Atrial Fibrillation
Conditions
Keywords
Atrial Fibrillation, Betrixaban, Factor Xa inhibitor, Warfarin
Brief summary
Prevention of stroke in patients with atrial fibrillation (AF). Hypothesis: In patients with non-valvular AF, orally administered betrixaban will provide similar or better efficacy and safety than warfarin and it will offer the advantage of not requiring dose adjustments due to international normalized ratios (INRs) outside the target range of 2.0 to 3.0 and a more consistent level of anticoagulation over time.
Detailed description
To assess the safety and tolerability of betrixaban at doses of 40 mg, 60 mg and 80 mg given orally once a day for at least 3 months compared to dose-adjusted warfarin in patients with non-valvular atrial fibrillation (AF). This is a Phase 2, exploratory, randomized, parallel group, multicenter, active comparator, dose finding study of patients with documented non-valvular AF. Patients will be randomized (1:1:1:1) to 1 of 4 treatment groups (approximately 125 patients per group) using an interactive voice response system (IVRS). A dynamic randomization will be used to balance patients by country, concurrent aspirin use (yes or no) and antecedent warfarin (yes or no). The study will be open label for randomization to warfarin versus betrixaban, but the three daily doses of betrixaban, 40 mg, 60 mg or 80 mg, will be double-blind (identical capsules for all three dose levels). The warfarin-treated patients will be managed according to each center's usual clinical routine with INR monitoring and dose-adjustments in order to maintain a target INR of 2.0 to 3.0 at maximum intervals of four weeks. No loading doses or dose titrations will be used for betrixaban. The betrixaban dose should be ingested in the evening (e.g. at bedtime), preferably at least 2 hours after the evening meal. Note: acenocumerol may be substituted for warfarin as indicated by local practice.
Interventions
DRUGbetrixaban
orally, once daily for at least 3 months
DRUGWarfarin
Warfarin will be prescribed by the investigator according to the standard of care.
Sponsors
Portola Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, age ≥18 years. * If the patient is a woman, she must be without reproductive potential (i.e., postmenopausal for ≥2 years or after hysterectomy). * AF at the time of enrollment (randomization) or documented within the last year by Holter, ECG, rhythm strip, pacemaker or other intracardiac recording, resulting in an indication for anticoagulation with warfarin, acenocumerol, phenprocoumon, or other Vitamin K antagonist in the opinion of the treating physician. * One or more of the following risk factor(s) for stroke: 1. Age 75 years or older. 2. Prior stroke, TIA or systemic (i.e., central nervous system) embolus at least 30 days remote from the time of screening. 3. Symptomatic congestive heart failure within 3 months echocardiography, radionuclide study or contrast angiography. 4. Hypertension requiring pharmacological treatment. 5. Diabetes. 6. Age of 55 years or older and previous coronary artery disease or known peripheral artery disease.
Exclusion criteria
* Body weight less than 40 kg (88 lbs). * Need for either hemodialysis or peritoneal dialysis (or likely to require it within one year). * AF due to reversible causes (e.g., thyrotoxicosis, pericarditis, cardiac surgery, pulmonary embolism). * Mechanical prosthetic valve (bioprosthetic valve is allowed) or valvular disease likely to be operated on within one year. * History (including family history) or symptoms of a congenital or acquired bleeding disorder or vascular malformation; or a history of intracranial, retroperitoneal, or intraocular bleeding within the last 6 months; or is felt to be at high risk for bleeding for other reasons including from significant liver disease. This also includes gastrointestinal bleeding within 90 days before randomization or endoscopically verified ulcer disease within 30 days of screening. * Conditions other than AF that require chronic anticoagulation (e.g. prosthetic mechanical heart valve). * Persistent, uncontrolled hypertension (SBP \>160 mm Hg on repeated measurements). * Active infective endocarditis. * Scheduled major surgery. * Planned pulmonary vein ablation or surgical procedure for cure of AF or flutter. * Recent ischemic stroke, systemic embolic event or acute coronary syndrome within 30 days. * Severe co-morbid condition with life expectancy of ≤1 year. * Previous known history of genetic coagulopathy (e.g., Factor V Leiden, Protein C Deficiency, Protein S Deficiency, Antiphospholipid Syndrome, etc.). * Evidence at Screening of: 1. Platelet count \<100,000/mm3. 2. Serum alanine aminotransferase (ALT) or aspirate aminotransferase (AST) \>2 times upper limit of normal (ULN). 