Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00452530
First received: March 23, 2007
Last updated: July 8, 2014
Last verified: July 2014

March 23, 2007
July 8, 2014
June 2007
January 2009   (final data collection date for primary outcome measure)
Rate of Adjudicated Venous Thromboembolic Event-related and All-cause Deaths With Onset During the Intended-treatment Period [ Time Frame: 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 ] [ Designated as safety issue: No ]
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.
A combination of adjudicated asymptomatic and symptomatic DVT, non-fatal PE and all-cause death after 12 days of treatment
Complete list of historical versions of study NCT00452530 on ClinicalTrials.gov Archive Site
  • Rate of Adjudicated Proximal Deep Vein Thrombosis (DVT), Nonfatal Pulmonary Embolism, and Venous Thromboembolic Event-related Death With Onset During the Intended Treatment Period [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.
  • Rate of Major Bleeding, Clinically Relevant Nonmajor Bleeding (CRNM), and Major Bleeding or CRNM [ Time Frame: Days 1 to 12 ] [ Designated as safety issue: Yes ]
    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.
  • Number of Participants With Serious Adverse Events (SAE), Bleeding Adverse Events (AEs), Discontinuations Due to AEs, and Death as Outcome [ Time Frame: Days 1 through 12 + 2 days (nonserious AEs, bleeding AES) or 30 days (SAES, deaths) after last dose of study drug ] [ Designated as safety issue: Yes ]
    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.
A combination of adjudicated asymptomatic and symptomatic proximal DVT, non-fatal PE, & VTE-related death after 12 days of treatment
  • Summary of Laboratory Marked Abnormalities on Hematology and Liver and Kidney Function Test Results During the Treatment Period (Patients With Available Measurements) [ Time Frame: Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (±5 days) of follow-up ] [ Designated as safety issue: Yes ]
    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.
  • Summary of Laboratory Marked Abnormalities in Electrolyte and Other Clinical Test Results During the Treatment Period (Patients With Available Measurements) [ Time Frame: Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (±5 days) of follow-up ] [ Designated as safety issue: Yes ]
    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.
  • Summary of Laboratory Marked Abnormalities in Urinalysis Results During the Treatment Period-Treated Subjects With Available Measurements (Urinalysis) [ Time Frame: Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (± 5 days) of follow-up ] [ Designated as safety issue: Yes ]
    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.
Not Provided
 
Study of an Investigational Drug for the Prevention of Thrombosis-related Events Following Knee Replacement Surgery
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.

Not Provided
Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
  • Deep Vein Thrombosis
  • Pulmonary Embolism
  • Drug: Enoxaparin
    40 mg, administered once daily by subcutaneous injection, for 12 days
    Other Name: Lovenox®
  • Drug: Apixaban
    2.5 mg, administered twice daily as tablets, for 12 days
    Other Name: BMS-562247
  • Drug: Enoxaparin-matching placebo
    Administered once daily by subcutaneous injection
  • Drug: Apixaban-matching placebo
    Oral tablet administered twice daily
  • 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.
    Interventions:
    • Drug: Apixaban
    • Drug: Enoxaparin-matching placebo
  • 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.
    Interventions:
    • Drug: Enoxaparin
    • Drug: Apixaban-matching placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
3221
January 2009
January 2009   (final data collection date for primary outcome measure)

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)
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
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
 
NCT00452530
CV185-047, EUdraCT: 2006-006896-19
Yes
Bristol-Myers Squibb
Bristol-Myers Squibb
Not Provided
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
Bristol-Myers Squibb
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP