Atrial Fibrillation
Conditions
Keywords
Atrial fibrillation, Factor Xa inhibition
Brief summary
The primary objective of this study is to compare the incidence of hemorrhagic events in patients treated for non-valvular atrial fibrillation with DU-176b at each dose level versus warfarin potassium (warfarin). The secondary objective includes between-group comparisons with regard to incidence of thromboembolic events, pharmacodynamic parameters, and biomarkers for the efficacy evaluation, as well as incidence of adverse events and adverse reaction for the safety evaluation.
Interventions
DRUGDU-176b tablets
DU-176b tablets taken once daily for up to 12 weeks
DRUGWarfarin potassium tablets
Warfarin potassium tablets taken once daily for up to 12 weeks
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
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with non-valvular atrial fibrillation who meet all of the following requirements will be considered for admission to the study: * Age≧20years * Atrial fibrillation confirmed by at least 2 electrocardiographic(ECG) tracings taken at an interval of ≧1week during the year before enrollment * Presence of any (at least )one of the following risk factors for embolism: * Hypertension * Diabetes mellitus * Congestive heart failure * Previous transient ischemic attack (TIA) or cerebral infarction (more than 30 days before giving informed consent ) * Age≧75 years * At time of giving informed consent. * To be confirmed on ECG charts, etc.
Exclusion criteria
* Presence of any of the following conditions with increased risk of hemorrhage: * History of intracranial, intraocular (excluding bleeding beneath the bulbar conjunctiva ), intrathecal, retroperitoneal, or non-traumatic intraarticular hemorrhage * History of gastrointestinal hemorrhage during the year before giving informed consent * History of peptic ulcers during the 90 days before giving informed consent * Surgical treatment or trauma requiring hospitalization during the 30 days before giving informed consent * Hemoglobin level \<10 g/dL platelet count \<10 ×10000 /μL at screening examinations * Active hemorrhage\* present at giving informed consent or at enrollment * Any invasive therapeutic or diagnostic procedure (e.g., surgery, tissue, biopsy, and tooth extraction) scheduled during the period from the time of informed consent until completion of the trial treatment. * Any congenital hemorrhagic disease * History of cerebral infarction or TIA within 30 days before giving informed consent * Current treatment with any anticoagulant(other than warfarin) * Concurrent rheumatic valvular disease * History of valvular surgery * Concurrent infectious endocarditis * Concurrent cardiac myxoma * Confirmed left ventricular or left atrial thrombosis * Any congenital condition with a tendency toward thrombosis * Electrical or pharmacological defibrillation scheduled during the trial treatment * Uncontrolled hypertension (persistently high systolic ［\>160mmHg］or diastolic \[\>100mmHg\] pressure) * Uncontrolled diabetes mellitus * Renal or hepatic dysfunction (as defined below ), confirmed at screening examinations * Serum creatinine\>1.5mg/dL * AST(GOT)or ALT(GPT)≧twice the upper limit of the reference range * Total bilirubin ≧twice the upper limit of the reference range * Current antiplatelet therapy for any concomitant illness that may be aggravated after discontinuation of the therapy. * Any concurrent severe cardiac disease * Known allergy to warfarin or any condition contraindicating its use * Inability to discontinue current treatment with vitamin K * Confirmed or potential pregnancy, wish to become pregnant during the study period, or current breast feeding * Previous treatment with DU-176b * Participation in a trial of any other drug during the 6 month before giving informed consent * Any other condition that disqualifies the patient for the study in the opinion of the investigator/subinvestigator \*This includes ecchymosis identified as at least one hematoma sized ≧5 cm in longer diameter, macroscopic hematuria, and microscopic hematuria defined as a ≧2+test or a 1+ test for occult blood with a urine sediment containing ≧10 red cells per high-power field (except for a 2+ occult blood test persisting for 1 year before giving informed consent).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Bleeding Events (Major Bleeding, Clinically Relevant Non-major Bleeding and Minor Bleeding ) Identified During the Period From the Entry Into the Treatment Period Until Completion or Termination of the Treatment. | 12 weeks | The primary endpoint was the incidence of bleeding events (major bleeding, clinically relevant non-major bleeding, or minor bleeding) that occurred during the treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Thromboembolic Events (Cerebral Infarction and Systemic Embolism) Identified During the Period From the Entry to the Treatment Period Until Completion or Termination of the Treatment. | 12 weeks | — |
| Incidence of Adverse Events and Adverse Reactions Identified During the Period From the Entry to the Treatment Period Until Completion or Termination of the Treatment | 12 weeks | — |
| Pharmacodynamic Parameters (PT, PT-INR, and APTT) | 12 weeks | PT - prothrombin time INR - International Normalized Ratio APTT - Activated Partial Thromboplastin time |
| Plasma DU-176 Concentration | 12 weeks | — |
| Pharmacodynamic Biomarkers (F1+2, TAT, and D-dimer ) | 12 weeks | — |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DU-176b Low Dose 30mg DU-176b tablets taken once daily for 12 weeks | 131 |
| DU-176b Intermediate Dose 45mg DU-176b tablets taken once daily for 12 weeks | 134 |
| DU-176b High Dose 60mg DU-176b tablets taken once daily for 12 weeks | 131 |
| Warfarin Warfarin potassium tablets taken once daily for 12 weeks while adjusting dose | 129 |
| Total | 525 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 | 2 | 1 |
| Overall Study | Death | 0 | 0 | 1 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 5 | 7 | 8 | 1 |
| Overall Study | Pregnancy | 0 | 0 | 0 | 2 |
| Overall Study | Protocol Violation | 2 | 1 | 0 | 0 |
| Overall Study | withdrew before treatment started | 5 | 1 | 2 | 9 |
Baseline characteristics
| Characteristic | Warfarin | Total | DU-176b Low Dose 30mg | DU-176b Intermediate Dose 45mg | DU-176b High Dose 60mg |
|---|---|---|---|---|---|
| Age, Continuous | 68.8 years STANDARD_DEVIATION 8.2 | 69.0 years STANDARD_DEVIATION 8.2 | 69.4 years STANDARD_DEVIATION 7.5 | 69.5 years STANDARD_DEVIATION 8.8 | 68.4 years STANDARD_DEVIATION 8.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 129 Participants | 525 Participants | 131 Participants | 134 Participants | 131 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 129 participants | 525 participants | 131 participants | 134 participants | 131 participants |
| Sex: Female, Male Female | 22 Participants | 92 Participants | 21 Participants | 25 Participants | 24 Participants |
| Sex: Female, Male Male | 107 Participants | 433 Participants | 110 Participants | 109 Participants | 107 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 | 85 / 130 | 103 / 134 | 103 / 130 | 88 / 125 |
| serious Total, serious adverse events | 4 / 130 | 2 / 134 | 2 / 130 | 7 / 125 |
Outcome results
Primary
Incidence of Bleeding Events (Major Bleeding, Clinically Relevant Non-major Bleeding and Minor Bleeding ) Identified During the Period From the Entry Into the Treatment Period Until Completion or Termination of the Treatment.
The primary endpoint was the incidence of bleeding events (major bleeding, clinically relevant non-major bleeding, or minor bleeding) that occurred during the treatment period.
Time frame: 12 weeks
Population: Primary endpoint analyzed for subjects who proceeded to treatment period in FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DU-176b Low Dose 30mg | Incidence of Bleeding Events (Major Bleeding, Clinically Relevant Non-major Bleeding and Minor Bleeding ) Identified During the Period From the Entry Into the Treatment Period Until Completion or Termination of the Treatment. | 18.5 percent of subjects with bleeding event |
| DU-176b Intermediate Dose 45mg | Incidence of Bleeding Events (Major Bleeding, Clinically Relevant Non-major Bleeding and Minor Bleeding ) Identified During the Period From the Entry Into the Treatment Period Until Completion or Termination of the Treatment. | 22.4 percent of subjects with bleeding event |
| DU-176b High Dose 60mg | Incidence of Bleeding Events (Major Bleeding, Clinically Relevant Non-major Bleeding and Minor Bleeding ) Identified During the Period From the Entry Into the Treatment Period Until Completion or Termination of the Treatment. | 27.7 percent of subjects with bleeding event |
| Warfarin | Incidence of Bleeding Events (Major Bleeding, Clinically Relevant Non-major Bleeding and Minor Bleeding ) Identified During the Period From the Entry Into the Treatment Period Until Completion or Termination of the Treatment. | 20.0 percent of subjects with bleeding event |
Comparison: For the incidence of bleeding events, paired comparison between the DU-176b groups was performed using the χ2 test.p-value: 0.429Chi-squared
p-value: 0.077Chi-squared
95% CI: [-11.2, 8.1]Wilcoxon (Mann-Whitney)
p-value: 0.32Chi-squared
95% CI: [-7.6, 12.3]Wilcoxon (Mann-Whitney)
95% CI: [-2.7, 18.1]Wilcoxon (Mann-Whitney)
Secondary
Incidence of Adverse Events and Adverse Reactions Identified During the Period From the Entry to the Treatment Period Until Completion or Termination of the Treatment
Time frame: 12 weeks
Secondary
Incidence of Thromboembolic Events (Cerebral Infarction and Systemic Embolism) Identified During the Period From the Entry to the Treatment Period Until Completion or Termination of the Treatment.
Time frame: 12 weeks
Secondary
Pharmacodynamic Biomarkers (F1+2, TAT, and D-dimer )
Time frame: 12 weeks
Secondary
Pharmacodynamic Parameters (PT, PT-INR, and APTT)
PT - prothrombin time INR - International Normalized Ratio APTT - Activated Partial Thromboplastin time
Time frame: 12 weeks
Secondary
Plasma DU-176 Concentration
Time frame: 12 weeks