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

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ClinicalTrials.gov Identifier: NCT02313909
Recruitment Status : Terminated (Study halted early due to no efficacy improvement over aspirin at an interim analysis and very little chance of showing overall benefit if study were completed)
First Posted : December 10, 2014
Results First Posted : January 9, 2019
Last Update Posted : January 9, 2019
Sponsor:
Collaborators:
Janssen Research & Development, LLC
Population Health Research Institute
Information provided by (Responsible Party):
Bayer

Brief 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.

Condition or disease Intervention/treatment Phase
Stroke Drug: Rivaroxaban (Xarelto, BAY59-7939) Drug: Acetylsalicylic acid (Aspirin, BAY1019036) Other: Rivaroxaban-Placebo Other: Aspirin-Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7213 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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
Actual Study Start Date : December 23, 2014
Actual Primary Completion Date : February 15, 2018
Actual Study Completion Date : February 15, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Rivaroxaban
Rivaroxaban 15 mg orally once daily
Drug: Rivaroxaban (Xarelto, BAY59-7939)
15 mg, once daily, orally, tablet

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

Active Comparator: Aspirin
Aspirin 100 mg orally once daily
Drug: Acetylsalicylic acid (Aspirin, BAY1019036)
100 mg, once daily, orally, tablet

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




Primary Outcome Measures :
  1. Incidence Rate of the Composite Efficacy Outcome (Adjudicated) [ Time Frame: From randomization until the efficacy cut-off date (median 326 days) ]
    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.

  2. Incidence Rate of a Major Bleeding Event According to the International Society on Thrombosis and Haemostasis (ISTH) Criteria (Adjudicated) [ Time Frame: From randomization until the efficacy cut-off date (median 326 days) ]
    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.


Secondary Outcome Measures :
  1. Incidence Rate of Any of the Following: Cardiovascular Death, Recurrent Stroke, Systemic Embolism and Myocardial Infarction [ Time Frame: From randomization until the efficacy cut-off date (median 326 days) ]
    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.

  2. Incidence Rate of All-Cause Mortality [ Time Frame: From randomization until the efficacy cut-off date (median 326 days) ]
    All-cause mortality includes all deaths of participants due to any cause.

  3. Incidence Rate of the Following: Stroke, Ischemic Stroke, Disabling Stroke, Cardiovascular (CV) Death, Myocardial Infarction [ Time Frame: From randomization until the efficacy cut-off date (median 326 days) ]
    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.

  4. Incidence Rate of Life-Threatening Bleeding Events [ Time Frame: From randomization until the efficacy cut-off date (median 326 days) ]
    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.

  5. Incidence Rate of Clinically Relevant Non-Major Bleeding Events [ Time Frame: From randomization until the efficacy cut-off date (median 326 days) ]
    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.

  6. Incidence Rate of Intracranial Hemorrhage [ Time Frame: From randomization until the efficacy cut-off date (median 326 days) ]
    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.



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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02313909


  Show 454 Study Locations
Sponsors and Collaborators
Bayer
Janssen Research & Development, LLC
Population Health Research Institute
Investigators
Study Director: Bayer Study Director Bayer
  Study Documents (Full-Text)

Documents provided by Bayer:
Statistical Analysis Plan  [PDF] December 20, 2017
Study Protocol  [PDF] November 5, 2015


Additional Information:
Publications of Results:
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): 146-154.

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02313909     History of Changes
Other Study ID Numbers: 16573
2013-000768-27 ( EudraCT Number )
First Posted: December 10, 2014    Key Record Dates
Results First Posted: January 9, 2019
Last Update Posted: January 9, 2019
Last Verified: December 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Bayer:
ESUS
Rivaroxaban
Xarelto
Aspirin
Acetylsalicylic acid (ASA)
Oral Anticoagulant
Blood Thinner
Stroke
Ischemic Stroke
Cryptogenic Stroke
Embolic stroke of undetermined source
Transient Ischemic Attack
Thromboembolism
Cerebrovascular Disease

Additional relevant MeSH terms:
Stroke
Embolism
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Embolism and Thrombosis
Aspirin
Rivaroxaban
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors