E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with - Stable peripheral artery disease and - 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 og - Asymptomatisk, aterosklerotisk plaque/stenose in carotis; asymptomatisk vedr. iskæmisk apopleksi inkluderende stroke og transient cerebral iskæmi (TCI) eller amaurosis fugax. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with: - Atherosclerosis in limb arteries and - Atherosclerosis in carotid artery with no symptoms of major or minor stroke or temporary vision loss.
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Patienter med: - Åreforkalkning i underekstremitets blodkar og - Åreforkalkning i halspulsåren uden symptomer på slagtilfælde eller forbigående synstab. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10075495 |
E.1.2 | Term | Internal carotid artery atherosclerosis |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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). |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(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. |
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E.5.2 | Secondary 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. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Primarily after 12 months but also after 3 and 6 months.
2) 1-5 years.
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1) Primært efter 12 måneder men også efter 3 og 6 måneder.
2) 1-5 år.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |