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Comparative Investigation of Low Molecular Weight (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus (LMW) Heparin/Warfarin in the Treatment of Symptomatic Deep-Vein Blood Clots and/or Lung Blood Clots. (The Edoxaban Hokusai-VTE Study).

A Phase 3, Randomized, Parallel-Group, Multi-Center, Multi-National Study for the Evaluation of Efficacy and Safety of (LMW) Heparin/Edoxaban Versus (LMW) Heparin/Warfarin in Subjects With Symptomatic Deep-Vein Thrombosis (DVT) and or Pulmonary Embolism (PE).

Status
Completed
Phases
Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00986154
Enrollment
8292
Registered
2009-09-29
Start date
2009-10-31
Completion date
2013-04-30
Last updated
2019-03-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Thromboembolism, Venous Thromboembolism, Venous Thrombosis

Keywords

Recurrent Thrombosis, Recurrent Pulmonary Embolism, Symptomatic Deep Vein Thrombosis, Symptomatic Pulmonary Embolism, Venous Thromboembolism (VTE)

Brief summary

Evaluation of heparin/edoxaban tosylate (DU176b) versus heparin/warfarin in preventing recurrence of blood clots in patients with acute symptomatic deep-vein blood clots in the legs and/or blood clots in the lungs.

Interventions

DRUGedoxaban tosylate(DU-176b)

edoxaban tosylate(DU-176b), film-coated tablet for oral use, 30 mg, two tablets (60 mg) once daily, maximum of 12 months treatment

DRUGlow molecular weight heparin/unfractionated heparin

LMW heparin - subcutaneous injection, 1 mg/Kg twice daily or 1.5 mg/Kg once daily. Unfractionated heparin - 5,000 IU bolus intravenous administration, 1,300 IU/hour continuous infusion, minimum of 5 days and maximum of about 12 days treatment

DRUGwarfarin

tablet for oral use; 0.5 mg, 1 mg, 2.5 mg, 5 mg; daily dosage, adjusted to maintain international normalized ratio (INR) between 2.0 and 3.0; maximum of 12 months treatment

Sponsors

Daiichi Sankyo
Lead SponsorINDUSTRY

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)

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 and/or symptomatic PE confirmed at the site by appropriate diagnostic imaging; * Able to provide written informed consent

Exclusion criteria

* thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of DVT and/or PE; * More than 48 hours pre-treatment with anticoagulant therapy prior to randomization; * Calculated Creatinine clearance (CrCL) \< 30 mL/min; * significant liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis) or alanine transaminase (ALT) \>\\= 2 times the upper limit of normal (ULN), or total bilirubin (TBL) x 1.5 times the ULN; * patients with active cancer for whom long term treatment with (LMW) heparin is anticipated; * active bleeding or high risk for bleeding contraindicating treatment with (LMW) heparin or warfarin; * chronic treatment with non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs); * treatment with aspirin in a dosage of more than 100 mg/per day or dual antiplatelet therapy; * concurrent treatment with potent P-gp inhibitors; * subjects with any condition that, as judged by the investigator, would place the subject at increased risk of harm if he/she participated in the study

Design outcomes

Primary

MeasureTime frameDescription
Symptomatic Recurrent VTE, i.e., the Composite of DVT, Non-fatal PE, and Fatal PE12 months from time of randomizationSymptomatic recurrent Venous Thromboembolism (VTE), i.e., the composite of deep Vein Thrombosis (DVT), non-fatal Pulmonary Embolism (PE), and fatal PE occurring during the Overall Study Period. Overall Study Period defined as The time from the reference date (randomization date/initial dose of study drug date) to the last study follow-up visit.

Secondary

MeasureTime frameDescription
The Composite Clinical Outcome of Symptomatic Recurrent VTE and All-cause Mortality12 months from time of randomization—
Clinically Relevant Bleeding (i.e., Major or Clinically Relevant Non-major Bleeding) Occurring During Treatment12 months from time of randomizationClinically relevant bleeding (i.e., major or clinically relevant non-major bleeding) occurring during treatment plus 3 days after their last dose for that time period.

