Study of Apixaban for the Prevention of Thrombosis-related Events Following Knee Replacement Surgery

Pulmonary Embolism Clinical Trial

Official title:

A Phase 3 Randomized, Double-Blind Active-Controlled (Enoxaparin), Parallel-Group, Multi-Center Study to Evaluate the Safety and Efficacy of Oral Apixaban in Subjects Undergoing Elective Total Knee Replacement Surgery

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00371683
• Other study ID #: CV185-034
• Status: Completed
• Phase: Phase 3
• First received: August 30, 2006
• Last updated: November 25, 2015
• Start date: November 2006
• Est. completion date: May 2008

Study information

• Verified date: November 2015
• 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 if apixaban can prevent blood clots in the leg (deep vein Thrombosis [DVT]) and lung (pulmonary embolism [PE]) that sometimes occur after knee replacement surgery and to learn how apixaban compares to enoxaparin (Lovenox®) for preventing these clots. The safety of apixaban will also be studied.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3608
• Est. completion date: May 2008
• Est. primary completion date: May 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Men and non-pregnant, non-breastfeeding women

• 18 years or older

• Scheduled for knee replacement surgery

Key Exclusion Criteria:

• hereditary or acquired bleeding disorders

• clotting disorders

• bleeding or high risk for bleeding

• drugs that affect bleeding or coagulation

• need for ongoing parenteral or oral anticoagulation

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 + Placebo
Syringes + tablets, Subcutaneous + Oral, 30mg, twice daily, 12 day treatment period
• Apixaban + Placebo
Tablet + Syringes, Oral + subcutaneous, 2.5 mg, twice daily, 12 day treatment period

Locations

Country	Name	City	State
Argentina	Local Institution	Buenos Aires
Argentina	Local Institution	Buenos Aires
Argentina	Local Institution	Buenos Aires
Argentina	Local Institution	Buenos Aires
Argentina	Local Institution	Capital Federal	Buenos Aires
Argentina	Local Institution	Capital Federal	Buenos Aires
Argentina	Local Institution	Cordoba
Australia	Local Institution	Adelaide	South Australia
Australia	Local Institution	Bedford Park	South Australia
Australia	Local Institution	Box Hill	Victoria
Australia	Local Institution	Camperdown	New South Wales
Australia	Local Institution	Caringbah	New South Wales
Australia	Local Institution	Garran	Australian Capital Territory
Australia	Local Institution	Gold Coast	Queensland
Australia	Local Institution	Lismore	New South Wales
Australia	Local Institution	Perth	Western Australia
Australia	Local Institution	Windsor	Victoria
Brazil	Local Institution	Campinas	Sao Paulo
Brazil	Local Institution	Curitiba	Parana
Brazil	Local Institution	Porto Alegre	Rio Grande Do Sul
Brazil	Local Institution	Porto Alegre, Rs	Rio Grande Do Sul
Brazil	Local Institution	Sao Paulo
Canada	Local Institution	Ajax	Ontario
Canada	Local Institution	Burlington	Ontario
Canada	Local Institution	Cambridge	Ontario
Canada	Local Institution	Charlottetown	Prince Edward Island
Canada	Local Institution	Chatham	Ontario
Canada	Local Institution	Dartmouth	Ontario
Canada	Local Institution	Edmonton	Alberta
Canada	Local Institution	Guelph	Ontario
Canada	Local Institution	Lindsay	Ontario
Canada	Local Institution	Montreal	Quebec
Canada	Local Institution	Newmarket	Ontario
Canada	Local Institution	Niagara Falls	Ontario
Canada	Local Institution	Quebec
Canada	Local Institution	Sarnia	Ontario
Canada	Local Institution	Scarborough	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
Denmark	Local Institution	Horsholm
Denmark	Local Institution	Kopenhamn S
Hungary	Local Institution	Kecskemet
Hungary	Local Institution	Szekesfehervar
Hungary	Local Institution	Szolnok
Israel	Local Institution	Afula
Israel	Local Institution	Beer-Sheva
Israel	Local Institution	Haifa
Israel	Local Institution	Holon
Israel	Local Institution	Kfar-Saba
Israel	Local Institution	Petach-Tikva
Israel	Local Institution	Rehovot
Israel	Local Institution	Zerifin
Mexico	Local Institution	Cd Madero	Tamaulipas
Mexico	Local Institution	Chihuahua
Mexico	Local Institution	Df	Distrito Federal
Mexico	Local Institution	Df	Distrito Federal
Mexico	Local Institution	Df	Distrito Federal
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Jalapa	Veracruz
Mexico	Local Institution	Merida	Yucatan
Mexico	Local Institution	Merida	Yucatan
Mexico	Local Institution	Monterrey	Nuevo Leon
Mexico	Local Institution	Monterrey	Nuevo Leon
Mexico	Local Institution	Tijuana	Baja California
Poland	Local Institution	Bialystok
Poland	Local Institution	Krakow
Poland	Local Institution	Lodz
Poland	Local Institution	Lublin
Poland	Local Institution	Szczecin
Poland	Local Institution	Warszawa
Poland	Local Institution	Warszawa
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Samara
Russian Federation	Local Institution	St. Petersburg
Sweden	Local Institution	Goteborg
Turkey	Local Institution	Adana
Turkey	Local Institution	Bursa
Turkey	Local Institution	Mersin
Turkey	Local Institution	Trabzon
United States	Colorado Orthopedic Consultants, Pc	Aurora	Colorado
United States	Bay Pines Va Medical Center	Bay Pines	Florida
United States	Capstone Clinical Trials, Inc	Birmingham	Alabama
United States	Capstone Clinical Trials, Inc	Birmingham	Alabama
United States	Americana Orthopedics	Boise	Idaho
United States	Intermountain Orthopaedics	Boise	Idaho
United States	Pab Clinical Research	Brandon	Florida
United States	Charleston Orthopaedic Assocs.	Charleston	South Carolina
United States	Atlanta Knee And Sports Medicine	Decatur	Georgia
United States	Colorado Joint Replacement	Denver	Colorado
United States	Jdpmedical Research	Denver	Colorado
United States	Orhtopaedic Physicians Of Colorado, P.C.	Englewood	Colorado
United States	Orthopedics Assocs Of Hartford	Hartford	Connecticut
United States	Bone & Joint Clinic Of Houston	Houston	Texas
United States	Kelsey Seybold Clinic	Houston	Texas
United States	Jacksonville Center For Clinical Research	Jacksonville	Florida
United States	Bluegrass Orthopaedics/Bmr	Lexington	Kentucky
United States	Martin Bowen Hefley Orthopedics	Little Rock	Arkansas
United States	Gill Orthopedic Center	Lubbock	Texas
United States	Robert R. King, Md	Lubbock	Texas
United States	Mark W. Hollmann, Md	Orange City	Florida
United States	Unlimited Research	San Antonio	Texas
United States	West Alabama Research, Inc.	Tuscaloosa	Alabama
United States	Anthony S. Unger, Md	Washington	District of Columbia
United States	Jewett Orthopaedic Clinic	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  Denmark,  Hungary,  Israel,  Mexico,  Poland,  Russian Federation,  Sweden,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event Rate of the Composite of Adjudicated Venous Thromboembolism (VTE) Events and All-Cause Death With Onset During the Intended Treatment Period - Primary Subjects	An Independent Central Adjudication Committee (ICAC) adjudicated all venograms, suspected symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), acute clinically overt bleeding events, suspected thrombocytopenia, suspected acute MI, suspected acute stroke, and cause of death. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed and reported as percentage (%). Surgery=Day 1; Randomization/Treatment started on Day of Surgery or the next day (Day 1 or Day 2). A mandatory bilateral ascending contrast venogram was performed on all participants after 12 days (±2 days) of study treatment. Intended Treatment Period=starts on the day of randomization; for treated participants, the period ends at the latter of 2 days after last dose of study drug or 14 days after the first dose of study drug; for randomized participants who were not treated, the period ends 14 days after randomization.	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	No
Primary	Event Rate for Participants With Major Bleeding, Clinically Relevant Non-Major Bleeding, Major or Clinically Relevant Non-Major Bleeding, Any Bleeding With Onset During the Treatment Period - Treated Population	ICAC adjudicated acute clinically overt bleeding events as per International Society on Thrombosis and Hemostasis (ISTH) guidelines modified for surgical patients. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%). Clinically relevant (CR); Non-Major (N-M) Bleeding. Day 1=Day of surgery. Treatment started (first dose) day of surgery or next day. Treatment continued for 12 days.	First dose of study drug to last dose, plus 2 days post last dose	Yes
Primary	Event Rate for Participants With Major Bleeding, Clinically Relevant (CR) Non-Major (N-M) Bleeding , Major or Clinically Relevant (CR) Non-Major (N-M) Bleeding, Any Bleeding With Onset During the Follow-Up Period	ICAC adjudicated acute clinically overt bleeding events as per International Society on Thrombosis and Hemostasis (ISTH) guidelines modified for surgical patients. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%). Follow up Period was from the end of the treatment period (last dose) up to 60 days post last dose, Day 72.	Last dose of study drug to Day 72 (60 days)	Yes
Secondary	Event Rate of Composite of Adjudicated Proximal DVT, Non-Fatal PE and All-Cause Death With Onset During the Intended Treatment Period PE and All-cause Death During the Intended Treatment Period	A mandatory bilateral ascending contrast venogram was performed on all participants after 12 days (±2 days) of study treatment. An ICAC adjudicated all venograms, suspected proximal DVT and non-fatal PE, and all-cause of death. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed and reported as percentage (%).	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	No
Secondary	Event Rate of Adjudicated VTE / VTE-related Death With Onset During the Treatment Period	VTE / VTE-related death was defined as the combination of fatal or non-fatal PE, and symptomatic or asymptomatic DVT. A mandatory bilateral ascending contrast venogram was performed on all participants after 12 days (±2 days) of study treatment. An ICAC adjudicated all venograms, suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	No
Secondary	Event Rate for Participants With Proximal DVT/Non-Fatal PE/ VTE-Related Death With Onset During the Intended Treatment Period	An ICAC adjudicated all venograms, suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	No
Secondary	Event Rate for Total Participants With Adjudicated VTE/All-Cause Death With Onset During the Intended Treatment Period	ICAC adjudicated all venograms, suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	Yes
Secondary	Event Rate for Total Participants With VTE/ VTE-Related Death With Onset During the Intended Treatment Period	ICAC adjudicated all venograms, suspected symptomatic DVT and PE, and cause of death. VTE includes DVT and PE. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	Yes
Secondary	Event Rate for Participants With All-Cause Death During the Intended Treatment Period	Event rate was number of participants with all-cause death divided by the number of participant's analyzed (%).	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	No
Secondary	Event Rate for Participants With VTE-Related Death With Onset During the Intended Treatment Period	ICAC adjudicated cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	No
Secondary	Event Rate for Participants With Symptomatic VTE/ All-Cause Death With Onset During the Intended Treatment Period	ICAC adjudicated suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	No
Secondary	Event Rate for Participants With Symptomatic VTE/ VTE-Related Death With Onset During the Intended Treatment Period	ICAC adjudicated suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	No
Secondary	Event Rate for Participants With VTE/Major Bleeding/All-Cause Death With Onset During the Intended Treatment Period	ICAC adjudicated VTE, acute clinically overt bleeding events, suspected thrombocytopenia, and cause of death. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%).	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	No
Secondary	Event Rate for Participants With PE (Fatal or Non-Fatal), DVT (All, Symptomatic Proximal, and Distal, Asymptomatic) With Onset During the Intended Treatment Period	An ICAC adjudicated all venograms, suspected symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), acute clinically overt bleeding events, suspected thrombocytopenia, suspected acute MI, suspected acute stroke, and cause of death. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%).	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	No
Secondary	Event Rate for Participants With Proximal DVT, Distal DVT, Asymptomatic Proximal DVT, Asymptomatic Distal DVT With Onset During the Intended Treatment Period	ICAC adjudicated all venograms and suspected symptomatic DVT. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).	From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization	No
