Dabigatran Etexilate in Extended Venous Thromboembolism (VTE) Prevention After Hip Replacement Surgery

Study Overview
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Brief Summary
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The objective of this study is to determine the comparative efficacy and safety of two oral regimens of dabigatran etexilate, compared to a standard subcutaneous regimen of enoxaparin, in prevention of venous thromboembolism in patients with primary elective total hip replacement surgery.

Official Title
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A Phase III Randomised, Parallel Group, Double-blind, Active Controlled Study to Investigate the Efficacy and Safety of Two Different Dose Regimens of Orally Administered Dabigatran Etexilate Capsules [150 or 220 mg Once Daily Starting With Half Dose (75 or 110 mg) on the Day of Surgery] Compared to Subcutaneous Enoxaparin 40 mg Once Daily for 28-35 Days, in Prevention of Venous Thromboembolism in Patients With Primary Elective Total Hip Replacement Surgery. RE-NOVATE (Extended Thromboembolism Prevention After Hip Surgery)

Conditions
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Thromboembolism, Arthroplasty, Replacement, Hip

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


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, elective total hip 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, 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 AST or 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 potential and are not practising or do not plan to continue practising acceptable methods of birth control Allergy to radio opaque contrast media or iodine, heparins (incl. heparin induced 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 75 mg<br>daily dose 150 mg once daily, half a dose on the day of surgery | Drug: dabigatran etexilate<br>* daily dose 150 mg once daily, half a dose on the day of surgery<br>|
| Experimental: dabigatran etexilate 110 mg<br>daily dose 220 mg once daily, half a dose on the day of surgery | Drug: dabigatran etexilate<br>* daily dose 150 mg once daily, half a dose on the day of surgery<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 |
| --- | --- | --- |
| 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 31-38 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 31-38 days | 
| Proximal Deep Vein Thrombosis During Treatment Period | Proximal Deep Vein Thrombosis as adjudicated by the VTE events committee | First administration until 31-38 days | 
| Total Deep Vein Thrombosis During Treatment Period | Total Deep Vein Thrombosis as adjudicated by the VTE events committee | First administration until 31-38 days | 
| 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 31-38 days | 
| 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 31-38 days | 
| Death During Treatment Period | All cause death, as adjudicated by the VTE events committee | First administration until 31-38 days | 
| 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). | end of treatment to day 91±7 | 
| 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 31-38 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 |