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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)

Primary Purpose

Stroke

Status

Terminated

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Rivaroxaban (Xarelto, BAY59-7939)

Acetylsalicylic acid (Aspirin, BAY1019036)

Rivaroxaban-Placebo

Aspirin-Placebo

About this trial

This is an interventional prevention trial for Stroke focused on measuring Rivaroxaban, Xarelto, Aspirin, Acetylsalicylic acid (ASA), Oral Anticoagulant, Blood Thinner, Stroke, Ischemic Stroke, Cryptogenic Stroke, Embolic stroke of undetermined source, ESUS, Transient Ischemic Attack, Thromboembolism, Cerebrovascular Disease

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Rivaroxaban

Aspirin

Arm Description

Rivaroxaban 15 mg orally once daily

Aspirin 100 mg orally once daily

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

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.

Incidence Rate of All-Cause Mortality

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

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

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

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

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.

Full Information

NCT ID

NCT02313909

First Posted

December 8, 2014

Last Updated

December 20, 2018

Sponsor

Bayer

Collaborators

Janssen Research & Development, LLC, Population Health Research Institute

1. Study Identification

Unique Protocol Identification Number

NCT02313909

Brief Title

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

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2018

Overall Recruitment Status

Terminated

Why Stopped

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

Study Start Date

December 23, 2014 (Actual)

Primary Completion Date

February 15, 2018 (Actual)

Study Completion Date

February 15, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Bayer

Collaborators

Janssen Research & Development, LLC, Population Health Research Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Stroke

Keywords

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

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

7213 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Rivaroxaban

Arm Type

Experimental

Arm Description

Rivaroxaban 15 mg orally once daily

Arm Title

Aspirin

Arm Type

Active Comparator

Arm Description

Aspirin 100 mg orally once daily

Intervention Type

Drug

Intervention Name(s)

Rivaroxaban (Xarelto, BAY59-7939)

Intervention Description

15 mg, once daily, orally, tablet

Intervention Type

Drug

Intervention Name(s)

Acetylsalicylic acid (Aspirin, BAY1019036)

Intervention Description

100 mg, once daily, orally, tablet

Intervention Type

Other

Intervention Name(s)

Rivaroxaban-Placebo

Intervention Description

Matching placebo, once daily, orally, tablet

Intervention Type

Other

Intervention Name(s)

Aspirin-Placebo

Intervention Description

Matching placebo, once daily, orally, tablet

Primary Outcome Measure Information:

Title

Incidence Rate of the Composite Efficacy Outcome (Adjudicated)

Description

Time Frame