Atrial Fibrillation
Conditions
Keywords
BAY59-7939, Rivaroxaban, Non-Valvular Atrial Fibrillation, Japanese Patients, Phase III, 12620
Brief summary
This is a clinical study evaluating the efficacy and safety of rivaroxaban for stroke prevention in patients with atrial fibrillation (originally described in Japanese).
Detailed description
Within the US 'Johnson & Johnson Pharmaceutical Research & Development, L.L.C.' is sponsor.
Interventions
DRUGRivaroxaban (Xarelto, BAY59-7939)
Participants orally administered rivaroxaban 15 mg OD (CrCL \[creatinine clearance\] \>= 50 mL/min) or 10 mg OD (CrCL 30-49 mL/min)
DRUGWarfarin
Participants orally administered a warfarin potassium tablet (INR \[international normalized ratio\] target was 1.6-2.6 for patients \>70 years and 2.0-3.0 for patients \<70 years)
Participants orally administered a rivaroxaban placebo tablet
DRUGWarfarin placebo
Participants orally administered a warfarin placebo tablet (adjusted based upon sham INR values)
Sponsors
Janssen R&D, L.L.C.
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 20 years or older * Japanese male or female * Non- valvular atrial fibrillation documented by ECG * Patients with a risk of stroke and non-CNS systemic embolism
Exclusion criteria
* Significant mitral stenosis * Patients in whom anticoagulants are contraindicated
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Rate of the Composite Endpoint of Adjudicated Major Bleeding or Adjudicated Non-major Clinically Relevant Bleeding | Up to 2 days after the last dose | Major bleeding: clinically overt bleeding (COB) associated with a fall in hemoglobin ≥2 g/dL, leading to transfusion ≥2 units of packed red blood cells or whole blood, occurring in a critical site or contributing to death. Non-major clinically relevant bleeding: COB that does not meet the definition of major bleeding, but requires medical intervention or unscheduled contact with the physician, (temporary) discontinuation of the study treatment, discomfort to the subject such as pain, or impairment of activities of daily life. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, and Vascular Death | Up to 2 days after the last dose | Stroke included hemorrhagic, ischemic infarction and unknown. Arterial emboli in the following areas were non-CNS systemic embolism: peripheral arterial in the upper and lower extremities, renal, mesenteric, splenic, hepatic, ocular/retinal and others. Pulmonary embolism or myocardial infarction was excluded. Any death that was not clearly non-vascular. |
| Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, Myocardial Infarction, and Vascular Death | Up to 2 days after the last dose | Stroke included hemorrhagic, ischemic infarction and unknown. Arterial emboli in the following areas were non-CNS systemic embolism: peripheral arterial in the upper and lower extremities, renal, mesenteric, splenic, hepatic, ocular/retinal and others. Pulmonary embolism or myocardial infarction was excluded. Myocardial infarction: assessed based on either cardiac biomarkers, new abnormal Q waves appeared on electrocardiogram for ≥2 leads, or autopsy confirmation. Any death that was not clearly non-vascular. |
| Event Rate of Stroke | Up to 2 days after the last dose | All events were adjudicated and confirmed by a central independent committee blinded to treatment. Stroke included hemorrhagic (Stroke with local collections of intraparenchymal blood. Subarachnoid hemorrhage, subdural hemorrhage, and epidural hemorrhage were excluded.), ischemic infarction (Stroke without focal collection of intracranial blood) and unknown (No imaging data and anatomic findings were available.). |
| Event Rate of Non-CNS Systemic Embolism | Up to 2 days after the last dose | All events were adjudicated and confirmed by a central independent committee blinded to treatment. Non-CNS systemic embolism was abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms (such as trauma, atherosclerosis, and instrumentation). Arterial emboli in the following areas were non-CNS systemic embolism: peripheral arterial in the upper and lower extremities, renal, mesenteric, splenic, hepatic, ocular/retinal and others. Pulmonary embolism or myocardial infarction was excluded from this category. |
| Event Rate of Myocardial Infarction | Up to 2 days after the last dose | All events were adjudicated and confirmed by a central independent committee blinded to treatment. Myocardial infarction was assessed based on either cardiac bio-markers (troponin I, troponin T, or creatine kinase-muscle and brain subunit isozyme), new abnormal Q waves appeared on ECG for 2 or more leads, or autopsy confirmation. |
| Event Rate of the Composite Endpoint of Adjudicated Stroke and Non-central Nervous System (CNS) Systemic Embolism | Up to 2 days after the last dose | This is the principal efficacy endpoint. Stroke included hemorrhagic, ischemic infarction and unknown. Arterial emboli in the following areas were non-CNS systemic embolism: peripheral arterial in the upper and lower extremities, renal, mesenteric, splenic, hepatic, ocular/retinal and others. Pulmonary embolism or myocardial infarction was excluded. |
| Event Rate of Stroke With Serious Residual Disability | Up to 2 days after the last dose | All events were adjudicated and confirmed by a central independent committee blinded to treatment. A stroke was considered disabling if the participant's modified Rankin score was between 3 and 5, inclusive. |
| Event Rate of All-cause Death | Up to 2 days after the last dose | All events were adjudicated and confirmed by a central independent committee blinded to treatment. All-cause death included vascular death and non-vascular death. |
| Event Rate of Adjudicated Major Bleeding | Up to 2 days after the last dose | All events were adjudicated and confirmed by a central independent committee blinded to treatment. Major bleeding was clinically overt bleeding associated with a fall in hemoglobin of 2 g/dL or higher, leading to a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site or contributing to death. |
| Event Rate Adjudicated Non-major Clinically Relevant Bleeding | Up to 2 days after the last dose | All events were adjudicated and confirmed by a central independent committee blinded to treatment. Non-major clinically relevant bleeding was clinically overt bleeding that does not meet the definition of major bleeding, but requires medical intervention or unscheduled contact with the physician, (temporary) discontinuation of the study treatment, discomfort to the subject such as pain, or impairment of activities of daily life. |
| Event Rate of Vascular Death | Up to 2 days after the last dose | All events were adjudicated and confirmed by a central independent committee blinded to treatment. Any death that was not clearly non-vascular (e.g., deaths due to spontaneous bleeding, myocardial infarction, stroke, cardiac failure, and arrhythmia) |
Countries
Japan
Participant flow
Recruitment details
The first participant entered the study on 08 Jun 2007, and the last participant completed the study on 19 Jan 2010. The study was conducted at 167 centers in Japan. 164 study centers enrolled at least 1 participant.
Pre-assignment details
In total, 1439 participants were screened for study eligibility; 159 participants were screening failures and were not randomized. Therefore, 1280 participants (640 in each group) were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period | 640 |
| Warfarin Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period | 640 |
| Total | 1,280 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind (DB) Treatment Period | Adverse Event | 73 | 70 |
| Double-blind (DB) Treatment Period | Clinical Endpoint Reached | 18 | 28 |
| Double-blind (DB) Treatment Period | Death | 8 | 3 |
| Double-blind (DB) Treatment Period | Drop out before Treatment Start | 1 | 1 |
| Double-blind (DB) Treatment Period | Lost to Follow-up | 4 | 1 |
| Double-blind (DB) Treatment Period | Non-compliant with Study Medication | 3 | 1 |
| Double-blind (DB) Treatment Period | Physician Decision | 4 | 13 |
| Double-blind (DB) Treatment Period | Protocol Driven Decision Point | 12 | 8 |
| Double-blind (DB) Treatment Period | Protocol Violation | 9 | 9 |
| Double-blind (DB) Treatment Period | Site Closed by Investigator | 1 | 2 |
| Double-blind (DB) Treatment Period | Site Closed by Sponsor | 1 | 1 |
| Double-blind (DB) Treatment Period | Withdrawal by Subject | 26 | 35 |
| Follow-up (FU) Period | Adverse Event | 1 | 1 |
| Follow-up (FU) Period | Clinical Endpoint Reached | 3 | 2 |
| Follow-up (FU) Period | Death | 13 | 12 |
| Follow-up (FU) Period | Lost to Follow-up | 6 | 2 |
| Follow-up (FU) Period | Physician Decision | 0 | 1 |
| Follow-up (FU) Period | Protocol Violation | 1 | 0 |
| Follow-up (FU) Period | Withdrawal by Subject | 5 | 5 |
Baseline characteristics
| Characteristic | Total | Rivaroxaban (Xarelto, BAY59-7939) | Warfarin |
|---|---|---|---|
| Age, Continuous | 71.1 Years STANDARD_DEVIATION 8.1 | 71.0 Years STANDARD_DEVIATION 8.3 | 71.2 Years STANDARD_DEVIATION 7.9 |
| CL(CR) [creatinine clearance] <50 mL/min | 284 Participants | 141 Participants | 143 Participants |
| CL(CR) [creatinine clearance] 50 to <80 mL/min | 658 Participants | 329 Participants | 329 Participants |
| CL(CR) [creatinine clearance] ≥80 mL/min | 338 Participants | 170 Participants | 168 Participants |
| Sex: Female, Male Female | 250 Participants | 110 Participants | 140 Participants |
| Sex: Female, Male Male | 1030 Participants | 530 Participants | 500 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 474 / 639 | 470 / 639 | 73 / 628 | 61 / 630 |
| serious Total, serious adverse events | 151 / 639 | 155 / 639 | 50 / 628 | 37 / 630 |
Outcome results
Primary
Event Rate of the Composite Endpoint of Adjudicated Major Bleeding or Adjudicated Non-major Clinically Relevant Bleeding
Major bleeding: clinically overt bleeding (COB) associated with a fall in hemoglobin ≥2 g/dL, leading to transfusion ≥2 units of packed red blood cells or whole blood, occurring in a critical site or contributing to death. Non-major clinically relevant bleeding: COB that does not meet the definition of major bleeding, but requires medical intervention or unscheduled contact with the physician, (temporary) discontinuation of the study treatment, discomfort to the subject such as pain, or impairment of activities of daily life.
Time frame: Up to 2 days after the last dose
Population: The safety analysis population consisted of randomized participants who took at least one dose of study treatment (639 in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Event Rate of the Composite Endpoint of Adjudicated Major Bleeding or Adjudicated Non-major Clinically Relevant Bleeding | 18.04 Events per 100 patient-years |
| Warfarin | Event Rate of the Composite Endpoint of Adjudicated Major Bleeding or Adjudicated Non-major Clinically Relevant Bleeding | 16.42 Events per 100 patient-years |
p-value: 0.02595% CI: [0.87, 1.42]Regression, Cox
Secondary
Event Rate Adjudicated Non-major Clinically Relevant Bleeding
All events were adjudicated and confirmed by a central independent committee blinded to treatment. Non-major clinically relevant bleeding was clinically overt bleeding that does not meet the definition of major bleeding, but requires medical intervention or unscheduled contact with the physician, (temporary) discontinuation of the study treatment, discomfort to the subject such as pain, or impairment of activities of daily life.
Time frame: Up to 2 days after the last dose
Population: The safety analysis population consisted of randomized participants who took at least one dose of study treatment (639 in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Event Rate Adjudicated Non-major Clinically Relevant Bleeding | 15.42 Events per 100 patient-years |
| Warfarin | Event Rate Adjudicated Non-major Clinically Relevant Bleeding | 12.99 Events per 100 patient-years |
95% CI: [0.92, 1.56]
Secondary
Event Rate of Adjudicated Major Bleeding
All events were adjudicated and confirmed by a central independent committee blinded to treatment. Major bleeding was clinically overt bleeding associated with a fall in hemoglobin of 2 g/dL or higher, leading to a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site or contributing to death.
Time frame: Up to 2 days after the last dose
Population: The safety analysis population consisted of randomized participants who took at least one dose of study treatment (639 in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Event Rate of Adjudicated Major Bleeding | 3.00 Events per 100 patient-years |
| Warfarin | Event Rate of Adjudicated Major Bleeding | 3.59 Events per 100 patient-years |
95% CI: [0.5, 1.43]
Secondary
Event Rate of All-cause Death
All events were adjudicated and confirmed by a central independent committee blinded to treatment. All-cause death included vascular death and non-vascular death.
Time frame: Up to 2 days after the last dose
Population: The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Event Rate of All-cause Death | 0.80 Events per 100 patient-years |
| Warfarin | Event Rate of All-cause Death | 0.59 Events per 100 patient-years |
95% CI: [0.43, 4.31]
Secondary
Event Rate of Myocardial Infarction
All events were adjudicated and confirmed by a central independent committee blinded to treatment. Myocardial infarction was assessed based on either cardiac bio-markers (troponin I, troponin T, or creatine kinase-muscle and brain subunit isozyme), new abnormal Q waves appeared on ECG for 2 or more leads, or autopsy confirmation.
Time frame: Up to 2 days after the last dose
Population: The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Event Rate of Myocardial Infarction | 0.34 Events per 100 patient-years |
| Warfarin | Event Rate of Myocardial Infarction | 0.12 Events per 100 patient-years |
95% CI: [0.3, 28.16]
Secondary
Event Rate of Non-CNS Systemic Embolism
All events were adjudicated and confirmed by a central independent committee blinded to treatment. Non-CNS systemic embolism was abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms (such as trauma, atherosclerosis, and instrumentation). Arterial emboli in the following areas were non-CNS systemic embolism: peripheral arterial in the upper and lower extremities, renal, mesenteric, splenic, hepatic, ocular/retinal and others. Pulmonary embolism or myocardial infarction was excluded from this category.
Time frame: Up to 2 days after the last dose
Population: The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Event Rate of Non-CNS Systemic Embolism | 0.11 Events per 100 patient-years |
| Warfarin | Event Rate of Non-CNS Systemic Embolism | 0.12 Events per 100 patient-years |
95% CI: [0.06, 15.85]
Secondary
Event Rate of Stroke
All events were adjudicated and confirmed by a central independent committee blinded to treatment. Stroke included hemorrhagic (Stroke with local collections of intraparenchymal blood. Subarachnoid hemorrhage, subdural hemorrhage, and epidural hemorrhage were excluded.), ischemic infarction (Stroke without focal collection of intracranial blood) and unknown (No imaging data and anatomic findings were available.).
Time frame: Up to 2 days after the last dose
Population: The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Event Rate of Stroke | 1.15 Events per 100 patient-years |
| Warfarin | Event Rate of Stroke | 2.49 Events per 100 patient-years |
95% CI: [0.22, 0.98]
Secondary
Event Rate of Stroke With Serious Residual Disability
All events were adjudicated and confirmed by a central independent committee blinded to treatment. A stroke was considered disabling if the participant's modified Rankin score was between 3 and 5, inclusive.
Time frame: Up to 2 days after the last dose
Population: The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Event Rate of Stroke With Serious Residual Disability | 0.57 Events per 100 patient-years |
| Warfarin | Event Rate of Stroke With Serious Residual Disability | 1.19 Events per 100 patient-years |
95% CI: [0.16, 1.4]
Secondary
Event Rate of the Composite Endpoint of Adjudicated Stroke and Non-central Nervous System (CNS) Systemic Embolism
This is the principal efficacy endpoint. Stroke included hemorrhagic, ischemic infarction and unknown. Arterial emboli in the following areas were non-CNS systemic embolism: peripheral arterial in the upper and lower extremities, renal, mesenteric, splenic, hepatic, ocular/retinal and others. Pulmonary embolism or myocardial infarction was excluded.
Time frame: Up to 2 days after the last dose
Population: The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Event Rate of the Composite Endpoint of Adjudicated Stroke and Non-central Nervous System (CNS) Systemic Embolism | 1.26 Events per 100 patient-years |
| Warfarin | Event Rate of the Composite Endpoint of Adjudicated Stroke and Non-central Nervous System (CNS) Systemic Embolism | 2.61 Events per 100 patient-years |
95% CI: [0.24, 1]
Secondary
Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, and Vascular Death
Stroke included hemorrhagic, ischemic infarction and unknown. Arterial emboli in the following areas were non-CNS systemic embolism: peripheral arterial in the upper and lower extremities, renal, mesenteric, splenic, hepatic, ocular/retinal and others. Pulmonary embolism or myocardial infarction was excluded. Any death that was not clearly non-vascular.
Time frame: Up to 2 days after the last dose
Population: The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, and Vascular Death | 1.83 Events per 100 patient-years |
| Warfarin | Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, and Vascular Death | 2.85 Events per 100 patient-years |
95% CI: [0.34, 1.22]
Secondary
Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, Myocardial Infarction, and Vascular Death
Stroke included hemorrhagic, ischemic infarction and unknown. Arterial emboli in the following areas were non-CNS systemic embolism: peripheral arterial in the upper and lower extremities, renal, mesenteric, splenic, hepatic, ocular/retinal and others. Pulmonary embolism or myocardial infarction was excluded. Myocardial infarction: assessed based on either cardiac biomarkers, new abnormal Q waves appeared on electrocardiogram for ≥2 leads, or autopsy confirmation. Any death that was not clearly non-vascular.
Time frame: Up to 2 days after the last dose
Population: The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, Myocardial Infarction, and Vascular Death | 2.18 Events per 100 patient-years |
| Warfarin | Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, Myocardial Infarction, and Vascular Death | 2.97 Events per 100 patient-years |
95% CI: [0.41, 1.34]
Secondary
Event Rate of Vascular Death
All events were adjudicated and confirmed by a central independent committee blinded to treatment. Any death that was not clearly non-vascular (e.g., deaths due to spontaneous bleeding, myocardial infarction, stroke, cardiac failure, and arrhythmia)
Time frame: Up to 2 days after the last dose
Population: The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Event Rate of Vascular Death | 0.69 Events per 100 patient-years |
| Warfarin | Event Rate of Vascular Death | 0.24 Events per 100 patient-years |
95% CI: [0.6, 14.7]