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

NCT ID: NCT00742859

Last Updated: 2023-08-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 508 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-10-31
• Study Completion Date: 2009-11-30

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.

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.

Conditions

Atrial Fibrillation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Arm 1: Betrixaban

Betrixaban, 40 mg, orally, once daily for at least 3 months.

Group Type: EXPERIMENTAL

betrixaban

Intervention Type: DRUG

orally, once daily for at least 3 months

Arm 2: Betrixaban

Betrixaban, 60 mg, orally, once daily for at least 3 months

Group Type: EXPERIMENTAL

betrixaban

Intervention Type: DRUG

orally, once daily for at least 3 months

Arm 3: Betrixaban

Betrixaban, 80 mg, orally, once daily for at least 3 months

Group Type: EXPERIMENTAL

betrixaban

Intervention Type: DRUG

orally, once daily for at least 3 months

Arm 4: Warfarin

Warfarin will be prescribed by investigators according to the standard of care.

Group Type: ACTIVE_COMPARATOR

Warfarin

Intervention Type: DRUG

Warfarin will be prescribed by the investigator according to the standard of care.

Interventions

betrixaban

orally, once daily for at least 3 months

Intervention Type: DRUG

Warfarin

Warfarin will be prescribed by the investigator according to the standard of care.

Intervention Type: DRUG

Other Intervention Names

Coumadin; Acenocoumarol

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Portola Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stuart Connolly, MD, FRCP

Role: STUDY_CHAIR

Population Health Research Institute, McMaster University

Rafael Diaz, MD

Role: STUDY_DIRECTOR

Instituto Cardiovascular de Rosario, Argentina

Paul Dorian, MD

Role: STUDY_DIRECTOR

University of Toronto, Canada

Michael Ezekowitz, MD, PhD,

Role: STUDY_DIRECTOR

Lankenau Institute for Medical Research and The Heart Center, United States

Stefan H. Hohnloser, MD

Role: STUDY_DIRECTOR

Johann Wolgang Goethe University, Frankfurt, Germany

Locations

Portola Investigational Site

Anaheim, California, United States

Portola Investigational Site

Colorado Springs, Colorado, United States

Portola Investigational Site

Melbourne, Florida, United States

Portola Investigational Site

Miami, Florida, United States

Portola Investigational Site

Ormond Beach, Florida, United States

Portola Investigational Site

Pensacola, Florida, United States

Portola Investigational Site

Port Charlotte, Florida, United States

Portola Investigational Site

Aurora, Illinois, United States

Portola Investigational Site

Auburn, Maine, United States

Portola Investigational Site

Columbia, Maryland, United States

Portola Investigational Site

Salisbury, Maryland, United States

Portola Investigational Site

Towson, Maryland, United States

Portola Investigational Site

Tupelo, Mississippi, United States

Portola Investigational Site

St Louis, Missouri, United States

Portola Investigational Site

Poughkeepsie, New York, United States

Portola Investigational Site

Hillsboro, Oregon, United States

Portola Investigational Site

Wynnewood, Pennsylvania, United States

Portola Investigational Site

Rapid City, South Dakota, United States

Portola Investigational Site

Norfolk, Virginia, United States

Portola Investigational Site

Longueuil, Quebec, Canada

Portola Investigational Site

Montreal, Quebec, Canada

Countries

United States; Canada

Other Identifiers

08-015

Identifier Type: -

Identifier Source: org_study_id