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

NCT00452530 | Completed Phase 3 Results DMC

• 2 other identifiers: CV185-047EUdraCT: 2006-006896-19
• Study Type: interventional
• Target: 3,221
• Locations: 27 countries
• Sites: 122

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.

Conditions

Deep Vein Thrombosis; Pulmonary Embolism

Keywords

Prevention of deep vein thrombosis and pulmonary embolism after total knee replacement surgery

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Rate of Adjudicated Proximal Deep Vein Thrombosis (DVT), Nonfatal Pulmonary Embolism, and Venous Thromboembolic Event-related Death With Onset During the Intended Treatment Period

  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

  Days 1 to 12

• Number of Participants With Serious Adverse Events (SAE), Bleeding Adverse Events (AEs), Discontinuations Due to AEs, and Death as Outcome

  Days 1 through 12 + 2 days (nonserious AEs, bleeding AES) or 30 days (SAES, deaths) after last dose of study drug

Other Outcomes (3)

• Summary of Laboratory Marked Abnormalities on Hematology and Liver and Kidney Function Test Results During the Treatment Period (Patients With Available Measurements)

  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)

  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)

  Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (± 5 days) of follow-up

Study Arms (2)

Apixaban, 2.5 mg BID + Placebo

EXPERIMENTAL

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; Drug: Enoxaparin-matching placebo

Enoxaparin, 40 mg QD + Placebo

ACTIVE COMPARATOR

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; Drug: Apixaban-matching placebo

Interventions

Enoxaparin DRUG

40 mg, administered once daily by subcutaneous injection, for 12 days

Also known as: Lovenox®

Enoxaparin, 40 mg QD + Placebo

Apixaban DRUG

2.5 mg, administered twice daily as tablets, for 12 days

Also known as: BMS-562247

Apixaban, 2.5 mg BID + Placebo

Enoxaparin-matching placebo DRUG

Administered once daily by subcutaneous injection

Apixaban, 2.5 mg BID + Placebo

Apixaban-matching placebo DRUG

Oral tablet administered twice daily

Enoxaparin, 40 mg QD + Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Bristol-Myers Squibb: lead

Study Sites (122)

