RE-MODEL Dabigatran Etexilate 150mg or 220mg Once Daily (o.d.) Versus (v.s.) Enoxaparin 40mg o.d. for Prevention of Thrombosis After Knee Surgery

Study Overview
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Brief Summary
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A phase III, randomised, parallel-group, double-blind, active controlled study to investigate the ef ficacy and safety of two different dose regimens of orally administered dabigatran etexilate capsule s [150 or 220 mg once daily starting with a half dose (i.e.75 or 110 mg) on the day of surgery] comp ared to subcutaneous enoxaparin 40 mg once daily for 6 to 10 days, in prevention of venous thromboem bolism in patients with primary elective total knee replacement surgery. RE-MODEL (Thromboembolism prevention after knee surgery)

Official Title
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RE-MODEL (Thromboembolism Prevention After Knee Surgery). Two Different Dose Regimens of Orally Administered Dabigatran Etexilate Capsules [150 or 220 mg Once Daily Starting With a Half Dose (i.e.75 or 110 mg) on the Day of Surgery] Compared to Subcutaneous Enoxaparin 40 mg Once Daily for 6-10 Days

Conditions
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Arthroplasty, Replacement, Knee, Thromboembolism

Intervention / Treatment
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* Drug: enoxaparin
* Drug: dabigatran etexilate
* Drug: dabigatran etexilate


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Inclusion criteria (selected): Patients (18 years or older) scheduled to undergo a primary, unilateral, elect ive total knee replacement Written Informed Consent Exclusion criteria Exclusion criteria (selected): Patients with an excessive risk of bleeding, for example because of history of bleeding diathesis major surgery or trauma within the last 3 months history of haemorrhagic stroke or any of the following intracranial pathologies: bleeding, neoplasm, arteriovenous (AV) malformation or aneurysm clinically relevant bleeding or gastric / duodenal ulcer within the last 6 months treatment with anticoagulants within 7 days prior to joint replacement surgery or anticipated need during the study treatment period thrombocytopenia. Active malignant disease or current cytostatic treatment Known severe renal insufficiency Liver disease expected to have any potential impact on survival, or elevated aspartate aminotransferase (AST) or alanine transaminase (ALT) > 2x upper limit of normal Recent unstable cardiovascular disease or history of myocardial infarction within the last 3 months Pre-menopausal women who are pregnant or nursing, or are of child-bearing pote ntial and are not practising or do not plan to continue practising acceptable me thods of birth control Allergy to radio opaque contrast media or iodine, heparins (incl. heparin indu ced thrombocytopenia) or dabigatran Contraindications to enoxaparin Participation in a clinical trial during the last 30 days

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 etexilate 220 mg<br>220 mg once daily | Drug: dabigatran etexilate<br>* 220 mg once daily<br>|
| Experimental: dabigatran etexilate 150 mg<br>150 mg once daily | Drug: dabigatran etexilate<br>* 150 mg once daily<br>|
| Active Comparator: enoxaparin<br>40 mg once daily | Drug: enoxaparin<br>* 40 mg once 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 6-10 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 6-10 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 6-10 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 6-10 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 6-10 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 6-10 days | 
| Number of Participants Who Died During Treatment Period | All cause death, as adjudicated by the VTE events committee | First administration until 6-10 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 6-10 days | 
| Blood Transfusion | Blood transfusion for treated and operated patients on Day of surgery. | Day 1 | 
| Volume of Blood Loss | Volume of blood loss for treated and operated patients during surgery. | Day 1 | 
| Laboratory Analyses | Frequency of patients with possible clinically significant abnormalities. | First administration to end of study |