Deep Vein Thrombosis, Venous Thrombosis
Conditions
Brief summary
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
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.
Interventions
DRUGedoxaban 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
DRUGenoxaparin/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.
DRUGwarfarin
tablet for oral use; daily dosage, adjusted to maintain international normalized ratio (INR) between 2.0 and 3.0; 90 days treatment.
Sponsors
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in Thrombus Volume Assessed by MRI [Using the Magnetic Resonance Venography (MRV) Method] | Baseline to final visit (Day 14-21) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Relevant Bleeding | Initial dose of study drug up to 3 days after last dose | Clinically relevant bleeding was defined as major or clinically relevant non-major bleeding |
| Number of Participants With Recurrence of Venous Thromboembolism (VTE) | Baseline to final visit (Day 14-21) | 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) |
| Number of Participants With Major Adverse Cardiovascular Events (MACE) | Initial dose of study drug up to 3 days after last dose | MACE is defined as a composite of non-fatal myocardial infarction (MI), non-fatal stroke, non-fatal systemic embolic event (SEE) and cardiovascular death |
| Number of Participants With Change From Baseline in the Presence or Absence of Thrombus by Vessel | Baseline to final visit (Day 14-21) | — |
Countries
Canada, United States
Participant flow
Recruitment details
From September 2012 through January 2014, a total of 85 patients were enrolled at 26 centers in North America (US and Canada). One subject was not included in either the full analysis set or the safety analysis set because of major protocol violation - he did not take any dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Edoxaban Participants treated with edoxaban | 56 |
| Warfarin Participants treated with warfarin | 28 |
| Total | 84 |
Baseline characteristics
| Characteristic | Edoxaban | Warfarin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 15 Participants | 6 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 41 Participants | 22 Participants | 63 Participants |
| Region of Enrollment Canada | 16 participants | 6 participants | 22 participants |
| Region of Enrollment United States | 40 participants | 22 participants | 62 participants |
| Sex: Female, Male Female | 15 Participants | 7 Participants | 22 Participants |
| Sex: Female, Male Male | 41 Participants | 21 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 56 | 17 / 28 |
| serious Total, serious adverse events | 4 / 56 | 4 / 28 |
Outcome results
Primary
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
Time frame: Baseline to final visit (Day 14-21)
Population: Modified intention to treat (mITT), defined as intention to treat minus the one patient who did not take the investigational product
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edoxaban | Relative Change From Baseline in Thrombus Volume Assessed by MRI [Using the Magnetic Resonance Venography (MRV) Method] | -46.6 percentage of change | Standard Deviation 45.53 |
| Warfarin | Relative Change From Baseline in Thrombus Volume Assessed by MRI [Using the Magnetic Resonance Venography (MRV) Method] | -51.4 percentage of change | Standard Deviation 32.96 |
95% CI: [-12.7, 30.2]
Secondary
Number of Participants With Change From Baseline in the Presence or Absence of Thrombus by Vessel
Time frame: Baseline to final visit (Day 14-21)
Population: mITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban | Number of Participants With Change From Baseline in the Presence or Absence of Thrombus by Vessel | 0 Participants |
| Warfarin | Number of Participants With Change From Baseline in the Presence or Absence of Thrombus by Vessel | 0 Participants |
Secondary
Number of Participants With Clinically Relevant Bleeding
Clinically relevant bleeding was defined as major or clinically relevant non-major bleeding
Time frame: Initial dose of study drug up to 3 days after last dose
Population: Adjudicated in the mITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban | Number of Participants With Clinically Relevant Bleeding | 3 Participants |
| Warfarin | Number of Participants With Clinically Relevant Bleeding | 2 Participants |
Secondary
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
Time frame: Initial dose of study drug up to 3 days after last dose
Population: Adjudicated confirmed events in the mITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban | Number of Participants With Major Adverse Cardiovascular Events (MACE) | 2 Participants |
| Warfarin | Number of Participants With Major Adverse Cardiovascular Events (MACE) | 0 Participants |
Secondary
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)
Time frame: Baseline to final visit (Day 14-21)
Population: mITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban | Number of Participants With Recurrence of Venous Thromboembolism (VTE) | 4 Participants |
| Warfarin | Number of Participants With Recurrence of Venous Thromboembolism (VTE) | 2 Participants |