E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with aortic stenosis undergoing transcatheter aortic valve implantation. |
|
E.1.1.1 | Medical condition in easily understood language |
Narrowing of the heart valve between the heart and the large blood vessel |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
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 perform a PROBE-design randomized controlled trial to assess the efficacy and safety of oral anticoagulation therapy versus the standard acetylsalicylic acid after transcatheter aortic valve implantation for aortic stenosis. |
|
E.2.2 | Secondary objectives of the trial |
To assess the association between early signs of structural valve degeneration and patient outcome. |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-studies are being drafted; one on the effect of intervention with anticoagulation on MR-verified cerebral microembolizations and one on transoesophageal echocardiography to identify structural valve degeneration. |
|
E.3 | Principal inclusion criteria |
Patients with aortic stenosis who are accepted for transcatheter aortic valve implantation by the heart team and are less than 80 years old at the time of the procedure. |
|
E.4 | Principal exclusion criteria |
- Any clinical indication for either anticoagulation (atrial fibrillation, venous thrombosis) or antiplatelet drug (recent percutaneous coronary intervention, etc) - Any contraindication for either anticoagulation or antiplatelet drugs - Failure to provide signed consent - Unable to start study medication within 72 hours - Overt cognitive impairment |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The research question translates into two co-primary endpoints at 12 months; one efficacy endpoint powered for superiority of anticoagulation, and one safety endpoint powered for non-inferiority. The important clinical translation is into MACE at 5 and 10 years. All trial endpoints will comply with the VARC-3 definitions.
Co-primary endpoints at 12 months: Hypo-attenuated leaflet thickening - CT evidence of increased hypo-attenuated leaflet thickness - Intention-to-treat, superiority, at 12 months
Cardiovascular events, composite of - VARC-3 bleeding events (type 1, 2, 3 or 4) - Thromboembolic events (myocardial infarction or stroke of any cause) - All-cause mortality - Per-protocol, non-inferiority, at 12 months
At 5 and 10 years, major adverse cardiac events (MACE) will be defined as the rate of the composite of: - Cardiac death - Aortic valve re-intervention - Stroke - Myocardial infarction - Heart failure hospitalization, or - Major, life-threatening, or disabling bleeding
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 months, 5 years and 10 yeras |
|
E.5.2 | Secondary end point(s) |
Key secondary endpoints (hierarchical): - Clinical efficacy, intention-to-treat, superiority, composite of: o Freedom from all-cause mortality o Freedom from all stroke o Freedom from hospitalization for procedure- or valve-related causes o Freedom from KCCQ overall summary score <45 or decline from baseline of >10 points - Cardiovascular events, intention-to-treat, superiority - Thromboembolic events - Bleeding events - All-cause mortality
Secondary safety endpoints: - The number of adverse events - The number of serious adverse events - Life-threatening or disabling bleeding - Major bleeding - Minor bleeding
Exploratory secondary endpoints: - CT signs of valve degeneration - Echocardiographic signs of valve degeneration - Non-procedure-related life-threatening or disabling bleeding (VARC-3) - Number of major adverse clinical events, defined as stroke or transient ischemic attack of any cause, myocardial infarction, re-intervention on the aortic valve, death (cardiac, all-cause, non-cardiac) and heart failure hospitalization - Quality of life as assessed by the KCCQ and the EQ5D 5L EuroQoL questionnaires, and HADS - Per-protocol primary efficacy endpoint sensitivity analysis - Intention-to-treat primary safety endpoint sensitivity analysis - Cognitive function as assessed by the Mini-cog - N-terminal pro-B-type natriuretic peptide (change) - Cardiac troponin T (change) - Infective endocarditis
At 5 and 10 years, the secondary endpoints will be: - Individual components of MACE - Progression of valve degeneration - Deterioration of NYHA-class
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
12 months, 5 years and 10 years |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
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) | 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 | 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 | No |
E.8.1.7.1 | Other trial design description |
prospective randomized open label blinded endpoint trial (PROBE) |
|
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 | 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 | 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
|
The trial may be discontinued at the discretion of the primary investigator or the sponsor in the event of any of the following: - Recommendation of the data safety monitoring board - Occurrence of AEs unknown to date in respect of their nature, severity and duration - Medical or ethical reasons affecting the continued performance of the trial - Difficulties in the recruitment of patients |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |