An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation

Phase 3

Completed

• Conditions: Atrial Fibrillation; Stroke; Embolism
• Interventions: Drug: Rivaroxaban; Drug: Warfarin; Drug: Matching placebo for Rivaroxaban arm (Warfarin placebo); Drug: Matching placebo for Warfarin arm (Rivaroxaban placebo)

• Registration Number: NCT00403767
• Lead Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Brief Summary

The purpose of this study is to compare the efficacy and safety of rivaroxaban with warfarin for the prevention of blood clots in the brain (referred to as stroke) and blood clots in other parts of the body referred to as non-central nervous system systemic embolism) in patients with non-valvular atrial fibrillation (a heart rhythm disorder).

Detailed Description

Patients with non-valvular atrial fibrillation who are at risk for stroke and non-central nervous system (non-CNS) systemic embolism, will be randomized (assigned by chance) to receive treatment with rivaroxaban or warfarin, two different anticoagulants (substances that prevent blood clots). Treatment will be double-blinded (neither the patient nor study staff will know which study drug is assigned to patients during the study). Patients assigned to rivaroxaban will receive rivaroxaban 20 mg orally (p.o.) once daily (OD) plus warfarin placebo p.o. OD titrated to a target sham international normalized ratio (INR) of 2.5. Patients with moderate renal impairment at screening will receive rivaroxaban 15 mg p.o. OD. Patients assigned to warfarin will receive warfarin p.o. OD titrated to a target INR of 2.5 plus rivaroxaban placebo p.o. OD. The maximum expected length of treatment is up to 32 months but may be extended up to 4 years.

Study Timeline

• Study First Submitted: 2006-11-23
• Study First Submitted QC: 2006-11-23
• Study First Posted: 2006-11-27
• Study Start: 2006-12
• Primary Completion: 2010-09
• Study Completion: 2010-09
• Disposition First Submitted: 2011-04-22
• Disposition First Submitted QC: 2011-04-22
• Disposition First Posted: 2011-04-29
• Results First Submitted: 2011-12-02
• Results First Submitted QC: 2012-06-13
• Results First Posted: 2012-07-17
• Status Verified: 2014-04
• Last Update Submitted: 2014-04-10
• Last Update Posted: 2014-04-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 14269

Inclusion Criteria

• Patients must have documented atrial fibrillation on 2 separate occasions within 6 months before screening
• History of a prior stroke, transient ischemic attack or non-neurologic systemic embolism believed to be cardiac in origin, or at least two of the following risk factors: heart failure, hypertension, age 75 years or greater, diabetes mellitus

Exclusion Criteria

• Significant mitral stenosis
• Transient atrial fibrillation caused by a reversible disorder
• Active internal bleeding
• Severe disabling stroke
• History of intracranial bleeding
• Hemorrhagic disorders

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rivaroxaban	Matching placebo for Rivaroxaban arm (Warfarin placebo)	-
Warfarin	Matching placebo for Warfarin arm (Rivaroxaban placebo)	-
Rivaroxaban	Rivaroxaban	-
Warfarin	Warfarin	-

Primary Outcome Measures

Name	Time	Method
The Composite Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Non-Inferiority)	Up to 4 years	The number of patients with the first occurrence of a stroke or non-CNS systemic embolism while on treatment (defined as the time interval from the first dose to the last dose of study drug plus 2 days). The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
The Composite of Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Superiority)	Up to 4 years	The number of patients with the first occurrence of a stroke or non-CNS systemic embolism while on treatment (defined as the time interval from the first dose to the last dose of study drug plus 2 days). The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
The Composite Event of Major/Non-major Clinically Relevant Bleeding Events: Primary Safety	Up to 4 years	The number of patients with the first occurrence of a major or non-major clinically relevant bleeding event while on treatment. The statistical analysis is based on time from the first dose of study drug to the first occurrence of the event while on treatment.

Secondary Outcome Measures

Name	Time	Method
The Composite Event of Stroke/Non-CNS Systemic Embolism/Vascular Death	Up to 4 years	The number of patients with the first occurrence of a stroke, non-CNS systemic embolism, or vascular death while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
The Composite Event of Stroke/Non-CNS Systemic Embolism/Myocardial Infarction/Vascular Death	Up to 4 years	The number of patients with the first occurrence of a stroke, non-CNS systemic embolism, myocardial infarction, or vascular death while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Stroke	Up to 4 years	The number of patients with the first occurrence of a stroke while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Non-CNS Systemic Embolism	Up to 4 years	The number of patients with the first occurrence of a non-CNS systemic embolism while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Myocardial Infarction	Up to 4 years	The number of patients with the first occurrence of a myocardial infarction while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Vascular Death	Up to 4 years	The number of patients with the occurrence of vascular death while on treatment. The statistical analysis is based on time from randomization to the event while on treatment.
All-cause Mortality	Up to 4 years	The number of patients who died due to any cause while on treatment. The statistical analysis is based on time from randomization to the event while on treatment.