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 | 19.0 |
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 | 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. |
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E.3 | Principal inclusion criteria |
1. Embolic stroke of undetermined source (ESUS) defined as: • Recent ischemic stroke (including TIA with positive neuroimaging) visualized by brain CT or MRI that is not lacunar (i.e., lacunar infarcts are subcortical infarcts ≤1.5 cm in the territory of middle cerebral artery or pons; infarcts involving the cerebellum or lateral medulla are not considered as lacunar infarcts). Patients with multiple simultaneous acute lacunar infarcts on DWI imaging may be included. In case of embolic large artery occlusions clearly documented on angiography who undergo successful recanalization, visualization of infarct on neuroimaging is not mandated), and • Absence of cervical carotid atherosclerotic stenosis (or vertebral and basilar atherosclerotic stenosis in case of posterior circulation stroke), that is > 50%, or occlusion in arteries supplying the area of ischemia in CT or magnetic resonance (MR) angiography or conventional angiography or ultrasound, and • No history of AF, no documented AF on 12-lead electrocardiogram (ECG) or episode of AF lasting 6 minutes or longer detected after ≥ 24-hour cardiac rhythm monitoring (Holter or telemetry; at least 20 hours acceptable), and • No intra-cardiac thrombus on either transesophageal or transthoracic echocardiography, and • No other specific cause of stroke identified by routine clinical care (e.g., arteritis, dissection, migraine/vasospasm, drug abuse)
2 . Time from recent ischemic stroke to randomization and first study medication intake (and only if the investigator regards it as safe to initiate therapy with an anticoagulant) between 7 days and 6 months except: • in case of minor strokes (NIHSS ≤ 3), study medication may be initiated as early as 3 days after stroke onset. • in case of intravenous thrombolysis treatment or hemorrhagic transformation seen on the qualifying CT or MRI, study medication will not be initiated before 10 days after the acute stroke event unless a repeat CT or MRI scan performed before randomization documents the absence of no new or extension of hemorrhage.
3. All planned diagnostic tests for stroke evaluation must be completed. Brain imaging and 24-hour cardiac monitoring must be repeated if new symptoms of stroke/TIA occurred after the initial stroke evaluation, as does 24-hour cardiac monitoring if symptoms suggestive of AF occur.
4. Age ≥50 years
5. For patients with age 50-59 years at least one of the following risk factors: stroke or TIA prior to index stroke (includes covert/silent strokes on neuroimaging), diabetes, hypertension, current tobacco smoker, or heart failure.
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E.4 | Principal exclusion criteria |
1. Severely disabling stroke (modified Rankin score ≥4 at screening) 2. If imaging of intracranial arteries is performed by CT or MR angiography or transcranial Doppler: > 50% luminal stenosis or occlusion in arteries supplying the area of ischemia 3. Patent foramen ovale with plans for closure 4. Known serious infection or inflammatory disease that may be the cause of stroke 5. Patient has or is intended to receive an implantable ECG loop recorder 6. Indication for chronic anticoagulation based on guideline recommendations or investigator´s judgment; e.g., patient with prosthetic mechanical valve, venous thromboembolism, hypercoagulable state 7. Indication for chronic antiplatelet therapy based on investigator´s judgment, in which anticoagulation is not a reasonable substitute, or chronic therapy with a conventional nonsteroid anti-inflammatory drug (NSAID) for a non-stroke indication 9. Active bleeding, major bleeding within last 6 months, high risk for serious bleeding contraindicating anticoagulant or antiplatelet therapy or history of primary intracranial hemorrhage 10. Hepatic disease associated with coagulopathy (prothrombin time prolonged beyond the normal range) and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C 11. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 as assessed at local laboratory within 1 month of screening 14. Female of childbearing potential who are not surgically sterile, or, if sexually active not willing to use adequate contraceptive measures with a failure rate less than 1% per year (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, male partner sterilization) before entry and throughout the study, as well as pregnant or breast feeding women
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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 | 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 |
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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 | 37 |
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 |
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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 | 0 |
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 |