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

Pulmonary Embolism Clinical Trial

— ADVANCE-2  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00452530
• Other study ID #: CV185-047
• Secondary ID: EUdraCT: 2006-00
• Status: Completed
• Phase: Phase 3
• First received: March 23, 2007
• Last updated: July 8, 2014
• Start date: June 2007
• Est. completion date: January 2009

Study information

• Verified date: July 2014
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3221
• Est. completion date: January 2009
• Est. primary completion date: January 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Deep Vein Thrombosis
• Embolism
• Pulmonary Embolism
• Thrombosis
• Venous Thrombosis

Intervention

Drug:
• Enoxaparin
40 mg, administered once daily by subcutaneous injection, for 12 days
• Apixaban
2.5 mg, administered twice daily as tablets, for 12 days
• Enoxaparin-matching placebo
Administered once daily by subcutaneous injection
• Apixaban-matching placebo
Oral tablet administered twice daily

Locations

Country	Name	City	State
Austria	Local Institution	Graz
Austria	Local Institution	Innsbruck
Austria	Local Institution	Linz
Austria	Local Institution	Wels
Austria	Local Institution	Wien
Austria	Local Institution	Wien
Austria	Local Institution	Wiener Neustadt
Belgium	Local Institution	Antwerpen
Belgium	Local Institution	Hasselt
Brazil	Local Institution	Belo Horizonte - Mg	Minas Gerais
Brazil	Local Institution	Sao Paulo
Chile	Local Institution	Santiago	Metropolitana
Chile	Local Institution	Santiago	Metropolitana
China	Local Institution	Beijing	Beijing
China	Local Institution	Beijing	Beijing
China	Local Institution	Qingdao	Shandong
China	Local Institution	Shanghai	Shanghai
China	Local Institution	Shanghai	Shanghai
China	Local Institution	Shanghai	Shanghai
Colombia	Local Institution	Bogota
Colombia	Local Institution	Bogota
Colombia	Local Institution	Cali
Colombia	Local Institution	Medelin
Czech Republic	Local Institution	Brno
Czech Republic	Local Institution	Chomutov
Czech Republic	Local Institution	Pardubice
Czech Republic	Local Institution	Prague 8
Czech Republic	Local Institution	Uherske Hradiste
Denmark	Local Institution	Hellerup
Denmark	Local Institution	Hvidovre
Denmark	Local Institution	Kolding
Denmark	Local Institution	Viborg
France	Local Institution	Monaco
France	Local Institution	Nice
France	Local Institution	Paris
France	Local Institution	Paris
France	Local Institution	Paris
France	Local Institution	Saint-Saulve
Germany	Local Institution	Bad Mergentheim
Germany	Local Institution	Bochum
Germany	Local Institution	Brandenburg
Germany	Local Institution	Dresden
Germany	Local Institution	Frankfurt
Germany	Local Institution	Frankfurt Am Main
Germany	Local Institution	Halle/S
Germany	Local Institution	Kremmen Ot Sommerfeld
Germany	Local Institution	Rheinfelden
Germany	Local Institution	Witten
Hungary	Local Institution	Szeged
Hungary	Local Institution	Szekszard
India	Local Institution	Ahmedabad	Gujarat
India	Local Institution	Bangalore
India	Local Institution	Baroda
India	Local Institution	Ludhiana	Punjab
India	Local Institution	Mangalore
Israel	Local Institution	Jeruselem
Israel	Local Institution	Petach-Tikva
Israel	Local Institution	Safed
Israel	Local Institution	Tel Aviv
Israel	Local Institution	Tel Hashomer
Italy	Local Institution	Abano Terme (Pd)
Italy	Local Institution	Bologna
Italy	Local Institution	Pordenone
Italy	Local Institution	Roma
Italy	Local Institution	San Donato Milanese (Mi)
Korea, Republic of	Local Institution	Jeonnam
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Malaysia	Local Institution	Kuala Lumpur
Malaysia	Local Institution	Kuala Lumpur
Mexico	Local Institution	Aguascalientes
Mexico	Local Institution	Hermosillo	Sonora
Mexico	Local Institution	San Luis Potosi
Mexico	Local Institution	Veracruz
Mexico	Local Institution	Zapopan	Jalisco
Norway	Local Institution	Alesund
Norway	Local Institution	Gjettum
Norway	Local Institution	Kongsvinger
Philippines	Local Institution	Manila
Philippines	Local Institution	Quezon City
Philippines	Local Institution	Quezon City
Poland	Local Institution	Bytom
Poland	Local Institution	Gdansk
Poland	Local Institution	Warszawa
Poland	Local Institution	Wroclaw
Russian Federation	Local Institution	Chelyabinsk
Russian Federation	Local Institution	Kazan
Russian Federation	Local Institution	Lipetsk
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Rostov-Na-Donu
Russian Federation	Local Institution	Saint Petersburg
Russian Federation	Local Institution	Saint Petersburg
Russian Federation	Local Institution	Saint Petersburg
Russian Federation	Local Institution	Saint Petersburg
Russian Federation	Local Institution	Samara
Singapore	Local Institution	Singapore
Singapore	Local Institution	Singapore
South Africa	Local Institution	Johannesburg	Gauteng
South Africa	Local Institution	Johannesburg	Gauteng
South Africa	Local Institution	Pretoria	Gauteng
South Africa	Local Institution	Randburg	Free State
South Africa	Local Institution	Somerset West	Western Cape
South Africa	Local Institution	Tygerberg	Western Cape
South Africa	Local Institution	Worcester	Western Cape
Spain	Local Institution	Badalona-Barcelona
Spain	Local Institution	Barcelona
Spain	Local Institution	Barcelona
Spain	Local Institution	Barcelona
Spain	Local Institution	Madrid
Spain	Local Institution	Santiago De Compostela
Spain	Local Institution	Valencia
Sweden	Local Institution	Boras
Ukraine	Local Institution	Cherkassy
Ukraine	Local Institution	Chernivtsy
Ukraine	Local Institution	Dnipropetrovsk
Ukraine	Local Institution	Ivano-Frankivsk
Ukraine	Local Institution	Kyiv
Ukraine	Local Institution	Kyiv
Ukraine	Local Institution	Sevastopol
United Kingdom	Local Institution	Epsom	Surrey
United Kingdom	Local Institution	London	Greater London

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

Austria,  Belgium,  Brazil,  Chile,  China,  Colombia,  Czech Republic,  Denmark,  France,  Germany,  Hungary,  India,  Israel,  Italy,  Korea, Republic of,  Malaysia,  Mexico,  Norway,  Philippines,  Poland,  Russian Federation,  Singapore,  South Africa,  Spain,  Sweden,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (±5 days) of follow-up	Yes
Other	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	Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (±5 days) of follow-up	Yes
Other	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	Yes
Primary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	Yes

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm
•   Investigator Inquiry form