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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)

Primary Purpose

Atrial Fibrillation

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

betrixaban

Warfarin

About this trial

This is an interventional treatment trial for Atrial Fibrillation focused on measuring Atrial Fibrillation, Betrixaban, Factor Xa inhibitor, Warfarin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Arm Label

Arm 1: Betrixaban

Arm 2: Betrixaban

Arm 3: Betrixaban

Arm 4: Warfarin

Arm Description

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

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

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

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

Outcomes

Primary Outcome Measures

Exposure-adjusted Incidence Rate of Major or Clinically Relevant Non-major Bleeding Episode

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)

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.

Full Information

NCT ID

NCT00742859

First Posted

August 26, 2008

Last Updated

August 3, 2023

Sponsor

Portola Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT00742859

Brief Title

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

Acronym

EXPLORE-Xa

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 Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Completed

Study Start Date

October 2008 (undefined)

Primary Completion Date

August 2009 (Actual)

Study Completion Date

November 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Portola Pharmaceuticals

4. Oversight

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Atrial Fibrillation

Keywords

Atrial Fibrillation, Betrixaban, Factor Xa inhibitor, Warfarin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

508 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1: Betrixaban

Arm Type

Experimental

Arm Description

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

Arm Title

Arm 2: Betrixaban

Arm Type

Experimental

Arm Description

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

Arm Title

Arm 3: Betrixaban

Arm Type

Experimental

Arm Description

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

Arm Title

Arm 4: Warfarin

Arm Type

Active Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

betrixaban

Intervention Description

orally, once daily for at least 3 months

Intervention Type

Drug

Intervention Name(s)

Warfarin

Other Intervention Name(s)

Coumadin, Acenocoumarol

Intervention Description

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

Primary Outcome Measure Information:

Title

Exposure-adjusted Incidence Rate of Major or Clinically Relevant Non-major Bleeding Episode

Description

Time Frame

A maximum of 1 year

Secondary Outcome Measure Information:

Title

Exposure-adjusted Incidence Rate of Any Bleeding (Major, Clinically Relevant Non-major, or Minimal)

Description

Time Frame

A maximum of 1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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: Age 75 years or older. Prior stroke, TIA or systemic (i.e., central nervous system) embolus at least 30 days remote from the time of screening. Symptomatic congestive heart failure within 3 months echocardiography, radionuclide study or contrast angiography. Hypertension requiring pharmacological treatment. Diabetes. 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: Platelet count <100,000/mm3. Serum alanine aminotransferase (ALT) or aspirate aminotransferase (AST) >2 times upper limit of normal (ULN). 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.

Overall Study Officials: