A Phase III Study of Apixaban in Patients With Atrial Fibrillation (AVERROES)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00496769
First received: July 2, 2007
Last updated: August 19, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Atrial Fibrillation
Drug: Apixaban
Drug: Acetylsalicylic acid
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Event Rate of Stroke/Systemic Embolism During the Intended-treatment Period [ Time Frame: Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) ] [ Designated as safety issue: No ]
    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.)

  • Rate of Unrefuted Bleeding From First Dose of Double-blind Study Drug to First Occurence of Unrefuted Bleeding During the Double-blind Treatment Period [ Time Frame: Day 1 to first bleeding event up to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) ] [ Designated as safety issue: Yes ]
    Event rate=percent of participants with an event divided by the total participants in the arm.


Secondary Outcome Measures:
  • Event Rates of Major Vascular Events (Stroke/Systemic Embolism, Myocardial Infarction, Death) in the Intended-treatment Period [ Time Frame: Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) ] [ Designated as safety issue: No ]
    Event rate=percent of participants with an event divided by the total participants in the arm.

  • Event Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Event rate=percent of participants with an event divided by the total participants in the arm.

  • Number of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs), Bleeding AEs, Discontinuations Due to AEs, and Death as Outcome [ Time Frame: First dose of study drug (Day 1) to 30 days after last dose of blinded study drug ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality [ Time Frame: First dose of study drug (Day 1) to 30 days after last dose of blinded study drug ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued) [ Time Frame: First dose of study drug (Day 1) to 30 days after last dose of blinded study drug ] [ Designated as safety issue: Yes ]
    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

  • Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued) [ Time Frame: First dose of study drug (Day 1) to 30 days after last dose of blinded study drug ] [ Designated as safety issue: Yes ]
    ULN=upper limit of normal; LLN=lower limit ofnormal; 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.

  • Event Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death [ Time Frame: Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) ] [ Designated as safety issue: No ]
    Event rate=percent of participants with an event divided by the total participants in the arm.


Enrollment: 6421
Study Start Date: August 2007
Estimated Study Completion Date: December 2014
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Apixaban Drug: Apixaban
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
Other Name: BMS-562247
Active Comparator: Acetylasalicylic acid Drug: Acetylsalicylic acid
Tablets, oral, 81-324 mg, once daily, up to 156 weeks

Detailed Description:

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

  Eligibility

Ages Eligible for Study:   50 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00496769

  Show 503 Study Locations
Sponsors and Collaborators
Bristol-Myers Squibb
Pfizer
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided by Bristol-Myers Squibb

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00496769     History of Changes
Other Study ID Numbers: CV185-048
Study First Received: July 2, 2007
Results First Received: August 1, 2013
Last Updated: August 19, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Brazil: National Health Surveillance Agency
Chile: Instituto de Salud Pública de Chile
Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos
Mexico: Federal Commission for Sanitary Risks Protection
Austria: Agency for Health and Food Safety
Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment
Denmark: Danish Medicines Agency
Finland: Finnish Medicines Agency
France: Ministry of Health
Germany: Ministry of Health
Greece: National Organization of Medicines
Israel: Ministry of Health
Italy: Ministry of Health
Norway: Ministry of Health and Social Affairs
Spain: Spanish Agency of Medicines
South Africa: Department of Health
Sweden: The National Board of Health and Welfare
Turkey: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Czech Republic: Ministry of Health
Poland: Ministry of Health
Russia: Ministry of Health of the Russian Federation
Ukraine: Ministry of Health
Australia: Department of Health and Ageing Therapeutic Goods Administration
China: National Institute for the Control of Pharmaceutical and Biological Products
Hong Kong: Department of Health
India: Central Drugs Standard Control Organization
Indonesia: Ministry of Health
Korea: Food and Drug Administration
Malaysia: National Pharmaceutical Control Bureau
Philippines: Department of Health
Singapore: Ministry of Health
Taiwan: Department of Health

Additional relevant MeSH terms:
Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Aspirin
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents
Hematologic Agents
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Central Nervous System Agents

ClinicalTrials.gov processed this record on September 22, 2014