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

• ClinicalTrials.gov Identifier: NCT00742859
• Recruitment Status: Completed
• First Posted: August 28, 2008
• Results First Posted: September 26, 2017
• Last Update Posted: October 26, 2017
• Sponsor: Portola Pharmaceuticals
• Information provided by (Responsible Party): Portola Pharmaceuticals

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Atrial Fibrillation	Drug: betrixaban; Drug: Warfarin	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 508 participants
• 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)
• Study Start Date: October 2008
• Actual Primary Completion Date: August 2009
• Actual Study Completion Date: November 2009

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. 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 :

1. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• 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

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
• Other Study ID Numbers: 08-015
• First Posted: August 28, 2008
• 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; Warfarin; Acenocoumarol; Betrixaban; Anticoagulants; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action