E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Embolic stroke of undetermined source (ESUS)
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E.1.1.1 | Medical condition in easily understood language |
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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 | 18.1 |
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 |
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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 |
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. |
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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. |
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E.2.3 | Trial contains a sub-study | No |
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, and
• No intra-cardiac thrombus on transthoracic echocardiography, and
• No other specific cause of stroke (for example, arteritis, dissection, migraine/vasospasm, drug abuse)
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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
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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) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Monitored throughout study |
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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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Monitored throughout study |
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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 | No |
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 |
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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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 197 |
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 |
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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
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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. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 1 |
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 |