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 for stroke. This study is to evaluate the occurrence and extent of cerebral embolization (total new lesion volume) in patients before TAVR versus 3 months after TAVR. |
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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. |
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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 | 19.0 |
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 |
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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 evaluate the occurrence and extent of cerebral embolization (total new lesion volume) in patients before TAVR versus 3 months after TAVR by cerebral MRI scans. |
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E.2.2 | Secondary objectives of the trial |
Objectives analysed in the patient group included in EARTH TAVR and GALILEO:
To describe for this patient population and for both treatment groups (from GALILEO) separately:
- to compare cerebral embolization in patients on a Rivaroxaban-based strategy with ASS and rivaroxaban 10mg OD versus an antiplatelet –based strategy with ASS/Clopidogrel 3 months after TAVR
- extent and location of new cerebral lesions early after TAVR and after 3 months
- possible changes in neurocognitive and neurologic function after TAVR
- extent and localization of clinically apparent non-cerebral emboli after TAVR
- possible changes in quality of life after TAVR
Additional secondary objectives can be found in the study protocol. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Potential patients must satisfy the following criteria to be enrolled in the study:
- Man or woman of 18 years of age or older, who are planned for TAVR
- TAVR of a native aortic valve stenosis
- By iliofemoral or subclavian access
- With any approved/marketed TAVR device
- EARTH Written informed consent
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E.4 | Principal exclusion criteria |
Patients are NOT eligible to participate in this study 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)
3. Any contraindication for cerebral MRI, in particular:
- non-MRI-conditional pacemakers
- MRI conditional pacemakers <4 weeks after implant
- any metal fragments in the eye
- aneurysm clip in the brain
- severe claustrophobia
Bleeding risks or systemic conditions
4. 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
5. Any indication for dual-antiplatelet therapy (DAPT) for more than 3 months’ after TAVR (such as coronary, carotid or peripheral stent implantation)
6. 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
7. Routine use of oral non-steroidal anti-inflammatory drugs (NSAID)
8. Concomitant therapy with systemic drugs that are strong inhibitors of both CYP3A4 and P-gp (azole antimycotics such as ketoconazole and itraconazole or HIV protease inhibitors such as ritonavir)
9. Concomitant therapy with drugs that are strong CYP 3A4 inducers (e.g. carbamazepine, phenytoin, rifampin, St. John’s wort)
10. Concomitant therapy with omeprazole or esomeprazole that cannot be switched to an alternate medication.
Concomitant conditions
11. Planned coronary or vascular intervention or major surgery
12. Clinically overt stroke within the last 3 months
13. Severe renal impairment (eGFR < 30 mL/min/1.73 m2) or on dialysis before TAVR, or unresolved kidney injury with renal dysfunction stage 2 or higher
14. Moderate and severe hepatic impairment (Child-Pugh Class B or C) or any hepatic disease associated with coagulopathy
15. Active infective endocarditis
16. Active malignancy (diagnosed within 5 years) except for adequately treated Nonmelanoma skin cancer or other non-invasive or in situ neoplasm (e.g.,cervical cancer in situ that has been successfully treated)
Other exclusion criteria
17. Dementia or forgetfulness hindering compliance with medication intake or other Study procedures
18. Legally incompetent to provide IC
19. Previous (30 days before enrolment) or concomitant participation in another clinical study with investigational medicinal product(s).
20. Previous assignment to treatment during this study
21. 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
22. 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Occurrence and extent of cerebral embolization (total new lesion volume) in patients 3 months after TAVR.
Total new lesion volume is defined as the sum volume of all new cerebral ischemic lesions on the 3 months post-procedural MRI relative to the pre-TAVR cerebral MRI scan (on diffusion weighted and FLAIR MRI images).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Potential TAVR candidates will be included into the EARTH TAVR study and receive a pre- and a post-TAVR MRI examination.
Only patients, who are finally included into the GALILEO trial AND receive the 3 months’ follow-up MRI scan will contribute to the main objective.
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E.5.2 | Secondary end point(s) |
Occurrence and extent of cerebral embolization (total new lesion volume) in patients 3 months after TAVR.
Total new lesion volume is defined as the sum volume of all new cerebral ischemic lesions on the 3 months post-procedural MRI relative to the pre-TAVR cerebral MRI scan (on diffusion weighted and FLAIR MRI images).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Potential TAVR candidates will be included into the EARTH TAVR study and receive a pre- and a post-TAVR MRI examination.
Only patients, who are finally included into the GALILEO trial AND receive the 3 months’ follow-up MRI scan will contribute to the main objective.
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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 | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 15 |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |