Thromboembolism
Conditions
Keywords
Prevention of Venous Thromboembolism
Brief summary
Randomized study of PRT054021 40 mg and 15 mg bid vs. enoxaparin 30 mg q12h for the prophylaxis of venous thromboembolic events after unilateral knee replacement surgery.
Detailed description
Approximately 200 patients undergoing unilateral knee replacement will be entered into the study and randomized to receive either enoxaparin 30 mg sq bid, PRT054021 15 mg po bid, or PRT054021 40 mg po bid for 10 to 14 days, at which time patients will undergo venography.
Interventions
DRUGBetrixaban
Capsule
DRUGEnoxaparin
Administered subcutaneously
Sponsors
Portola Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* • The subject has undergone elective primary unilateral TKR (not unicompartmental). Demographic * The subject is between the ages of 18 and 75 years. * If the subject is a woman, she is without reproductive potential (postmenopausal for \>2 years or after hysterectomy). * The subject weighs between 50 kg (110 lbs) and 120 kg (265 lbs). Laboratory and Procedures * The subject is willing and able to undergo unilateral venography. Medications * The subject is willing and able to self-inject enoxaparin or receive injections q12h by a caregiver. Ethical • The subject is able to read and give written informed consent and has signed an informed consent form approved by the Investigator's IRB/IEC.
Exclusion criteria
* Disease Related * Major medical and/or surgical condition which may impair oral drug absorption or metabolism. * Immobilization for 3 or more days before surgery. * 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. * Gastrointestinal bleeding within 90 days before surgery or endoscopically verified ulcer disease within 30 days before surgery. * Indwelling intrathecal or epidural catheter during the prophylaxis period (except for epidural catheter if removed after surgery); or unusual difficulty in administering spinal or epidural anesthesia (eg, 3 or more attempts, traumatic taps). * Major surgery, ischemic stroke, or myocardial infarction within 3 months before Screening. * Uncontrolled hypertension defined as systolic blood pressure (SBP) \> 180 mmHg or diastolic blood pressure (DBP) \>105 mmHg. * Hypotension defined as SBP \<95 mmHg. * Evidence at Screening of symptomatic congestive heart failure requiring treatment. * Chronic atrial fibrillation treated with oral anticoagulants, recurrent atrial arrhythmia(s) or a history of recurrent ventricular tachycardia. Laboratory and Procedures • Evidence at Screening of: platelet count \<100,000/mm3 potassium \<3.5 mEq/L hemoglobin concentration \<10 g/dL or hematocrit \<30% serum ALT or AST \>2 times ULN serum creatinine \>2.0 mg/dL (180 µm/L) * Contraindication to venography, including to iodinated contrast medium * QTc on Screening ECG \>450 msec and/or a personal or family history of Long QT Syndrome. Medications * Contraindication to anticoagulation for VTE prophylaxis, including a contraindication to receiving heparin or heparinoids. * Administration of the following drugs within 7 days before TKR: thrombolytic agents, anticoagulants and/or anti-platelet agents (eg, heparins, warfarin, dipyridamole, sulfinpyrazone, ticlopidine, dextran, clopidogrel). Aspirin up to 325 mg once daily and NSAIDs are allowed but discouraged. * Use of class III antiarrhythmics drugs (eg, dofetilide, ibutilide, amiodarone, bretylium, sotalol) within 30 days prior to TKR. General * Participation in any investigational drug study 30 days prior to enrollment is prohibited. Participation in a device trial prior to enrollment is acceptable. * Any condition which could interfere with or for which the treatment of might interfere with the conduct of the study, or which would, in the opinion of the Investigator, unacceptably increase the risk of the subject's participation in the study. This would include, but is not limited to alcoholism, drug dependency or abuse, psychiatric disease, epilepsy or any unexplained blackouts.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adjudicated Venous Thromboembolism (VTE) | Through Day 10-14 following TKR surgery, at time of mandatory venogram | Incidence of adjudicated venous thromboembolism (VTE) through Day 10-14 following TKR where VTE is defined as DVT (proximal and/or distal) and/or PE. Patients were evaluated for VTE daily while hospitalized and were contacted every 2 to 4 days after discharge and before the day of the mandatory venogram to monitor for study endpoints |
| Incidence of Adjudicated Overt Bleeding Events: Primary Safety Endpoint | Through follow-up at approximately 6 (±2) weeks after TKR surgery | The incidence of adjudicated major and clinical relevant non-major bleeding. Major bleeding was defined as fatal, involving vital organs, requiring additional surgery or a new therapeutic procedure, or a bleeding index \>=2. Bleeding Index was defined as the number of units of packed red blood cells or whole blood transfused plus the haemoglobin values before the bleeding episode minus the haemoglobin values after the bleed had stabilized (in g/dL) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adjudicated Pulmonary Embolism (PE) and All Deep Vein Thrombosis (DVT) (Proximal and Distal) | At follow-up at approximately 6 (±2) weeks after TKR surgery | Incidence of adjudicated pulmonary embolism (PE) and all deep vein thrombosis (DVT) (proximal and distal) through the time of venography on Day 10 to 14 and at follow-up at approximately 6 (±2) weeks after TKR surgery |
Countries
Canada
Participant flow
Recruitment details
Between 10 May 2006 and 12 February 2007, 215 patients were enrolled. After undergoing unilateral total knee replacement surgery, patients were randomized to 1 of 3 treatment groups (2:2:1 allocation). The study was open-label for randomization to enoxaparin versus betrixaban, but the 15 mg versus 40 mg dose of betrixaban was double-blind.
Pre-assignment details
Patients scheduled to undergo elective primary unilateral total knee replacement (TKR) surgery were evaluated for eligibility 1 to 30 days before surgery (Screening). Consenting subjects who remained eligible for the study after TKR were randomized. 215 patients were randomized and all but 1 received at least 1 dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Betrixaban 15 mg Betrixaban 15 mg oral twice daily for 10 to 14 days | 87 |
| Betrixaban 40 mg Betrixaban 40 mg oral twice daily for 10 to 14 days | 84 |
| Enoxaparin Enoxaparin 30 mg administered subcutaneously every 12 hours for 10 to 14 days | 43 |
| Total | 214 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 | 0 |
| Overall Study | Did not receive treatment | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Neurologist Wanted Pt to start Plavix | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 4 | 0 |
Baseline characteristics
| Characteristic | Betrixaban 15 mg | Betrixaban 40 mg | Enoxaparin | Total |
|---|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 7.2 | 65.0 years STANDARD_DEVIATION 7.9 | 61.9 years STANDARD_DEVIATION 9.6 | 63.7 years STANDARD_DEVIATION 8.1 |
| Sex: Female, Male Female | 55 Participants | 52 Participants | 22 Participants | 129 Participants |
| Sex: Female, Male Male | 32 Participants | 32 Participants | 21 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 83 / 87 | 80 / 84 | 29 / 43 |
| serious Total, serious adverse events | 3 / 87 | 6 / 84 | 1 / 43 |
Outcome results
Primary
Incidence of Adjudicated Overt Bleeding Events: Primary Safety Endpoint
The incidence of adjudicated major and clinical relevant non-major bleeding. Major bleeding was defined as fatal, involving vital organs, requiring additional surgery or a new therapeutic procedure, or a bleeding index \>=2. Bleeding Index was defined as the number of units of packed red blood cells or whole blood transfused plus the haemoglobin values before the bleeding episode minus the haemoglobin values after the bleed had stabilized (in g/dL)
Time frame: Through follow-up at approximately 6 (±2) weeks after TKR surgery
Population: All randomized patients who took at least 1 dose of study medication after randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Betrixaban 15 mg | Incidence of Adjudicated Overt Bleeding Events: Primary Safety Endpoint | 0 Percentage of Participants |
| Betrixaban 40 mg | Incidence of Adjudicated Overt Bleeding Events: Primary Safety Endpoint | 2.4 Percentage of Participants |
| Enoxaparin | Incidence of Adjudicated Overt Bleeding Events: Primary Safety Endpoint | 7.0 Percentage of Participants |
Primary
Incidence of Adjudicated Venous Thromboembolism (VTE)
Incidence of adjudicated venous thromboembolism (VTE) through Day 10-14 following TKR where VTE is defined as DVT (proximal and/or distal) and/or PE. Patients were evaluated for VTE daily while hospitalized and were contacted every 2 to 4 days after discharge and before the day of the mandatory venogram to monitor for study endpoints
Time frame: Through Day 10-14 following TKR surgery, at time of mandatory venogram
Population: All randomized patients who took at least 1 dose of study medication after randomization and for whom an evaluable venogram was available
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Betrixaban 15 mg | Incidence of Adjudicated Venous Thromboembolism (VTE) | 20 Percentage of Participants |
| Betrixaban 40 mg | Incidence of Adjudicated Venous Thromboembolism (VTE) | 15.4 Percentage of Participants |
| Enoxaparin | Incidence of Adjudicated Venous Thromboembolism (VTE) | 10 Percentage of Participants |
Secondary
Incidence of Adjudicated Pulmonary Embolism (PE) and All Deep Vein Thrombosis (DVT) (Proximal and Distal)
Incidence of adjudicated pulmonary embolism (PE) and all deep vein thrombosis (DVT) (proximal and distal) through the time of venography on Day 10 to 14 and at follow-up at approximately 6 (±2) weeks after TKR surgery
Time frame: At follow-up at approximately 6 (±2) weeks after TKR surgery
Population: All randomized patients who took at least 1 dose of study medication after randomization and for whom an evaluable venogram was available
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Betrixaban 15 mg | Incidence of Adjudicated Pulmonary Embolism (PE) and All Deep Vein Thrombosis (DVT) (Proximal and Distal) | 20 Percentage of Participants |
| Betrixaban 40 mg | Incidence of Adjudicated Pulmonary Embolism (PE) and All Deep Vein Thrombosis (DVT) (Proximal and Distal) | 15.4 Percentage of Participants |
| Enoxaparin | Incidence of Adjudicated Pulmonary Embolism (PE) and All Deep Vein Thrombosis (DVT) (Proximal and Distal) | 12.5 Percentage of Participants |