-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-06-24
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