Atrial Fibrillation, Thromboembolism
Conditions
Keywords
Anti-coagulant, Non-valvular, Venous Thromboembolism, Prevention of Blood Clots, Atrial Fibrillation, Non-valvular atrial fibrillation
Brief summary
This study is to assess the safety of a potential new drug DU-176b for the prevention of stroke/systemic embolic event (SEE) in individuals with non-valvular atrial fibrillation (AF). The duration is 3 months of treatment and a 30 day follow-up visit.
Interventions
DRUGEdoxaban (DU-176b)
30mg tablet once daily
DRUGwarfarin
warfarin tablets
Sponsors
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, 18 to 80 years old. 2. Able to provide written informed consent. 3. Persistent non-valvular AF supported by abnormal electrocardiogram (ECG) 4. A congestive heart failure, hypertension, age ≥ 75 years, diabetes, and prior stroke (CHADS2) index score of at least 2
Exclusion criteria
1. Subjects with mitral valve disease or previous valvular heart surgery 2. Known contraindication to any anticoagulant including vitamin K antagonists such as warfarin 3. Known or suspected hereditary or acquired bleeding or coagulation disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjudicated Incidence of Bleeding Events | 3 months | Adjudicated Incidence of Bleeding Events during treatment period |
| Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | 3 months | liver enzyme (ALT and/or AST) and/or bilirubin (TBL) abnormalities |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effects on Biomarker Prothrombin Fragments | 3 months | Mean (SD) change from baseline in Prothrombin Fragments 1 and 2 (F1 and F2) |
| Pharmacokinetics (Cmin, Cmax) of DU-176b in Subjects Receiving DU-176b | 3 months | Median (min, max) values of Cmin,ss; Cmax,ss |
| Pharmacokinetics (AUC) of DU-176b in Subjects Receiving DU-176b | 3 months | Median (min, max) values of AUCss |
| Effects on Pharmacodynamic Biomarker Anti-Factor Xa Activity in Subjects Receiving DU-176b | Day 28 | Mean (SD) change from baseline in biomarker anti-Factor Xa \[FXa\] activity on Day 28, 1-3 hours post dose. |
| Incidence of Major Adverse Cardiac Events MACE) | 3 months | MACE is defined as the composite of stroke \[ischemic or hemorrhagic\], Systemic embolic event (SEE), Myocardial Infarction (MI), Cardiovascular (CV) death, and hospitalization for any cardiac condition |
| Effects on Pharmacodynamic Biomarker PICT Activity in Subjects Receiving DU-176b | Day 28 | Mean (SD) change from baseline in biomarker prothrombinase induced clotting time \[PICT\] on Day 28, 1-3 hours post dose. PICT was determined by PICT aasay which is a plasma based functional assay to determine the anticoagulant activity on FXa and FIIa inhibition. |
| Effects on Pharmacodynamic Biomarker PT in Subjects Receiving DU-176b | Day 28 | Mean (SD) change from baseline in biomarker prothrombin time (PT) on Day 28, 1-3 hours post dose. |
| Effects on Pharmacodynamic Biomarker INR in Subjects Receiving DU-176b | Day 28 | Mean (SD) change from baseline in biomarker International Normalized Ratio (INR) on Day 28, 1-3 hours post dose. |
| Effects on Pharmacodynamic Biomarker (Endogenous FX Activity) in Subjects Receiving DU-176b | Day 28 | Mean (SD) change from baseline in biomarker endogenous FX activity on Day 28, 1-3 hours post dose. |
| Effects on Biomarker D-dimer | 3 months | Mean (SD) change from baseline in D-dimer |
Countries
Belarus, Belgium, Bosnia and Herzegovina, Canada, Chile, Latvia, Mexico, Moldova, Russia, Slovakia, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DU-176b 30mg qd DU-176b 30mg tablet once daily (qd)
Edoxaban (DU-176b): 30mg tablet once daily | 235 |
| DU-176b 30mg Bid DU-176b 30mg twice daily (bid)
Edoxaban (DU-176b): 30mg tablet twice daily | 244 |
| DU-176b 60mg qd DU-176b 60mg once daily (qd)
Edoxaban (DU-176b): 60mg tablet once daily | 234 |
| DU-176b 60mg Bid DU-176b 60mg tablet two times a day
Edoxaban (DU-176b): 60mg tablet two times a day | 180 |
| Warfarin Tablets warfarin tablets
warfarin: warfarin tablets | 250 |
| Total | 1,143 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | administrative reasons | 0 | 2 | 2 | 1 | 2 |
| Overall Study | Adverse Event | 11 | 11 | 14 | 13 | 5 |
| Overall Study | data monitor committee decision | 0 | 0 | 0 | 100 | 0 |
| Overall Study | Death | 3 | 3 | 1 | 0 | 2 |
| Overall Study | did not meet entry criteria | 2 | 0 | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 1 | 1 |
| Overall Study | not in safety analysis set | 0 | 1 | 1 | 0 | 1 |
| Overall Study | Other | 2 | 2 | 2 | 3 | 0 |
| Overall Study | Protocol Violation | 1 | 3 | 2 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 16 | 16 | 7 | 8 | 12 |
Baseline characteristics
| Characteristic | Total | DU-176b 30mg qd | DU-176b 30mg Bid | DU-176b 60mg qd | DU-176b 60mg Bid | Warfarin Tablets |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 630 Participants | 126 Participants | 125 Participants | 129 Participants | 97 Participants | 153 Participants |
| Age, Categorical Between 18 and 65 years | 513 Participants | 109 Participants | 119 Participants | 105 Participants | 83 Participants | 97 Participants |
| Age, Continuous | 64.9 years STANDARD_DEVIATION 8.71 | 65.2 years STANDARD_DEVIATION 8.34 | 64.8 years STANDARD_DEVIATION 8.83 | 64.9 years STANDARD_DEVIATION 8.81 | 64.7 years STANDARD_DEVIATION 8.96 | 66.0 years STANDARD_DEVIATION 8.49 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 23 Participants | 3 Participants | 4 Participants | 5 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) White | 1116 Participants | 230 Participants | 239 Participants | 228 Participants | 176 Participants | 243 Participants |
| Region of Enrollment Belarus | 22 participants | 5 participants | 5 participants | 6 participants | 1 participants | 5 participants |
| Region of Enrollment Bosnia and Herzegovina | 55 participants | 13 participants | 11 participants | 11 participants | 8 participants | 12 participants |
| Region of Enrollment Canada | 11 participants | 2 participants | 3 participants | 2 participants | 2 participants | 2 participants |
| Region of Enrollment Chile | 23 participants | 6 participants | 4 participants | 6 participants | 2 participants | 5 participants |
| Region of Enrollment Latvia | 27 participants | 5 participants | 6 participants | 6 participants | 4 participants | 6 participants |
| Region of Enrollment Mexico | 15 participants | 2 participants | 3 participants | 3 participants | 3 participants | 4 participants |
| Region of Enrollment Moldova, Republic of | 57 participants | 11 participants | 12 participants | 11 participants | 11 participants | 12 participants |
| Region of Enrollment Russian Federation | 432 participants | 91 participants | 93 participants | 87 participants | 64 participants | 97 participants |
| Region of Enrollment Slovakia | 64 participants | 13 participants | 14 participants | 12 participants | 10 participants | 15 participants |
| Region of Enrollment Ukraine | 391 participants | 77 participants | 80 participants | 81 participants | 70 participants | 83 participants |
| Region of Enrollment United States | 46 participants | 10 participants | 13 participants | 9 participants | 5 participants | 9 participants |
| Sex: Female, Male Female | 433 Participants | 95 Participants | 94 Participants | 79 Participants | 66 Participants | 99 Participants |
| Sex: Female, Male Male | 710 Participants | 140 Participants | 150 Participants | 155 Participants | 114 Participants | 151 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 235 | 8 / 244 | 4 / 234 | 10 / 180 | 22 / 250 |
| serious Total, serious adverse events | 10 / 235 | 16 / 244 | 15 / 234 | 14 / 180 | 11 / 250 |
Outcome results
Primary
Adjudicated Incidence of Bleeding Events
Adjudicated Incidence of Bleeding Events during treatment period
Time frame: 3 months
Population: safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DU-176b 30mg qd | Adjudicated Incidence of Bleeding Events | All bleeding | 5.5 percent of subjects with outcome event |
| DU-176b 30mg qd | Adjudicated Incidence of Bleeding Events | Major bleed | 0 percent of subjects with outcome event |
| DU-176b 30mg qd | Adjudicated Incidence of Bleeding Events | Major or clinically relevant non-major bleed | 3.0 percent of subjects with outcome event |
| DU-176b 30mg Bid | Adjudicated Incidence of Bleeding Events | Major or clinically relevant non-major bleed | 7.8 percent of subjects with outcome event |
| DU-176b 30mg Bid | Adjudicated Incidence of Bleeding Events | All bleeding | 12.7 percent of subjects with outcome event |
| DU-176b 30mg Bid | Adjudicated Incidence of Bleeding Events | Major bleed | 2.0 percent of subjects with outcome event |
| DU-176b 60mg qd | Adjudicated Incidence of Bleeding Events | Major or clinically relevant non-major bleed | 3.8 percent of subjects with outcome event |
| DU-176b 60mg qd | Adjudicated Incidence of Bleeding Events | All bleeding | 7.3 percent of subjects with outcome event |
| DU-176b 60mg qd | Adjudicated Incidence of Bleeding Events | Major bleed | 0.4 percent of subjects with outcome event |
| DU-176b 60mg Bid | Adjudicated Incidence of Bleeding Events | All bleeding | 18.3 percent of subjects with outcome event |
| DU-176b 60mg Bid | Adjudicated Incidence of Bleeding Events | Major bleed | 3.3 percent of subjects with outcome event |
| DU-176b 60mg Bid | Adjudicated Incidence of Bleeding Events | Major or clinically relevant non-major bleed | 10.6 percent of subjects with outcome event |
| Warfarin Tablets | Adjudicated Incidence of Bleeding Events | Major or clinically relevant non-major bleed | 3.2 percent of subjects with outcome event |
| Warfarin Tablets | Adjudicated Incidence of Bleeding Events | All bleeding | 8.0 percent of subjects with outcome event |
| Warfarin Tablets | Adjudicated Incidence of Bleeding Events | Major bleed | 0.4 percent of subjects with outcome event |
Comparison: All bleedsp-value: 0.367Fisher Exact
Comparison: All bleedsp-value: 0.104Fisher Exact
Comparison: All bleedsp-value: 0.864Fisher Exact
Comparison: All bleedsp-value: 0.002Fisher Exact
Comparison: Major or Clinically Relevant (CR) non-major bleedingp-value: 1Fisher Exact
Comparison: Major or Clinically Relevant (CR) non-major bleedingp-value: 0.029Fisher Exact
Comparison: Major or Clinically Relevant (CR) non-major bleedingp-value: 0.807Fisher Exact
Comparison: Major or Clinically Relevant (CR) non-major bleedingp-value: 0.002Fisher Exact
Comparison: Major bleedsp-value: 1Fisher Exact
Comparison: Major bleedsp-value: 0.119Fisher Exact
Comparison: Major bleedsp-value: 1Fisher Exact
Comparison: Major bleedsp-value: 0.023Fisher Exact
Primary
Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA)
liver enzyme (ALT and/or AST) and/or bilirubin (TBL) abnormalities
Time frame: 3 months
Population: safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DU-176b 30mg qd | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT or AST >=3 x ULN | 1.3 percent subjects with liver related MA |
| DU-176b 30mg qd | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT, total >= 3x ULN | 1.3 percent subjects with liver related MA |
| DU-176b 30mg qd | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | AST, total >= 3x ULN | 0.9 percent subjects with liver related MA |
| DU-176b 30mg qd | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | total bilirubin, total >= 2x ULN | 0.9 percent subjects with liver related MA |
| DU-176b 30mg qd | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT or AST >=3 x ULN and TBL >=2 x ULN | 0 percent subjects with liver related MA |
| DU-176b 30mg Bid | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT or AST >=3 x ULN | 0.9 percent subjects with liver related MA |
| DU-176b 30mg Bid | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT, total >= 3x ULN | 0.9 percent subjects with liver related MA |
| DU-176b 30mg Bid | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT or AST >=3 x ULN and TBL >=2 x ULN | 0.4 percent subjects with liver related MA |
| DU-176b 30mg Bid | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | total bilirubin, total >= 2x ULN | 1.3 percent subjects with liver related MA |
| DU-176b 30mg Bid | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | AST, total >= 3x ULN | 0.9 percent subjects with liver related MA |
| DU-176b 60mg qd | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | total bilirubin, total >= 2x ULN | 0.4 percent subjects with liver related MA |
| DU-176b 60mg qd | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT or AST >=3 x ULN and TBL >=2 x ULN | 0 percent subjects with liver related MA |
| DU-176b 60mg qd | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT or AST >=3 x ULN | 3.1 percent subjects with liver related MA |
| DU-176b 60mg qd | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | AST, total >= 3x ULN | 1.3 percent subjects with liver related MA |
| DU-176b 60mg qd | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT, total >= 3x ULN | 2.6 percent subjects with liver related MA |
| DU-176b 60mg Bid | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | total bilirubin, total >= 2x ULN | 2.9 percent subjects with liver related MA |
| DU-176b 60mg Bid | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | AST, total >= 3x ULN | 1.2 percent subjects with liver related MA |
| DU-176b 60mg Bid | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT or AST >=3 x ULN and TBL >=2 x ULN | 0.6 percent subjects with liver related MA |
| DU-176b 60mg Bid | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT, total >= 3x ULN | 1.7 percent subjects with liver related MA |
| DU-176b 60mg Bid | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT or AST >=3 x ULN | 1.7 percent subjects with liver related MA |
| Warfarin Tablets | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT or AST >=3 x ULN | 1.6 percent subjects with liver related MA |
| Warfarin Tablets | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | total bilirubin, total >= 2x ULN | 1.6 percent subjects with liver related MA |
| Warfarin Tablets | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT or AST >=3 x ULN and TBL >=2 x ULN | 0 percent subjects with liver related MA |
| Warfarin Tablets | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | AST, total >= 3x ULN | 0.8 percent subjects with liver related MA |
| Warfarin Tablets | Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | ALT, total >= 3x ULN | 1.2 percent subjects with liver related MA |
Secondary
Effects on Biomarker D-dimer
Mean (SD) change from baseline in D-dimer
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DU-176b 30mg qd | Effects on Biomarker D-dimer | -225 ng/mL | Standard Deviation 809.3 |
| DU-176b 30mg Bid | Effects on Biomarker D-dimer | -187.8 ng/mL | Standard Deviation 776.8 |
| DU-176b 60mg qd | Effects on Biomarker D-dimer | -100.5 ng/mL | Standard Deviation 461.6 |
| DU-176b 60mg Bid | Effects on Biomarker D-dimer | -129.8 ng/mL | Standard Deviation 771.4 |
| Warfarin Tablets | Effects on Biomarker D-dimer | -160.7 ng/mL | Standard Deviation 635.9 |
Secondary
Effects on Biomarker Prothrombin Fragments
Mean (SD) change from baseline in Prothrombin Fragments 1 and 2 (F1 and F2)
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DU-176b 30mg qd | Effects on Biomarker Prothrombin Fragments | -23.5 pmol/L | Standard Deviation 1312 |
| DU-176b 30mg Bid | Effects on Biomarker Prothrombin Fragments | -47.4 pmol/L | Standard Deviation 1169.6 |
| DU-176b 60mg qd | Effects on Biomarker Prothrombin Fragments | -51.4 pmol/L | Standard Deviation 868.8 |
| DU-176b 60mg Bid | Effects on Biomarker Prothrombin Fragments | 6.4 pmol/L | Standard Deviation 1353.8 |
| Warfarin Tablets | Effects on Biomarker Prothrombin Fragments | -74.6 pmol/L | Standard Deviation 849.5 |
Secondary
Effects on Pharmacodynamic Biomarker Anti-Factor Xa Activity in Subjects Receiving DU-176b
Mean (SD) change from baseline in biomarker anti-Factor Xa \[FXa\] activity on Day 28, 1-3 hours post dose.
