Atrial Fibrillation, Stroke
Conditions
Brief summary
This study will be conducted in male and female subjects aged 18 to 80 years, inclusive, with non-valvular AF and a CHADS2 Score of at least 1. Subjects will be treated on an outpatient basis. The subjects will be allocated randomly to the open-label warfarin or any double-blind DU-176b dosages. DU-176b will be administered orally for 12 weeks at two fixed doses. Warfarin will be used as active control. Warfarin dosing will be managed and monitored by the Investigator with the dose adjusted to achieve an INR of 2.0 to 3.0, inclusive. The primary endpoints are incidence of major, clinically relevant non-major and minor bleeding events (all bleeding).
Interventions
DRUGDU-176b tablets
DU-176b tablets taken once daily for up to 3 months
DRUGWarfarin tablets
Warfarin tablets taken once daily for up to 3 months
Sponsors
Daiichi Sankyo Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subjects 18 to 80 years of age * Non-valvular AF supported by abnormal ECG documented for two times (interval of more than 1 week) within 6 months prior to randomization. * CHADS2 Score of at least 1.
Exclusion criteria
* Subjects with mitral valve disease * Subjects with previous valvular heart surgery * Contraindication for anticoagulants * Conditions associated with high risk of bleeding * Acute coronary syndromes (ACS), percutaneous coronary intervention (PCI), MI, stroke, transient ischemic attack (TIA) or coronary artery/cardiac/other major surgery within the previous 30 days * Active infective endocarditis or life-expectancy \< 12 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of All Bleeding | 6 months | Incidence of all bleeding (major, clinically relevant non-major and minor) in two fixed dosage of DU-176b in comparison with warfarin as active control in subjects with non-valvular AF. |
Secondary
| Measure | Time frame |
|---|---|
| Evaluation of Incidence of Major Adverse Cardiovascular Events: Stroke, Systemic Embolic Event, Myocardial Infarction, Cardiovascular Death, and Hospitalization for Any Cardiac Condition | 6 months |
| Evaluation of Effects on Biomarkers of Thrombus Formation | 6 months |
| Evaluation of Plasma Concentration of DU-176 | 6 months |
| Evaluation of Effects on Pharmacodynamic Biomarkers | 6 months |
| Evaluation of All Clinical and Laboratory Safety Data. | 6 months |
Countries
China, Singapore, South Korea, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DU176b 30mg 30 mg of DU-176b was administered once daily in the morning in principle for 3 months. | 79 |
| DU-176b 60 mg 60 mg of DU-176b was administered once daily in the morning in principle for 3 months. | 80 |
| Warfarin Potassium Warfarin was administered once daily at the dose to achieve an INR between 2.0 and 3.0 for 3 months. | 75 |
| Total | 234 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 8 | 0 |
| Overall Study | Death | 0 | 1 | 1 |
| Overall Study | discontinued before start of treatment | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 3 | 3 |
Baseline characteristics
| Characteristic | DU-176b 60 mg | DU176b 30mg | Warfarin Potassium | Total |
|---|---|---|---|---|
| Age, Continuous | 65.9 years STANDARD_DEVIATION 7.71 | 64.9 years STANDARD_DEVIATION 9.12 | 64.5 years STANDARD_DEVIATION 9.51 | 65.1 years STANDARD_DEVIATION 8.78 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 80 Participants | 79 Participants | 75 Participants | 234 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 8 participants | 7 participants | 7 participants | 22 participants |
| Region of Enrollment Korea, Republic of | 33 participants | 32 participants | 30 participants | 95 participants |
| Region of Enrollment Singapore | 4 participants | 5 participants | 4 participants | 13 participants |
| Region of Enrollment Taiwan | 35 participants | 35 participants | 34 participants | 104 participants |
| Sex: Female, Male Female | 25 Participants | 28 Participants | 28 Participants | 81 Participants |
| Sex: Female, Male Male | 55 Participants | 51 Participants | 47 Participants | 153 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 62 / 79 | 65 / 80 | 59 / 75 |
| serious Total, serious adverse events | 3 / 79 | 10 / 80 | 5 / 75 |
Outcome results
Primary
Incidence of All Bleeding
Incidence of all bleeding (major, clinically relevant non-major and minor) in two fixed dosage of DU-176b in comparison with warfarin as active control in subjects with non-valvular AF.
Time frame: 6 months
Population: The Safety Analysis Set was defined as all subjects who received at least one dose of study drug and had at least one post-dose safety assessment. The primary endpoint were analyzed for the subjects who proceeded to the treatment period in the Safety Analysis Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DU176b 30mg | Incidence of All Bleeding | 20.3 percentage of subjects with bleeds |
| DU-176b 60 mg | Incidence of All Bleeding | 23.8 percentage of subjects with bleeds |
| Warfarin Potassium | Incidence of All Bleeding | 29.3 percentage of subjects with bleeds |
95% CI: [-16.2, 9.4]
95% CI: [-22.4, 4.5]
95% CI: [-19.3, 8.2]
Secondary
Evaluation of All Clinical and Laboratory Safety Data.
Time frame: 6 months
Secondary
Evaluation of Effects on Biomarkers of Thrombus Formation
Time frame: 6 months
Secondary
Evaluation of Effects on Pharmacodynamic Biomarkers
Time frame: 6 months
Secondary
Evaluation of Incidence of Major Adverse Cardiovascular Events: Stroke, Systemic Embolic Event, Myocardial Infarction, Cardiovascular Death, and Hospitalization for Any Cardiac Condition
Time frame: 6 months
Secondary
Evaluation of Plasma Concentration of DU-176
Time frame: 6 months