Study of an Investigational Drug for the Prevention of Thrombosis-related Events Following Hip Replacement Surgery (ADVANCE-3)
- Conditions
- Deep Vein ThrombosisPulmonary Embolism
- Interventions
- Registration Number
- NCT00423319
- Lead Sponsor
- Bristol-Myers Squibb
- Brief Summary
The purpose of this study is to learn whether apixaban can prevent the blood clots in the leg (deep vein thrombosis) and lung (pulmonary embolism) that sometimes occur after hip replacement surgery and to learn how apixaban compares with enoxaparin in preventing these clots. The safety of apixaban will also be studied
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 5407
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Apixaban, 2.5 mg BID plus placebo Apixaban Participants received apixaban, 2.5 mg twice daily (BID), as oral tablets, and matching enoxaparin-placebo injection once daily (QD) Apixaban, 2.5 mg BID plus placebo Enoxaparin-matching placebo Participants received apixaban, 2.5 mg twice daily (BID), as oral tablets, and matching enoxaparin-placebo injection once daily (QD) Enoxaparin, 40 mg QD plus placebo Enoxaparin Participants received enoxaparin, 40 mg QD subcutaneously, and matching apixaban-placebo tablets BID Enoxaparin, 40 mg QD plus placebo Apixaban-matching placebo Participants received enoxaparin, 40 mg QD subcutaneously, and matching apixaban-placebo tablets BID
- Primary Outcome Measures
Name Time Method Rate of Composite of Adjudicated Venous Thromboembolic Event (VTE)-Related (Pulmonary Embolism and Symptomatic and Asymptomatic Deep Vein Thrombosis[DVT]) and All-cause Death During the Intended Treatment Period Day 1 (first dose of study drug) to later of 2 days after last dose or 38 days after first dose Event rate=Number of events divided by the number of patients evaluated. A mandatory bilateral ascending contrast venogram was to be obtained on Day 35 (± 3). Patients with confirmed symptomatic DVT at any time, or asymptomatic DVT upon venography, were to receive treatment for DVT according to the investigator's standard of care. Signs and symptoms suggestive of VTE included, but were not limited to: 1) lower extremity DVT: erythema, warmth, pain, swelling, tenderness; and 2) PE: pleuritic chest pain, dyspnea, cough, hemoptysis, syncope, light-headedness/dizziness, tachypnea, and tachycardia. Intended Treatment Period started on day of randomization and, for patients who received treatment, ended at the later of 2 days after last dose of study drug or 38 days after the first dose (presurgery) of study drug. For randomized patients who did not receive study drug, the period ended 38 days after randomization.
- Secondary Outcome Measures
Name Time Method Rate of Major Bleeding, Clinically Relevant Nonmajor Bleeding (CRNM), Major or CRNM, and Any Bleeding During the Treatment Period First dose of study drug (presurgery) through 2 days after the last dose of study drug Event rate=Number of events divided by the number of patients evaluated. Major bleeding event defined as a bleeding event that was 1) Acute clinically overt bleeding accompanied by at least 1 of the following: decrease in hemoglobin of ≥ 2 g/dL over a 24-hour period, transfusion of ≥2 units of packed red blood cells; bleeding that occurred in at least 1 of the following sites: intracranial, intra-spinal, intraocular, pericardial, an operated joint and requires reoperation or intervention, intramuscular with compartment syndrome, or retroperitoneal; 2) Fatal. CRNM was defined as acute clinically overt bleeding that did not satisfy the criteria for a major bleeding event and met at least 1 of the following: epistaxis, gastrointestinal bleed, hematuria, bruising/ecchymosis, or hemoptysis. Minor bleeding was defined as an acute clinically overt bleeding event that did not meet the criteria for major bleeding or a CRNM. Fatal bleeding event was defined as bleeding that was the primary
Number of Participants With a Bleeding-related Adverse Events During the Treatment Period (Continued) First dose of study drug (presurgery) through 2 days after the last dose of study drug All suspected bleeding events were to be reported by the investigator as either an adverse event or serious adverse event or and adjudicated by the Independent Central Adjudication Committee (ICAC). Definitions of bleeding outcomes: Acute clinically overt bleeding =new onset, visible bleeding, or signs or symptoms suggestive of bleeding with confirmatory imaging techniques that could detect the presence of blood. All acute clinically overt bleeding events were adjudicated by the ICAC as a major bleeding event or a clinically relevant nonmajor bleeding event; suspected minor bleeding events were not sent for adjudication.
Number of Participants With Serious Adverse Events (SAEs), Bleeding Adverse Events (AEs), and Death as Outcome First dose of study drug (presurgery) through 30 days after the last dose of study drug 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. All suspected bleeding events were to be reported by the investigator as either an AE or SAE and adjudicated by the Independent Central Adjudication Committee (ICAC). Definitions of bleeding outcomes: Acute clinically overt bleeding =new onset, visible bleeding, or signs or symptoms suggestive of bleeding with confirmatory imaging techniques that could detect the presence of blood.
Number of Participants With a Bleeding-related Adverse Event During the Treatment Period (Continued) First dose of study drug (presurgery) through 2 days after the last dose of study drug All suspected bleeding events were to be reported by the investigator as either an adverse event or serious adverse event or and adjudicated by the Independent Central Adjudication Committee (ICAC). Definitions of bleeding outcomes: Acute clinically overt bleeding =new onset, visible bleeding, or signs or symptoms suggestive of bleeding with confirmatory imaging techniques that could detect the presence of blood. All acute clinically overt bleeding events were adjudicated by the ICAC as a major bleeding event or a clinically relevant nonmajor bleeding event; suspected minor bleeding events were not sent for adjudication.
Rates of Adjudicated Myocardial Infarction (MI)/Stroke, MI, Stroke, and Thrombocytopenia During the Intended Treatment Period Day 1 (first dose of study drug) to later of 2 days after last dose or 38 days after first dose Event rate=Number of events divided by the number of patients evaluated. All suspected events were reported by investigator. Acute MI=the presence of a clinical situation (eg, abnormal history, physical examination, new electrocardiogram changes) suggestive of an MI and at least 1 of the following: elevated creatine kinase (CK)-MB or troponin T or troponin I ≥2\*upper limit of normal (ULN); if CK-MB or troponin values not available, total CK ≥2\*ULN; or new significant (≥0.04 sec) Q waves in ≥2 contiguous leads. Stroke=a new focal neurologic deficit of sudden onset lasting at least 24 hours that was not due to a readily identifiable nonvascular cause. Adjudication classified each reported stroke as primary hemorrhagic, nonhemorrhagic, infarction with hemorrhagic conversion, or unknown type. Thrombocytopenia=after 3 days as drop in platelet count to \<100,000/mm\^3 for patients with a baseline value \>150,000/mm\^3 or a \>50% decline, if the baseline value was ≤150,000/mm\^3.
Number of Participants With a Bleeding-related Adverse Event During the Treatment Period First dose of study drug (presurgery) through 2 days after the last dose of study drug All suspected bleeding events were to be reported by the investigator as either an adverse event or serious adverse event or and adjudicated by the Independent Central Adjudication Committee (ICAC). Definitions of bleeding outcomes: Acute clinically overt bleeding =new onset, visible bleeding, or signs or symptoms suggestive of bleeding with confirmatory imaging techniques that could detect the presence of blood. All acute clinically overt bleeding events were adjudicated by the ICAC as a major bleeding event or a clinically relevant nonmajor bleeding event; suspected minor bleeding events were not sent for adjudication.
Rate of Composite of Adjudicated Proximal Deep Vein Thrombosis (DVT), Nonfatal Pulmonary Embolism, and Venous Thromboembolic Event-related Death With Onset During Intended Treatment Period Day 1 (first dose of study drug) to later of 2 days after last dose or 38 days after first dose Event rate=Number of events divided by the number of patients evaluated. Each patient was categorized as having no proximal DVT, having proximal DVT, being nonevaluable for proximal DVT, having no distal DVT, having distal DVT, or being nonevaluable for distal DVT. Adjudication criteria were: Normal=All deep veins were visualized, and there was no intraluminal filling defect (ILFD). ILFD=An area of reduced, or absent filling, at least partially surrounded with contrast medium in ≥ 2 projections or a lack of filling in a vessel in which there was a cut-off that had the configuration of a thrombus. Indeterminate=A lack of filling of a region of the deep vein system, proximal or distal, without the presence of an ILFD elsewhere in the same region. Not Done=A venography was not performed. Proximal DVT was found if any of the proximal veins had an ILFD. Pulmonary embolism was radiographically (angiography, V/Q scan, computed tomography) determined.
Rates of Adjudicated All-cause Death, VTE-related Death, Pulmonary Embolism (PE), Nonfatal PE, Deep Vein Thrombosis (DVT) (Symptomatic and Asymptomatic), Symptomatic and Asymptomatic Proximal and Distal DVT During the Intended Treatment Period Day 1 (first dose of study drug) to later of 2 days after last dose or 38 days after first dose VTE=venous thromboembolic event; VTE-related death=combination of fatal or nonfatal PE and symptomatic or asymptomatic DVT. Event rate=Number of events divided by the number of patients evaluated.
