A Study of BIBR 1048 in Prevention of Venous Thromboembolism in Patients With TKR Surgery.

Study Overview
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Brief Summary
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The goal of this study is to evaluate the comparative efficacy and safety of three different doses ( 110 mg, 150 mg, 220 mg) of BIBR 1048 (Dabigatran etexilate) orally, compared to placebo, in prevention of venous thromboembolism in patient with primary elective total knee replacement surgery, and to evaluate dose-response.

Official Title
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A Randomised, Parallel-group, Double-blind, Placebo Controlled Study to Investigate the Efficacy and Safety of BIBR 1048 in Prevention of Venous Thromboembolism in Patients With Primary Elective Total Knee Replacement Surgery

Conditions
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Arthroplasty, Replacement, Knee, Venous Thrombosis

Intervention / Treatment
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* Drug: Dabigatran etexilate
* Drug: Dabigatran etexilate
* Drug: Dabigatran Etexilate
* Drug: placebo


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 replacement Male or Female 20 years of age or order 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 Any history of hemorrhagic stroke or any of the following intracranial pathologies: bleeding, neoplasm, AV (arteriovenous) malformation or aneurysm or recent bleeding history Condition requiring anti-coagulant therapy Elevated AST(Aspartate Aminotransferase) , ALT(Alanine Aminotransferase), or any history of clinically relevant liver disease Patients with a history of clinically significant renal diseases or with elevated creatinine values

Ages Eligible for Study
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Minimum Age: 20 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 etexilate 110 mg<br>Dabigatran etexilate 110 mg capsule, once a day, oral administration | Drug: Dabigatran etexilate<br>* Dabigatran etexilate 110 mg capsule, once a day, oral administration<br>|
| Experimental: Dabigatran etexilate 150 mg<br>Dabigatran etexilate 150 mg capsule, once a day, oral administration | Drug: Dabigatran etexilate<br>* Dabigatran etexilate 150 mg capsule, once a day, oral administration<br>|
| Experimental: Dabigatran etexilate 220 mg<br>Dabigatran etexilate 110 mg capsule, 2capsules, once a day, oral administration | Drug: Dabigatran Etexilate<br>* Dabigatran etexilate 220 mg capsule, once a day, oral administration<br>|
| Placebo Comparator: Placebo<br>matching placebo capsule, once a day, oral administration | Drug: placebo<br>* matching placebo capsule, once a day, oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Have a Composite Endpoint Consisting of Total Venous Thromboembolic Event (VTE) and All Cause Mortality During the Treatment Period. | number of participants with the composite endpoint (total Venous Thromboembolic Event (VTE) and all cause mortality | 2 weeks study medication | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Have a Composite of Major VTE (Defined as Proximal DVT and PE) and VTE Related Mortality | Number of participants with the composite of major VTE (defined as proximal DVT and PE) and VTE related mortality | 2 weeks | 
| Percentage of Participants Who Have Proximal DVT (Deep Vein Thrombosis) During Treatment Period | Number of participants who have Proximal DVT during treatment period | 2 weeks | 
| Percentage of Participants With Symptomatic DVT (Deep Vein Thrombosis) | Number of Participants expressing DVT with symptoms | 2 weeks | 
| Percentage of Participants Who Have Total DVT (Deep Vein Thrombosis) During Treatment Period | Number of participants who have Total DVT during treatment period | 2 weeks | 
| Number of Participants With Pulmonary Embolism During Treatment Period | Pulmonary embolism confirmed by pulmonary scintigraphy, pulmonary angiography or contrast CT. | 2 weeks | 
| Number of Participants Who Died During Treatment Period | All cause death, as adjudicated by the VTE events committee. | 2 weeks | 
| Number of Participants With Bleeding Events During Treatment Period | Major bleeding events were defined as fatal clinically overt associated with loss of haemoglobin >=2g/dL 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 >=25 cm² wound hematoma >=100 cm² spontaneous nose bleed >5 min macroscopic hematuria spontaneous or >24 hours if associated with an intervention spontaneous rectal bleeding (more than a spot on toilet paper) gingival bleeding >5 min any other bleeding event considered clinically relevant by the investigator Any bleeding events were defined as major, clinically-relevant and minor bleeding events. Minor bleeding events were defined as all other bleeding events that did not fulfil the criteria from above. | 2 weeks | 
| Blood Transfusion | Blood transfusion for treated and operated patients on Day of surgery. | Day 0 | 
| Volume of Blood Loss | Volume of blood loss for treated and operated patients during surgery. | Day 0 | 
| Laboratory Analyses | Frequency of patients with possible clinically significant abnormalities. | First administration to end of study |