Study of an Investigational Drug for the Prevention of Thrombosis-related Events Following Knee Replacement Surgery

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to learn whether apixaban prevents the development of blood clots in the leg (deep vein thrombosis) and lung (pulmonary embolism), which sometimes occur after knee replacement surgery, and to compare the efficacy of apixaban with that of enoxaparin (Lovenox®) in the prevention of these clots. The safety of apixaban will also be studied.

Official Title
-----------------
A Phase 3, Randomized, Double-blind, Active-controlled (Enoxaparin 40 mg QD), Parallel-group, Multi-center Study to Evaluate the Safety and Efficacy of Apixaban in Subjects Undergoing Elective Total Knee Replacement Surgery (The ADVANCE - 2 Study)

Conditions
-----------------
Deep Vein Thrombosis, Pulmonary Embolism

Intervention / Treatment
-----------------
* Drug: Enoxaparin
* Drug: Apixaban
* Drug: Enoxaparin-matching placebo
* Drug: Apixaban-matching placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria Patients scheduled for either elective unilateral or same-day bilateral total knee replacement surgery (TKR) or a revision of at least 1 component of a TKR Patients willing and able to undergo bilateral ascending contrast venography Key Exclusion Criteria Known or suspected hereditary or acquired bleeding or coagulation disorders in the participant or his or her first-degree relative Known or suspected history of heparin-induced thrombocytopenia Known coagulopathy Active bleeding or at high risk for bleeding Brain, spinal, ophthalmologic, or major surgery or trauma within the past 90 days Active hepatobiliary disease Alcohol and/or substance abuse within the past year Any condition for which, in the opinion of the investigator, surgery or administration of an anticoagulant was contraindicated Two consecutive blood pressure readings within 15 to 30 minutes with supine systolic blood pressure >180 mm Hg or supine diastolic blood pressure >105 mm Hg Clinically significant laboratory abnormalities at the enrollment visit: Hemoglobin <10 g/dL Platelet count <100,000/mm^3 Creatinine clearance <30 mL/min, as estimated by the method of Cockcroft and Gault Alanine aminotransferase or aspartate aminotransferase level >2*upper limit of normal (ULN) or a total bilirubin ≥1.5*ULN (unless an alternative causative factor such as Gilbert's syndrome was identified)

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

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apixaban, 2.5 mg BID + Placebo<br>Participants received apixaban, 2.5-mg tablets twice daily (BID), plus a matching enoxaparin-placebo injection 12 (±3) hours prior to hip-replacement surgery through 11 (±2) days after the day of surgery. | Drug: Apixaban<br>* 2.5 mg, administered twice daily as tablets, for 12 days<br>* Other names: BMS-562247;Drug: Enoxaparin-matching placebo<br>* Administered once daily by subcutaneous injection<br>|
| Active Comparator: Enoxaparin, 40 mg QD + Placebo<br>Participants received enoxaparin, 40-mg subcutaneous injection once daily (QD), plus a matching apixaban-placebo tablet 12 (±3) hours prior to hip-replacement surgery through 11 (±2) days after the day of surgery. | Drug: Enoxaparin<br>* 40 mg, administered once daily by subcutaneous injection, for 12 days<br>* Other names: Lovenox®;Drug: Apixaban-matching placebo<br>* Oral tablet administered twice daily<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Adjudicated Venous Thromboembolic Event-related and All-cause Deaths With Onset During the Intended-treatment Period | Event rate=Number of events divided by the number of patients evaluated. Intended treatment period starts on the day of randomization, and for those who received study drug, ends at the later of 2 days after last dose or 14 days after the first dose of study drug; for randomized patients who did not receive study drug, the period ends 14 days after randomization.Venous thromboembolic event (VTE)=nonfatal pulmonary embolism (PE), symptomatic deep vein thrombosis (DVT), or asymptomatic proximal DVT detected by ultrasound. VTE-related death=fatal PE or sudden death for which VTE could not be excluded as a cause. | Day of randomization to later of 2 days after last dose or 14 days after first dose; 14 days after randomization for those who did not receive study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Adjudicated Proximal Deep Vein Thrombosis (DVT), Nonfatal Pulmonary Embolism, and Venous Thromboembolic Event-related Death With Onset During the Intended Treatment Period | Event rate=Number of events divided by the number of patients evaluated. Intended treatment period starts on the day of randomization, and for those who received study drug, ends at the later of 2 days after last dose or 14 days after the first dose of study drug; for randomized patients who did not receive study drug, the period ends 14 days after randomization; for randomized patients who did not receive study drug, the period ends 14 days after randomization. Venous thromboembolic event (VTE)=nonfatal pulmonary embolism (PE), symptomatic DVT, or asymptomatic proximal DVT detected by ultrasound. VTE-related death=fatal PE or sudden death for which VTE could not be excluded as a cause. | Day of randomization to later of 2 days after last dose or 14 days after first dose; 14 days after randomization for those who did not receive study | 
| Rate of Major Bleeding, Clinically Relevant Nonmajor Bleeding (CRNM), and Major Bleeding or CRNM | Event rate=Number of events divided by number of patients evaluated. Adjusted difference of event rates takes into consideration type of surgery as a stratification factor. Bleeding Criteria: Major bleeding=an event consisting of clinically overt bleeding accompanied by a decrease in hemoglobin of 2 g/dL or more and/or a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least 1 of the following critical sites: intracranial, intraspinal, intraocular (within the corpus of the eye; a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, and retroperitoneal; bleeding that was fatal. CRNM bleeding= clinically overt bleeding; that satisfies none of the additional criteria required for the event to be adjudicated as a major bleeding event; that led to either hospital admission for bleeding, physician-guided medical or surgical treatment for bleeding; or a change in antithrombic treatment. | Days 1 to 12 | 
| Number of Participants With Serious Adverse Events (SAE), Bleeding Adverse Events (AEs), Discontinuations Due to AEs, and Death as Outcome | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Bleeding AEs=all serious or nonserious bleeding-related AEs. | Days 1 through 12 + 2 days (nonserious AEs, bleeding AES) or 30 days (SAES, deaths) after last dose of study drug | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Prevention of deep vein thrombosis and pulmonary embolism after total knee replacement surgery