Phase 2 Study of the Safety, Tolerability and Pilot Efficacy of Oral Factor Xa Inhibitor Betrixaban Compared to Warfarin

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2, Randomized, Parallel Group, Dose-Finding, Multicenter, Multinational Study of the Safety, Tolerability and Pilot Efficacy of Three Blinded Doses of the Oral Factor Xa Inhibitor Betrixaban Compared With Open-Label Dose-Adjusted Warfarin in Patients With Non-Valvular Atrial Fibrillation (EXPLORE Xa)

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: betrixaban
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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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: Age 75 years or older. Prior stroke, TIA or systemic (i.e., central nervous system) embolus at least 30 days remote from the time of screening. Symptomatic congestive heart failure within 3 months echocardiography, radionuclide study or contrast angiography. Hypertension requiring pharmacological treatment. Diabetes. 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: Platelet count <100,000/mm3. Serum alanine aminotransferase (ALT) or aspirate aminotransferase (AST) >2 times upper limit of normal (ULN). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Betrixaban<br>Betrixaban, 40 mg, orally, once daily for at least 3 months. | Drug: betrixaban<br>* orally, once daily for at least 3 months<br>|
| Experimental: Arm 2: Betrixaban<br>Betrixaban, 60 mg, orally, once daily for at least 3 months | Drug: betrixaban<br>* orally, once daily for at least 3 months<br>|
| Experimental: Arm 3: Betrixaban<br>Betrixaban, 80 mg, orally, once daily for at least 3 months | Drug: betrixaban<br>* orally, once daily for at least 3 months<br>|
| Active Comparator: Arm 4: Warfarin<br>Warfarin will be prescribed by investigators according to the standard of care. | Drug: Warfarin<br>* Warfarin will be prescribed by the investigator according to the standard of care.<br>* Other names: Acenocoumarol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | A maximum of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | A maximum of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial Fibrillation, Betrixaban, Factor Xa inhibitor, Warfarin