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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

Tracking Information
First Submitted Date  ICMJE December 8, 2014
First Posted Date  ICMJE December 10, 2014
Results First Submitted Date  ICMJE November 20, 2018
Results First Posted Date  ICMJE January 9, 2019
Last Update Posted Date January 9, 2019
Actual Study Start Date  ICMJE December 23, 2014
Actual Primary Completion Date February 15, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 20, 2018)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 9, 2014)
  • 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 [ Time Frame: Approximately 3 years ]
  • Time from randomization to the first occurrence of major bleeding (acc. to the International Society on Thrombosis and Haemostasis) [ Time Frame: Approximately 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 20, 2018)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 9, 2014)
  • Time from randomization to first occurrence of any of the following: Cardiovascular death (including death due to hemorrhage), recurrent stroke, systemic embolism, and myocardial infarction [ Time Frame: Approximately 3 years ]
  • Time from randomization to first occurrence of: All cause mortality [ Time Frame: Approximately 3 years ]
  • Time from randomization to first occurrence of any of the following: stroke, CV death, and myocardial infarction as well as ischemic stroke, and disabling stroke (modified Rankin score 4 and 5) [ Time Frame: Approximately 3 years ]
  • Time from randomization to the first occurrence of life-threatening bleeding [ Time Frame: Approximately 3 years ]
  • Time from randomization to the first occurrence of clinically relevant non-major bleeding [ Time Frame: Approximately 3 years ]
  • Time from randomization to the first occurrence of intracranial hemorrhage [ Time Frame: Approximately 3 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source (ESUS)
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Stroke
Intervention  ICMJE
  • Drug: Rivaroxaban (Xarelto, BAY59-7939)
    15 mg, once daily, orally, tablet
  • Drug: Acetylsalicylic acid (Aspirin, BAY1019036)
    100 mg, once daily, orally, tablet
  • Other: Rivaroxaban-Placebo
    Matching placebo, once daily, orally, tablet
  • Other: Aspirin-Placebo
    Matching placebo, once daily, orally, tablet
Study Arms  ICMJE
  • Experimental: Rivaroxaban
    Rivaroxaban 15 mg orally once daily
    Interventions:
    • Drug: Rivaroxaban (Xarelto, BAY59-7939)
    • Other: Rivaroxaban-Placebo
  • Active Comparator: Aspirin
    Aspirin 100 mg orally once daily
    Interventions:
    • Drug: Acetylsalicylic acid (Aspirin, BAY1019036)
    • Other: Aspirin-Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: December 20, 2018)
7213
Original Estimated Enrollment  ICMJE
 (submitted: December 9, 2014)
7000
Actual Study Completion Date  ICMJE February 15, 2018
Actual Primary Completion Date February 15, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Chile,   Russian Federation,   Argentina,   Australia,   Austria,   Belgium,   Brazil,   Canada,   China,   Czechia,   Denmark,   Finland,   France,   Germany,   Greece,   Hungary,   Ireland,   Israel,   Italy,   Japan,   Korea, Republic of,   Mexico,   Poland,   Portugal,   South Africa,   Spain,   Sweden,   Switzerland,   Turkey,   United Kingdom,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02313909
Other Study ID Numbers  ICMJE 16573
2013-000768-27 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Bayer
Study Sponsor  ICMJE Bayer
Collaborators  ICMJE
  • Janssen Research & Development, LLC
  • Population Health Research Institute
Investigators  ICMJE
Study Director: Bayer Study Director Bayer
PRS Account Bayer
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP