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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Deep Vein Thrombosis, Pulmonary Embolism

Intervention / Treatment
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* Drug: Enoxaparin + Placebo
* Drug: Apixaban + Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A1<br>+ placebo | Drug: Enoxaparin + Placebo<br>* Syringes + tablets, Subcutaneous + Oral, 30mg, twice daily, 12 day treatment period<br>* Other names: Lovenox®;|
| Experimental: A2<br>+ placebo | Drug: Apixaban + Placebo<br>* Tablet + Syringes, Oral + subcutaneous, 2.5 mg, twice daily, 12 day treatment period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| 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) | 
| 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) | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 <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. | First dose to last dose of study drug (12 days), plus 2 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prevention of deep vein thrombosis and pulmonary embolism after total knee replacement surgery