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    EudraCT Number:2020-001053-44
    Sponsor's Protocol Code Number:Carotis-Rivaroxaban_CEUS_001
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-04-16
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2020-001053-44
    A.3Full title of the trial
    Stabilization of vulnerable atherosclerotic carotid plaques by Rivaroxaban as evaluated by 3D contrast enhanced ultrasound (CEUS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Stabilization of atherosclerosis in carotid artery by Rivaroxaban as evaluated by 3D ultrasound with contrast
    A.4.1Sponsor's protocol code numberCarotis-Rivaroxaban_CEUS_001
    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 SponsorRigshospitalet, Department of Vascular Surgery
    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 supportBayer AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRigshospitalet, Department of Vascular Surgery
    B.5.2Functional name of contact pointCarotis-Rivaroxaban Trial
    B.5.3 Address:
    B.5.3.1Street AddressBlegdamsvej 9
    B.5.3.2Town/ cityCopenhagen
    B.5.3.3Post code2100
    B.5.4Telephone number+4535459616
    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. name Xarelto®
    D. of the Marketing Authorisation holderBayer AG
    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.3.4Pharmaceutical 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 INNRIVAROXABAN
    D.3.9.1CAS number 366789-02-8
    D.3.9.4EV Substance CodeSUB29263
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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. 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 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
    Patients with
    - Stable peripheral artery disease
    - Asymptomatic, atherosclerotic plaque/stenosis in the carotid artery; asymptomatic regarding cerebral ischaemia including stroke and transient ischaemic attack (TIA) or amaurosis fugax.
    Patienter med
    - Stabil perifer arteriel sygdom
    - Asymptomatisk, aterosklerotisk plaque/stenose in carotis; asymptomatisk vedr. iskæmisk apopleksi inkluderende stroke og transient cerebral iskæmi (TCI) eller amaurosis fugax.
    E.1.1.1Medical condition in easily understood language
    Patients with:
    - Atherosclerosis in limb arteries
    - Atherosclerosis in carotid artery with no symptoms of major or minor stroke or temporary vision loss.
    Patienter med:
    - Åreforkalkning i underekstremitets blodkar
    - Åreforkalkning i halspulsåren uden symptomer på slagtilfælde eller forbigående synstab.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10075495
    E.1.2Term Internal carotid artery atherosclerosis
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To observe the effect of rivaroxaban on atherosclerotic plaque morphology in carotid artery over time, registered by 3D contrast enhanced ultrasound.
    At observere rivaroxabans effekt på morfologien af aterosklerotiske plaque i arterie carotis over tid visualiseret ved 3D kontrastforstærket ultralyd.
    E.2.2Secondary objectives of the trial
    Optimizing the risk stratification of future major cardiovascular events by using carotid plaque morphology as a surrogate measure determined by contrast enhanced ultrasound.
    At carotisplaques morfologi bestemt ved kontrastforstærket ultralyd kan anvendes som surrogatmål i risikovurderingen for fremtidige kardiovaskulære iskæmiske events.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Oral and written informed consent.
    - Adults > 18 years of age.
    - Acetylsalic acid (aspirin) therapy > 6 months.
    - Statin therapy > 6 months.
    - Asymptomatic carotid stenosis.
    - Hypoechoic carotid plaque with a thickness of 2.5 mm at least.
    - Stable peripheral artery disease (PAD) defined as at least one of the following:
    * Previous revascularization with aorta-femoral bypass, infrainguinal bypass, thrombendarterectomy, thrombectomy, endovascular procedures or farmeceutical with heparine and/or thrombolysis.
    * Previous amputation of food or leg due to arteriel insufficiency.
    * Current of previous intermittent claudication with one or more of the following: ankle/brachial (ABI) index < 0.9 and/or significant peripheral arterial stenosis > 50% verificed by angiography or duplex ultrasound.
    - Informeret samtykke til deltagelse mundtligt og skriftlig.
    - Voksne habile patienter > 18 år.
    - I acetylsalicylsyre behandling > 6 måneder.
    - I statinbehandling > 6 måneder.
    - Asymptomatisk carotisstenose.
    - Ekkosvag carotisplaque med en tykkelse på mindst 2,5 mm.
    - Stabil perifer arteriel karsygdom (PAD) defineret som et eller flere af følgende:
    * Tidligere revaskularisering: åben kirurgi med aorta-femoral bypass, infraligamentær bypass, TEA, trombektomi, endovaskulære procedurer, farmaka revaskularisering med heparin og/eller trombolyse.
    * Tidligere ben- eller fodamputation grundet arteriel karsygdom.
    * Nuværende eller tidligere claudicatio intermittens med ét eller flere af følgende: Ankel/arm systolisk blodtryksratio < 0,9 (ABI-index) og/eller signifikant perifer arteriestenose på > 50% verificeret ved angiografi eller duplex ultralyd.
    E.4Principal exclusion criteria
    General exclusion criteria:
    - Subjects who are pregnant, breastfeeding, or are of childbearing potential and sexually active and not practicing an effective method of contraception.
    - Severe cardiac insufficiency with ejection fraction < 30% or New York Heart Association (NYHA) Class III or IV symptoms.
    - Current acute condition/disease.

    CEUS exclusion criteria:
    - Previous allergic reaction towards the contrast SonoVue®
    - Electronic implantation e.g. pacemaker, ICD, due to use of magnetic field ultrasound.
    - Patients who cannot cooperate to the ultrasound examination.

    Rivaroxaban exclusion criteria:
    - Concomitant participation in another study with investigational drug.
    - History of hypersensitivity or known contraindication for rivaroxaban, aspirin (acetylsalicyl acid), pantoprazole, or excipients.
    - Need for other anticoagulant therapy e.g. warferin or other direct oral anticoagulants than rivaroxaban.
    - Already in treatment with rivaroxaban.
    - Need for dual antiplatelets therapy or other non-aspirin antiplatelet therapy.
    - High risk of bleeding e.g.: active significant bleeding, previous or current lesions or conditions with significant risk of major bleedings, recent cerebral, spinal or ocular surgery, recent intracranial bleeding, esophageal varices, arteriovenous malformations, vascular aneurysms or majour intraspinal og intracerebral vascular abnormalities.
    - Stroke within 1 year or previous haemorrhagic or lacunar stroke.
    - Any known hepatic disease associated with coagulopathy.
    - Estimated glomerular filtration rate < 30 mL/min/m2
    - Other severe, non-cardiovascular condition/disease associated with poor prognosis (e.g. metastatic cancer) and limits life expectancy.
    - Systemic treatment with strong inhibitors of CYP3A4 as well as p-glycoprotein (e.g., systemic azole antimycotics, such as ketoconazole, and HIV-protease inhibitors, such as ritonavir).
    - Strong inducers of CYP3A4 (i.e., rifampicin, rifabutin, phenobarbital, phenytoin, and carbamazepine).
    General eksklusionskriterier:
    - Graviditet, ammende kvinder, kvinder som planlægger at blive gravide eller kvinder som ikke bruger godkendt antikonception.
    - Svær hjerteinsufficiens med ejection fraction < 30% eller New York Heart Association (NYHA) Class III eller IV symptomer.
    - Aktuel akut sygdom.

    CEUS eksklusionskriterier:
    - Tidligere allergisk reaktion af kontraststoffet SonoVue®.
    - Elektroniske implantationer, for eksempel pacemaker, ICD-enhed grundet brug af ultralyd med magnetisk felt.
    - Patienter der ikke kan samarbejde til ultralydsundersøgelsen.

    Rivaroxaban eksklusionskriterier:
    - Deltagelse i et andet lægemiddel interventionsstudie.
    - Kendt hypersensitivitet eller kontraindikation for rivaroxaban, acetylsalicylsyre (ASA), pantoprazol eller lægemiddelhjælpestoffer.
    - Patienter behandlet med andet antikoagulantia såsom warferin og andet DOAK end rivaroxaban.
    - Patienter allerede i rivaroxaban-behandling.
    - Patienter med behov for dobbeltpladehæmmer-behandling eller anden pladehæmmer-behandling end ASA.
    - Højrisiko for blødning som for eksempel: aktiv klinisk signifikant blødning, tidligere eller aktuelle læsioner eller tilstande med signifikant risiko for større blødning, nyligt gennemgået hjerne-, spinal- eller øjenkirurgi, nylig intrakraniel blødning, øsofagusvaricer, arteriovenøse misdannelser, vaskulære aneurismer eller større intraspinale eller intracerebrale vaskulære abnormiteter.
    - Stroke/apopleksi inden for 1 måned eller tidligere hæmoragisk eller lakunær stroke.
    - Leversygdom, da forbundet med koagulationsdefekt og klinisk relevant blødningsrisiko, herunder cirrosepatienter med Child-Pugh B-C.
    - Estimeret glomerulær filtrationshastighed < 30 ml/min/m2.
    - Anden alvorlig, non-kardiovaskulær tilstand/sygdom associeret med dårlig prognose (eksempel metastatisk cancer) og begrænser forventet restlevetid.
    - Systemisk behandling med stærke CYP3A4-hæmmere såvel som p-glycoprotein, f.eks. systemisk azol antimykotika (såsom ketoconazole) og HIV-protease hæmmere (såsom ritonavir).
    E.5 End points
    E.5.1Primary end point(s)
    More hyperechoic carotid plaques in the intervention group, with 1 year rivaroxaban treatment, compared to placebo over time determined by increase in plaque echogenicity with at least 20 % in grey-median-scale (GSM) registered by ultrasound, as an expression of plaque stabilizaton by rivaroxaban.
    Carotis plaques i interventionsgruppen, med 1 års rivaroxaban behandling, bliver mere ekkorige over tid sammenlignet med placebo med en forøgelse i ekkogenicitet på mindst 20 % gray-median-scale (GSM) registreret ved ultralyd, som et udtryk for rivaroxabans stabiliserende effekt på plaque morfologi.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primarily after 12 months but also after 3 and 6 months.
    Primært efter 12 måneder men også efter 3 og 6 måneder.
    E.5.2Secondary end point(s)
    1) Secondary ultrasound endpoints: Reduction of carotis plaque volumen, thrombus volumen and intraplaque contrastfilling over time in the intervention-rivaroxaban group compared to placebo.

    2) Secondary major events endpoints including but not necessary limited to:
    - Death (all cause mortality).
    - MACE (Major Adverse Cardiovascular Events): myocardial infarction, stroke, cardiovascular death.
    - MALE (Major Adverse Limb Events) e.g. acute og chronic critical limb ischaemia and including amputation above the ankle.
    - Transient ischaemic attack (TIA)
    - Major bleedings.
    - Need for cardiovascular revascularization procedure:
    * Cardiac: percutanous coronary intervention (PCI), coronary artery bypass grafting (CABG).
    * Carotid: carotid endarterectomy (CEA), endovascular carotid stent (CAS), thrombectomy.
    * Limb: aorta-femoral bypass, infrainguinal bypass, thrombendarterectomy, thrombectomy, endovascular procedures or farmeceutical with heparine and/or thrombolysis.
    1) Sekundære ultralyd endepunkter: Reduktion i carotisplaquets volumen samt formindskelse af trombevolumen og intraplaque kontrastfyldning over tid i rivaroxaban-gruppen i modsætning til placebogruppen.

    2) Sekundære alvorlige event-punkter inkluderende men ikke nødvendigvis begrænsende til:
    - Død (all cause mortality).
    - Alvorlige kardiovaskulær events (MACE – Major Adverse Cardiovascular events): MI, apopleksi, kardovaskulær død.
    - Alvorlige ekstremitets iskæmiske events (MALE – Major Adverse Limb events) som for eksempel akut eller kronisk kritisk underekstremitetsiskæmi og inkluderer amputationer over ankelniveau.
    - Transitorisk cerebral iskæmi (TCI)
    - Større blødninger.
    - CV revaskularisering procedure:
    * Kardiel: Perkutan koronar intervention (PCI), koronar bypass (CABG).
    * Carotis: carotis endarterektomi (CEA), endovaskulær carotis stentning (CAS), trombektomi.
    * Perifer underekstremitetsiskæmi: ben kirurgi med aorta-femoral bypass, infraligamentær bypass, TEA, trombektomi, endovaskulære procedurer, farmaka revaskularisering med heparin og/eller trombolyse.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Primarily after 12 months but also after 3 and 6 months.

    2) 1-5 years.
    1) Primært efter 12 måneder men også efter 3 og 6 måneder.

    2) 1-5 år.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 No
    E.8.7Trial has a data monitoring committee No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned 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: 12
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state102
    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)
    Patients will be invited back to a voluntary follow-up visit 1 year after the subject has exited their trial period. On this visit, the patient may be offered treatment with rivaroxaban if indicated, evaluated by the trial physician.
    Patienter vil blive inviteret til et frivilligt follow-up besøg 1 år efter den enkelte patient har afsluttet eller udgået fra forsøget. Ved dette besøg kan patienten tilbydes behandling med rivaroxaban, hvis der findes sundhedsfaglig og helbredsmæssig indikation vurderet af forsøgslægen.
    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 Decision2020-05-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-09-30
    P. End of Trial
    P.End of Trial StatusOngoing
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