Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism

Study Overview
=================
Brief Summary
-----------------
The purpose of this trial is to determine the comparative safety and efficacy of dabigatran etexilate 150 mg bid administered orally and warfarin as needed (pro re nata - prn) to maintain an International Normalised Ratio (INR) of 2.0-3.0 for 6 month treatment of acute symptomatic venous thromboembolism (VTE), following initial treatment (5-10 days) with a parenteral anticoagulant approved for this indication. This trial aims to demonstrate non-inferiority of dabigatran compared with warfarin in patients with acute symptomatic VTE. After achieving non-inferiority, this trial also aims to establish superiority (by means of hierarchical tests) of dabigatran over warfarin.

Official Title
-----------------
A Phase III, Randomised, Double Blind, Parallel-group Study of the Efficacy and Safety of Oral Dabigatran Etexilate 150 mg Twice Daily Compared to Warfarin (INR 2.0-3.0) for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism (VTE), Following Initial Treatment (5-10 Days) With a Parenteral Anticoagulant Approved for This Indication.

Conditions
-----------------
Thromboembolism

Intervention / Treatment
-----------------
* Drug: dabigatran etexilate 150 mg
* Drug: warfarin (INR 2-3)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria Acute deep vein thrombosis (DVT) of the leg involving proximal veins, and/or pulmonary embolism (PE) iin patients for whom at least 6 months of anticoagulant therapy is considered appropriate Male or female, being 18 years of age or older Written informed consent for study participation Exclusion criteria Overt symptoms of VTE for longer than 2 weeks prior to enrolment PE satisfying at least one of the following criteria: Haemodynamic instability, embolectomy is indicated or performed, thrombolytic therapy is indicated or performed, or suspected source of PE is other than the legs Actual or anticipated use of vena cava filter Contraindications to anticoagulant therapy Patients who in the investigators opinion should not be treated with warfarin Allergy to heparins or other alternate approved therapy used for initial treatment, warfarin or dabigatran, or to one of the excipients included in these medications Patients who in the investigators judgement are perceived as having an excessive risk of bleeding Known anaemia Need of anticoagulant treatment for disorders other than VTE Recent unstable cardiovascular disease Elevated AST or ALT > 2x ULN Liver disease expected to have any potential impact on survival Patients who have developed transaminase elevations upon exposure to ximelagatran Severe renal impairment Women who are pregnant, nursing, or of childbearing potential who refuse to use a medically acceptable form of contraception Participation in another clinical trial with an investigational drug during the last 30 days or previous participation in this study Patients considered unsuitable for inclusion by the investigator

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dabigatran etexilate 150 mg<br>twice daily | Drug: dabigatran etexilate 150 mg<br>* twice daily<br>|
| Active Comparator: warfarin (INR 2-3)<br>prn to maintain INR (2-3) | Drug: warfarin (INR 2-3)<br>* prn to maintain INR (2-3)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Recurrent Symptomatic Venous Thromboembolism (VTE) and Deaths Related to VTE | All suspected recurrent VTEs and all deaths and bleeding events were evaluated by an independent central adjudication committee, and all analyses are based on the events that were centrally confirmed by this committee. | For statistical analysis 1: from randomisation to end of post treatment period (ptp), planned to be up to day 224. For statistical analysis 2: from randomisation to 6 months (up to day 180) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Recurrent Symptomatic VTE and All Deaths | VTE or any death which occured from randomisation to end of post treatment period. All suspected recurrent VTEs and all deaths and bleeding events were evaluated by an independent central adjudication committee, and all analyses are based on the events that were centrally confirmed by this committee. | For statistical analysis 1: from randomisation to 6 months (up to day 180) For statistical analysis 2: from randomisation to end of ptp, planned to be up to day 224. | 
| Number of Participants With Recurrent Symptomatic DVT | Symptomatic DVT which occured from randomisation to end of post treatment period. All suspected recurrent VTEs and all deaths and bleeding events were evaluated by an independent central adjudication committee, and all analyses are based on the events that were centrally confirmed by this committee. | For statistical analysis 1: from randomisation to 6 months (up to day 180) For statistical analysis 2: from randomisation to end of ptp, planned to be up to day 224. | 
| Number of Participants With Recurrent Symptomatic Non-fatal PE | Symptomatic non-fatal PE which occured from randomisation to end of post treatment period. All suspected recurrent VTEs and all deaths and bleeding events were evaluated by an independent central adjudication committee, and all analyses are based on the events that were centrally confirmed by this committee. | For statistical analysis 1: from randomisation to 6 months (up to day 180) For statistical analysis 2: from randomisation to end of ptp, planned to be up to day 224. | 
| Number of Participants Who Died Due to VTE | VTE - related deaths which occured from randomisation to end of post treatment period. All suspected recurrent VTEs and all deaths and bleeding events were evaluated by an independent central adjudication committee, and all analyses are based on the events that were centrally confirmed by this committee. | For statistical analysis 1: from randomisation to 6 months (up to day 180) For statistical analysis 2: from randomisation to end of ptp, planned to be up to day 224. | 
| Number of Participants Who Died (Any Cause) | Any deaths which occured from randomisation to end of post treatment period. All suspected recurrent VTEs and all deaths and bleeding events were evaluated by an independent central adjudication committee, and all analyses are based on the events that were centrally confirmed by this committee. | For statistical analysis 1: from randomisation to 6 months (up to day 180) For statistical analysis 2: from randomisation to end of ptp, planned to be up to day 224. | 
| Number of Participants With Bleeding Events | Major bleeding events (MBE) were defined as 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 Clinically-relevant bleeding events (CRBE) was defined as spontaneous skin hematoma >=25 cm² spontaneous nose bleed >5 min macroscopic hematuria spontaneous or >24 hours if associated with an intervention spontaneous rectal bleeding (more than spotting on toilet paper) gingival bleeding >5 min leading to hospitalisation and / or requiring surgical treatment leading to a transfusion of <2 units of whole blood or red cells any other bleeding event considered clinically relevant by the investigator Any bleeding events were defined as major, clinically-relevant and nuisance bleeding events. Nuisance bleeding events were defined as all other bleeding events that did not fulfil the criteria from above. | From first intake of study drug to last intake of study drug + 6 days washout (washout time can be reduced until 0 day if the patient takes an other anti-coagulant therapy on and after last intake of active study drug) | 
| Number of Participants With Acute Coronary Syndrome (ACS) | Any ACS occurring during the conduct of the study (centrally adjudicated as definite). Counts of patients having a centrally adjudicated definite ACS during intake of active study drug, after stopping active study drug and before or without intake of active study drug, according to treatment group. All suspected recurrent VTEs and all deaths and bleeding events were evaluated by an independent central adjudication committee, and all analyses are based on the events that were centrally confirmed by this committee. | From first intake of study drug to end of study conduct | 
| Laboratory Analyses | Frequency of patients with possible clinically significant abnormalities. | From first intake of study drug to last intake of study drug + 6 days washout (washout time can be reduced until 0 day if the patient takes an other anti-coagulant therapy on and after last intake of active study drug) |