3. A history (including family history) of Long QT Syndrome. * Aspirin \>162 mg daily. * Use of verapamil (pending the availability of a drug interaction study with betrixaban). * Active alcohol or drug abuse, or psychosocial reasons that make study participation impractical. * Use of an investigational drug or device within the past 30 days. * Inability to comply with INR monitoring or other protocol-related activities. * Unable to give written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Exposure-adjusted Incidence Rate of Major or Clinically Relevant Non-major Bleeding Episode | A maximum of 1 year | The primary endpoint is the time to the first occurrence of major or clinically relevant non-major bleeding. This was presented as the exposure adjusted incidence rate which was calculated as number of subjects experiencing the event divided by total person years across all subjects, where if a patient experiencing the event, year was from first dose date to the first occurrence of the event, and to last study date if not. The confidence interval was calculated via the exact Poisson distribution. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Exposure-adjusted Incidence Rate of Any Bleeding (Major, Clinically Relevant Non-major, or Minimal) | A maximum of 1 year | The time to the first occurrence of any bleeding event. This was presented as the exposure adjusted incidence rate which was calculated as number of subjects experiencing the event divided by total person years across all subjects, where if a patient experiencing the event, year was from first dose date to the first occurrence of the event, and to last study date if not. The confidence interval was calculated via the exact Poisson distribution. |
Countries
Canada, United States
Participant flow
Recruitment details
Between 31 October 2008 and 05 November 2009, 508 patients were enrolled by 35 study centers in 3 countries (USA, Canada, Germany). Patients were randomized to 1 of 4 treatment groups (1:1:1:1 allocation). The study was open-label for warfarin, while the 3 daily doses of betrixaban (40, 60, or 80 mg) were double-blinded.
Pre-assignment details
561 patients were screened for study participation. Of these patients, 508 were randomized, all of whom received at least 1 dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Betrixaban 40 mg Betrixaban 40 mg once daily for at least 3 months and no longer than approximately 11 months | 127 |
| Betrixaban 60 mg Betrixaban 60 mg once daily for at least 3 months and no longer than approximately 11 months | 127 |
| Betrixaban 80 mg Betrixaban 80 mg once daily for at least 3 months and no longer than approximately 11 months | 127 |
| Warfarin Dose-adjusted warfarin to maintain an INR of 2.0 to 3.0 with INR measured at maximum intervals of 4 weeks. Treatment duration was at least 3 months and no longer than approximately 11 months | 127 |
| Total | 508 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 6 | 3 | 1 |
| Overall Study | Amendment 2 patient off study drug >4wks | 0 | 1 | 1 | 0 |
| Overall Study | Death | 1 | 0 | 0 | 1 |
| Overall Study | Endpoint | 0 | 1 | 1 | 2 |
| Overall Study | Physician Decision | 1 | 2 | 0 | 0 |
| Overall Study | Site error | 0 | 0 | 1 | 1 |
| Overall Study | Sponsor request patient out of town | 0 | 0 | 1 | 1 |
| Overall Study | Sponsor req visit schedule noncompliance | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 2 | 4 | 1 |
Baseline characteristics
| Characteristic | Betrixaban 40 mg | Betrixaban 60 mg | Betrixaban 80 mg | Warfarin | Total |
|---|---|---|---|---|---|
| Age, Continuous | 73.3 years STANDARD_DEVIATION 8.5 | 73.8 years STANDARD_DEVIATION 8.35 | 72.0 years STANDARD_DEVIATION 7.65 | 72.7 years STANDARD_DEVIATION 8.75 | 73.0 years STANDARD_DEVIATION 8.32 |
| Age, Customized <75 years | 64 Count of Participants | 61 Count of Participants | 76 Count of Participants | 67 Count of Participants | 268 Count of Participants |
| Age, Customized >=75 years | 63 Count of Participants | 66 Count of Participants | 51 Count of Participants | 60 Count of Participants | 240 Count of Participants |
| Sex: Female, Male Female | 48 Participants | 46 Participants | 38 Participants | 38 Participants | 170 Participants |
| Sex: Female, Male Male | 79 Participants | 81 Participants | 89 Participants | 89 Participants | 338 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 | 61 / 127 | 68 / 127 | 53 / 127 | 50 / 127 |
| other Total, other adverse events | 61 / 127 | 68 / 127 | 53 / 127 | 50 / 127 |
| serious Total, serious adverse events | 12 / 127 | 12 / 127 | 11 / 127 | 12 / 127 |
Outcome results
Primary
Exposure-adjusted Incidence Rate of Major or Clinically Relevant Non-major Bleeding Episode
The primary endpoint is the time to the first occurrence of major or clinically relevant non-major bleeding. This was presented as the exposure adjusted incidence rate which was calculated as number of subjects experiencing the event divided by total person years across all subjects, where if a patient experiencing the event, year was from first dose date to the first occurrence of the event, and to last study date if not. The confidence interval was calculated via the exact Poisson distribution.
Time frame: A maximum of 1 year
Population: All randomized patients who took at least 1 dose of study medication after randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Betrixaban 40 mg | Exposure-adjusted Incidence Rate of Major or Clinically Relevant Non-major Bleeding Episode | 2.02 Number of Patients per 100 Patient years |
| Betrixaban 60 mg | Exposure-adjusted Incidence Rate of Major or Clinically Relevant Non-major Bleeding Episode | 10.1 Number of Patients per 100 Patient years |
| Betrixaban 80 mg | Exposure-adjusted Incidence Rate of Major or Clinically Relevant Non-major Bleeding Episode | 10.5 Number of Patients per 100 Patient years |
| Warfarin | Exposure-adjusted Incidence Rate of Major or Clinically Relevant Non-major Bleeding Episode | 14.6 Number of Patients per 100 Patient years |
Comparison: Betrixaban 40mg compared to Warfarinp-value: 0.03595% CI: [0.017, 1.14]Log Rank
Comparison: Betrixaban 60mg compared to Warfarinp-value: 0.54695% CI: [0.225, 2.24]Log Rank
Comparison: Betrixaban 80mg compared to Warfarinp-value: 0.71295% CI: [0.239, 2.39]Log Rank
Secondary
Exposure-adjusted Incidence Rate of Any Bleeding (Major, Clinically Relevant Non-major, or Minimal)
The time to the first occurrence of any bleeding event. This was presented as the exposure adjusted incidence rate which was calculated as number of subjects experiencing the event divided by total person years across all subjects, where if a patient experiencing the event, year was from first dose date to the first occurrence of the event, and to last study date if not. The confidence interval was calculated via the exact Poisson distribution.
Time frame: A maximum of 1 year
Population: All randomized patients who took at least 1 dose of study medication after randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Betrixaban 40 mg | Exposure-adjusted Incidence Rate of Any Bleeding (Major, Clinically Relevant Non-major, or Minimal) | 50.5 Number of Patients per 100 Patient years |
| Betrixaban 60 mg | Exposure-adjusted Incidence Rate of Any Bleeding (Major, Clinically Relevant Non-major, or Minimal) | 77.9 Number of Patients per 100 Patient years |
| Betrixaban 80 mg | Exposure-adjusted Incidence Rate of Any Bleeding (Major, Clinically Relevant Non-major, or Minimal) | 56.0 Number of Patients per 100 Patient years |
| Warfarin | Exposure-adjusted Incidence Rate of Any Bleeding (Major, Clinically Relevant Non-major, or Minimal) | 103 Number of Patients per 100 Patient years |
Comparison: Betrixaban 40mg compared to Warfarinp-value: 0.01195% CI: [0.301, 0.856]Log Rank
Comparison: Betrixaban 60mg compared to Warfarinp-value: 0.30895% CI: [0.481, 1.22]Log Rank
Comparison: Betrixaban 80mg compared to Warfarinp-value: 0.02295% CI: [0.332, 0.914]Log Rank