Clinical trial NCT00452530: Study of an Investigational Drug for the Prevention of Thrombosis-related Events Following Knee Replacement Surgery
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Deep Vein Thrombosis
Pulmonary Embolism
Keywords: Prevention of deep vein thrombosis and pulmonary embolism after total knee replacement surgery
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2007-03-27
Enrollment: 3221
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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)

Primary outcomes:
measure: Rate of Adjudicated Venous Thromboembolic Event-related and All-cause Deaths With Onset During the Intended-treatment Period
timeFrame: 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:
measure: Rate of Adjudicated Proximal Deep Vein Thrombosis (DVT), Nonfatal Pulmonary Embolism, and Venous Thromboembolic Event-related Death With Onset During the Intended Treatment Period
timeFrame: 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
measure: Rate of Major Bleeding, Clinically Relevant Nonmajor Bleeding (CRNM), and Major Bleeding or CRNM
timeFrame: Days 1 to 12
measure: Number of Participants With Serious Adverse Events (SAE), Bleeding Adverse Events (AEs), Discontinuations Due to AEs, and Death as Outcome
timeFrame: Days 1 through 12 + 2 days (nonserious AEs, bleeding AES) or 30 days (SAES, deaths) after last dose of study drug
Other outcomes:
measure: Summary of Laboratory Marked Abnormalities on Hematology and Liver and Kidney Function Test Results During the Treatment Period (Patients With Available Measurements)
timeFrame: Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (±5 days) of follow-up
measure: Summary of Laboratory Marked Abnormalities in Electrolyte and Other Clinical Test Results During the Treatment Period (Patients With Available Measurements)
timeFrame: Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (±5 days) of follow-up
measure: Summary of Laboratory Marked Abnormalities in Urinalysis Results During the Treatment Period-Treated Subjects With Available Measurements (Urinalysis)
timeFrame: Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (± 5 days) of follow-up
Locations:
city: Graz
country: Austria
facility: Local Institution
city: Innsbruck
country: Austria
facility: Local Institution
city: Linz
country: Austria
facility: Local Institution
city: Wels
country: Austria
facility: Local Institution
city: Wiener Neustadt
country: Austria
facility: Local Institution
city: Wien
country: Austria
facility: Local Institution
city: Wien
country: Austria
facility: Local Institution
city: Antwerpen
country: Belgium
facility: Local Institution
city: Hasselt
country: Belgium
facility: Local Institution
city: Belo Horizonte - Mg
country: Brazil
facility: Local Institution
state: Minas Gerais
city: Sao Paulo
country: Brazil
facility: Local Institution
city: Santiago
country: Chile
facility: Local Institution
state: Metropolitana
city: Santiago
country: Chile
facility: Local Institution
state: Metropolitana
city: Beijing
country: China
facility: Local Institution
state: Beijing
city: Beijing
country: China
facility: Local Institution
state: Beijing
city: Qingdao
country: China
facility: Local Institution
state: Shandong
city: Shanghai
country: China
facility: Local Institution
state: Shanghai
city: Shanghai
country: China
facility: Local Institution
state: Shanghai
city: Shanghai
country: China
facility: Local Institution
state: Shanghai
city: Bogota
country: Colombia
facility: Local Institution
city: Bogota
country: Colombia
facility: Local Institution
city: Cali
country: Colombia
facility: Local Institution
city: Medelin
country: Colombia
facility: Local Institution
city: Brno
country: Czech Republic
facility: Local Institution
city: Chomutov
country: Czech Republic
facility: Local Institution
city: Pardubice
country: Czech Republic
facility: Local Institution
city: Prague 8
country: Czech Republic
facility: Local Institution
city: Uherske Hradiste
country: Czech Republic
facility: Local Institution
city: Hellerup
country: Denmark
facility: Local Institution
city: Hvidovre
country: Denmark
facility: Local Institution
city: Kolding
country: Denmark
facility: Local Institution
city: Viborg
country: Denmark
facility: Local Institution
city: Monaco
country: France
facility: Local Institution
city: Nice
country: France
facility: Local Institution
city: Paris
country: France
facility: Local Institution
city: Paris
country: France
facility: Local Institution
city: Paris
country: France
facility: Local Institution
city: Saint-Saulve
country: France
facility: Local Institution
city: Bad Mergentheim
country: Germany
facility: Local Institution
city: Bochum
country: Germany
facility: Local Institution
city: Brandenburg
country: Germany
facility: Local Institution
city: Dresden
country: Germany
facility: Local Institution
city: Frankfurt Am Main
country: Germany
facility: Local Institution
city: Frankfurt
country: Germany
facility: Local Institution
city: Halle/S
country: Germany
facility: Local Institution
city: Kremmen Ot Sommerfeld
country: Germany
facility: Local Institution
city: Rheinfelden
country: Germany
facility: Local Institution
city: Witten
country: Germany
facility: Local Institution
city: Szeged
country: Hungary
facility: Local Institution
city: Szekszard
country: Hungary
facility: Local Institution
city: Ahmedabad
country: India
facility: Local Institution
state: Gujarat
city: Ludhiana
country: India
facility: Local Institution
state: Punjab
city: Bangalore
country: India
facility: Local Institution
city: Baroda
country: India
facility: Local Institution
city: Mangalore
country: India
facility: Local Institution
city: Jeruselem
country: Israel
facility: Local Institution
city: Petach-Tikva
country: Israel
facility: Local Institution
city: Safed
country: Israel
facility: Local Institution
city: Tel Aviv
country: Israel
facility: Local Institution
city: Tel Hashomer
country: Israel
facility: Local Institution
city: Abano Terme (Pd)
country: Italy
facility: Local Institution
city: Bologna
country: Italy
facility: Local Institution
city: Pordenone
country: Italy
facility: Local Institution
city: Roma
country: Italy
facility: Local Institution
city: San Donato Milanese (Mi)
country: Italy
facility: Local Institution
city: Jeonnam
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Kuala Lumpur
country: Malaysia
facility: Local Institution
city: Kuala Lumpur
country: Malaysia
facility: Local Institution
city: Zapopan
country: Mexico
facility: Local Institution
state: Jalisco
city: Hermosillo
country: Mexico
facility: Local Institution
state: Sonora
city: Aguascalientes
country: Mexico
facility: Local Institution
city: San Luis Potosi
country: Mexico
facility: Local Institution
city: Veracruz
country: Mexico
facility: Local Institution
city: Alesund
country: Norway
facility: Local Institution
city: Gjettum
country: Norway
facility: Local Institution
city: Kongsvinger
country: Norway
facility: Local Institution
city: Manila
country: Philippines
facility: Local Institution
city: Quezon City
country: Philippines
facility: Local Institution
city: Quezon City
country: Philippines
facility: Local Institution
city: Bytom
country: Poland
facility: Local Institution
city: Gdansk
country: Poland
facility: Local Institution
city: Warszawa
country: Poland
facility: Local Institution
city: Wroclaw
country: Poland
facility: Local Institution
city: Chelyabinsk
country: Russian Federation
facility: Local Institution
city: Kazan
country: Russian Federation
facility: Local Institution
city: Lipetsk
country: Russian Federation
facility: Local Institution
city: Moscow
country: Russian Federation
facility: Local Institution
city: Rostov-Na-Donu
country: Russian Federation
facility: Local Institution
city: Saint Petersburg
country: Russian Federation
facility: Local Institution
city: Saint Petersburg
country: Russian Federation
facility: Local Institution
city: Saint Petersburg
country: Russian Federation
facility: Local Institution
city: Saint Petersburg
country: Russian Federation
facility: Local Institution
city: Samara
country: Russian Federation
facility: Local Institution
city: Singapore
country: Singapore
facility: Local Institution
city: Singapore
country: Singapore
facility: Local Institution
city: Randburg
country: South Africa
facility: Local Institution
state: Free State
city: Johannesburg
country: South Africa
facility: Local Institution
state: Gauteng
city: Johannesburg
country: South Africa
facility: Local Institution
state: Gauteng
city: Pretoria
country: South Africa
facility: Local Institution
state: Gauteng
city: Somerset West
country: South Africa
facility: Local Institution
state: Western Cape
city: Tygerberg
country: South Africa
facility: Local Institution
state: Western Cape
city: Worcester
country: South Africa
facility: Local Institution
state: Western Cape
city: Badalona-Barcelona
country: Spain
facility: Local Institution
city: Barcelona
country: Spain
facility: Local Institution
city: Barcelona
country: Spain
facility: Local Institution
city: Barcelona
country: Spain
facility: Local Institution
city: Madrid
country: Spain
facility: Local Institution
city: Santiago De Compostela
country: Spain
facility: Local Institution
city: Valencia
country: Spain
facility: Local Institution
city: Boras
country: Sweden
facility: Local Institution
city: Cherkassy
country: Ukraine
facility: Local Institution
city: Chernivtsy
country: Ukraine
facility: Local Institution
city: Dnipropetrovsk
country: Ukraine
facility: Local Institution
city: Ivano-Frankivsk
country: Ukraine
facility: Local Institution
city: Kyiv
country: Ukraine
facility: Local Institution
city: Kyiv
country: Ukraine
facility: Local Institution
city: Sevastopol
country: Ukraine
facility: Local Institution
city: London
country: United Kingdom
facility: Local Institution
state: Greater London
city: Epsom
country: United Kingdom
facility: Local Institution
state: Surrey
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.