Time frame: Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DU-176b 30mg qd | Effects on Pharmacodynamic Biomarker Anti-Factor Xa Activity in Subjects Receiving DU-176b | 1.46 IU/mL | Standard Deviation 0.96 |
| DU-176b 30mg Bid | Effects on Pharmacodynamic Biomarker Anti-Factor Xa Activity in Subjects Receiving DU-176b | 1.91 IU/mL | Standard Deviation 0.97 |
| DU-176b 60mg qd | Effects on Pharmacodynamic Biomarker Anti-Factor Xa Activity in Subjects Receiving DU-176b | 2.42 IU/mL | Standard Deviation 1.63 |
| DU-176b 60mg Bid | Effects on Pharmacodynamic Biomarker Anti-Factor Xa Activity in Subjects Receiving DU-176b | 3.28 IU/mL | Standard Deviation 1.46 |
Secondary
Effects on Pharmacodynamic Biomarker (Endogenous FX Activity) in Subjects Receiving DU-176b
Mean (SD) change from baseline in biomarker endogenous FX activity on Day 28, 1-3 hours post dose.
Time frame: Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DU-176b 30mg qd | Effects on Pharmacodynamic Biomarker (Endogenous FX Activity) in Subjects Receiving DU-176b | -40.3 percent change of Endogenous FX activity | Standard Deviation 26.4 |
| DU-176b 30mg Bid | Effects on Pharmacodynamic Biomarker (Endogenous FX Activity) in Subjects Receiving DU-176b | -40.2 percent change of Endogenous FX activity | Standard Deviation 25.5 |
| DU-176b 60mg qd | Effects on Pharmacodynamic Biomarker (Endogenous FX Activity) in Subjects Receiving DU-176b | -44.4 percent change of Endogenous FX activity | Standard Deviation 25.7 |
| DU-176b 60mg Bid | Effects on Pharmacodynamic Biomarker (Endogenous FX Activity) in Subjects Receiving DU-176b | -45.2 percent change of Endogenous FX activity | Standard Deviation 26.7 |
Secondary
Effects on Pharmacodynamic Biomarker INR in Subjects Receiving DU-176b
Mean (SD) change from baseline in biomarker International Normalized Ratio (INR) on Day 28, 1-3 hours post dose.
Time frame: Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DU-176b 30mg qd | Effects on Pharmacodynamic Biomarker INR in Subjects Receiving DU-176b | 0.05 ratio | Standard Deviation 0.51 |
| DU-176b 30mg Bid | Effects on Pharmacodynamic Biomarker INR in Subjects Receiving DU-176b | 0.03 ratio | Standard Deviation 0.62 |
| DU-176b 60mg qd | Effects on Pharmacodynamic Biomarker INR in Subjects Receiving DU-176b | 0.17 ratio | Standard Deviation 0.61 |
| DU-176b 60mg Bid | Effects on Pharmacodynamic Biomarker INR in Subjects Receiving DU-176b | 0.26 ratio | Standard Deviation 0.61 |
Secondary
Effects on Pharmacodynamic Biomarker PICT Activity in Subjects Receiving DU-176b
Mean (SD) change from baseline in biomarker prothrombinase induced clotting time \[PICT\] on Day 28, 1-3 hours post dose. PICT was determined by PICT aasay which is a plasma based functional assay to determine the anticoagulant activity on FXa and FIIa inhibition.
Time frame: Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DU-176b 30mg qd | Effects on Pharmacodynamic Biomarker PICT Activity in Subjects Receiving DU-176b | 14.0 seconds | Standard Deviation 5.2 |
| DU-176b 30mg Bid | Effects on Pharmacodynamic Biomarker PICT Activity in Subjects Receiving DU-176b | 15.4 seconds | Standard Deviation 5.6 |
| DU-176b 60mg qd | Effects on Pharmacodynamic Biomarker PICT Activity in Subjects Receiving DU-176b | 18.3 seconds | Standard Deviation 11.9 |
| DU-176b 60mg Bid | Effects on Pharmacodynamic Biomarker PICT Activity in Subjects Receiving DU-176b | 19.6 seconds | Standard Deviation 6.4 |
Secondary
Effects on Pharmacodynamic Biomarker PT in Subjects Receiving DU-176b
Mean (SD) change from baseline in biomarker prothrombin time (PT) on Day 28, 1-3 hours post dose.
