Factor Xa Inhibitor, PRT054021, Against Enoxaparin for the Prevention of Venous Thromboembolic Events (EXPERT)

Study Overview
=================
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.

Official Title
-----------------
Evaluation of the Factor Xa Inhibitor, PRT054021, Against Enoxaparin in a Randomized Trial for the Prevention of Venous Thromboembolic Events After Unilateral Total Knee Replacement (EXPERT)

Conditions
-----------------
Thromboembolism

Intervention / Treatment
-----------------
* Drug: Betrixaban
* Drug: Enoxaparin


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Betrixaban 15 mg<br>Betrixaban 15 mg oral twice daily for 10 to 14 days | Drug: Betrixaban<br>* Capsule<br>|
| Experimental: Betrixaban 40 mg<br>Betrixaban 40 mg oral twice daily for 10 to 14 days | Drug: Betrixaban<br>* Capsule<br>|
| Experimental: Enoxaparin<br>Enoxaparin 30 mg administered subcutaneously every 12 hours for 10 to 14 days | Drug: Enoxaparin<br>* Administered subcutaneously<br>* Other names: Lovenox;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Through Day 10-14 following TKR surgery, at time of mandatory venogram | 
| 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) | Through follow-up at approximately 6 (±2) weeks after TKR surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | At follow-up at approximately 6 (±2) weeks after TKR surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Prevention of Venous Thromboembolism