Secondary Prevention of Venous Thrombo Embolism (VTE).

Study Overview
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Brief Summary
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The general aim of this study is to determine the comparative safety and efficacy of dabigatran etexilate administered orally and warfarin (International Normalized Ratio (INR) of 2.0-3.0) for the long-term treatment and secondary prevention of symptomatic venous thromboembolism in patients who have been successfully treated with standard doses of an approved anticoagulant for three to twelve months for confirmed acute symptomatic Venous Thrombo-embolism.

Official Title
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A Phase III, Randomised, Multicenter, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Efficacy and Safety of Oral Dabigatran Etexilate (150 mg Bid) Compared to Warfarin (INR 2.0-3.0) for the Secondary Prevention of Venous Thromboembolism.

Conditions
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Thromboembolism

Intervention / Treatment
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* Drug: Dabigatran
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Inclusion_Criteria Acute symptomatic deep vein thrombosis (DVT) Pulmonary embolism (PE) 3-12 months prior to screening, which has been documented by objective testing Exclusion criteria: Exclusion_Criteria Symptomatic DVT or PE at screening Interruption of anticoagulant therapy for 2 or more weeks during the 3-12 months of treatment for the prior VTE. Patients who in the investigators judgement are perceived as having an excessive risk of bleeding Elevated Aspartate aminotransferase (AST) or Alanine tranminase (ALT) > 2x ULN Severe renal impairment (estimated creatinine clearance <= 30 ml/min)

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabigatran<br>Patient to receive 1 capsule containing dabigatran 150 mg twice daily plus placebo tablets for warfarin as decided by sham INR measurements | Drug: Dabigatran<br>* Dabigatran 150 mg BID (twice daily)<br>|
| Active Comparator: Warfarin (INR of 2.0-3.0)<br>Patient to receive warfarin tablets to target INR 2.0-3.0 plus placebo capsules for dabigatran twice daily | Drug: Warfarin<br>* Warfarin dosed individually to maintain INR 2.0-3.0<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of Recurrent VTE or VTE Death at 36 Months | Endpoint is a composite of recurrent Venous Thromboembolic Event (VTE) and death related to VTE. VTE was defined as the composite of symptomatic Deep Vein Thrombosis (DVT) of the leg and Pulmonary embolism (PE). All recurrent VTEs required objective verification by definitive diagnostic evaluation. In case of death, autopsy was an additional way to confirm VTE. | 36 months | 
| Composite of Recurrent VTE or VTE Death at 18 Months | Endpoint is a composite of recurrent Venous Thromboembolic Event (VTE) and death related to VTE. VTE was defined as the composite of symptomatic Deep Vein Thrombosis (DVT) of the leg and Pulmonary embolism (PE). All recurrent VTEs required objective verification by definitive diagnostic evaluation. In case of death, autopsy was an additional way to confirm VTE. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of Recurrent VTE or All Cause Death at 36 Months | Endpoint is a composite of recurrent Venous Thromboembolic Event (VTE) and all cause death. VTE was defined as the composite of symptomatic Deep Vein Thrombosis (DVT) of the leg and Pulmonary embolism (PE). All recurrent VTEs required objective verification by definitive diagnostic evaluation. | 36 months | 
| Composite of Recurrent VTE or All Cause Death at 18 Months | Endpoint is a composite of recurrent Venous Thromboembolic Event (VTE) and all cause death. VTE was defined as the composite of symptomatic Deep Vein Thrombosis (DVT) of the leg and Pulmonary embolism (PE). All recurrent VTEs required objective verification by definitive diagnostic evaluation. | 18 months | 
| Deep Vein Thrombosis (DVT) at 36 Months | Symptomatic Deep vein thrombosis (DVT). All DVT events required objective verification through definitive diagnostic evaluation. | 36 months | 
| DVT at 18 Months | Symptomatic Deep vein thrombosis (DVT). All DVT events required objective verification through definitive diagnostic evaluation. | 18 months | 
| Symptomatic Pulmonary Embolism (PE) at 36 Months | Symptomatic pulmonary embolism (PE) at 36 Months (fatal or non-fatal). All suspected PEs required confirmation by one of the following: ventilation-perfusion (V-Q) lung scan, pulmonary angiography, or spiral (helical) Computed tomography. | 36 months | 
| Symptomatic Pulmonary Embolism (PE) at 18 Months | Symptomatic pulmonary embolism (PE) at 18 Months (fatal or non-fatal). All suspected PEs required confirmation by one of the following: ventilation-perfusion (V-Q) lung scan, pulmonary angiography, or spiral (helical) Computed tomography. | 18 months | 
| Deaths Related to VTE at 36 Months | Deaths related to VTE (i.e. fatal PE) at 36 Months. Deaths related to VTE (i.e. fatal PE) at 18 Months. All deaths were centrally adjudicated by the Independent Central Adjudication Committee for VTE and death in a treatment-blinded way. | 36 months | 
| Deaths Related to VTE at 18 Months | Deaths related to VTE (i.e. fatal PE) at 18 Months. All deaths were centrally adjudicated by the Independent Central Adjudication Committee for VTE and death in a treatment-blinded way. | 18 months | 
| Deaths of All Causes at 36 Months | Deaths of all causes at 36 Months. All components of the primary efficacy endpoint and all deaths were centrally adjudicated by the Independent Central Adjudication Committee for VTE and death without knowledge of any individual treatment assignments. | 36 months | 
| Deaths of All Causes at 18 Months | Deaths of all causes at 18 Months. All components of the primary efficacy endpoint and all deaths were centrally adjudicated by the Independent Central Adjudication Committee for VTE and death without knowledge of any individual treatment assignments. | 18 months | 
| Number of Participants With Bleeding Events | MBE (major bleeding event) if it fulfilled at least one of the following criteria Fatal bleeding Symptomatic bleeding in a critical area or organ. Bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells. Minor bleeding event was any bleeding that did not fulfil any of the criteria for MBEs CRBE (clinically relevant bleeding event) if it is a minor bleeding events which fulfilled at least one of the following criteria Spontaneous skin haematoma ≥25 cm2 Spontaneous nose bleed >5 min duration Macroscopic haematuria, either spontaneous or, if associated with an intervention, lasting >24 h Spontaneous rectal bleeding Gingival bleeding >5 min Bleeding leading to hospitalisation or requiring surgical treatment Bleeding leading to a transfusion of <2 units of whole blood or red cells Any other bleeding event considered clinically relevant by the investigator | first intake of study drug until 6 days following last intake of study drug | 
| Laboratory Analysis | Patients with LFT (liver function tests) increases of possible clinical significance during treatment. Increases of possible clinical significance were defined as: ≥3 x ULN (AST, ALT), ≥2 x ULN (AP), and ≥2 mg/dL (total bilirubin). Only patients with a baseline value which was not of possible clinical significance (or without any baseline value) could have a PCSA (Possible clinically significant abnormality). | 18 months + 30 days follow up | 
| Number of Participants With Definite Acute Coronary Syndrome (ACS) | All suspected ACS occurring during the trial were to be recorded on the CRF and were to be centrally adjudicated by an independent ACS/AC in a treatment-blinded manner. | day of first study drug intake until last day of study drug intake; from the day after last intake of study drug until trial termination |