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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00742859
First Posted: August 28, 2008
Last Update Posted: October 26, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Portola Pharmaceuticals
  Purpose
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.

Condition Intervention Phase
Atrial Fibrillation Drug: betrixaban Drug: Warfarin Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by Portola Pharmaceuticals:

Primary Outcome Measures:
  • Exposure-adjusted Incidence Rate of Major or Clinically Relevant Non-major Bleeding Episode [ Time Frame: 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 Outcome Measures:
  • Exposure-adjusted Incidence Rate of Any Bleeding (Major, Clinically Relevant Non-major, or Minimal) [ Time Frame: 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.


Enrollment: 508
Study Start Date: October 2008
Study Completion Date: November 2009
Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1: Betrixaban
Betrixaban, 40 mg, orally, once daily for at least 3 months.
Drug: betrixaban
orally, once daily for at least 3 months
Experimental: Arm 2: Betrixaban
Betrixaban, 60 mg, orally, once daily for at least 3 months
Drug: betrixaban
orally, once daily for at least 3 months
Experimental: Arm 3: Betrixaban
Betrixaban, 80 mg, orally, once daily for at least 3 months
Drug: betrixaban
orally, once daily for at least 3 months
Active Comparator: Arm 4: Warfarin
Warfarin will be prescribed by investigators according to the standard of care.
Drug: Warfarin
Warfarin will be prescribed by the investigator according to the standard of care.
Other Names:
  • Coumadin
  • Acenocoumarol

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.

  Eligibility

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00742859


Locations
United States, California
Portola Investigational Site
Anaheim, California, United States, 92801
United States, Colorado
Portola Investigational Site
Colorado Springs, Colorado, United States, 80909
United States, Florida
Portola Investigational Site
Melbourne, Florida, United States, 32901
Portola Investigational Site
Miami, Florida, United States, 33173
Portola Investigational Site
Ormond Beach, Florida, United States, 32174
Portola Investigational Site
Pensacola, Florida, United States, 32501
Portola Investigational Site
Port Charlotte, Florida, United States, 33952
United States, Illinois
Portola Investigational Site
Aurora, Illinois, United States, 60504
United States, Maine
Portola Investigational Site
Auburn, Maine, United States, 04210
United States, Maryland
Portola Investigational Site
Columbia, Maryland, United States, 21044
Portola Investigational Site
Salisbury, Maryland, United States, 21804
Portola Investigational Site
Towson, Maryland, United States, 21204
United States, Mississippi
Portola Investigational Site
Tupelo, Mississippi, United States, 38801
United States, Missouri
Portola Investigational Site
Saint Louis, Missouri, United States, 63110
United States, New York
Portola Investigational Site
Poughkeepsie, New York, United States, 12601
United States, Oregon
Portola Investigational Site
Hillsboro, Oregon, United States, 97123
United States, Pennsylvania
Portola Investigational Site
Wynnewood, Pennsylvania, United States, 19096
United States, South Dakota
Portola Investigational Site
Rapid City, South Dakota, United States, 57701
United States, Virginia
Portola Investigational Site
Norfolk, Virginia, United States, 23507
Canada, Quebec
Portola Investigational Site
Longueuil, Quebec, Canada
Portola Investigational Site
Montreal, Quebec, Canada
Sponsors and Collaborators
Portola Pharmaceuticals
Investigators
Study Chair: Stuart Connolly, MD, FRCP Population Health Research Institute, McMaster University
Study Director: Rafael Diaz, MD Instituto Cardiovascular de Rosario, Argentina
Study Director: Paul Dorian, MD University of Toronto, Canada
Study Director: Michael Ezekowitz, MD, PhD, Lankenau Institute for Medical Research and The Heart Center, United States
Study Director: Stefan H. Hohnloser, MD Johann Wolgang Goethe University, Frankfurt, Germany
  More Information

Responsible Party: Portola Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00742859     History of Changes
Other Study ID Numbers: 08-015
First Submitted: August 26, 2008
First Posted: August 28, 2008
Results First Submitted: July 20, 2017
Results First Posted: September 26, 2017
Last Update Posted: October 26, 2017
Last Verified: July 2017

Keywords provided by Portola Pharmaceuticals:
Atrial Fibrillation
Betrixaban
Factor Xa inhibitor
Warfarin

Additional relevant MeSH terms:
Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Betrixaban
Warfarin
Acenocoumarol
Factor Xa Inhibitors
Anticoagulants
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action