E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
prevention of stroke and non-central nervous system systemic embolism in subjects with non-valvular atrial fibrillation scheduled for cardioversion |
|
E.1.1.1 | Medical condition in easily understood language |
prevention of cardiovascular events in subjects with nonvalvular atrial fibrillation scheduled for Cardioversion |
|
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003658 |
E.1.2 | Term | Atrial fibrillation |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
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 |
The primary efficacy and safety objectives are to explore the efficacy of rivaroxaban compared with that of dose-adjusted vitamin K antagonists (VKA) in the prevention of the events with regard to the combined efficacy endpoint of all stroke or transient ischemic attack (TIA), non-central nervous system (CNS) systemic embolism, myocardial infarction (MI), and cardiovascular death in subjects with atrial fibrillation scheduled for cardioversion; and to explore the safety of rivaroxaban compared with dose-adjusted VKA with regard to the safety endpoint of major bleeding events in subjects with atrial fibrillation scheduled for cardioversion. |
|
E.2.2 | Secondary objectives of the trial |
Secondary objectives are to explore rivaroxaban treatment as compared with dose-adjusted VKA treatment with regard to the composite efficacy endpoint of stroke, TIA, non-central nervous system (CNS) systemic embolism, MI, and all-cause mortality (including cardiovascular death); the individual efficacy endpoints of all stroke, TIA, non-CNS systemic embolism, MI, cardiovascular death, and all-cause mortality (including cardiovascular death); and all bleeding events (major and non-major bleeding events). |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Men or women aged ≥ 18 years
• Hemodynamically stable nonvalvular atrial fibrillation longer than 48 hours or of unknown duration
• Scheduled for cardioversion (electrical or pharmacological) of nonvalvular atrial fibrillation
• Written informed consent
• Women of childbearing potential and men must agree to use adequate contraception when sexually active. This applies from the time of signing of the informed consent form until 30 days after the last study drug administration. The definition of adequate contraception will be based on the judgment of the investigator and local requirements. Acceptable methods of contraception include (i) condoms (male or female) with or without a spermicidal agent; (ii) diaphragm or cervical cap with spermicide; (iii) intrauterine device; and (iv) hormone-based contraception.
|
|
E.4 | Principal exclusion criteria |
• Severe, disabling stroke (modified Rankin score of 45, inclusive; see Section 14.2) within 3 months or any stroke within 14 days before the randomization visit
• Transient ischemic attack within 3 days prior to randomization
• Acute thromboembolic events or thrombosis (venous/arterial) within the last 14 days prior to randomization
• Acute MI within the last 14 days prior to randomization
• Cardiac-related criteria:
o Known presence of left atrial/LAA thrombus before study inclusion
o Known presence of atrial myxoma
o Known left ventricular or aortic thrombus
o Valvular heart disease (either hemodynamically significant mitral valve stenosis or prosthetic heart valve)
• Active bleeding or high risk for bleeding contraindicating anticoagulant therapy
• Concomitant drugs/therapies:
o Indication for anticoagulant therapy for a condition other than atrial fibrillation (eg, VTE)
o Chronic aspirin therapy > 100 mg daily or dual antiplatelet therapy
o Concomitant use of strong inhibitors of both cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), ie, all human immunodeficiency virus protease inhibitors and the following azole antimycotic agents: ketoconazole, itraconazole, voriconazole, posaconazole, if used systemically
• Concomitant conditions:
o Childbearing potential without proper contraceptive measures, pregnancy, or breast feeding
o Hypersensitivity to investigational treatment or comparator treatment
o Calculated CrCl < 30 mL/minute (see Section 14.1)
o Hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk
o Any severe condition that would limit life expectancy to less than 6 months (eg, advanced malignancy, etc.)
o Planned invasive procedure with potential for uncontrolled bleeding, including major surgery or cardiac catheterization
o Inability to take oral medication
o Ongoing drug addiction or alcohol abuse
• Any other contraindication listed in the local labeling for the comparator treatment or experimental treatment
• Participation in a study with an investigational drug or medical device within 30 days prior to randomization
• Previous randomization in this study
• Inability to cooperate with the study procedures |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint variable is the composite of the following efficacy outcomes (adjudicated centrally): stroke, transient ischemic attack, non-central nervous system systemic embolism, myocardial infarction and cardiovascular death.
The primary safety endpoint variable is major bleeding (as per central adjudication) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
From randomization date up to the date of the last dose of study medication + 2 calendar days for subjects who complete the planned study medication period (about 45-49 days in direct cardiversion strategy, 65-100 days in delayed cardioversion arm)
For Safety endpoint from the date of first administration of study medication up to the date of the last study medication administration +2 calendar days for subjects who complete planned study (about 45-49 days in direct cardiversion strategy, 65-100 days in delayed arm) |
|
E.5.2 | Secondary end point(s) |
Composite of stroke and non-central nervous system systemic embolism
Composite of stroke, transient ischemic attack, non-central nervous system systemic embolism, myocardial infarction, all- cause mortality
Stroke
Transient ischemic attack
Non-central nervous system systemic embolism
Myocardial infarction
Cardiovascular death
All cause mortality |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
From randomization date up to the date of the last dose of study medication + 2 calendar days for subjects who complete the planned study medication period (about 45-49 days in direct cardiversion strategy, 65-100 days in delayed cardioversion arm) |
|
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 | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
o Biomarkers of thrombolysis/fibrinolysis (D-dimers, plasma prothrombin fragment 1+2 [F 1+2] levels, and thrombin-antithrombin [TAT] complex)
o Biomarkers of inflammatory response (interleukin-6 [IL-6] and high-sensitivity C-reactive protein [hs-CRP]) |
|
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 | No |
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 |
|
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 72 |
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 |
Belgium |
Brazil |
Canada |
China |
Denmark |
Finland |
France |
Germany |
Greece |
Italy |
Netherlands |
Portugal |
Spain |
Singapore |
South Africa |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |