Atrial Fibrillation
Conditions
Keywords
anticoagulants, DU-176b, edoxaban, factor Xa, oral, prevention, atrial fibrillation
Brief summary
The purpose of this study is to evaluate the efficacy and safety of edoxaban in patients with non-valvular NVAF aged 80 years or older who are ineligible for available oral anticoagulation therapy.
Interventions
DRUGDu-176b
DU-176b orally administered at a dose of 15 mg once daily.
DRUGplacebo
Placebo orally administered once daily.
Sponsors
Daiichi Sankyo Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
80 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with Nonvalvular Atrial Fibrillation (NVAF) aged 80 years or older who are ineligible for available oral anticoagulation therapy
Exclusion criteria
* Patients with active bleeding * Patients who have poorly controlled hypertension * Patients who have liver dysfunction accompanied with disorder of blood coagulation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Composite Endpoint of Stroke and Systemic Embolic Events (SEE) in Participants Who Were Administered DU-176b Compared With Placebo | Randomization up to the time of onset of the initial composite event of stroke or systemic embolic event, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time) | Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. A systemic embolic event (SEE) was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation). |
| Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo | Randomization up to the time of onset of the initial composite event of stroke or systemic embolic event, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time) | Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. Subcomponents of stroke (ischemic and hemorrhagic) were also reported. A systemic embolic event (SEE) was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Composite Endpoint of Stroke, Systemic Embolic Events (SEE), and All-Cause Mortality in Participants Who Were Administered DU-176b Compared With Placebo | Randomization up to the time of onset of the initial composite event of stroke, SEE, all-cause mortality, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time) | Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. A systemic embolic event (SEE) was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation). All-cause mortality was defined as death due to cardiovascular and mortality due to all other causes. |
| Number of Participants With Net Clinical Benefit in Participants Who Were Administered DU-176b Compared With Placebo | Randomization up to the time of onset of the initial composite event of stroke, SEE, major bleeding, all-cause mortality, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time) | Net clinical benefit included a composite of stroke, systemic embolic events (SEE), major bleeding, and all-cause mortality. Stroke was defined as an abrupt onset of symptoms representing focal neurological deficit in the domain supplied by a single brain artery that was not due to an identifiable non-vascular cause. The deficit symptoms had to either last \>24 hours or result in death within 24 hours of symptom onset. A SEE was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms. Major bleeding was defined as overt bleeding that met at least 1 of the following criteria: fatal bleeding; retroperitoneal, intracranial, intraocular, intrathecal, intraarticular, or pericardial bleeding, or symptomatic intramuscular bleeding accompanied by compartment syndrome; or clinically overt bleeding that decreased hemoglobin by at least 2.0 g/dL and required blood transfusion. |
| Number of Participants With All-Cause Mortality in Participants Who Were Administered DU-176b Compared With Placebo | Randomization up to death (due to any cause), or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time) | All-cause mortality was defined as death due to cardiovascular and mortality due to all other causes. |
| Number of Participants With a Composite Endpoint of Stroke, Systemic Embolic Events (SEE), and Death Due to Cardiovascular in Participants Who Were Administered DU-176b Compared With Placebo | Randomization up to the time of onset of the initial composite event of stroke, systemic embolic event, or death due to CV, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time) | Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. A systemic embolic event (SEE) was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation). |
| Number of Participants With Major Bleeding or Clinically Relevant Non-major Bleedings During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Baseline up to study discontinuation or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time) | Major bleeding was defined as overt bleeding that met at least 1 of the following criteria: fatal bleeding; retroperitoneal, intracranial, intraocular, intrathecal, intraarticular, or pericardial bleeding, or symptomatic intramuscular bleeding accompanied by compartment syndrome; or clinically overt bleeding that decreased hemoglobin by at least 2.0 g/dL and required blood transfusion. Clinically overt bleeding that required treatment was taken to be clinically relevant non-major bleeding, including for example (but was not limited to) the bleeding that led to the diagnostic tests and treatments as specified in the protocol. The clinically overt bleeding requiring treatment did not include outpatient examinations that did not involve any of the medical procedures (diagnostic tests or treatments) as specified in the protocol. |
| Number of Participants With All Bleeding Events and Minor Bleeding Events During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Baseline up to study discontinuation or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time) | All bleeding events include major and clinically relevant non-major bleeding events. Other overt bleeding events that did not meet the criteria for major bleeding or clinically relevant non-major bleeding were taken to be minor bleeding (for example, epistaxis that did not require treatment). All events other than the above (such as a decrease in hemoglobin without overt bleeding) were classified as non-bleeding event. |
| Plasma Concentration of DU-176 in Participants Who Were Administered DU-176b | Week 8: Predose,1-3 hours (h) and 4-8 h postdose | — |
| Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Baseline up to study discontinuation or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time) | Major bleeding was defined as overt bleeding that met at least 1 of the following criteria: fatal bleeding; retroperitoneal, intracranial, intraocular, intrathecal, intraarticular, or pericardial bleeding, or symptomatic intramuscular bleeding accompanied by compartment syndrome; or clinically overt bleeding that decreased hemoglobin by at least 2.0 g/dL and required blood transfusion. |
| Number of Participants With a Composite Endpoint of a Major Adverse Cardiovascular Event (MACE) in Participants Who Were Administered DU-176b Compared With Placebo | Randomization up to the time of onset of the initial MACE event, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time) | Major adverse cardiovascular events (MACE) included a composite of non-fatal myocardial infarction (MI), non-fatal stroke, non-fatal systemic embolic events (SEE), and deaths due to cardiovascular (CV) or bleeding. Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. A SEE was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation). |
Countries
Japan
Participant flow
Recruitment details
A total of 984 participants who met all inclusion criteria and no exclusion criteria were randomized to treatment at 164 clinic centers in Japan. Of the 984 participants, 982 received treatment.
Pre-assignment details
Participants were assigned to the DU-176b or placebo group in a 1:1 ratio using a stratified randomization method with the CHADS2 index score (≤2, ≥3) as a stratification factor.
Participants by arm
| Arm | Count |
|---|---|
| DU-176b 15 mg Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily. | 492 |
| Placebo Participants who were randomized to oral placebo administered once daily. | 492 |
| Total | 984 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 66 | 69 |
| Overall Study | Other | 4 | 6 |
| Overall Study | Withdrawal by Subject | 81 | 77 |
Baseline characteristics
| Characteristic | Placebo | DU-176b 15 mg | Total |
|---|---|---|---|
| Age, Continuous | 86.4 years STANDARD_DEVIATION 4.27 | 86.7 years STANDARD_DEVIATION 4.22 | 86.6 years STANDARD_DEVIATION 4.24 |
| Age, Customized 85 to <90 years | 184 Participants | 190 Participants | 374 Participants |
| Age, Customized <85 years | 181 Participants | 173 Participants | 354 Participants |
| Age, Customized 90 to <95 years | 106 Participants | 110 Participants | 216 Participants |
| Age, Customized 95 years or older | 21 Participants | 19 Participants | 40 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 492 Participants | 492 Participants | 984 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 492 participants | 492 participants | 984 participants |
| Sex: Female, Male Female | 285 Participants | 280 Participants | 565 Participants |
| Sex: Female, Male Male | 207 Participants | 212 Participants | 419 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 66 / 492 | 69 / 490 |
| other Total, other adverse events | 461 / 492 | 454 / 490 |
| serious Total, serious adverse events | 220 / 492 | 238 / 490 |
Outcome results
Primary
Number of Participants With a Composite Endpoint of Stroke and Systemic Embolic Events (SEE) in Participants Who Were Administered DU-176b Compared With Placebo
Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. A systemic embolic event (SEE) was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation).
Time frame: Randomization up to the time of onset of the initial composite event of stroke or systemic embolic event, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)
Population: The primary outcome was assessed in the Intent-to-Treat (ITT) analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DU-176b 15 mg | Number of Participants With a Composite Endpoint of Stroke and Systemic Embolic Events (SEE) in Participants Who Were Administered DU-176b Compared With Placebo | 15 Participants |
| Placebo | Number of Participants With a Composite Endpoint of Stroke and Systemic Embolic Events (SEE) in Participants Who Were Administered DU-176b Compared With Placebo | 44 Participants |
Comparison: This statistical analysis assesses the annual incidence of composite event of stroke and SEE between treatment groups.p-value: 0.000395% CI: [0.188, 0.608]Regression, Cox
Primary
Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo
Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. Subcomponents of stroke (ischemic and hemorrhagic) were also reported. A systemic embolic event (SEE) was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation).
Time frame: Randomization up to the time of onset of the initial composite event of stroke or systemic embolic event, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)
Population: The primary outcome was assessed in the Intent-to-Treat (ITT) analysis set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DU-176b 15 mg | Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo | Systemic Embolic Events (SEE) | 3 Participants |
| DU-176b 15 mg | Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo | Hemorrhagic Stroke | 0 Participants |
| DU-176b 15 mg | Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo | Ischaemic Stroke | 12 Participants |
| DU-176b 15 mg | Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo | Ischemic Stroke/SEE | 15 Participants |
| DU-176b 15 mg | Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo | Stroke | 12 Participants |
| Placebo | Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo | Ischemic Stroke/SEE | 43 Participants |
| Placebo | Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo | Stroke | 40 Participants |
| Placebo | Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo | Systemic Embolic Events (SEE) | 6 Participants |
| Placebo | Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo | Ischaemic Stroke | 39 Participants |
| Placebo | Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo | Hemorrhagic Stroke | 2 Participants |
Comparison: This statistical analysis assesses the annual incidence of stroke between treatment groups.95% CI: [0.157, 0.57]
Comparison: This statistical analysis assesses the annual incidence of SEE between treatment groups.95% CI: [0.126, 2.011]
Comparison: This statistical analysis assesses the annual incidence of ischemic stroke between treatment groups.95% CI: [0.16, 0.585]
Comparison: This statistical analysis assesses the annual incidence of ischemic stroke/SEE between treatment groups.95% CI: [0.193, 0.624]
Secondary
Number of Participants With a Composite Endpoint of a Major Adverse Cardiovascular Event (MACE) in Participants Who Were Administered DU-176b Compared With Placebo
Major adverse cardiovascular events (MACE) included a composite of non-fatal myocardial infarction (MI), non-fatal stroke, non-fatal systemic embolic events (SEE), and deaths due to cardiovascular (CV) or bleeding. Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. A SEE was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation).
Time frame: Randomization up to the time of onset of the initial MACE event, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)
Population: Secondary outcomes were assessed in the Intent-to-Treat (ITT) analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DU-176b 15 mg | Number of Participants With a Composite Endpoint of a Major Adverse Cardiovascular Event (MACE) in Participants Who Were Administered DU-176b Compared With Placebo | 51 Participants |
| Placebo | Number of Participants With a Composite Endpoint of a Major Adverse Cardiovascular Event (MACE) in Participants Who Were Administered DU-176b Compared With Placebo | 72 Participants |
Secondary
Number of Participants With a Composite Endpoint of Stroke, Systemic Embolic Events (SEE), and All-Cause Mortality in Participants Who Were Administered DU-176b Compared With Placebo
Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. A systemic embolic event (SEE) was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation). All-cause mortality was defined as death due to cardiovascular and mortality due to all other causes.
Time frame: Randomization up to the time of onset of the initial composite event of stroke, SEE, all-cause mortality, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)
Population: Secondary outcomes were assessed in the Intent-to-Treat (ITT) analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DU-176b 15 mg | Number of Participants With a Composite Endpoint of Stroke, Systemic Embolic Events (SEE), and All-Cause Mortality in Participants Who Were Administered DU-176b Compared With Placebo | 74 Participants |
| Placebo | Number of Participants With a Composite Endpoint of Stroke, Systemic Embolic Events (SEE), and All-Cause Mortality in Participants Who Were Administered DU-176b Compared With Placebo | 98 Participants |
Secondary
Number of Participants With a Composite Endpoint of Stroke, Systemic Embolic Events (SEE), and Death Due to Cardiovascular in Participants Who Were Administered DU-176b Compared With Placebo
Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. A systemic embolic event (SEE) was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation).
