A Randomized, Open-Label, Parallel-Group, Multi-Center Study for the Evaluation of Efficacy and Safety of Edoxaban Monotherapy Versus Low Molecular Weight (LMW) Heparin/Warfarin in Subjects With Symptomatic Deep-Vein Thrombosis

Study Overview
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Brief Summary
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Assess the relative change in thrombus volume as determined by two assessments (Baseline and Day 14-21) with magnetic resonance venography (MRV) in subjects with deep-vein thrombosis (DVT) treated with either an edoxaban monotherapy regimen or a low molecular weight (LMW) heparin/warfarin regimen.

Detailed Description
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The classical management of patients with venous thromboembolism (VTE) consists of an initial treatment of at least five days of a (LMW) heparin followed by long-term treatment with a vitamin K antagonist (VKA), such as warfarin. The eTRIS study will address the clinically important question of whether edoxaban monotherapy, without concomitant (LMW) heparin at the time of treatment initiation is comparable to or better than standard treatment with (LMW) heparin/warfarin therapy in subjects with acute symptomatic DVT as assessed by the relative change from baseline in thrombus volume (measured by MRI) at Day 14-21.

Official Title
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A Randomized, Open-Label, Parallel-Group, Multi-Center Study for the Evaluation of Efficacy and Safety of Edoxaban Monotherapy Versus (LMW) Heparin/Warfarin in Subjects With Symptomatic Deep-Vein Thrombosis - Edoxaban Thrombus Reduction Imaging Study

Conditions
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Deep Vein Thrombosis, Venous Thrombosis

Intervention / Treatment
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* Drug: edoxaban tosylate
* Drug: enoxaparin/unfractionated heparin
* Drug: warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects older than the minimum legal adult age (country specific) Acute symptomatic proximal DVT involving the popliteal, femoral or iliac veins confirmed by compression ultrasonography (CUS) or other appropriate imaging techniques (such as venography or spiral/contrast CT) with symptom onset < or = 1week prior to randomization Able to provide signed informed consent Exclusion Criteria: Concomitant pulmonary embolism known to the investigator at the time of randomization Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of DVT Indication for warfarin other than DVT More than 48 hours pre-treatment with therapeutic dosages of anti-coagulant treatment [low molecular weight heparin (LMWH), unfractionated heparin (UFH), fondaparinux, VKA, factor Xa inhibitor or other anti coagulant per local labeling] prior to randomization to treat the current episode Treatment with any investigational drug within 30 days prior to randomization Calculated creatinine clearance (CrCL) < 30 mL/min Significant liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis) or alanine aminotransferase (ALT) > or = 2 times the upper limit of normal (ULN), or total bilirubin (TBL) > or = to 1.5 times the ULN (however subjects whose elevated TBL is due to known Gilbert's syndrome may be included in the study) Subjects with active cancer for whom long term treatment with (LMW) heparin is anticipated Life expectancy < 3 months Active bleeding or high risk for bleeding contraindicating treatment with (LMW) heparin or warfarin Uncontrolled hypertension as judged by the Investigator (e.g., systolic blood pressure > 170 mmHg or diastolic blood pressure > 100 mmHg despite antihypertensive medications confirmed by repeat measurement) Women of childbearing potential without proper contraceptive measures (i.e., a method of contraception with a failure rate < 1 % during the course of the study including the observational period) and women who are pregnant or breast feeding Any contraindication listed in the local labeling of LMWH, UFH, or warfarin Chronic treatment with non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) including both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX- 2) inhibitors for > or = 4 days/week anticipated to continue during the study. Treatment with aspirin in a dosage of more than 100 mg/per day or dual antiplatelet therapy (any two antiplatelet agents including aspirin plus any other oral or intravenous [IV] antiplatelet drug) anticipated to continue during the study Treatment with P-gp inhibitors is not permitted at the time of randomization; subsequent use is permitted, with a dose reduction in the edoxaban monotherapy treatment arm. Known history of positive Hepatitis B antigen or Hepatitis C antibody Subjects with any condition that, as judged by the investigator, would put the subject at increased risk of harm if he/she participated in the study; including, but not limited to, subjects at increased risk of harm if given a gadolinium-based contrast agent such as gadofosveset trisodium (Ablavar®) Subjects for whom MRI would be contraindicated (e.g., subjects with metal implants) or for whom the use of a gadolinium-based contrast agent such as gadofosveset trisodium (Ablavar®) would be contraindicated Subject has previously entered this study or another edoxaban study

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: edoxaban tosylate<br> | Drug: edoxaban tosylate<br>* edoxaban tosylate (DU-176b), film-coated for oral use, 90 mg once daily (QD) for 10 days (±2 days) followed by 60 mg QD for a total of approximately 90 days of edoxaban treatment<br>|
| Active Comparator: heparin/warfarin<br> | Drug: enoxaparin/unfractionated heparin<br>* enoxaparin - administered by subcutaneous injection;1 mg/kg/ twice daily or 1.5 mg/kg once daily unfractionated heparin - started with 5000 IU bolus intravenous administration, 1300 IU/h continuous infusion, minimum of 5 days of treatment and stopped when target INR (2.0 - 3.0) is achieved.<br>Drug: warfarin<br>* tablet for oral use; daily dosage, adjusted to maintain international normalized ratio (INR) between 2.0 and 3.0; 90 days treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Change From Baseline in Thrombus Volume Assessed by MRI [Using the Magnetic Resonance Venography (MRV) Method] | Thrombus Volume (mm^3) was measured at baseline and between days 14 to 21 using MRI results as determined by Magnetic Resonance Venography (MRV) method, and the relative percentage change from baseline was calculated | Baseline to final visit (Day 14-21) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinically Relevant Bleeding | Clinically relevant bleeding was defined as major or clinically relevant non-major bleeding | Initial dose of study drug up to 3 days after last dose | 
| Number of Participants With Recurrence of Venous Thromboembolism (VTE) | Number of participants with investigator-confirmed recurrent VTE events that start or worsen after the first dose of study drug and prior to the date of the final visit or telephone contact (inclusive) | Baseline to final visit (Day 14-21) | 
| Number of Participants With Major Adverse Cardiovascular Events (MACE) | MACE is defined as a composite of non-fatal myocardial infarction (MI), non-fatal stroke, non-fatal systemic embolic event (SEE) and cardiovascular death | Initial dose of study drug up to 3 days after last dose | 
| Number of Participants With Change From Baseline in the Presence or Absence of Thrombus by Vessel |  | Baseline to final visit (Day 14-21) |