Local Institution

Graz, 8036, Austria

Location

Local Institution

Innsbruck, 6020, Austria

Location

Local Institution

Linz, 4010, Austria

Location

Local Institution

Vienna, 1090, Austria

Location

Local Institution

Vienna, 1130, Austria

Location

Local Institution

Wels, 4600, Austria

Location

Local Institution

Wiener Neustadt, 2700, Austria

Location

Local Institution

Antwerp, 2020, Belgium

Location

Local Institution

Hasselt, 3500, Belgium

Location

Local Institution

Belo Horizonte - Mg, Minas Gerais, 30130, Brazil

Location

Local Institution

São Paulo, São Paulo, 04023, Brazil

Location

Local Institution

Santiago, Santiago Metropolitan, 7500922, Chile

Location

Local Institution

Santiago, Santiago Metropolitan, 8330033, Chile

Location

Local Institution

Beijing, Beijing Municipality, 100035, China

Location

Local Institution

Beijing, Beijing Municipality, 100835, China

Location

Local Institution

Qingdao, Shandong, 266003, China

Location

Local Institution

Shanghai, Shanghai Municipality, 200011, China

Location

Local Institution

Shanghai, Shanghai Municipality, 200025, China

Location

Local Institution

Shanghai, Shanghai Municipality, 200233, China

Location

Local Institution

Bogotá, XXXXX, Colombia

Location

Local Institution

Bogotá, Colombia

Location

Local Institution

Cali, Colombia

Location

Local Institution

Medellín, Colombia

Location

Local Institution

Brno, 662 50, Czechia

Location

Local Institution

Chomutov, 430 12, Czechia

Location

Local Institution

Pardubice, 532 03, Czechia

Location

Local Institution

Prague, 180 81, Czechia

Location

Local Institution

Uherské Hradiště, 686 68, Czechia

Location

Local Institution

Hellerup, 2900, Denmark

Location

Local Institution

Hvidovre, 2650, Denmark

Location

Local Institution

Kolding, 6000, Denmark

Location

Local Institution

Viborg, 8800, Denmark

Location

Local Institution

Monaco, 98000, France

Location

Local Institution

Nice, 06200, France

Location

Local Institution

Paris, 75014, France

Location

Local Institution

Paris, 75019, France

Location

Local Institution

Paris, 75679, France

Location

Local Institution

Saint-Saulve, 59880, France

Location

Local Institution

Bad Mergentheim, 97980, Germany

Location

Local Institution

Bochum, 44791, Germany

Location

Local Institution

Brandenburg, 14770, Germany

Location

Local Institution

Dresden, 01307, Germany

Location

Local Institution

Frankfurt, 65929, Germany

Location

Local Institution

Frankfurt am Main, 60528, Germany

Location

Local Institution

Halle/S, 06112, Germany

Location

Local Institution

Kremmen Ot Sommerfeld, 16766, Germany

Location

Local Institution

Rheinfelden, 79618, Germany

Location

Local Institution

Witten, 58455, Germany

Location

Local Institution

Szeged, 6725, Hungary

Location

Local Institution

Szekszárd, 7100, Hungary

Location

Local Institution

Ahmedabad, Gujarat, 380054, India

Location

Local Institution

Ludhiana, Punjab, 141001, India

Location

Local Institution

Bangalore, 560034, India

Location

Local Institution

Baroda, 390007, India

Location

Local Institution

Mangalore, 575001, India

Location

Local Institution

Jeruselem, 91031, Israel

Location

Local Institution

Petah Tikva, 49372, Israel

Location

Local Institution

Safed, 13110, Israel

Location

Local Institution

Tel Aviv, 64239, Israel

Location

Local Institution

Tel Litwinsky, 52621, Israel

Location

Local Institution

Abano Terme (Pd), 35031, Italy

Location

Local Institution

Bologna, 40136, Italy

Location

Local Institution

Pordenone, 33170, Italy

Location

Local Institution

Roma, 00168, Italy

Location

Local Institution

San Donato Milanese (Mi), 20097, Italy

Location

Local Institution

Kuala Lumpur, Kuala Lumpur, 50586, Malaysia

Location

Local Institution

Kuala Lumpur, Kuala Lumpur, 56000, Malaysia

Location

Local Institution

Aguascalientes, Aguascalientes, 20010, Mexico

Location

Local Institution

Zapopan, Jalisco, 45200, Mexico

Location

Local Institution

San Luis Potosí City, San Luis Potosí, 78340, Mexico

Location

Local Institution

Hermosillo, Sonora, 83190, Mexico

Location

Local Institution

Veracruz, Veracruz, 91700, Mexico

Location

Local Institution

Ålesund, 6026, Norway

Location

Local Institution

Gjettum, 1346, Norway

Location

Local Institution

Kongsvinger, 2212, Norway

Location

Local Institution

Manila, 1000, Philippines

Location

Local Institution

Quezon City, 1102, Philippines

Location

Local Institution

Quezon City, 1114, Philippines

Location

Local Institution

Bytom, 41-902, Poland

Location

Local Institution

Gdansk, 80-803, Poland

Location

Local Institution

Warsaw, 03-242, Poland

Location

Local Institution

Wroclaw, 50-556, Poland

Location

Local Institution

Chelyabinsk, 454021, Russia

Location

Local Institution

Kazan', 420029, Russia

Location

Local Institution

Lipetsk, 398035, Russia

Location

Local Institution

Moscow, 115522, Russia

Location

Local Institution

Rostov-on-Don, 344010, Russia

Location

Local Institution

Saint Petersburg, 193312, Russia

Location

Local Institution

Saint Petersburg, 194354, Russia

Location

Local Institution

Saint Petersburg, 195427, Russia

Location

Local Institution

Saint Petersburg, 199106, Russia

Location

Local Institution

Samara, 443095, Russia

Location

Local Institution

Singapore, 169608, Singapore

Location

Local Institution

Singapore, 529889, Singapore

Location

Local Institution

Randburg, Free State, 2194, South Africa

Location

Local Institution

Johannesburg, Gauteng, 2031, South Africa

Location

Local Institution

Johannesburg, Gauteng, 2193, South Africa

Location

Local Institution

Pretoria, Gauteng, 0083, South Africa

Location

Local Institution

Somerset West, Western Cape, 7130, South Africa

Location

Local Institution

Tygerberg, Western Cape, 7505, South Africa

Location

Local Institution

Worcester, Western Cape, 6850, South Africa

Location

Local Institution

Jeonnam, 519-809, South Korea

Location

Local Institution

Seoul, 110-744, South Korea

Location

Local Institution

Seoul, 136-705, South Korea

Location

Local Institution

Seoul, 138-736, South Korea

Location

Local Institution

Badalona-Barcelona, 08916, Spain

Location

Local Institution

Barcelona, 08006, Spain

Location

Local Institution

Barcelona, 08024, Spain

Location

Local Institution

Barcelona, 08035, Spain

Location

Local Institution

Madrid, 28034, Spain

Location

Local Institution

Santiago de Compostela, 15706, Spain

Location

Local Institution

Valencia, 46010, Spain

Location

Local Institution

Borås, 501 82, Sweden

Location

Local Institution

Cherkassy, 18009, Ukraine

Location

Local Institution

Chernivtsy, 58013, Ukraine

Location

Local Institution

Dnipropetrovsk, 49005, Ukraine

Location

Local Institution

Ivano-Frankivsk, 76008, Ukraine

Location

Local Institution

Kyiv, 01601, Ukraine

Location

Local Institution

Kyiv, 04107, Ukraine

Location

Local Institution

Sevastopol, 99018, Ukraine

Location

Local Institution

London, Greater London, SE5 9PJ, United Kingdom

Location

Local Institution

Epsom, Surrey, KT18 7EG, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 35570249 DERIVED

• 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.

  PMID: 23279103 DERIVED

• 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.

  PMID: 20206776 DERIVED

Related Links

• Investigator Inquiry form

MeSH Terms

Conditions

Venous Thrombosis; Pulmonary Embolism

Interventions

Enoxaparin; apixaban

Condition Hierarchy (Ancestors)

Thrombosis; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases; Embolism

Intervention Hierarchy (Ancestors)

Heparin, Low-Molecular-Weight; Heparin; Glycosaminoglycans; Polysaccharides; Carbohydrates

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 23, 2007
• First Posted: March 27, 2007
• Study Start: June 1, 2007
• Primary Completion: January 1, 2009
• Study Completion: January 1, 2009
• Last Updated: July 9, 2014
• Results First Posted: May 13, 2014

Record last verified: 2014-07

Locations

CO (4); BE (2); DK (4); DE (10); IN (5); IL (5); NO (3); ZA (7); UA (7); BR (2); SE (1); PL (4); ES (7); SG (2); GB (2); FR (6); HU (2); PH (3); KR (4); ME (5); MY (2); RU (10); IT (5); CZ (5); CL (2); CN (6); AU (7)