Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Vein Thromboembolism (DVT) and Pulmonary Embolism (PE). A Study of BAY59-7939 in the Prevention of Venous Thrombo Embolism (VTE) in Subjects Undergoing Elective Total Knee Replacement.

Study Overview
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Brief Summary
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The purpose of this study is to assess if 10 mg BAY59-7939, taken once daily as a tablet, is safe and prevents blood clot which may form after a knee replacement operation.

Official Title
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RECORD 4 Study: REgulation of Coagulation in ORthopedic Surgery to Prevent DVT and PE; a Controlled, Double-blind, Randomized Study of BAY59-7939 in the Prevention of VTE in Subjects Undergoing Elective Total Knee Replacement

Conditions
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Venous Thromboembolism

Intervention / Treatment
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* Drug: Rivaroxaban (Xarelto, BAY59-7939)
* Drug: Enoxaparin
* Drug: Placebo: tablet of Rivaroxaban
* Drug: Placebo: syringes of Enoxaparin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients aged 18 years or above Patients scheduled for elective total knee replacement Exclusion Criteria: Active bleeding or high risk of bleeding contraindicating treatment with Low Molecular Weight Heparin (LMWH) Contraindication listed in the labeling or conditions precluding subject treatment with enoxaparin or requiring dose adjustment (e.g. severe renal impairment, please refer to the local label of enoxaparin in your country) Conditions prohibiting bilateral venography (e.g. amputation of 1 leg, allergy to contrast media)

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivaroxaban 10 mg Once Daily (OD) ((Xarelto, BAY59-7939))<br>Rivaroxaban (Xarelto, BAY59-7939) 10 mg tablet administered once daily (od) in the evening plus placebo syringes of enoxaparin twice a day (bid) administered once in the morning and once in the evening. | Drug: Rivaroxaban (Xarelto, BAY59-7939)<br>* Rivaroxaban (Xarelto, BAY59-7939) 10 mg tablet administered once daily (od) in the evening.<br>Drug: Placebo: syringes of Enoxaparin<br>* Placebo syringes of enoxaparin twice a day (bid) administered once in the morning and once in the evening.<br>|
| Active Comparator: Enoxaparin 30 mg twice a day (bid)<br>Placebo tablet of rivaroxaban administered once daily in the evening plus syringes of enoxaparin active substance 30 mg twice a day administered once in the morning and once in the evening. | Drug: Enoxaparin<br>* Syringes of enoxaparin active substance 30 mg twice a day administered once in the morning and once in the evening.<br>Drug: Placebo: tablet of Rivaroxaban<br>* Placebo tablet of rivaroxaban administered once daily in the evening.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Endpoint of Total Venous Thrombo Embolism (VTE) i.e.: Any Deep Vein Thromboembolism (DVT) (Proximal and/or Distal), Non Fatal Pulmonary Embolism (PE), Death of All Causes Per Protocol Population | Blinded, adjudicated assessment of bilateral venography, clinical signs of deep vein thrombosis (DVT) and pulmonary embolism (PE), ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 16 days after surgery | 
| Composite Endpoint of Total VTE i.e.: Any DVT (Proximal and/or Distal), Non Fatal PE, Death of All Causes Per Modified Intent to Treat Population. | Blinded, adjudicated assessment of bilateral venography, clinical signs of deep vein thrombosis (DVT) and pulmonary embolism (PE), ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 16 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of the Composite Endpoint Comprising Proximal DVT, Non-fatal PE and VTE- Related Death (Major VTE) Per Protocol Population of Major VTE | Blinded, adjudicated assessment of bilateral venography, clinical signs of deep vein thrombosis (DVT) and pulmonary embolism (PE), ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 16 days after surgery | 
| Incidence of the Composite Endpoint Comprising Proximal DVT, Non-fatal PE and VTE- Related Death (Major VTE) Per Modified Intent to Treat Population of Major VTE. | Blinded, adjudicated assessment of bilateral venography, clinical signs of deep vein thrombosis (DVT) and pulmonary embolism (PE), ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 16 days after surgery | 
| Incidence of Symptomatic VTE (DVT, PE) Per Protocol Population. | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 16 days after surgery | 
| Incidence of Symptomatic VTE (DVT, PE) Per Modified Intent to Treat Population. | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 16 days after surgery | 
| Incidence of DVT (Proximal, Distal) Per Protocol Population. | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 16 days after surgery | 
| Incidence of DVT (Proximal, Distal) Per Modified Intent to Treat Population. | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 16 days after surgery | 
| Incidence of Symptomatic VTE During Follow-up Per Protocol Population. | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 47 days after surgery | 
| Incidence of Symptomatic VTE During Follow-up Per Modified Intent to Treat Population. | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 47 days after surgery | 
| The Composite Endpoint Comprising Major VTE and Treatment-emergent Major Bleeding Per Subjects Valid for Analysis of Net Clinical Benefit | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography, anesthesia and surgery reports, number of transfusions | Up to 47 days after surgery | 
| Incidence of the Composite Endpoint That Results From the Primary Endpoint by Substituting VTE Related Death for All Death Per Protocol Population. | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 16 days after surgery | 
| Incidence of the Composite Endpoint That Results From the Primary Endpoint by Substituting VTE Related Death for All Death Per Modified Intent to Treat Population. | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 16 days after surgery | 
| Incidence of the Composite Endpoint That Results From Major VTE by Substituting All Cause Mortality for VTE-related Death Per Protocol of Major VTE Population. | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 16 days after surgery | 
| Incidence of the Composite Endpoint That Results From Major VTE by Substituting All Cause Mortality for VTE-related Death Per Modified Intent to Treat of Major VTE Population. | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography | Up to 16 days after surgery | 
| Treatment-emergent Major Bleedings Per Safety Population. | Blinded, adjudicated assessments of all available information (eg, anesthesia and surgery reports, laboratory results, number of transfusions, autopsy report) | from start of double-blind study medication to last dose of double-blind study medication plus two days. The average duration of double-blind treatment was 12 days in each treatment group (safety population). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prevention of venous thromboembolism