Number of Participants With Marked Abnormalities (MA) in Clinical Laboratory Test Results During the Treatment Period (Continued) First dose of study drug (presurgery) through 2 days after the last dose of study drug preRx=predose; LLN=lower limit of normal; ULN=upper limit of normal. Glucose, fasting (mg/dL): \<.8\*LLN or \>1.5\*ULN, or if preRx \<LLN use \<.8\*preRx or \>ULN if preRx \>ULN use \>2\*preRx or \<LLN; protein, total (g/L): If missing preRx use ≥2, or if value ≥4 or preRx =0 or .5 use ≥2, or if preRx=1 use ≥3, or if preRx =2 or 3 use ≥4; creatine kinase (U/L): \>5\*ULN; uric acid (mg/dL): \>.5\* ULN, or if preRx \>ULN use \>2\*preRx; 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 .5 use ≥2, or if preRx=1 use ≥3, or if preRx=2 or 3 use ≥4; RBC, urine (hpf): If missing preRx use ≥2, or if value ≥4, or if preRx=0 or 0.5 use ≥2, or if preRx dose= 1 use ≥3, or if preRx=2 or 3 use ≥4; WBC, urine (h): If missing preRx use ≥2, or if value ≥4, or if preRx =0 or .5 use ≥2, or if preRx =1 use ≥3, or if preRx=2 or 3 use ≥4.
Number of Participants With Adverse Events Related to Elevations in Liver Function Test Results With Onset During the Treatment Period First dose of study drug (presurgery) through 30 days after the last dose of study drug Treatment guidelines were provided for jaundice and elevated results of liver function tests.
Number of Participants With Neurologic Adverse Events With Onset During the Treatment Period First dose of study drug (presurgery) through 2 days after the last dose of study drug Neurologic events were based on Medical Dictionary for Regulatory Activities search categories.For new or worsening events that were not related to the site of surgery, additional information was collected on a specific form. In addition, neurology consultation was to be obtained for these patients.
Number of Participants With Marked Abnormalities (MA) in Clinical Laboratory Test Results During the Treatment Period First dose of study drug (presurgery) through 2 days after the last dose of study drug preRx=predose; LLN=lower limit of normal; ULN=upper limit of normal. MA criteria: Hemoglobin: \>2 g/dL decrease from preRx or value ≤ 8 g/dL; hematocrit (%): \<0.75\*preRx; platelet count (\*10\^9 cells/L): \<100,000/mm\^3; erythrocytes (\*10\^6 cells/μL): \<0.75\*preRx level; leukocytes (\*10\^3 cells/μL): \< 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; basophils (\*10\^3 cells/μL): \>400/mm\^3; eosinophils (\*10\^3 cells/μL): \> 0.75\*10\^3 cells/μL; lymphocytes (\*10\^3 cells/μL): \>0.75\*10\^3 cells/μL; monocytes (\*10\^3 cells/μL): \>2000/mm\^3; neutrophils (\*10\^3 cells/μL): \<1.0;
Trial Locations
- Locations (20)
Shrock Orthopedic Research
🇺🇸Ft. Lauderdale, Florida, United States
Orthoarkansas, P.A.
🇺🇸Little Rock, Arkansas, United States
Pab Clinical Research
🇺🇸Brandon, Florida, United States
Phoenix Clinical Research, Llc
🇺🇸Tamarac, Florida, United States
Americana Orthopedics
🇺🇸Boise, Idaho, United States
Bosie Orthopedic Clinic
🇺🇸Meridian, Idaho, United States
Local Institution
🇬🇧Epsom, Surrey, United Kingdom
University Orthopedic Center
🇺🇸Altoona, Pennsylvania, United States
Gill Orthopedic Center
🇺🇸Lubbock, Texas, United States
Martin Bowen Hefley Orthopedics
🇺🇸Little Rock, Arkansas, United States
Uc Davis Medical Center
🇺🇸Sacramento, California, United States
Robert R. King, Md
🇺🇸Lubbock, Texas, United States
Research Alliance, Inc.
🇺🇸Clearwater, Florida, United States
Atlanta Knee And Sports Medicine
🇺🇸Decatur, Georgia, United States
Colorado Orthopedic Consultants, Pc
🇺🇸Aurora, Colorado, United States
Capstone Clinical Trials, Inc
🇺🇸Birmingham, Alabama, United States
West Alabama Research, Llc
🇺🇸Birmingham, Alabama, United States
Advanced Orthopedic And Sports Medicine Specilists
🇺🇸Denver, Colorado, United States
Denver-Vail Orthopedics, P.C.
🇺🇸Denver, Colorado, United States
Unlimited Research
🇺🇸San Antonio, Texas, United States