Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source (ESUS)

Stroke Clinical Trial

— NAVIGATE ESUS  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02313909
• Other study ID #: 16573
• Secondary ID: 2013-000768-27
• Status: Terminated
• Phase: Phase 3
• Start date: December 23, 2014
• Est. completion date: February 15, 2018

Study information

• Verified date: December 2018
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a study in patients who recently had a brain attack (stroke) and in whom no clear cause of the stroke could be identified. These strokes are likely due to a blood clot and therefore, can be called embolic stroke of undetermined source. The abbreviation is ESUS. The study will compare 2 blood thinners. Patients will be randomly assigned to either Rivaroxaban 15 mg or Aspirin 100 mg and the study is intended to show, if patients given rivaroxaban have fewer blood clots in the brain (stroke) or in other blood vessels.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 7213
• Est. completion date: February 15, 2018
• Est. primary completion date: February 15, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

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 either transesophageal or transthoracic echocardiography, and

• No other specific cause of stroke (for example, arteritis, dissection, migraine/vasospasm, drug abuse)

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 m^2

Related Conditions & MeSH terms

• Embolism
• Stroke

Intervention

Drug:
• Rivaroxaban (Xarelto, BAY59-7939)
15 mg, once daily, orally, tablet
• Acetylsalicylic acid (Aspirin, BAY1019036)
100 mg, once daily, orally, tablet

Other:
• Rivaroxaban-Placebo
Matching placebo, once daily, orally, tablet
• Aspirin-Placebo
Matching placebo, once daily, orally, tablet

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
Bayer	Janssen Research & Development, LLC, Population Health Research Institute

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Chile,  China,  Czechia,  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, 

References & Publications (3)

Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, Swaminathan B, Lavados P, Wang Y, Wang Y, Davalos A, Shamalov N, Mikulik R, Cunha L, Lindgren A, Arauz A, Lang W, Czlonkowska A, Eckstein J, Gagliardi RJ, Amarenco P, Ameriso SF, Tatlisum — View Citation

Hart RG, Sharma M, Mundl H, Shoamanesh A, Kasner SE, Berkowitz SD, et al. Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial. European Stroke Journal. 2016; 1(3

Kasner SE, Lavados P, Sharma M, Wang Y, Wang Y, Dávalos A, Shamalov N, Cunha L, Lindgren A, Mikulik R, Arauz A, Lang W, Czlonkowska A, Eckstein J, Gagliardi R, Amarenco P, Ameriso SF, Tatlisumak T, Veltkamp R, Hankey GJ, Toni DS, Bereczki D, Uchiyama S, N — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence Rate of the Composite Efficacy Outcome (Adjudicated)	Components of composite efficacy outcome (adjudicated) includes stroke (ischemic, hemorrhagic, and undefined stroke, TIA with positive neuroimaging) and systemic embolism. Incidence rate estimated as number of participants with incident events divided by cumulative at-risk time, where participant is no longer at risk once an incident event occurred.	From randomization until the efficacy cut-off date (median 326 days)
Primary	Incidence Rate of a Major Bleeding Event According to the International Society on Thrombosis and Haemostasis (ISTH) Criteria (Adjudicated)	Major bleeding event (as per ISTH), defined as bleeding event that met at least one of following: fatal bleeding; symptomatic bleeding in a critical area or organ (intraarticular, intramuscular with compartment syndrome, intraocular, intraspinal, pericardial, or retroperitoneal); symptomatic intracranial haemorrhage; clinically overt bleeding associated with a recent decrease in the hemoglobin level of greater than or equal to (>=) 2 grams per decilitre (g/dL) (20 grams per liter [g/L]; 1.24 millimoles per liter [mmol/L]) compared to the most recent hemoglobin value available before the event; clinically overt bleeding leading to transfusion of 2 or more units of packed red blood cells or whole blood. The results were based on classification of events that have been positively adjudicated as major bleeding events. Incidence rate estimated as number of subjects with incident events divided by cumulative at-risk time, where subject is no longer at risk once an incident event occurred.	From randomization until the efficacy cut-off date (median 326 days)
Secondary	Incidence Rate of Any of the Following: Cardiovascular Death, Recurrent Stroke, Systemic Embolism and Myocardial Infarction	Incidence rate estimated as number of participants with incident events divided by cumulative at-risk time, where participant is no longer at risk once an incident event occurred. Cardiovascular death includes death due to hemorrhage and death with undetermined/unknown cause. Systemic embolism is defined as abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms. The diagnosis of myocardial infarction requires the combination of: 1)evidence of myocardial necrosis (either changes in cardiac biomarkers or post-mortem pathological findings); and 2)supporting information derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery imaging.	From randomization until the efficacy cut-off date (median 326 days)
Secondary	Incidence Rate of All-Cause Mortality	All-cause mortality includes all deaths of participants due to any cause.	From randomization until the efficacy cut-off date (median 326 days)
Secondary	Incidence Rate of the Following: Stroke, Ischemic Stroke, Disabling Stroke, Cardiovascular (CV) Death, Myocardial Infarction	Disabling stroke is defined as stroke with modified Rankin score (mRS) greater than or equal to (>=) 4 as assessed by investigator. mRS spans 0-6, running from perfect health to death. A score of 0-3 indicates functional status ranging from no symptoms to "moderate disability" (defined in the mRS as requiring some help, but able to walk without assistance); mRS 4-6 indicates functional status ranging from "moderately severe disability" (unable to walk or to attend to own bodily needs without assistance)through to death. CV death includes death due to hemorrhage and death with undetermined/unknown cause. Diagnosis of myocardial infarction requires combination of: 1) evidence of myocardial necrosis either changes in cardiac biomarkers or post-mortem pathological findings); 2) supporting information derived from clinical presentation, electrocardiographic changes, or results of myocardial or coronary artery imaging.	From randomization until the efficacy cut-off date (median 326 days)
Secondary	Incidence Rate of Life-Threatening Bleeding Events	Life-threatening bleeding was defined as a subset of major bleeding that met at least one of the following criteria: 1) fatal bleeding; 2) symptomatic intracranial haemorrhage; 3) reduction in hemoglobin of at least 5 g/dl (50 g/l; 3.10 mmol/L); 4) transfusion of at least 4 units of packed red cells or whole blood; 5) associated with hypotension requiring the use of intravenous inotropic agents; 6) necessitated surgical intervention. Incidence rate estimated as number of participants with incident events divided by cumulative at-risk time, where participant is no longer at risk once an incident event occurred.	From randomization until the efficacy cut-off date (median 326 days)
Secondary	Incidence Rate of Clinically Relevant Non-Major Bleeding Events	Non-major clinically relevant bleeding was defined as non-major overt bleeding but required medical attention (example: hospitalization, medical treatment for bleeding), and/or was associated with the study drug interruption of more than 14 days. The results were based on the outcome events at or after randomization until the efficacy cut-off date. Incidence rate estimated as number of participants with incident events divided by cumulative at-risk time, where participant is no longer at risk once an incident event occurred.	From randomization until the efficacy cut-off date (median 326 days)
Secondary	Incidence Rate of Intracranial Hemorrhage	Intracranial hemorrhage included all bleeding events that occurred in intracerebral, sub arachnoidal as well as subdural or epidural sites. The below table displays results for all randomized participants and the outcomes at or after randomization until the efficacy cut-off date. Incidence rate estimated as number of participants with incident events divided by cumulative at-risk time, where participant is no longer at risk once an incident event occurred.	From randomization until the efficacy cut-off date (median 326 days)

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