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 (eTRIS)

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

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.

Study Overview

• Status: Completed
• Conditions: Venous Thrombosis; Deep Vein Thrombosis
• Intervention / Treatment: Drug: edoxaban tosylate; Drug: enoxaparin/unfractionated heparin; Drug: warfarin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada
  • Ontario
    • London, Ontario, Canada
    • New Market, Ontario, Canada
  • Quebec
    • Greenfield Park, Quebec, Canada
    • Montreal, Quebec, Canada
• United States
  • Alabama
    • Dothan, Alabama, United States
    • Montgomery, Alabama, United States
  • California
    • Sacramento, California, United States
  • Florida
    • Atlantis, Florida, United States
    • Clearwater, Florida, United States
    • Fort Myers, Florida, United States
    • Jacksonville, Florida, United States
    • Sarasota, Florida, United States
    • Tampa, Florida, United States
  • Georgia
    • Jonesboro, Georgia, United States
  • Indiana
    • Lafayette, Indiana, United States
  • Kentucky
    • Paducah, Kentucky, United States
  • Louisiana
    • Covington, Louisiana, United States
  • Maryland
    • Annapolis, Maryland, United States
    • Baltimore, Maryland, United States
    • Randallstown, Maryland, United States
  • Montana
    • Butte, Montana, United States
  • Nebraska
    • Grand Island, Nebraska, United States
  • New York
    • Rochester, New York, United States
  • North Carolina
    • Durham, North Carolina, United States
    • Greensboro, North Carolina, United States
    • Wilmington, North Carolina, United States
  • Ohio
    • Maumee, Ohio, United States
  • Pennsylvania
    • Camp Hill, Pennsylvania, United States
    • Ephrata, Pennsylvania, United States
    • Sellersville, Pennsylvania, United States
  • South Dakota
    • Rapid City, South Dakota, United States
  • Virginia
    • Fredericksburg, Virginia, United States
  • Washington
    • Tacoma, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: edoxaban tosylate	Drug: edoxaban tosylate; 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
Active Comparator: heparin/warfarin	Drug: enoxaparin/unfractionated heparin; 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.; Drug: warfarin; tablet for oral use; daily dosage, adjusted to maintain international normalized ratio (INR) between 2.0 and 3.0; 90 days treatment.

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.
• Investigators: Principal Investigator: Samuel Z Goldhaber, MD, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Piazza G, Mani V, Goldhaber SZ, Grosso MA, Mercuri M, Lanz HJ, Schussler S, Hsu C, Chinigo A, Ritchie B, Nadar V, Cannon K, Pullman J, Concha M, Schul M, Fayad ZA; edoxaban Thrombus Reduction Imaging Study (eTRIS) Investigators. Magnetic resonance venography to assess thrombus resolution with edoxaban monotherapy versus parenteral anticoagulation/warfarin for symptomatic deep vein thrombosis: A multicenter feasibility study. Vasc Med. 2016 Aug;21(4):361-8. doi: 10.1177/1358863X16645853. Epub 2016 May 10.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2012
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: August 2, 2012
• First Submitted That Met QC Criteria: August 8, 2012
• First Posted (Estimate): August 13, 2012

Study Record Updates

• Last Update Posted (Actual): February 26, 2019
• Last Update Submitted That Met QC Criteria: February 8, 2019
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Venous Thrombosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Heparin; Edoxaban; Enoxaparin; Calcium heparin; Warfarin
• Other Study ID Numbers: DU176b-D-U211

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)