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 - Full Text View

Purpose

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).

Condition	Intervention	Phase
Atrial Fibrillation Stroke Embolism	Drug: Rivaroxaban Drug: Warfarin Drug: Matching placebo for Rivaroxaban arm (Warfarin placebo) Drug: Matching placebo for Warfarin arm (Rivaroxaban placebo)	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Prevention
Official Title:	A Prospective, Randomized, Double-Blind, Parallel-Group, Multicenter, Non-inferiority Study Comparing the Efficacy and Safety of Rivaroxaban (BAY 59-7939) With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Subjects With Non-Valvular Atrial Fibrillation

Resource links provided by NLM:

Genetics Home Reference related topics: familial atrial fibrillation

MedlinePlus related topics: Arrhythmia Atrial Fibrillation Blood Thinners

Drug Information available for: Warfarin Warfarin sodium Rivaroxaban

U.S. FDA Resources

Further study details as provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.:

Primary Outcome Measures:

The Composite Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Non-Inferiority) [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
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) [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
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 [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
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:

The Composite Event of Stroke/Non-CNS Systemic Embolism/Vascular Death [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
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 [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
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 [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
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 [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
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 [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
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 [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
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 [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
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.

Enrollment:	14269
Study Start Date:	December 2006
Study Completion Date:	September 2010
Primary Completion Date:	September 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Rivaroxaban	Drug: Rivaroxaban 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) Drug: Matching placebo for Rivaroxaban arm (Warfarin placebo) 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
Active Comparator: Warfarin	Drug: Warfarin 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 Drug: Matching placebo for Warfarin arm (Rivaroxaban placebo) 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

Arms

Assigned Interventions

Experimental: Rivaroxaban

Drug: Rivaroxaban

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)

Drug: Matching placebo for Rivaroxaban arm (Warfarin placebo)

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

Active Comparator: Warfarin

Drug: Warfarin

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

Drug: Matching placebo for Warfarin arm (Rivaroxaban placebo)

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

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00403767

Show 930 Study Locations

Sponsors and Collaborators

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Bayer

Investigators

Study Director:

Johnson & Johnson Pharmaceutical Research & Development, L.L. C. Clinical Trial

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

More Information

No publications provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Singer DE, Hellkamp AS, Piccini JP, Mahaffey KW, Lokhnygina Y, Pan G, Halperin JL, Becker RC, Breithardt G, Hankey GJ, Hacke W, Nessel CC, Patel MR, Califf RM, Fox KA; ROCKET AF Investigators. Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the ROCKET AF clinical trial. J Am Heart Assoc. 2013 Feb 19;2(1):e000067. doi: 10.1161/JAHA.112.000067.

Piccini JP, Stevens SR, Chang Y, Singer DE, Lokhnygina Y, Go AS, Patel MR, Mahaffey KW, Halperin JL, Breithardt G, Hankey GJ, Hacke W, Becker RC, Nessel CC, Fox KA, Califf RM; ROCKET AF Steering Committee and Investigators. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation. 2013 Jan 15;127(2):224-32. doi: 10.1161/CIRCULATIONAHA.112.107128. Epub 2012 Dec 3.

Hankey GJ, Patel MR, Stevens SR, Becker RC, Breithardt G, Carolei A, Diener HC, Donnan GA, Halperin JL, Mahaffey KW, Mas JL, Massaro A, Norrving B, Nessel CC, Paolini JF, Roine RO, Singer DE, Wong L, Califf RM, Fox KA, Hacke W; ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012 Apr;11(4):315-22. Epub 2012 Mar 7.

Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. Epub 2011 Aug 10.

ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010 Mar;159(3):340-347.e1.

Responsible Party:	Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
ClinicalTrials.gov Identifier:	NCT00403767 History of Changes
Other Study ID Numbers:	CR012157, 39039039AFL3001, ROCKET AF, 2006-004595-13
Study First Received:	November 23, 2006
Results First Received:	December 2, 2011
Last Updated:	January 22, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.:

Atrial Fibrillation
Stroke
Embolism
Non-central nervous system systemic embolism
Non-valvular atrial fibrillation

Blood Clot
Rivaroxaban
Warfarin
Anticoagulants
Arrhythmias, Cardiac

Additional relevant MeSH terms:

Atrial Fibrillation
Embolism
Stroke
Cerebral Infarction
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Cerebrovascular Disorders

Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Brain Infarction
Brain Ischemia
Warfarin
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 22, 2013