Study of an Investigational Drug for the Prevention of Thrombosis-related Events Following Hip Replacement Surgery (ADVANCE-3)

Pulmonary Embolism Clinical Trial

Official title:

A Phase 3 Randomized, Double-blind, Active-controlled, Parallel-group, Multi-center Study to Evaluate the Safety and Efficacy of Apixaban in Subjects Undergoing Elective Total Hip Replacement Surgery (The Advance-3 Study Apixaban Dosed Orally Versus Anticoagulation With Injectable Enoxaparin to Prevent Venous Thromboembolism)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00423319
• Other study ID #: CV185-035
• Status: Completed
• Phase: Phase 3
• First received: January 17, 2007
• Last updated: April 14, 2014
• Start date: March 2007
• Est. completion date: September 2009

Study information

• Verified date: April 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 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5407
• Est. completion date: September 2009
• Est. primary completion date: September 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria

• Patients undergoing elective unilateral total hip replacement or a revision of at least 1 component of a total hip replacement.

• Patients who were willing and able to undergo bilateral ascending contrast venography

• Either sex, any race, 18 years and older

Key Exclusion Criteria

• Known or suspected bleeding or coagulation disorder in the patient 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 surgery or administration of an anticoagulant is 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 >2*upper limit of normal or a total bilirubin = 1.5*1 (unless an alternative causative factor such as Gilbert's syndrome was identified)

• Need for ongoing treatment with a parenteral or oral anticoagulant (eg, subjects with mechanical valves, warfarin eligible atrial fibrillation)

• Current use of dextrans or fibrinolytics

• Treatment with medications affecting coagulation or platelet function

Study Design

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Enoxaparin
Subcutaneous, 40 mg, once daily, 5 weeks
• Apixaban
Oral tablets, 2.5 mg, twice daily, 5weeks
• Enoxaparin-matching placebo
Administered as injection
• Apixaban-matching placebo
Administered as oral tablets

