Study of an Investigational Drug for the Prevention of Thrombosis-related Events Following Knee Replacement Surgery (ADVANCE-2)

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)

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.

Study Overview

• Status: Completed
• Conditions: Deep Vein Thrombosis; Pulmonary Embolism
• Intervention / Treatment: Drug: Apixaban; Drug: Enoxaparin-matching placebo; Drug: Enoxaparin; Drug: Apixaban-matching placebo

• Study Type: Interventional
• Enrollment (Actual): 3221
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Local Institution
  • Innsbruck, Austria, 6020
    • Local Institution
  • Linz, Austria, 4010
    • Local Institution
  • Wels, Austria, 4600
    • Local Institution
  • Wien, Austria, 1090
    • Local Institution
  • Wien, Austria, 1130
    • Local Institution
  • Wiener Neustadt, Austria, 2700
    • Local Institution
• Belgium
  • Antwerpen, Belgium, 2020
    • Local Institution
  • Hasselt, Belgium, 3500
    • Local Institution
• Brazil
  • Sao Paulo, Brazil, 04023
    • Local Institution
  • Minas Gerais
    • Belo Horizonte - Mg, Minas Gerais, Brazil, 30130
      • Local Institution
• Chile
  • Metropolitana
    • Santiago, Metropolitana, Chile, 7500922
      • Local Institution
    • Santiago, Metropolitana, Chile, 8330033
      • Local Institution
• China
  • Beijing
    • Beijing, Beijing, China, 100035
      • Local Institution
    • Beijing, Beijing, China, 100835
      • Local Institution
  • Shandong
    • Qingdao, Shandong, China, 266003
      • Local Institution
  • Shanghai
    • Shanghai, Shanghai, China, 200025
      • Local Institution
    • Shanghai, Shanghai, China, 200011
      • Local Institution
    • Shanghai, Shanghai, China, 200233
      • Local Institution
• Colombia
  • Bogota, Colombia
    • Local Institution
  • Bogota, Colombia, XXXXX
    • Local Institution
  • Cali, Colombia, - - - - -
    • Local Institution
  • Medelin, Colombia
    • Local Institution
• Czech Republic
  • Brno, Czech Republic, 662 50
    • Local Institution
  • Chomutov, Czech Republic, 430 12
    • Local Institution
  • Pardubice, Czech Republic, 532 03
    • Local Institution
  • Prague 8, Czech Republic, 180 81
    • Local Institution
  • Uherske Hradiste, Czech Republic, 686 68
    • Local Institution
• Denmark
  • Hellerup, Denmark, 2900
    • Local Institution
  • Hvidovre, Denmark, 2650
    • Local Institution
  • Kolding, Denmark, 6000
    • Local Institution
  • Viborg, Denmark, 8800
    • Local Institution
• France
  • Monaco, France, 98000
    • Local Institution
  • Nice, France, 06200
    • Local Institution
  • Paris, France, 75014
    • Local Institution
  • Paris, France, 75019
    • Local Institution
  • Paris, France, 75679
    • Local Institution
  • Saint-Saulve, France, 59880
    • Local Institution
• Germany
  • Bad Mergentheim, Germany, 97980
    • Local Institution
  • Bochum, Germany, 44791
    • Local Institution
  • Brandenburg, Germany, 14770
    • Local Institution
  • Dresden, Germany, 01307
    • Local Institution
  • Frankfurt, Germany, 65929
    • Local Institution
  • Frankfurt Am Main, Germany, 60528
    • Local Institution
  • Halle/S, Germany, 06112
    • Local Institution
  • Kremmen Ot Sommerfeld, Germany, 16766
    • Local Institution
  • Rheinfelden, Germany, 79618
    • Local Institution
  • Witten, Germany, 58455
    • Local Institution
• Hungary
  • Szeged, Hungary, 6725
    • Local Institution
  • Szekszard, Hungary, 7100
    • Local Institution
• India
  • Bangalore, India, 560034
    • Local Institution
  • Baroda, India, 390007
    • Local Institution
  • Mangalore, India, 575001
    • Local Institution
  • Gujarat
    • Ahmedabad, Gujarat, India, 380054
      • Local Institution
  • Punjab
    • Ludhiana, Punjab, India, 141001
      • Local Institution
• Israel
  • Jeruselem, Israel, 91031
    • Local Institution
  • Petach-Tikva, Israel, 49372
    • Local Institution
  • Safed, Israel, 13110
    • Local Institution
  • Tel Aviv, Israel, 64239
    • Local Institution
  • Tel Hashomer, Israel, 52621
    • Local Institution
• Italy
  • Abano Terme (Pd), Italy, 35031
    • Local Institution
  • Bologna, Italy, 40136
    • Local Institution
  • Pordenone, Italy, 33170
    • Local Institution
  • Roma, Italy, 00168
    • Local Institution
  • San Donato Milanese (Mi), Italy, 20097
    • Local Institution
• Korea, Republic of
  • Jeonnam, Korea, Republic of, 519-809
    • Local Institution
  • Seoul, Korea, Republic of, 110-744
    • Local Institution
  • Seoul, Korea, Republic of, 138-736
    • Local Institution
  • Seoul, Korea, Republic of, 136-705
    • Local Institution
• Malaysia
  • Kuala Lumpur, Malaysia, 50586
    • Local Institution
  • Kuala Lumpur, Malaysia, 56000
    • Local Institution
• Mexico
  • Aguascalientes, Mexico, 20010
    • Local Institution
  • San Luis Potosi, Mexico, 78340
    • Local Institution
  • Veracruz, Mexico, 91700
    • Local Institution
  • Jalisco
    • Zapopan, Jalisco, Mexico, 45200
      • Local Institution
  • Sonora
    • Hermosillo, Sonora, Mexico, 83190
      • Local Institution
• Norway
  • Alesund, Norway, 6026
    • Local Institution
  • Gjettum, Norway, 1346
    • Local Institution
  • Kongsvinger, Norway, 2212
    • Local Institution
• Philippines
  • Manila, Philippines, 1000
    • Local Institution
  • Quezon City, Philippines, 1102
    • Local Institution
  • Quezon City, Philippines, 1114
    • Local Institution
• Poland
  • Bytom, Poland, 41-902
    • Local Institution
  • Gdansk, Poland, 80-803
    • Local Institution
  • Warszawa, Poland, 03-242
    • Local Institution
  • Wroclaw, Poland, 50-556
    • Local Institution
• Russian Federation
  • Chelyabinsk, Russian Federation, 454021
    • Local Institution
  • Kazan, Russian Federation, 420029
    • Local Institution
  • Lipetsk, Russian Federation, 398035
    • Local Institution
  • Moscow, Russian Federation, 115522
    • Local Institution
  • Rostov-Na-Donu, Russian Federation, 344010
    • Local Institution
  • Saint Petersburg, Russian Federation, 199106
    • Local Institution
  • Saint Petersburg, Russian Federation, 193312
    • Local Institution
  • Saint Petersburg, Russian Federation, 194354
    • Local Institution
  • Saint Petersburg, Russian Federation, 195427
    • Local Institution
  • Samara, Russian Federation, 443095
    • Local Institution
• Singapore
  • Singapore, Singapore, 529889
    • Local Institution
  • Singapore, Singapore, 169608
    • Local Institution
• South Africa
  • Free State
    • Randburg, Free State, South Africa, 2194
      • Local Institution
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2193
      • Local Institution
    • Johannesburg, Gauteng, South Africa, 2031
      • Local Institution
    • Pretoria, Gauteng, South Africa, 0083
      • Local Institution
  • Western Cape
    • Somerset West, Western Cape, South Africa, 7130
      • Local Institution
    • Tygerberg, Western Cape, South Africa, 7505
      • Local Institution
    • Worcester, Western Cape, South Africa, 6850
      • Local Institution
• Spain
  • Badalona-Barcelona, Spain, 08916
    • Local Institution
  • Barcelona, Spain, 08035
    • Local Institution
  • Barcelona, Spain, 08006
    • Local Institution
  • Barcelona, Spain, 08024
    • Local Institution
  • Madrid, Spain, 28034
    • Local Institution
  • Santiago De Compostela, Spain, 15706
    • Local Institution
  • Valencia, Spain, 46010
    • Local Institution
• Sweden
  • Boras, Sweden, 501 82
    • Local Institution
• Ukraine
  • Cherkassy, Ukraine, 18009
    • Local Institution
  • Chernivtsy, Ukraine, 58013
    • Local Institution
  • Dnipropetrovsk, Ukraine, 49005
    • Local Institution
  • Ivano-Frankivsk, Ukraine, 76008
    • Local Institution
  • Kyiv, Ukraine, 01601
    • Local Institution
  • Kyiv, Ukraine, 04107
    • Local Institution
  • Sevastopol, Ukraine, 99018
    • Local Institution
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, SE5 9PJ
      • Local Institution
  • Surrey
    • Epsom, Surrey, United Kingdom, KT18 7EG
      • Local Institution

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Apixaban, 2.5 mg BID + Placebo; 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; 2.5 mg, administered twice daily as tablets, for 12 days; Other Names: BMS-562247; Drug: Enoxaparin-matching placebo; Administered once daily by subcutaneous injection
Active Comparator: Enoxaparin, 40 mg QD + Placebo; 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; 40 mg, administered once daily by subcutaneous injection, for 12 days; Other Names: Lovenox®; Drug: Apixaban-matching placebo; Oral tablet administered twice daily

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of Laboratory Marked Abnormalities on Hematology and Liver and Kidney Function Test Results During the Treatment Period (Patients With Available Measurements)	preRX=pretreatment; LLN=lower limit of normal; ULN=upper limit of normal; abs=absolute. Hemoglobin (g/dL): >2 decrease from preRx value or value <=8; hematocrit (%): <0.75*preRx; platelets: <100*10^9 cells/L; erythrocytes (*10^6 cells/μL): <0.75*preRx; leukocytes: <0.75*LLN or >1.25*ULN, or if preRx <LLN, use <0.8*preRx or >ULN if preRx >ULN use >1.2*preRx or <LLN; abs basophils: >400/mm^3; abs eosinophils: > 0.750*10^3 cells/µL; abs lymphocytes: <0.750*10*3 cells/ µL or >7.50*10^3 c/ µL; abs monocytes > 2000/mm^3; abs neutrophils: <1.0*10^3 cells/μL; ALP (U/L): >2*ULN; ALT, AST (U/L): >3*ULN; U/L; bilirubin, direct (mg/dL): >1.5*ULN; bilirubin, total (mg/dL): >2*ULN; BUN (mg/dL): >2*ULN; creatinine (mg/dL): >1.5*ULN.	Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (±5 days) of follow-up
Summary of Laboratory Marked Abnormalities in Electrolyte and Other Clinical Test Results During the Treatment Period (Patients With Available Measurements)	preRX=pretreatment; LLN=lower limit of normal; ULN=upper limit of normal. Calcium, total (mg/dL): <0.8*LLN or >1.2*ULN, or if preRx<LLN use <0.75*preRx or >ULN if preRx >ULN use >1.25*preRx or <LLN; chloride, serum (mEq/L): <0.9*LLN or >1.1*ULN, or if preRx<LLN use <0.9*preRx or >ULN if preRx>ULN use >1.1*preRx or <LLN; bicarbonate (mEq/L): <0.75*LLN or >1.25*ULN, or if preRx < LLN use <0.75*preRx or >ULN if preRx >ULN use >1.25*preRx or < LLN; potassium, serum (mEq/L): <0.9* LLN or >1.1*ULN, or if preRx<LLN use <0.9 *preRx or >ULN if preRx>ULN use >1.1*preRx or <LLN; sodium, serum (mEq/L): <0.95*LLN or >1.05*ULN, or if preRx <LLN use <0.95*preRx or >ULN if preRx>ULN use >1.05*preRx or <LLN; protein, total (g/dL): <0.9*LLN or >1.1*ULN, or if preRx <LLN use 0.9*preRx or >ULN if preRx >ULN use 1.1*preRx or <LLN; CK (U/L): >5*ULN; uric acid (mg/dL): >1.5*ULN, or if preRx >ULN use >2*preRx; glucose, fasting serum (mg/dL): <0.8*LLN or >1.5*ULN, or if preRx <LLN use <0.8*preRx or >ULN.	Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (±5 days) of follow-up
Summary of Laboratory Marked Abnormalities in Urinalysis Results During the Treatment Period-Treated Subjects With Available Measurements (Urinalysis)	preRX=pretreatment. Blood, urine: If missing preRx use ≥2, or if value ≥4, or if preRx=0 or 0.5 use ≥2, or if preRx=1 use ≥3, or if preRx=2 or 3 use ≥4; glucose, urine: If missing preRx use ≥2, or if value ≥4, or if preRx=0 or 0.5 use ≥2, or if preRx=1 use ≥3, or if preRx=2 or 3 use ≥4; protein, urine: If missing preRx use ≥ 2, or if value ≥4, or if preRx=0 or 0.5 use ≥2, or if preRx=1 use ≥3, or if preRx=2 or 3 use ≥4; Red blood cells , urine: If missing preRx use ≥2, or if value ≥4, or if preRx=0 or 0.5 use ≥2, or if preRx=1 use ≥3, or if preRx=2 or 3 use ≥4; white blood cells, urine: If missing preRx use ≥2, or if value ≥4, or if preRx=0 or 0.5 use ≥2, or if preRx=1 use ≥3, or if preRx=2 or 3 use ≥4.	Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (± 5 days) of follow-up

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Jamieson MJ, Byon W, Dettloff RW, Crawford M, Gargalovic PS, Merali SJ, Onorato J, Quintero AJ, Russ C. Apixaban Use in Obese Patients: A Review of the Pharmacokinetic, Interventional, and Observational Study Data. Am J Cardiovasc Drugs. 2022 Nov;22(6):615-631. doi: 10.1007/s40256-022-00524-x. Epub 2022 May 16.
• Pineo GF, Gallus AS, Raskob GE, Chen D, Ramirez LM, Ramacciotti E, Lassen MR, Wang L. Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups. J Thromb Haemost. 2013 Mar;11(3):444-51. doi: 10.1111/jth.12109.
• Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. doi: 10.1016/S0140-6736(09)62125-5.

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): January 1, 2009
• Study Completion (Actual): January 1, 2009

Study Registration Dates

• First Submitted: March 23, 2007
• First Submitted That Met QC Criteria: March 26, 2007
• First Posted (Estimate): March 27, 2007

Study Record Updates

• Last Update Posted (Estimate): July 9, 2014
• Last Update Submitted That Met QC Criteria: July 8, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: Prevention of deep vein thrombosis and pulmonary embolism after total knee replacement surgery
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Thrombosis; Venous Thrombosis; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban; Enoxaparin; Enoxaparin sodium
• Other Study ID Numbers: CV185-047; EUdraCT: 2006-006896-19