Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE

Study Overview
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Brief Summary
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The primary efficacy objective is to evaluate whether dabigatran etexilate is superior to placebo in the long-term prevention of recurrent symptomatic venous thrombo-embolism (VTE) in patients with symptomatic deep-vein thrombosis (DVT) or pulmonary embolism (PE) who completed 6 to 18 months of treatment with vitamin K antagonist (VKA).

Official Title
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Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long-term Prevention of Recurrent Symptomatic Proximal Venous Thromboembolism in Patients With Symptomatic Deep-vein Thrombosis or Pulmonary Embolism.

Conditions
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Venous Thromboembolism

Intervention / Treatment
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* Drug: dabigatran etexilate 150 mg twice daily (BID)
* Drug: matching placebo twice daily (BID)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with confirmed symptomatic PE or proximal DVT of the leg(s) who have been treated for 6 to 18 months with therapeutic dosages (intended INR between 2-3) of an oral VKA (e.g. warfarin, acenocoumarol, phenprocoumon, or fluindione) or RE-COVER study medication up to the moment of screening for the current study. Written informed consent Exclusion criteria: Younger then 18 years of age Indication for VKA other than DVT and/or PE Patients in whom anticoagulant treatment for their index PE or DVT should be continued Active liver disease or liver disease decreasing survival (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or ALAT > 3 x ULN Creatinine clearance < 30 ml/min Acute bacterial endocarditis Active bleeding or high risk for bleeding. Uncontrolled hypertension (investigators judgement) Intake of another experimental drug within the 30 days prior to randomization into the study Life expectancy <6 months Childbearing potential without proper contraceptive measures*, pregnancy or breast feeding

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 150 mg BID<br>Patient to receive dabigatran etexilatate capsules 150 mg twice daily | Drug: dabigatran etexilate 150 mg twice daily (BID)<br>* dabigatran etexilate capsules 150 mg BID<br>|
| Placebo Comparator: matching placebo twice daily (BID)<br>Patient to receive dabigatran extexilate matching placebo capsules twice daily | Drug: matching placebo twice daily (BID)<br>* Matching placebo BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Including Unexplained Death During the Intended Treatment Period | Symptomatic recurrent VTE is the composite of recurrent deep vein thrombosis (DVT) , fatal or non-fatal pulmonary embolism (PE). Whilst the endpoint is time to event, the measured values present the number of participant with event and the hazard ratio presents the time to event. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Excluding Unexplained Death During the Intended Treatment Period | Symptomatic recurrent VTE is the composite of recurrent deep vein thrombosis (DVT) , fatal or non-fatal pulmonary embolism (PE). Whilst the endpoint is time to event, the measured values present the number of participant with event and the hazard ratio presents the time to event. | 6 months | 
| Centrally Confirmed Symptomatic Recurrent Deep Venous Thrombotic (DVT) Events During the Intended Treatment Period | Number of the participants with centrally confirmed symptomatic recurrent deep venous thrombotic (DVT) events during the intended treatment period were described. | 6 months | 
| Centrally Confirmed Symptomatic Pulmonary Embolism (PE) Events During the Intended Treatment Period | Number of participants with centrally confirmed symptomatic pulmonary embolism (PE) events during the intended treatment period were described. | 6 months | 
| Centrally Confirmed Unexplained Deaths During the Intended Treatment Period | Number of participants with centrally confirmed unexplained deaths during the intended treatment period were described. | 6 months | 
| Centrally Confirmed Bleeding Event During the Treatment Period | Major bleeding events (MBE) had to fulfil at least 1 of the following criteria: Fatal bleeding Associated with a fall in haemoglobin of ≥2 g/dL Led to the transfusion of ≥2 units packed cells or whole blood Occurred in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal Other clinically relevant bleeding was defined as overt bleeding not meeting the criteria for an MBE but associated with medical intervention, unscheduled contact with a physician, (temporary) cessation of study treatment, or associated with discomfort such as pain, or impairment of activities of daily life. Examples of these bleedings were: Bleeding that compromised haemodynamics Bleeding that led to hospitalisation Trivial bleeding events were defined as all other bleeding events that did not fulfil the criteria of MBEs or CRBEs. All bleeding events include MBEs, CRBEs, and trivial bleeding events. | 6 months | 
| Centrally Confirmed Cardiovascular Events During the Treatment Period | Cardiovascular events that occurred during the treatment period + 3 days were summarised by treatment groups. | 6 months | 
| Laboratory Measures, Especially Liver Function Tests (LFTs) | Number of participants with possible clinically significant abnormalities during the treatment period. | 6 months |