Phase III Study Testing Efficacy & Safety of Oral Dabigatran Etexilate vs Warfarin for 6 m Treatment for Acute Symp Venous Thromboembolism (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 150 mg bid administered orally and warfarin Pro re nata (As needed/PRN) to maintain an International Normalised Ratio (INR) of 2.0-3.0 for 6 month treatment of acute symptomatic VTE. The primary objective is to investigate the efficacy of dabigatran compared to warfarin during the 6 month treatment period. The investigation of other selected efficacy aspects and safety are regarded as secondary objective of this trial.

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

Conditions
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Thromboembolism

Intervention / Treatment
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* Drug: Warfarin
* Drug: Dabigatran etexilate


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Acute symptomatic uni- or bilateral Deep Vein Thrombosis (DVT) of the leg involving proximal veins, and/or Pulmonary Embolism (PE) Male or female, being 18 years of age or older Written informed consent for study participation Exclusion criteria: Persistent symptoms of VTE PE requiring urgent intervention Use of vena cava filter Contraindications to anticoagulant therapy Allergy to study medications Elevated Aspartate-aminotransferase (AST) or Alanine-aminotransferase (ALT) > 3x Upper Limit of Normal (ULN) or known liver disease expected to have an impact on survival Severe renal impairment Patients considered unsuitable for inclusion

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 etexilate (150mg bid)<br>Patients will receive 1 capsule containing 150 mg dabigatran etexilate/matching placebo twice daily | Drug: Dabigatran etexilate<br>* 150mg bid<br>|
| Active Comparator: Warfarin (INR 2.0-3.0)<br>Patients will receive tablets PRN warfarin/matching placebo to maintain a target INR of 2.0-3.0 | Drug: Warfarin<br>* PRN (to maintain a target INR of 2.0-3.0)<br>|

What is the study measuring?
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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 ptp. 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 ptp. 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 ptp. 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 ptp. 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. Hazard ratios and 95% CI were not calculated because of insufficient number of events. | From randomisation to 6 months (up to day 180) and 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 ptp. 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 Fatal and Non-fatal PE | Symptomatic fatal and non-fatal PE which occured from randomisation to end of ptp. 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 MBE, MBE and/or CRBE, and Any Bleeding Events | Major bleeding events (MBE) are 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) are defined as spontaneous skin hematoma >=25 cm² wound hematoma >=100 cm² spontaneous nose bleed >5 min macroscopic hematuria spontaneous or >24 hours if associated with an intervention spontaneous rectal bleeding 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 | 
| Number of Participants With Acute Coronary Syndrome (ACS) | Any ACS occurring during the conduct of the study (centrally adjudicated as definite). Patients having a centrally adjudicated definite ACS during intake of study drug and after stopping study drug, according to treatment group. ACS assessments pre-specified in the protocol without adjudication. Prior to database lock, the steering committee asked to have ACS events adjudicated by an independent committee. After database lock, the committee was provided with source documentation that was blinded to the patient's treatment assignment. ACS results presented are based on adjudication findings. | From first intake of study drug to last contact date | 
| 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 |