Time frame: Randomization up to the time of onset of the initial composite event of stroke, systemic embolic event, or death due to CV, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)
Population: Secondary outcomes were assessed in the Intent-to-Treat (ITT) analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DU-176b 15 mg | Number of Participants With a Composite Endpoint of Stroke, Systemic Embolic Events (SEE), and Death Due to Cardiovascular in Participants Who Were Administered DU-176b Compared With Placebo | 52 Participants |
| Placebo | Number of Participants With a Composite Endpoint of Stroke, Systemic Embolic Events (SEE), and Death Due to Cardiovascular in Participants Who Were Administered DU-176b Compared With Placebo | 72 Participants |
Secondary
Number of Participants With All Bleeding Events and Minor Bleeding Events During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo
All bleeding events include major and clinically relevant non-major bleeding events. Other overt bleeding events that did not meet the criteria for major bleeding or clinically relevant non-major bleeding were taken to be minor bleeding (for example, epistaxis that did not require treatment). All events other than the above (such as a decrease in hemoglobin without overt bleeding) were classified as non-bleeding event.
Time frame: Baseline up to study discontinuation or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)
Population: Safety outcomes were assessed in the Safety analysis set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DU-176b 15 mg | Number of Participants With All Bleeding Events and Minor Bleeding Events During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | All bleeding | 241 Participants |
| DU-176b 15 mg | Number of Participants With All Bleeding Events and Minor Bleeding Events During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Minor bleeding | 190 Participants |
| Placebo | Number of Participants With All Bleeding Events and Minor Bleeding Events During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | All bleeding | 202 Participants |
| Placebo | Number of Participants With All Bleeding Events and Minor Bleeding Events During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Minor bleeding | 177 Participants |
Secondary
Number of Participants With All-Cause Mortality in Participants Who Were Administered DU-176b Compared With Placebo
All-cause mortality was defined as death due to cardiovascular and mortality due to all other causes.
Time frame: Randomization up to death (due to any cause), or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)
Population: Secondary outcomes were assessed in the Intent-to-Treat (ITT) analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DU-176b 15 mg | Number of Participants With All-Cause Mortality in Participants Who Were Administered DU-176b Compared With Placebo | 66 Participants |
| Placebo | Number of Participants With All-Cause Mortality in Participants Who Were Administered DU-176b Compared With Placebo | 69 Participants |
Secondary
Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo
Major bleeding was defined as overt bleeding that met at least 1 of the following criteria: fatal bleeding; retroperitoneal, intracranial, intraocular, intrathecal, intraarticular, or pericardial bleeding, or symptomatic intramuscular bleeding accompanied by compartment syndrome; or clinically overt bleeding that decreased hemoglobin by at least 2.0 g/dL and required blood transfusion.
Time frame: Baseline up to study discontinuation or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)
Population: Safety outcomes were assessed in the Safety analysis set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DU-176b 15 mg | Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Major bleeding | 20 Participants |
| DU-176b 15 mg | Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Major bleeding, Intracranial haemorrhage | 2 Participants |
| DU-176b 15 mg | Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Fatal bleeding | 0 Participants |
| DU-176b 15 mg | Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Fatal bleeding, Intracranial haemorrhage | 0 Participants |
| DU-176b 15 mg | Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Fatal bleeding, Non-Intracranial haemorrhage | 0 Participants |
| DU-176b 15 mg | Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Life-threatening bleeding | 8 Participants |
| Placebo | Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Fatal bleeding, Non-Intracranial haemorrhage | 1 Participants |
| Placebo | Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Major bleeding | 11 Participants |
| Placebo | Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Fatal bleeding, Intracranial haemorrhage | 1 Participants |
| Placebo | Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Major bleeding, Intracranial haemorrhage | 4 Participants |
| Placebo | Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Life-threatening bleeding | 4 Participants |
| Placebo | Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Fatal bleeding | 2 Participants |
Secondary
Number of Participants With Major Bleeding or Clinically Relevant Non-major Bleedings During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo
Major bleeding was defined as overt bleeding that met at least 1 of the following criteria: fatal bleeding; retroperitoneal, intracranial, intraocular, intrathecal, intraarticular, or pericardial bleeding, or symptomatic intramuscular bleeding accompanied by compartment syndrome; or clinically overt bleeding that decreased hemoglobin by at least 2.0 g/dL and required blood transfusion. Clinically overt bleeding that required treatment was taken to be clinically relevant non-major bleeding, including for example (but was not limited to) the bleeding that led to the diagnostic tests and treatments as specified in the protocol. The clinically overt bleeding requiring treatment did not include outpatient examinations that did not involve any of the medical procedures (diagnostic tests or treatments) as specified in the protocol.
Time frame: Baseline up to study discontinuation or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)
Population: Safety outcomes were assessed in the Safety analysis set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DU-176b 15 mg | Number of Participants With Major Bleeding or Clinically Relevant Non-major Bleedings During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Major or clinically relevant non-major bleeding | 97 Participants |
| DU-176b 15 mg | Number of Participants With Major Bleeding or Clinically Relevant Non-major Bleedings During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Clinically relevant non-major bleeding | 81 Participants |
| Placebo | Number of Participants With Major Bleeding or Clinically Relevant Non-major Bleedings During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Major or clinically relevant non-major bleeding | 62 Participants |
| Placebo | Number of Participants With Major Bleeding or Clinically Relevant Non-major Bleedings During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo | Clinically relevant non-major bleeding | 52 Participants |
Secondary
Number of Participants With Net Clinical Benefit in Participants Who Were Administered DU-176b Compared With Placebo
Net clinical benefit included a composite of stroke, systemic embolic events (SEE), major bleeding, and all-cause mortality. Stroke was defined as an abrupt onset of symptoms representing focal neurological deficit in the domain supplied by a single brain artery that was not due to an identifiable non-vascular cause. The deficit symptoms had to either last \>24 hours or result in death within 24 hours of symptom onset. A SEE was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms. Major bleeding was defined as overt bleeding that met at least 1 of the following criteria: fatal bleeding; retroperitoneal, intracranial, intraocular, intrathecal, intraarticular, or pericardial bleeding, or symptomatic intramuscular bleeding accompanied by compartment syndrome; or clinically overt bleeding that decreased hemoglobin by at least 2.0 g/dL and required blood transfusion.
Time frame: Randomization up to the time of onset of the initial composite event of stroke, SEE, major bleeding, all-cause mortality, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)
Population: Secondary outcomes were assessed in the Intent-to-Treat (ITT) analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DU-176b 15 mg | Number of Participants With Net Clinical Benefit in Participants Who Were Administered DU-176b Compared With Placebo | 87 Participants |
| Placebo | Number of Participants With Net Clinical Benefit in Participants Who Were Administered DU-176b Compared With Placebo | 103 Participants |
Secondary
Plasma Concentration of DU-176 in Participants Who Were Administered DU-176b
Time frame: Week 8: Predose,1-3 hours (h) and 4-8 h postdose
Population: Plasma concentration was assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DU-176b 15 mg | Plasma Concentration of DU-176 in Participants Who Were Administered DU-176b | Week 8: Predose (trough) | 17.3 ng/mL | Standard Deviation 13.9 |
| DU-176b 15 mg | Plasma Concentration of DU-176 in Participants Who Were Administered DU-176b | Week 8: 1-3 h | 93.3 ng/mL | Standard Deviation 57.8 |
| DU-176b 15 mg | Plasma Concentration of DU-176 in Participants Who Were Administered DU-176b | Week 8: 4-8 h | 93.4 ng/mL | Standard Deviation 37.5 |