Dabigatran Etexilate vs Enoxaparin in Prevention of Venous Thromboembolism (VTE) Post Total Knee Replacement

Study Overview
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Brief Summary
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To determine the comparative efficacy and safety of two different doses (75mg day 1 followed by 150 mg day 2-completion, and 110 mg day 1 followed by 220 mg day 2-completion) of dabigatran administered orally (capsules), compared to enoxaparin 30 mg twice a day subcutaneous, in prevention of venous thromboembolism in patients with primary elective total knee replacement surgery

Official Title
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A Phase III, Randomized, Parallel-group, Double-blind, Active Controlled Study to Investigate the Efficacy and Safety of Two Different Dose Regimens (75mg Day 1 Followed by 150 mg Day 2-completion, and 110 mg Day 1 Followed by 220 mg Day 2-completion) of Dabigatran Etexilate Administered Orally (Capsules), Compared to Enoxaparin 30 mg Twice a Day Subcutaneous for 12 - 15 Days in Prevention of Venous Thromboembolism in Patients With Primary Elective Total Knee Replacement Surgery

Conditions
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Arthroplasty, Replacement, Knee, Thromboembolism

Intervention / Treatment
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* Drug: Dabigatran Dose 1 - day 2 to completion
* Drug: Dabigatran Dose 1 - day 1
* Drug: Dabigatran Dose 2 - day 2 to completion
* Drug: Dabigatran Dose 2 - day 1
* Drug: Enoxaparin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria INCLUSION CRITERIA Patients scheduled to undergo a primary, unilateral elective total knee repla cement. Male or female 18 years of age or older. Patients weighing at least 40 kg. Written informed consent prior to the start of study participation. Exclusion criteria EXCLUSION CRITERIA History of bleeding diathesis. Constitutional or acquired coagulation disorders that in the investigator's judgment puts the patient at excessive risk for bleeding. Major surgery or trauma (e.g. hip fracture) within the last 3 months. Recent unstable cardiovascular disease, such as uncontrolled hypertension at the time of enrollment (investigator's judgment) or history of myocardial infarction within the last 3 months. Spinal or epidural anesthesia, for which more than 3 attempts (sticks) at placement were made, or the placement was traumatic. Please note that patients, who are not excluded under this criterion, are to have the catheter pulled at the completion of surgery. Any history of hemorrhagic stroke or any of the following intracranial pathologies: bleeding, neoplasm, arteriovenous (AV) malformation or aneurysm. History of VTE or pre-existing condition requiring anticoagulant therapy. Clinically relevant bleeding (e.g. gastrointestinal, pulmonary, intraocular or urogenital bleeding) within the last 6 months. Gastric or duodenal ulcer within the last 6 months. Liver disease expected to have any potential impact on survival (e.g. hepatitis B or C, cirrhosis, but not Gilbert's syndrome or hepatitis A with complete recovery). Elevated AST or ALT >2x upper limit of normal, based on central lab results or local lab results within 1 month before enrollment. Known severe renal insufficiency (CrCl < 30 mL/min). In order to determine patient inclusion/exclusion, creatinine clearance (CrCl) needs to be calculated only if serum creatinine is elevated or renal insufficiency is suspected.

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 |
| --- | --- |
| Experimental: Dabigatran Dose 1<br>low dose regimen taken once daily | Drug: Dabigatran Dose 1 - day 2 to completion<br>* low dose regimen taken once daily<br>Drug: Dabigatran Dose 1 - day 1<br>* low dose regimen taken once daily<br>|
| Experimental: Dabigatran Dose 2<br>high dose regimen taken once daily | Drug: Dabigatran Dose 2 - day 2 to completion<br>* high dose regimen taken once daily<br>Drug: Dabigatran Dose 2 - day 1<br>* high dose regimen taken once daily<br>|
| Active Comparator: Enoxaparin<br>30 mg subcutaneously twice daily | Drug: Enoxaparin<br>* 30 mg subcutaneously twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period | Total Venous Thromboembolic Event (VTE) includes both proximal and distal deep vein thrombosis (DVT) (detected by routine bilateral venography), symptomatic DVT (confirmed by venous compression ultrasound, venography or autopsy) and pulmonary embolism (PE) (confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy). All of these components and all deaths were centrally adjudicated by the VTE events committee, which was not aware of the treatment allocation of the patients. | First administration until 12-15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period | Major Venous Thromboembolic Event (VTE) is defined as proximal DVT and PE, as adjudicated by the VTE events committee | First administration until 12-15 days | 
| Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period | Proximal Deep Vein Thrombosis as adjudicated by the VTE events committee | First administration until 12-15 days | 
| Number of Participants With Total Deep Vein Thrombosis During Treatment Period | Total Deep Vein Thrombosis as adjudicated by the VTE events committee | First administration until 12-15 days | 
| Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period | Symptomatic Deep Vein Thrombosis, confirmed by venous compression ultrasound, venography or autopsy, and as adjudicated by the VTE events committee | First administration until 12-15 days | 
| Number of Participants With Pulmonary Embolism During Treatment Period | Pulmonary embolism confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy, and as adjudicated by the VTE events committee | First administration until 12-15 days | 
| Number of Participants Who Died During Treatment Period | All cause death, as adjudicated by the VTE events committee | First administration until 12-15 days | 
| Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | Total Venous Thromboembolic Event (VTE) includes both proximal and distal deep vein thrombosis (DVT) (detected by routine bilateral venography), symptomatic DVT (confirmed by venous compression ultrasound, venography or autopsy) and pulmonary embolism (PE) (confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy). | 3 months | 
| Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Major bleeding events were defined as fatal clinically overt associated with loss of haemoglobin >=20g/L in excess of what was expected clinically overt leading to the transfusion of >=2 units packed cells or whole blood in excess of what was expected symptomatic retroperitoneal, intracranial, intraocular or intraspinal requiring treatment cessation leading to re-operation Clinically-relevant was defined as spontaneous skin hematoma greater than or equal to 25 cm² wound hematoma greater than or equal to 100 cm² spontaneous nose bleed lasting longer than 5 min macroscopic hematuria spontaneous or lasting longer than 24 hours if associated with an intervention spontaneous rectal bleeding (more than a spot on toilet paper) gingival bleeding lasting longer than 5 min any other bleeding event considered clinically relevant by the investigator Minor bleeding events were defined as all other bleeding events that did not fulfil the criteria from above. | First administration until 12-15 days |