Time frame: Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DU-176b 30mg qd | Effects on Pharmacodynamic Biomarker PT in Subjects Receiving DU-176b | 0.6 seconds | Standard Deviation 5.5 |
| DU-176b 30mg Bid | Effects on Pharmacodynamic Biomarker PT in Subjects Receiving DU-176b | 0.4 seconds | Standard Deviation 6.6 |
| DU-176b 60mg qd | Effects on Pharmacodynamic Biomarker PT in Subjects Receiving DU-176b | 2.0 seconds | Standard Deviation 6.6 |
| DU-176b 60mg Bid | Effects on Pharmacodynamic Biomarker PT in Subjects Receiving DU-176b | 2.1 seconds | Standard Deviation 11.7 |
Secondary
Incidence of Major Adverse Cardiac Events MACE)
MACE is defined as the composite of stroke \[ischemic or hemorrhagic\], Systemic embolic event (SEE), Myocardial Infarction (MI), Cardiovascular (CV) death, and hospitalization for any cardiac condition
Time frame: 3 months
Population: safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DU-176b 30mg qd | Incidence of Major Adverse Cardiac Events MACE) | MI | .9 percent of subjects experiencing events |
| DU-176b 30mg qd | Incidence of Major Adverse Cardiac Events MACE) | CV death | .9 percent of subjects experiencing events |
| DU-176b 30mg qd | Incidence of Major Adverse Cardiac Events MACE) | any stroke | .4 percent of subjects experiencing events |
| DU-176b 30mg qd | Incidence of Major Adverse Cardiac Events MACE) | MACE | 1.7 percent of subjects experiencing events |
| DU-176b 30mg qd | Incidence of Major Adverse Cardiac Events MACE) | hospitalization for any cardiac condition | .9 percent of subjects experiencing events |
| DU-176b 30mg qd | Incidence of Major Adverse Cardiac Events MACE) | SEE | .4 percent of subjects experiencing events |
| DU-176b 30mg qd | Incidence of Major Adverse Cardiac Events MACE) | any stroke and/or SEE | .4 percent of subjects experiencing events |
| DU-176b 30mg Bid | Incidence of Major Adverse Cardiac Events MACE) | any stroke and/or SEE | 1.2 percent of subjects experiencing events |
| DU-176b 30mg Bid | Incidence of Major Adverse Cardiac Events MACE) | any stroke | .8 percent of subjects experiencing events |
| DU-176b 30mg Bid | Incidence of Major Adverse Cardiac Events MACE) | MACE | 2.5 percent of subjects experiencing events |
| DU-176b 30mg Bid | Incidence of Major Adverse Cardiac Events MACE) | SEE | .4 percent of subjects experiencing events |
| DU-176b 30mg Bid | Incidence of Major Adverse Cardiac Events MACE) | CV death | 1.6 percent of subjects experiencing events |
| DU-176b 30mg Bid | Incidence of Major Adverse Cardiac Events MACE) | MI | .4 percent of subjects experiencing events |
| DU-176b 30mg Bid | Incidence of Major Adverse Cardiac Events MACE) | hospitalization for any cardiac condition | .8 percent of subjects experiencing events |
| DU-176b 60mg qd | Incidence of Major Adverse Cardiac Events MACE) | SEE | 0 percent of subjects experiencing events |
| DU-176b 60mg qd | Incidence of Major Adverse Cardiac Events MACE) | MI | .9 percent of subjects experiencing events |
| DU-176b 60mg qd | Incidence of Major Adverse Cardiac Events MACE) | any stroke | .4 percent of subjects experiencing events |
| DU-176b 60mg qd | Incidence of Major Adverse Cardiac Events MACE) | any stroke and/or SEE | .4 percent of subjects experiencing events |
| DU-176b 60mg qd | Incidence of Major Adverse Cardiac Events MACE) | MACE | 4.3 percent of subjects experiencing events |
| DU-176b 60mg qd | Incidence of Major Adverse Cardiac Events MACE) | CV death | 0 percent of subjects experiencing events |
| DU-176b 60mg qd | Incidence of Major Adverse Cardiac Events MACE) | hospitalization for any cardiac condition | 3.0 percent of subjects experiencing events |
| DU-176b 60mg Bid | Incidence of Major Adverse Cardiac Events MACE) | SEE | 0 percent of subjects experiencing events |
| DU-176b 60mg Bid | Incidence of Major Adverse Cardiac Events MACE) | MACE | 1.1 percent of subjects experiencing events |
| DU-176b 60mg Bid | Incidence of Major Adverse Cardiac Events MACE) | any stroke | 1.1 percent of subjects experiencing events |
| DU-176b 60mg Bid | Incidence of Major Adverse Cardiac Events MACE) | any stroke and/or SEE | 1.1 percent of subjects experiencing events |
| DU-176b 60mg Bid | Incidence of Major Adverse Cardiac Events MACE) | MI | 0 percent of subjects experiencing events |
| DU-176b 60mg Bid | Incidence of Major Adverse Cardiac Events MACE) | CV death | 0 percent of subjects experiencing events |
| DU-176b 60mg Bid | Incidence of Major Adverse Cardiac Events MACE) | hospitalization for any cardiac condition | 0 percent of subjects experiencing events |
| Warfarin Tablets | Incidence of Major Adverse Cardiac Events MACE) | hospitalization for any cardiac condition | .4 percent of subjects experiencing events |
| Warfarin Tablets | Incidence of Major Adverse Cardiac Events MACE) | CV death | .8 percent of subjects experiencing events |
| Warfarin Tablets | Incidence of Major Adverse Cardiac Events MACE) | any stroke | 1.6 percent of subjects experiencing events |
| Warfarin Tablets | Incidence of Major Adverse Cardiac Events MACE) | MACE | 2.4 percent of subjects experiencing events |
| Warfarin Tablets | Incidence of Major Adverse Cardiac Events MACE) | SEE | 0 percent of subjects experiencing events |
| Warfarin Tablets | Incidence of Major Adverse Cardiac Events MACE) | MI | 0 percent of subjects experiencing events |
| Warfarin Tablets | Incidence of Major Adverse Cardiac Events MACE) | any stroke and/or SEE | 1.6 percent of subjects experiencing events |
Secondary
Pharmacokinetics (AUC) of DU-176b in Subjects Receiving DU-176b
Median (min, max) values of AUCss
Time frame: 3 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DU-176b 30mg qd | Pharmacokinetics (AUC) of DU-176b in Subjects Receiving DU-176b | 825 ng*h/mL |
| DU-176b 30mg Bid | Pharmacokinetics (AUC) of DU-176b in Subjects Receiving DU-176b | 1729 ng*h/mL |
| DU-176b 60mg qd | Pharmacokinetics (AUC) of DU-176b in Subjects Receiving DU-176b | 1728 ng*h/mL |
| DU-176b 60mg Bid | Pharmacokinetics (AUC) of DU-176b in Subjects Receiving DU-176b | 3301 ng*h/mL |
Secondary
Pharmacokinetics (Cmin, Cmax) of DU-176b in Subjects Receiving DU-176b
Median (min, max) values of Cmin,ss; Cmax,ss
Time frame: 3 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| DU-176b 30mg qd | Pharmacokinetics (Cmin, Cmax) of DU-176b in Subjects Receiving DU-176b | Cmin,ss (ng/mL) | 10.3 ng/mL |
| DU-176b 30mg qd | Pharmacokinetics (Cmin, Cmax) of DU-176b in Subjects Receiving DU-176b | Cmax,ss (ng/mL) | 84.9 ng/mL |
| DU-176b 30mg Bid | Pharmacokinetics (Cmin, Cmax) of DU-176b in Subjects Receiving DU-176b | Cmax,ss (ng/mL) | 173.0 ng/mL |
| DU-176b 30mg Bid | Pharmacokinetics (Cmin, Cmax) of DU-176b in Subjects Receiving DU-176b | Cmin,ss (ng/mL) | 21.2 ng/mL |
| DU-176b 60mg qd | Pharmacokinetics (Cmin, Cmax) of DU-176b in Subjects Receiving DU-176b | Cmin,ss (ng/mL) | 39.6 ng/mL |
| DU-176b 60mg qd | Pharmacokinetics (Cmin, Cmax) of DU-176b in Subjects Receiving DU-176b | Cmax,ss (ng/mL) | 115.0 ng/mL |
| DU-176b 60mg Bid | Pharmacokinetics (Cmin, Cmax) of DU-176b in Subjects Receiving DU-176b | Cmin,ss (ng/mL) | 75.7 ng/mL |
| DU-176b 60mg Bid | Pharmacokinetics (Cmin, Cmax) of DU-176b in Subjects Receiving DU-176b | Cmax,ss (ng/mL) | 221.4 ng/mL |