Study of Apixaban for the Prevention of Thrombosis-related Events Following Knee Replacement Surgery
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| ClinicalTrials.gov Identifier: NCT00371683 |
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Recruitment Status :
Completed
First Posted : September 4, 2006
Results First Posted : December 30, 2015
Last Update Posted : December 30, 2015
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Sponsor:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Bristol-Myers Squibb
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Brief 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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Deep Vein Thrombosis Pulmonary Embolism | Drug: Enoxaparin + Placebo Drug: Apixaban + Placebo | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 3608 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Prevention |
| 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 |
| Study Start Date : | November 2006 |
| Actual Primary Completion Date : | May 2008 |
| Actual Study Completion Date : | May 2008 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: A1
+ placebo
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Drug: Enoxaparin + Placebo
Syringes + tablets, Subcutaneous + Oral, 30mg, twice daily, 12 day treatment period
Other Name: Lovenox® |
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Experimental: A2
+ placebo
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Drug: Apixaban + Placebo
Tablet + Syringes, Oral + subcutaneous, 2.5 mg, twice daily, 12 day treatment period |
Primary Outcome Measures :
- Event Rate of the Composite of Adjudicated Venous Thromboembolism (VTE) Events and All-Cause Death With Onset During the Intended Treatment Period - Primary Subjects [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]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.
- 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 [ Time Frame: First dose of study drug to last dose, plus 2 days post last dose ]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.
- 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 [ Time Frame: Last dose of study drug to Day 72 (60 days) ]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.
Secondary Outcome Measures :
- 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 [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]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 (%).
- Event Rate of Adjudicated VTE / VTE-related Death With Onset During the Treatment Period [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]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 (%).
- Event Rate for Participants With Proximal DVT/Non-Fatal PE/ VTE-Related Death With Onset During the Intended Treatment Period [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]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 (%).
- Event Rate for Total Participants With Adjudicated VTE/All-Cause Death With Onset During the Intended Treatment Period [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]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 (%).
- Event Rate for Total Participants With VTE/ VTE-Related Death With Onset During the Intended Treatment Period [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]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 (%).
- Event Rate for Participants With All-Cause Death During the Intended Treatment Period [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]Event rate was number of participants with all-cause death divided by the number of participant's analyzed (%).
- Event Rate for Participants With VTE-Related Death With Onset During the Intended Treatment Period [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]ICAC adjudicated cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
- Event Rate for Participants With Symptomatic VTE/ All-Cause Death With Onset During the Intended Treatment Period [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]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 (%).
- Event Rate for Participants With Symptomatic VTE/ VTE-Related Death With Onset During the Intended Treatment Period [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]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 (%).
- Event Rate for Participants With VTE/Major Bleeding/All-Cause Death With Onset During the Intended Treatment Period [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]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 (%).
- Event Rate for Participants With PE (Fatal or Non-Fatal), DVT (All, Symptomatic Proximal, and Distal, Asymptomatic) With Onset During the Intended Treatment Period [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]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 (%).
- Event Rate for Participants With Proximal DVT, Distal DVT, Asymptomatic Proximal DVT, Asymptomatic Distal DVT With Onset During the Intended Treatment Period [ Time Frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization ]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 (%).
- Event Rate for Participants With Adjudicated Myocardial Infarction (MI) Acute Ischemic Stroke and Thromboembolic Events With Onset During the Treatment Period [ Time Frame: From first dose to last dose, plus 2 days (12 days, plus 2) ]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 (%).
- Event Rate of Adjudicated MI, Stroke, and Thrombocytopenia Events During the Follow-Up Period [ Time Frame: Post last dose of study drug to Day 72 (60 days) ]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.
- Number of Participants With Serious Adverse Events (SAEs), Bleeding Adverse Events (AEs), AEs Leading to Discontinuation, and Deaths - Treated Population [ Time Frame: First dose to last dose, plus 2 days for AEs (12 + 2 days) or plus 30 days for SAEs (12 + 30 days) ]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.
- Mean Change From Baseline in Systolic and Diastolic Blood Pressure During the Treatment Period [ Time Frame: Baseline to last dose of study drug, plus 2 days ]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).
- Mean Change From Baseline in Heart Rate During the Treatment Period [ Time Frame: Baseline to last dose of study drug, plus 2 days ]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).
- Number of Participants With Hematology Laboratory Marked Abnormality During the Treatment Period [ Time Frame: First dose to last dose of study drug (12 days), plus 2 days ]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.
- Number of Participants With Liver and Kidney Function Chemistry Laboratory Marked Abnormalities During the Treatment Period [ Time Frame: First dose to last dose of study drug (12 days), plus 2 days ]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.
- Number of Participants With Electrolyte Chemistry Laboratory Marked Abnormalities During the Treatment Period [ Time Frame: First dose to last dose of study drug (12 days), plus 2 days ]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.
- Number of Participants With Other Chemistry Laboratory Marked Abnormalities During the Treatment Period [ Time Frame: First dose to last dose of study drug (12 days), plus 2 days ]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 <LLN. Total Protein: < 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. Uric Acid: > 1.5*ULN, or if pre-dose > ULN then use > 2*predose. Creatine Kinase (CK): > 5*ULN.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00371683
Locations
Show 107 study locations
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
| Study Director: | Bristol-Myers Squibb | Bristol-Myers Squibb |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Bristol-Myers Squibb |
| ClinicalTrials.gov Identifier: | NCT00371683 |
| Other Study ID Numbers: |
CV185-034 |
| First Posted: | September 4, 2006 Key Record Dates |
| Results First Posted: | December 30, 2015 |
| Last Update Posted: | December 30, 2015 |
| Last Verified: | November 2015 |
Keywords provided by Bristol-Myers Squibb:
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Prevention of deep vein thrombosis and pulmonary embolism after total knee replacement surgery |
Additional relevant MeSH terms:
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Pulmonary Embolism Thrombosis Embolism Venous Thrombosis Embolism and Thrombosis Vascular Diseases Cardiovascular Diseases Lung Diseases Respiratory Tract Diseases Enoxaparin |
Apixaban Anticoagulants Fibrinolytic Agents Fibrin Modulating Agents Molecular Mechanisms of Pharmacological Action Factor Xa Inhibitors Antithrombins Serine Proteinase Inhibitors Protease Inhibitors Enzyme Inhibitors |