A Phase III Study of Apixaban in Patients With Atrial Fibrillation

Study Overview
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Brief Summary
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The purpose of this clinical research study is to determine whether apixaban is more effective than acetylsalicylic acid in the prevention of strokes associated with patients with atrial fibrillation. The safety of this treatment will also be studied.

Detailed Description
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An optional Long-term Open-label Extension Phase of treatment with apixaban will be provided for qualifying participants following the conclusion of the double-blind phase

Official Title
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Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment: A Randomized Double-blind Trial

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: Apixaban
* Drug: Acetylsalicylic acid


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male and female Age of 50 years or older Permanent, paroxysmal, or persistent atrial fibrillation (at screening or within 6 months prior to enrollment) documented by 12-lead electrocardiogram) At least 1 of the following risk factors for stroke: Prior stroke or transient ischemic attack Age of 75 years or older Arterial hypertension on treatment Diabetes mellitus Heart failure (New York Health Authority Class 2 or greater at time of enrollment) Left ventricular ejection fraction of 35% or less, documented within 6 months of enrollment Peripheral arterial disease (previous arterial revascularization, limb or foot amputation, or current intermittent claudication with ankle-arm systolic blood pressure ratio <0.9) Not currently receiving vitamin K antagonist therapy for 1 of the following reasons: Previous vitamin K antagonist therapy demonstrated as unsuitable and discontinued Vitamin K antagonist therapy not previously used but expected unsuitable Key Exclusion Criteria: Women who are pregnant or breast feeding Women of child bearing potential who are unwilling to meet the study requirements for pregnancy testing or are unwilling or unable to use an acceptable method to avoid pregnancy Atrial fibrillation due to reversible causes, such as thyrotoxicosis or pericarditis Valvular disease requiring surgery Planned ablation procedure for atrial fibrillation to be performed within 3 months Conditions other than atrial fibrillation that require chronic anticoagulation (such as, prosthetic mechanical heart valve, venous thromboembolism) Patients with serious bleeding in the last 6 months or at high risk for bleeding, including but not limited to those with: Active peptic ulcer disease Platelet count <100,000/mm^3 or hemoglobin <10g/dL Recent stroke (within 10 days) Documented hemorrhagic tendencies or blood dyscrasias Current alcohol or drug abuse or psychosocial reasons that make study participation impractical Severe comorbid condition with life expectancy <1 year Severe renal insufficiency; any patient with a serum creatinine level >2.5 mg/dL or a calculated creatinine clearance <25 mL/min is excluded Alanine transaminase or aspartate aminotransferase levels >2 times upper limit of normal (ULN) or a total bilirubin level >1.5 times ULN (unless an alternative causative factor [such as Gilbert's syndrome] is identified) Allergy or adverse reaction to acetylsalicylic acid Required treatment with a thienopyridine (clopidogrel or ticlopidine) Prisoners or participants who are compulsory detained (involuntarily incarcerated) Use of an investigational drug or device within the past 30 days or prior randomization into an apixaban clinical study Patients who are compulsorily detained for treatment for a psychiatric or physical illness

Ages Eligible for Study
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Minimum Age: 50 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apixaban<br> | Drug: Apixaban<br>* Tablets, oral, 5 mg (2.5 mg in patients meeting any 2 of the following criteria: 80 years of age and older, weight of 60 kilograms or less, and a serum creatinine level of 1.5 mg/dL or higher), twice daily, up to 156 weeks<br>* Other names: BMS-562247;|
| Active Comparator: Acetylasalicylic acid<br> | Drug: Acetylsalicylic acid<br>* Tablets, oral, 81-324 mg, once daily, up to 156 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Rate of Stroke/Systemic Embolism During the Intended-treatment Period | Event rate=percent of participants with an event divided by the total participants in the arm. Intended-treatment period=date of randomization to the efficacy cutoff date, which was to be the date on which at least 226 unrefuted original primary efficacy events occurred (date revised to May 28, 2010 following cessation of study for superior efficacy.) | Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Rate for the Composite of Stroke of Any Type, Systemic Embolism, Myocardial Infarction, or Vascular Death During the Double-blind Treatment Period | Event rate=percent of participants with an event divided by the total participants in the arm. | Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) | 
| Event Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death | Event rate=percent of participants with an event divided by the total participants in the arm. | Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) | 
| Event Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period | Event rate=percent of participants with an event divided by the total participants in the arm. | First dose of study drug (Day 1) to the earlier of a patient's discontinuation of double-blind study drug or the attainment of at least 226 primary efficacy events up to May 28, 2010 | 
| Rate of Unrefuted Bleeding From First Dose of Double-blind Study Drug to First Occurence of Unrefuted Bleeding During the Double-blind Treatment Period | Event rate=percent of participants with an event divided by the total participants in the arm. | Day 1 to first bleeding event up to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) | 
| Number of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs), Bleeding AEs, Discontinuations Due to AEs, and Death as Outcome | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. | First dose of study drug (Day 1) to 30 days after last dose of blinded study drug | 
| Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality | BL=baseline, LLN=lower limit of normal, ULN=upper limit of normal. Hemoglobin (g/dL), low: BL>2 or value ≤8; hematocrit(%), low: <0.75*BL; erythrocytes (*10^6 cells/μL), low: <0.75*BL; platelet count (*10^9 cells/L),low: <100*10^9 cells/L; leukocytes (*10^3 cells/μL), low if <0.8*BL and BL<LLN or <LLN and BL >ULN or <0.75*LLN when BL is missing or LLN ≤BL≤ ULN, high if >1.2*BL and BL>ULN or >ULN when BL and BL<LLN or >1.25*ULN when BL is missing or LLN≤BL≤ULN; neutrophils (absolute), low: <1.0*10^3 cells/μL; eosinophils (absolute), high: >0.750*10^3 cells/μL; basophils (absolute), high: >0.4*10^3 cells/μL; monocytes (absolute), high: 2*10^3 cells/μL; lymphocytes (absolute), low if <0.75*10^3 cells/μL, high if >7.50*10^3 cells/μL; ALP (U/L), high: 2*ULN; AST (U/L), high: 3*ULN; AST (U/L), high: 3*ULN; bilirubin, total (mg/dL), high: >2*ULN; bilirubin, direct (mg/dL), high: 1.5*ULN; BUN (mg/dL), high:>2*ULN; creatinine (mg/dL), high: >1.5*ULN. | First dose of study drug (Day 1) to 30 days after last dose of blinded study drug | 
| Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued) | LLN=lower limit of normal; ULN=upper limit of normal; BL=baseline. Sodium, serum (mEq/L):low if <0.95*BL and BL<LLN or <LLN and BL>ULN or <0.95*LLN when BL missing or LLN ≤BL≤ULN, high if >1.05*BL and BL>ULN or >ULN and BL<LLN or >1.05*ULN when BL missing or LLN≤BL≤ULN; potassium(mEq/L):low if <0.90*BL and BL<LLN or <LLN and BL>ULN or <0.90*LLN if BL missing or LLN≤BL≤ULN, high if >1.10*BL and BL>ULN or>ULN and BL<LLN or >1.10*ULN when BL missing or LLN≤BL≤ULN; chloride(mEq/L):low if <0.90*BL and BL<LLN or <LLN and BL>ULN or <0.90*LLN if BL missing or LLN≤BL ≤ULN, high if >1.10*BL and BL>ULN or >ULN and BL<LLN or >1.10* ULN if BL missing or LLN≤BL≤ULN; calcium(mg/dL):low if <0.75*BL and BL<LLN or <LLN and BL>ULN or <0.80*LLN if BL missing or LLN≤BL≤ULN, high if >1.25*BL and BL>ULN or >ULN if BL<LLN or >1.20*ULN if BL missing or LLN≤BL≤ULN ; bicarbonate(mEq/L):low if <0.75*BL when BL<LLN or <LLN when BL>ULN or <0.75*LLN if BL missing or LLN≤BL≤ULN, high if >1.25*BL when BL>ULN or >ULN | First dose of study drug (Day 1) to 30 days after last dose of blinded study drug | 
| Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued) | ULN=upper limit of normal; LLN=lower limit of normal; BL=baseline. Creatine kinase (U/L), high:>5*ULN; protein, total(g/L):low if <0.90*BL when BL<LLN or <LLN when B >ULN or <0.90*LLN when BL is missing or LLN≤BL≤ULN, high if >1.10*BL if BL>ULN or >ULN when BL<LLN or >1.10*ULN if BL missing or LLN≤BL≤ULN.Protein,total(g/L): low if <0.90*BL if BL<LLN or <LLN if BL>ULN or <0.90*LLN if BL missing or LLN≤BL≤ULN, high if >1.10*BL if BL>ULN or >ULN if BL<LLN or >1.10*ULN if BL or LLN≤BL≤ULN; glucose, serum fasting (mg/dL): low if <0.8*BL if BL<LLN or <LLN when BL>ULN or <0.8*LLN when BL missing or LLN≤BL≤ULN, high if >2*BL when BL>ULN or >ULN when BL<LLN or >1.5*ULN if BL missing or LLN≤BL≤ULN; uric acid (mg/dL), high: >2*BL and BL>ULN or>1.5*ULN when BL missing or BL≤ULN; glucose, urine, high; protein, urine, high; blood, urine, high; leukocyte esterase, urine, high; RBC count, urine (Hpf), high; WBC count, urine (Hpf), high: ≥2 if BL=missing,=0 or =0.5 or if ≥3 if BL=1, or if ≥4 and BL≥2. | First dose of study drug (Day 1) to 30 days after last dose of blinded study drug |