Secondary	Event Rate for Participants With Adjudicated Myocardial Infarction (MI) Acute Ischemic Stroke and Thromboembolic Events With Onset During the Treatment Period	ICAC adjudicated acute clinically overt bleeding events, suspected thrombocytopenia, suspected acute MI, suspected acute stroke per International Society on Thrombosis and Hemostasis (ISTH) guidelines modified for surgical patients. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%).	From first dose to last dose, plus 2 days (12 days, plus 2)	Yes
Secondary	Event Rate of Adjudicated MI, Stroke, and Thrombocytopenia Events During the Follow-Up Period	A 60-day follow-up period started after the last dose of study drug and continued until the End of Study Visit on Day 72 (60 days ± 3 days, after the last dose of study drug). Event rate was number of participants with the endpoint divided by the number of participants analyzed (%). ICAC adjudicated acute clinically overt bleeding events, suspected thrombocytopenia, suspected acute MI, suspected acute stroke per ISTH guidelines modified for surgical patients.	Post last dose of study drug to Day 72 (60 days)	Yes
Secondary	Number of Participants With Serious Adverse Events (SAEs), Bleeding Adverse Events (AEs), AEs Leading to Discontinuation, and Deaths - Treated Population	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.	First dose to last dose, plus 2 days for AEs (12 + 2 days) or plus 30 days for SAEs (12 + 30 days)	Yes
Secondary	Mean Change From Baseline in Systolic and Diastolic Blood Pressure During the Treatment Period	Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug (12 + 2 days). Baseline=measurement prior to first dose of study drug. Blood pressures (BP) were measured during screening (pre-operative, post-operative) and in the treatment period on Days 1 (day of first dose), 2, 3, 4,12 (end of treatment). Systolic and diastolic pressures were measured in millimeters of mercury (mmHg).	Baseline to last dose of study drug, plus 2 days	Yes
Secondary	Mean Change From Baseline in Heart Rate During the Treatment Period	Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug (12 + 2 days). Baseline=measurement prior to first dose of study drug. Heart rate was measured during screening (pre-operative, post-operative) and in the treatment period on Days 1 (day of first dose), 2, 3, 4,12 (end of treatment). Heart rate was measured in beats per minute (bpm).	Baseline to last dose of study drug, plus 2 days	Yes
Secondary	Number of Participants With Hematology Laboratory Marked Abnormality During the Treatment Period	Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug. Hematology profile was measured during screening (pre-operative, post-operative) and in the Treatment Period on Days 2, 3, 4, 12 (end of treatment). Upper limit of normal (ULN); lower limit of normal (LLN). Platelet Count low: < 100,000/mm^3 (or < 100*109 cells/L). Erythrocytes low: < 0.75 *pre-dose. Hemoglobin low: > 2 g/dL decrease compared to pre-dose or Value = 8 g/dL. Hematocrit low: < 0.75*pre-dose . Leukocytes: < 0.75*LLN or > 1.25* ULN, or if pre-dose < LLN then use < 0.8*predose or > ULN if pre-dose > ULN then use > 1.2*predose or < LLN. Lymphocytes (absolute): < 0.750*10^3 cells/µL or > 7.50*10^3 cells/ µL. Eosinophils (absolute) high: > 0.750*10^3 cells/µL. Basophils(absolute) high: > 400/mm^3 (or > 0.4*103 cells/µL). Monocytes (absolute) high: > 2000/mm^3 (or > 2*103 cells/µL). Neutrophils(absolute) high: < 1.0*103 cells/µL.	First dose to last dose of study drug (12 days), plus 2 days	Yes
Secondary	Number of Participants With Liver and Kidney Function Chemistry Laboratory Marked Abnormalities During the Treatment Period	Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug. Laboratory Chemistry profile was measured during screening (pre-operative, post-operative) and in the Treatment Period on Days 4, and 12 (end of treatment). Bilirubin (direct) high: > 1.5*ULN. Total bilirubin: : > 2*ULN, Alanine Aminotransferase (ALT) high: > 3*ULN. Alkaline Phosphatase (ALP): > 2*ULN. Aspartate Aminotransferase (AST): > 3*ULN. Creatinine: > 1.5*ULN.	First dose to last dose of study drug (12 days), plus 2 days	Yes
Secondary	Number of Participants With Electrolyte Chemistry Laboratory Marked Abnormalities During the Treatment Period	Laboratory Chemistry profile was measured during screening (pre-operative, post-operative) and in the Treatment Period on Days 4, and 12 (end of treatment). Potassium: < 0.9*LLN or > 1.1*ULN, or if pre-dose < LLN then use < 0.9*predose or > ULN if pre-dose > ULN then use > 1.1*predose or < LLN. Calcium: < 0.8*LLN or > 1.2*ULN, or if pre-dose < LLN then use < 0.75*predose or > ULN If pre-dose > ULN then use > 1.25*predose or < LLN. Chloride: < 0.9*LLN or > 1.1*ULN, or if pre-dose < LLN then use < 0.9*predose or > ULN if pre-dose > ULN then use > 1.1*predose or < LLN. Sodium: < 0.95*LLN or > 1.05*ULN, or if pre-dose < LLN then use < 0.95*predose or >ULN if pre-dose > ULN then use > 1.05*predose or < LLN. Bicarbonate: < 0.75*LLN or > 1.25*ULN, or if pre-dose < LLN then use < 0.75*predose or > ULN if pre-dose > ULN then use > 1.25*predose or < LLN.	First dose to last dose of study drug (12 days), plus 2 days	Yes
Secondary	Number of Participants With Other Chemistry Laboratory Marked Abnormalities During the Treatment Period	Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug. Laboratory Chemistry profile was measured during screening (pre-operative, post-operative) and in the Treatment Period on Days 4, and 12 (end of treatment). Fasting Glucose: if pre-dose < LLN then use < 0.8*predose; or > ULN if pre-dose > ULN then use > 2.0*predose or	First dose to last dose of study drug (12 days), plus 2 days	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