E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Embolic stroke of undetermined source (ESUS)
|
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10014498 |
E.1.2 | Term | Embolic stroke |
E.1.2 | System Organ Class | 10029205 - Nervous system 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 objective is to evaluate whether rivaroxaban is superior to aspirin in reducing the risk of recurrent stroke and systemic embolism in patients with a recent ESUS. |
|
E.2.2 | Secondary objectives of the trial |
The secondary efficacy objective is to evaluate whether rivaroxaban is superior to aspirin in reducing cerebrovascular events, cardiovascular events, and mortality in patients with a recent ESUS.
The safety objective is to document the incidence of clinically relevant bleeding. |
|
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 |
Two optional sub-studies (described in Section 14.1 of the protocol) will be conducted at selected sites:
1. MRI sub-study The primary objective of this substudy is to determine the effect of rivaroxaban compared with aspirin on MRI-defined covert and clinical infarcts (ie. all incident infarcts) in individuals with a recent ESUS. Secondary objectives will be to determine the effect of rivaroxaban compared to aspirin for reducing covert infarcts, the progression of volume of white matter hyperintensities (WMH), functional decline (SAGE), and cognitive decline (MoCA) in the patients with recent ESUS enrolled in this sub-study.
2. Biomarker sub-study Biomarker samples will be collected to promote, facilitate, and improve individualized healthcare by better understanding/predicting ESUS, recurrent stroke, and associated diseases as well as treatment response. Specifically, the intention is to establish ESUS as a distinct clinical entity in which propensity to coagulation is critical, both as a marker of ESUS and as a risk factor for recurrent stroke. |
|
E.3 | Principal inclusion criteria |
Recent ESUS (between 7 days and 6 months), defined as: • Recent ischemic stroke (including transient ischemic attack with positive neuroimaging) visualized by brain imaging that is not lacunar, and • Absence of cervical carotid atherosclerotic stenosis > 50% or occlusion, and • No atrial fibrillation after ≥ 24-hour cardiac rhythm monitoring (at least 20 hours acceptable), and • No intra-cardiac thrombus on either transesophageal or transthoracic echocardiography, and • No other specific cause of stroke (for example, arteritis, dissection, migraine/vasospasm, drug abuse)
|
|
E.4 | Principal exclusion criteria |
• Severely disabling stroke (modified Rankin score ≥4) • Indication for chronic anticoagulation or antiplatelet therapy • Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Time from randomization to first occurrence of any of the components of the composite outcome (adjudicated), including: • Stroke (ischemic, hemorrhagic, and undefined stroke, TIA with positive neuroimaging) • Systemic embolism
2. Time from randomization to the first occurrence of major bleeding (International Society on Thrombosis and Haemostasis) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Monitored throughout study |
|
E.5.2 | Secondary end point(s) |
1. Time from randomization to first occurrence of: • Cardiovascular death (including death due to hemorrhage), recurrent stroke, systemic embolism, and myocardial infarction
2. Time from randomization to first occurrence of: • All-cause mortality
3. Time from randomization to first occurrence of: Individual components of the primary and secondary efficacy outcomes (stroke, CV death, and myocardial infarction) as well as ischemic stroke, and disabling stroke (modified Rankin score 4 and 5)
4. Time from randomization to the first occurrence of life-threatening bleeding
5. Time from randomization to the first occurrence of clinically relevant non-major bleeding
6. Time from randomization to the first occurrence of intracranial hemorrhage |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Monitored throughout study |
|
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 | 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 | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | Yes |
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 |
Double-dummy, event-driven |
|
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
| 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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 217 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Chile |
China |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Greece |
Hungary |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
Poland |
Portugal |
Russian Federation |
South Africa |
Spain |
Sweden |
Switzerland |
Turkey |
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
|
The end of the study as a whole will be reached when the final efficacy outcome event has been adjudicated for patients from all participating clinical sites. |
|
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 | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |