| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with severe aortic stenosis that require Transcatheter aortic valve replacement are at risk of thrombus formation. Rivaroxaban (oral-anticoagulant) may reduce this risk, without increasing bleeding risk |
|
| E.1.1.1 | Medical condition in easily understood language |
| Narrowing of the aortic valve opening, called aortic stenosis, which is treated with Transcatheter aortic valve replacement, implanted by vascular catheterization in the aortic valve. |
|
| 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 | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002916 |
| E.1.2 | Term | Aortic valve replacement |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| 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 assess whether a rivaroxaban-based anticoagulation strategy, following successful TAVR, compared to an antiplatelet-based strategy, is superior in reducing death or first thromboembolic events (DTE).
To assess whether a rivaroxaban-based strategy, following TAVR, compared to an antiplatelet-based strategy, is non-inferior towards primary bleeding events (PBE). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives are to compare the effects of the rivaroxaban-based strategy and antiplatelet-based strategy with respect to the net-clinical-benefit, defined as the composite of death or first thromboembolic events and life-threatening, disabling, or major bleeding events classified according to the VARC definitions following the BARC classification.
Whereas the secondary safety objectives are safety criteria with respect to bleeding (thrombolysis in myocardial infarction [TIMI] major or minor bleeds, international society on thrombosis and haemostasis [ISTH] major bleeding, and BARC 2, 3, or 5 bleeds). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Potential subjects must satisfy the following criteria to be enrolled in the study:
• Man or woman of 18 years of age or older
• Have a successful TAVR of a native aortic valve stenosis
• Via iliofemoral or subclavian access
• With any approved/marketed TAVR device
• Provide written IC
Successful TAVR (29) is defined:
1. Correct positioning of a single prosthetic heart valve into the proper anatomical location.
2. Intended performance of the prosthetic heart valve - presence of all 3 conditions post-TAVR:
a. mean aortic valve gradient < 20 mmHg
b. peak transvalvular velocity < 3.0 m/s
c. no severe or moderate aortic valve regurgitation
3. Absence of periprocedural complications, such as:
a. Any type of stroke
b. VARC graded life-threatening bleeding
c. Acute coronary artery obstruction requiring intervention
d. Major vascular complication requiring intervention (including access-site vascular complications, any new ipsilateral peripheral ischemia, distal embolization from a vascular source, aortic dissection, aortic rupture, ventricular perforation, cardiac tamponade, and annulus rupture)
e. Unresolved acute valve thrombosis
f. Any requirement of a repeat procedure |
|
| E.4 | Principal exclusion criteria |
Subjects are NOT eligible to participate in this trial if they meet ANY of the following exclusion criteria:
GENERAL
1. Any atrial fibrillation (AF), at the time of randomization or previous, with an ongoing indication for oral anticoagulant treatment
2. Any other indication for continued treatment with any oral anticoagulant (OAC)
BLEEDING RISKS OR SYSTEMIC CONDITIONS
3. Known bleeding diathesis, such as but not limited to:
a. active internal bleeding, clinically significant bleeding, bleeding at a non-compressible site, or bleeding diathesis,
b. platelet count ≤ 50,000/mm3 at screening
c. Hemoglobin level < 8.5 g/dL
d. history of intracranial hemorrhage or subdural hematoma
e. major surgery, biopsy of a parenchymal organ, or serious trauma within 30 days before randomization
f. active peptic ulcer or known upper GI bleeding within the last 3 months
CONCOMITANT AND STUDY MEDICATION
4. Any indication for dual-antiplatelet therapy (DAPT) for more than 3 months after randomization (such as coronary, carotid or peripheral stent implantation)
5. Known hypersensitivity or contraindication to acetylsalicylic acid, clopidogrel or rivaroxaban or hypersensitivity to contrast media that could not be solved neither by switching to an alternate contrast media nor with pre-treatment with appropriate medication
6. Routine use of oral non-steroidal anti-inflammatory drugs (NSAID)
7. Concomitant therapy with systemic drugs that are strong inhibitors of both CYP 3A4 and P-gp (azole antimycotics such as ketoconazole and itraconazole or HIV protease inhibitors such as ritonavir)
8. Concomitant therapy with drugs that are strong CYP 3A4 inducers (e.g. carbamazepine, phenytoin, rifampin, St. John’s wort)
9. Concomitant therapy with omeprazole or esomeprazole that cannot be switched to an alternate medication.
Concomitant conditions
10. Planned coronary or vascular intervention or major surgery
11. Clinically overt stroke within the last 3 months
12. Severe renal impairment (eGFR < 30 mL/min/1.73 m2) or on dialysis, or post-TAVR unresolved acute kidney injury with renal dysfunction stage 2 or higher
13. Moderate and severe hepatic impairment (Child-Pugh Class B or C) or any hepatic disease associated with coagulopathy
14. Active infective endocarditis
15. Active malignancy (diagnosed within 5 years) except for adequately treated non-melanoma skin cancer or other non-invasive or in situ neoplasm (e.g., cervical cancer in situ that has been successfully treated)
OTHER EXCLUSION CRITERIA
16. Dementia or forgetfulness hindering compliance with medication intake or other study procedures
17. Legally incompetent to provide IC
18. Previous (30 days before enrolment) or concomitant participation in another clinical study with investigational medicinal product(s).
19. Previous assignment to treatment during this study
20. Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site) or sponsor
21. Female of childbearing potential
a. Who are not surgically sterile, or who are sexually active and not willing to use adequate contraceptive measures with a failure rate less than 1% per year (e.g. oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, male partner sterilization) before entry and throughout the study, or
b. For whom a negative pregnancy test is unavailable before study entry, or
c. Who are pregnant or breast feeding before study entry. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is death or first adjudicated thromboembolic event (DTE), defined as the adjudicated composite of:
• All-cause death
• Any stroke
• Myocardial infarction (MI)
• Symptomatic valve thrombosis
• Pulmonary embolism (PE)
• Deep vein thrombosis (DVT)
• Non-central nervous system (CNS) systemic embolism
The primary safety endpoint is primary bleeding event (PBE), defined according to VARC definitions following the BARC classification as the adjudicated composite of:
• life-threatening bleed
• disabling bleed
• major bleed
The endpoint definitions and the definitions of terms are located in Sections 16.1 and 16.2 of the protocol, respectively. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Subjects are treated and followed from randomization until the study ends, i.e. when the predefined number of primary efficacy endpoints is reached and study closure activities are completed. Therefore, the duration of the treatment period for a given subject will depend on the time required to collect these events. The expected duration of the study is 750 days, but depending upon the rate of subject recruitment and endpoint event rates it may be adapted. Regular assessments are planned to take place during the study. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints include:
• The adjudicated composite of cardiovascular death, any stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary embolism, deep vein thrombosis, or non-CNS systemic embolism
• The net-clinical-benefit defined as the adjudicated composite of all-cause death, any stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary embolism, deep vein thrombosis, non-CNS systemic embolism (efficacy); life-threatening, disabling andmajor bleeds (safety).
The secondary safety endpoints are bleeding complications according to:
• The composite of TIMI major or minor bleeds
• ISTH major bleeding
• The composite of BARC 2, 3, or 5 bleeding |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoints will be evaluated throughout the study, since it is an event driven study and follows intention to treat analysis. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Clopidogrel hydrogen sulfate (clopidogrel) and acetylsalicylic acid (ASA) |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial 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
|
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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