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

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.14,269 enrolled

Overview

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).

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

14,269

Conditions

Atrial Fibrillation

Interventions

RivaroxabanDRUG

Type=exact number, unit=mg, number=20, form=tablet, route=oral use. One 20 mg tablet once daily for an expected maximum treatment period of up to 32 months that may extend up to 4 years (Patients with moderate renal impairment at screening willl have a dose adaptation to rivaroxaban 15 mg, orally, once daily for an expected maximum treatment period of up to 32 months that may extend up to 4 years)

WarfarinDRUG

Type=exact number, unit=mg, number=1, 2.5, or 5 mg, form=tablet, route=oral use. Number of warfarin tablets to be determined based on target INR values once daily for an expected maximum treatment period of up to 32 months that may extend up to 4 years

Matching placebo for Rivaroxaban arm (Warfarin placebo)DRUG

Form=tablet, route=oral. One warfarin placebo tablet taken orally once daily for up to an expected maximum treatment period of 32 months that may extend up to 4 years

Matching placebo for Warfarin arm (Rivaroxaban placebo)DRUG

Form-tablet, Route=oral administration. Number of rivaroxaban placebo determined by the number of warfarin tablets taken. Duration of treatment is up to an expected maximum treatment period of 32 months that may extend up to 4 years

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (932)

Unnamed facility

Birmingham, Alabama, United States

Unnamed facility

Dothan, Alabama, United States

Unnamed facility

Geneva, Alabama, United States

Unnamed facility

Mobile, Alabama, United States

Unnamed facility

Pell City, Alabama, United States

Unnamed facility

Outcomes

Primary Outcomes

The Composite Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Non-Inferiority)

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.

Time frame: Up to 4 years

The Composite of Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Superiority)

Time frame: Up to 4 years

The Composite Event of Major/Non-major Clinically Relevant Bleeding Events: Primary Safety

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.

Time frame: Up to 4 years

Secondary Outcomes

The Composite Event of Stroke/Non-CNS Systemic Embolism/Vascular Death

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.

Time frame: Up to 4 years

The Composite Event of Stroke/Non-CNS Systemic Embolism/Myocardial Infarction/Vascular Death

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.

Time frame: Up to 4 years

The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Stroke

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.

Time frame: Up to 4 years

The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Non-CNS Systemic Embolism

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.

Time frame: Up to 4 years

The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Myocardial Infarction

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.

Time frame: Up to 4 years

The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Vascular Death

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.

Time frame: Up to 4 years

All-cause Mortality

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.

Time frame: Up to 4 years