Locations

Country	Name	City	State
Argentina	Local Institution	Capital Federal	Buenos Aires
Argentina	Local Institution	Capital Federal	Buenos Aires
Argentina	Local Institution	Capital Federal	Buenos Aires
Argentina	Local Institution	Ciudad De Buenos Aires	Buenos Aires
Argentina	Local Institution	Coronel Suarez	Buenos Aires
Argentina	Local Institution	Monte Grande	Buenos Aires
Australia	Local Institution	Bedford Park	South Australia
Australia	Local Institution	Box Hill	Victoria
Australia	Local Institution	Camperdown	New South Wales
Australia	Local Institution	Kogarah	New South Wales
Australia	Local Institution	Lismore	New South Wales
Australia	Local Institution	Malvern	Victoria
Australia	Local Institution	Perth	Western Australia
Australia	Local Institution	Southport	Queensland
Australia	Local Institution	Windsor	Victoria
Belgium	Local Institution	Antwerp
Belgium	Local Institution	Brasschaat
Belgium	Local Institution	Genk
Belgium	Local Institution	Hasselt
Belgium	Local Institution	Leuven
Canada	Local Institution	Ajax	Ontario
Canada	Local Institution	Cambridge	Ontario
Canada	Local Institution	Chatham	Ontario
Canada	Local Institution	Edmonton	Alberta
Canada	Local Institution	Guelph	Ontario
Canada	Local Institution	Montreal	Quebec
Canada	Local Institution	Newmarket	Ontario
Canada	Local Institution	Oshawa	Ontario
Canada	Local Institution	Quebec
Canada	Local Institution	Sarnia	Ontario
Canada	Local Institution	Scarborough	Ontario
Canada	Local Institution	St. Catharines	Ontario
Canada	Local Institution	Stratford	Ontario
Canada	Local Institution	Waterloo	Ontario
Canada	Local Institution	Windsor	Ontario
China	Local Institution	Beijing	Beijing
China	Local Institution	Beijing	Beijing
China	Local Institution	Guangzhou	Guangdong
China	Local Institution	Qingdao	Shandong
China	Local Institution	Shanghai	Shanghai
China	Local Institution	Shanghai	Shanghai
China	Local Institution	Shanghai	Shanghai
Denmark	Local Institution	Amager
Denmark	Local Institution	Frederiksberg
Denmark	Local Institution	Herlev
Denmark	Local Institution	Horsholm
Denmark	Local Institution	Hvidovre
Denmark	Local Institution	Kobenhavn Nv
Denmark	Local Institution	Silkeborg
France	Local Institution	Nice
France	Local Institution	Paris
France	Local Institution	Paris
France	Local Institution	Paris
France	Local Institution	Saint Etienne
France	Local Institution	Saint-Saulve
Germany	Local Institution	Frankfurt
Germany	Local Institution	Frankfurt / Main
Germany	Local Institution	Rheinfelden
Hungary	Local Institution	Budapest
Hungary	Local Institution	Kecskemet
Hungary	Local Institution	Szeged
Hungary	Local Institution	Szolnok
India	Local Institution	Ahmedabad	Gujarat
India	Local Institution	Bangalore
India	Local Institution	Lucknow	Uttar Prsdesh
India	Local Institution	Ludhiana	Punjab
India	Local Institution	Mangalore
Israel	Local Institution	Beer Sheva
Israel	Local Institution	Haifa
Israel	Local Institution	Holon
Israel	Local Institution	Kfar-Saba
Israel	Local Institution	Zerifin
Mexico	Local Institution	Aguascalientes
Mexico	Local Institution	Cd. Madero	Tamaulipas
Mexico	Local Institution	Chihuahua
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Mexico City	Distrito Federal
Mexico	Local Institution	Mexico City	Distrito Federal
Mexico	Local Institution	Monterrey	Nuevo Leon
Mexico	Local Institution	Tijuana	Baja California
Norway	Local Institution	Gjettum
Norway	Local Institution	Kongsvinger
Norway	Local Institution	Lillehammer
Norway	Local Institution	Tonsberg
Norway	Local Institution	Tynset
Poland	Local Institution	Gdansk
Poland	Local Institution	Lodz
Poland	Local Institution	Szczecin
Poland	Local Institution	Warszawa
Poland	Local Institution	Warszawa
Poland	Local Institution	Wroclaw
Romania	Local Institution	Bucharest
Romania	Local Institution	Cluj Napoca
Russian Federation	Local Institution	Chelyabinsk
Russian Federation	Local Institution	Kazan
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Moscow
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	Saint Petersburg
Russian Federation	Local Institution	Samara
Russian Federation	Local Institution	St.Petersburg
Russian Federation	Local Institution	Yaroslavl
Spain	Local Institution	Badalona-Barcelone
Spain	Local Institution	Barcelona
Spain	Local Institution	Barcelona
Spain	Local Institution	Barcelona
Spain	Local Institution	Barcelona
Sweden	Local Institution	Gothenburg
Sweden	Local Institution	Stockholm
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
United Kingdom	Local Institution	Wigan	Lancashire
United States	University Orthopedic Center	Altoona	Pennsylvania
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	Americana Orthopedics	Boise	Idaho
United States	Pab Clinical Research	Brandon	Florida
United States	Research Alliance, Inc.	Clearwater	Florida
United States	Atlanta Knee And Sports Medicine	Decatur	Georgia
United States	Advanced Orthopedic And Sports Medicine Specilists	Denver	Colorado
United States	Denver-Vail Orthopedics, P.C.	Denver	Colorado
United States	Shrock Orthopedic Research	Ft. Lauderdale	Florida
United States	Martin Bowen Hefley Orthopedics	Little Rock	Arkansas
United States	Orthoarkansas, P.A.	Little Rock	Arkansas
United States	Gill Orthopedic Center	Lubbock	Texas
United States	Robert R. King, Md	Lubbock	Texas
United States	Bosie Orthopedic Clinic	Meridian	Idaho
United States	Uc Davis Medical Center	Sacramento	California
United States	Unlimited Research	San Antonio	Texas
United States	Phoenix Clinical Research, Llc	Tamarac	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Canada,  China,  Denmark,  France,  Germany,  Hungary,  India,  Israel,  Mexico,  Norway,  Poland,  Romania,  Russian Federation,  Spain,  Sweden,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	Day 1 (first dose of study drug) to later of 2 days after last dose or 38 days after first dose	No
Secondary	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	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.	Day 1 (first dose of study drug) to later of 2 days after last dose or 38 days after first dose	No
Secondary	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	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.	Day 1 (first dose of study drug) to later of 2 days after last dose or 38 days after first dose	No
Secondary	Rate of Major Bleeding, Clinically Relevant Nonmajor Bleeding (CRNM), Major or CRNM, and Any Bleeding During the Treatment Period	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	First dose of study drug (presurgery) through 2 days after the last dose of study drug	Yes
Secondary	Number of Participants With Serious Adverse Events (SAEs), Bleeding Adverse Events (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. 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.	First dose of study drug (presurgery) through 30 days after the last dose of study drug	Yes
Secondary	Number of Participants With a Bleeding-related Adverse Event During the Treatment Period	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.	First dose of study drug (presurgery) through 2 days after the last dose of study drug	Yes
Secondary	Number of Participants With a Bleeding-related Adverse Events During the Treatment Period (Continued)	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.	First dose of study drug (presurgery) through 2 days after the last dose of study drug	Yes
Secondary	Number of Participants With a Bleeding-related Adverse Event During the Treatment Period (Continued)	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.	First dose of study drug (presurgery) through 2 days after the last dose of study drug	Yes
Secondary	Number of Participants With Neurologic Adverse Events With Onset During the Treatment Period	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.	First dose of study drug (presurgery) through 2 days after the last dose of study drug	Yes
Secondary	Number of Participants With Marked Abnormalities (MA) in Clinical Laboratory Test Results During the Treatment Period	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	First dose of study drug (presurgery) through 2 days after the last dose of study drug	Yes
Secondary	Number of Participants With Marked Abnormalities (MA) in Clinical Laboratory Test Results During the Treatment Period (Continued)	preRx=predose; LLN=lower limit of normal; ULN=upper limit of normal. Alanine aminotransferase (ALT) (U/L): >3 *ULN: alkaline phosphatase (ALP) (U/L): >2* ULN; aspartate aminotransferase (ASP) (U/L): >3 *ULN; bilirubin, direct (mg/dL): >2*ULN; bilirubin, total (mg/dL): >2*ULN; BUN (mg/dL): >2*ULN; creatinine (mg/dL): >1.5*ULN; calcium (mg/dL): < 0.8*LLN or >1.2 *ULN, or if preRx	First dose of study drug (presurgery) through 2 days after the last dose of study drug	Yes
Secondary	Number of Participants With Marked Abnormalities (MA) in Clinical Laboratory Test Results During the Treatment Period (Continued)	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	First dose of study drug (presurgery) through 2 days after the last dose of study drug	Yes
Secondary	Number of Participants With Adverse Events Related to Elevations in Liver Function Test Results With Onset During the Treatment Period	Treatment guidelines were provided for jaundice and elevated results of liver function tests.	First dose of study drug (presurgery) through 30 days after the last dose of study drug	Yes
Secondary	Rates of Adjudicated Myocardial Infarction (MI)/Stroke, MI, Stroke, and Thrombocytopenia During the Intended Treatment Period	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.	Day 1 (first dose of study drug) to later of 2 days after last dose or 38 days after first dose	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