Bayer Navigate ESUS

Principal Investigator: Adam  DeHavenon
Keywords: Acute Stroke , ESUS (Embolic Stroke of Unknown Source) Department: Neurology
IRB Number: 00080104 Co Investigator:  
Specialty: Neurology, Neurology
Sub Specialties: Neuro Critical Care, Stroke
Recruitment Status: Completed

Contact Information

Crystal Neate

Brief Summary

Primary efficacy variable
The primary efficacy variable is the 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
- Systemic embolism
Secondary efficacy variables
The secondary efficacy variables of this study are the time from randomization to first
occurrence of:
- Cardiovascular death (including death due to hemorrhage), recurrent stroke, systemic
embolism, and MI
- All-cause mortality
- Individual components of the primary and secondary efficacy outcomes (stroke, CV
death, and MI) as well as ischemic stroke, and disabling stroke (modified Rankin
score 4 and 5)

Detailed Description

Multicenter, randomized, double-blind, double-dummy, active-comparator, event-driven, superiority phase III study of secondary prevention of stroke and prevention of systemic embolism in patients with a recent Embolic Stroke of Undetermined Source (ESUS), comparing rivaroxaban 15 mg once daily with aspirin 100 mg (NAVIGATE ESUS)

Inclusion Criteria

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., subcortical infarct ≤1.5 cm in the territory of middle cerebral artery or pons; infarcts involving the cerebellum or lateral medulla are not considered 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 artery
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
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; 20 hours acceptable), and
 No intra-cardiac thrombus on transthoracic or transesophageal 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 s 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, and heart failure, current tobacco smoker
6. Written informed consent consistent with local regulations governing research in human

Exclusion Criteria

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
8. Hypersensitivity or any other contraindication listed in the local labeling for ASA or
9. Active bleeding, major bleeding within last 6 months, high risk for serious bleeding contraindicating anticoagulant or antiplatelet therapy or history of primary intracranial
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
12. Life expectancy less than 6 months
13. Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 (CYP3A4)
and P-glycoprotein (P-gp), i.e., human immunodeficiency virus protease inhibitors and
the following azole-antimycotics agents: ketoconazole, itraconazole, voriconazole, or
posaconazole, if used systemically
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
15. Inability to cooperate with the study procedures
16. Previous randomization to this study or participation in a study with an investigational
drug or medical device within 30 days prior to randomization
17. Close affiliation with the investigational site; e.g. a close relative of the investigator,
dependent person (e.g., employee or student of the investigational site)