Countries

Argentina, Australia, Austria, Belarus, Belgium, Brazil, Canada, Chile, China, Czechia, Denmark, Estonia, France, Germany, Hungary, India, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Norway, Philippines, Poland, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States

Participant flow

Participants by arm

ArmCount
Heparin/Edoxaban Tosylate
edoxaban tosylate(DU-176b): edoxaban tosylate(DU-176b), film-coated tablet for oral use, 30 mg, two tablets (60 mg) once daily, maximum of 12 months treatment low molecular weight heparin/unfractionated heparin: LMW heparin - subcutaneous injection, 1 mg/Kg twice daily or 1.5 mg/Kg once daily. Unfractionated heparin - 5,000 IU bolus intravenous administration, 1,300 IU/hour continuous infusion, minimum of 5 days and maximum of about 12 days treatment
4,118
Heparin/Warfarin
low molecular weight heparin/unfractionated heparin: LMW heparin - subcutaneous injection, 1 mg/Kg twice daily or 1.5 mg/Kg once daily. Unfractionated heparin - 5,000 IU bolus intravenous administration, 1,300 IU/hour continuous infusion, minimum of 5 days and maximum of about 12 days treatment warfarin: tablet for oral use; 0.5 mg, 1 mg, 2.5 mg, 5 mg; daily dosage, adjusted to maintain international normalized ratio (INR) between 2.0 and 3.0; maximum of 12 months treatment
4,122
Total8,240

Withdrawals & dropouts

PeriodReasonFG000FG001
Overall StudyDeath136127
Overall Studyinvestigator/subject decide not continue63
Overall StudyLost to Follow-up74
Overall Studynever received study drug2527
Overall StudyWithdrawal by Subject3233

Baseline characteristics

CharacteristicHeparin/Edoxaban TosylateTotalHeparin/Warfarin
Age, Continuous55.7 years
STANDARD_DEVIATION 16.3
55.8 years
STANDARD_DEVIATION 16.2
55.9 years
STANDARD_DEVIATION 16.2
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Asian
866 Participants1727 Participants861 Participants
Race (NIH/OMB)
Black or African American
156 Participants300 Participants144 Participants
Race (NIH/OMB)
More than one race
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants4 Participants4 Participants
Race (NIH/OMB)
Unknown or Not Reported
229 Participants447 Participants218 Participants
Race (NIH/OMB)
White
2867 Participants5762 Participants2895 Participants
Region of Enrollment
Argentina
26 participants47 participants21 participants
Region of Enrollment
Australia
90 participants179 participants89 participants
Region of Enrollment
Austria
80 participants166 participants86 participants
Region of Enrollment
Belarus
40 participants84 participants44 participants
Region of Enrollment
Belgium
98 participants177 participants79 participants
Region of Enrollment
Brazil
46 participants90 participants44 participants
Region of Enrollment
Canada
109 participants218 participants109 participants
Region of Enrollment
China
243 participants484 participants241 participants
Region of Enrollment
Czech Republic
216 participants427 participants211 participants
Region of Enrollment
Denmark
123 participants266 participants143 participants
Region of Enrollment
Estonia
40 participants76 participants36 participants
Region of Enrollment
France
364 participants714 participants350 participants
Region of Enrollment
Germany
243 participants473 participants230 participants
Region of Enrollment
Hungary
230 participants462 participants232 participants
Region of Enrollment
India
245 participants511 participants266 participants
Region of Enrollment
Israel
106 participants231 participants125 participants
Region of Enrollment
Italy
70 participants153 participants83 participants
Region of Enrollment
Japan
106 participants209 participants103 participants
Region of Enrollment
Korea, Republic of
140 participants270 participants130 participants
Region of Enrollment
Mexico
59 participants126 participants67 participants
Region of Enrollment
Netherlands
188 participants385 participants197 participants
Region of Enrollment
New Zealand
55 participants111 participants56 participants
Region of Enrollment
Norway
15 participants30 participants15 participants
Region of Enrollment
Philippines
17 participants32 participants15 participants
Region of Enrollment
Poland
22 participants43 participants21 participants
Region of Enrollment
Russian Federation
260 participants517 participants257 participants
Region of Enrollment
Singapore
7 participants11 participants4 participants
Region of Enrollment
South Africa
185 participants365 participants180 participants
Region of Enrollment
Spain
19 participants27 participants8 participants
Region of Enrollment
Sweden
36 participants58 participants22 participants
Region of Enrollment
Switzerland
27 participants47 participants20 participants
Region of Enrollment
Taiwan
74 participants138 participants64 participants
Region of Enrollment
Thailand
18 participants42 participants24 participants
Region of Enrollment
Turkey
27 participants51 participants24 participants
Region of Enrollment
Ukraine
143 participants291 participants148 participants
Region of Enrollment
United Kingdom
44 participants111 participants67 participants
Region of Enrollment
United States
307 participants618 participants311 participants
Sex: Female, Male
Female
1758 Participants3524 Participants1766 Participants
Sex: Female, Male
Male
2360 Participants4716 Participants2356 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
— / —— / —
other
Total, other adverse events
816 / 4,118997 / 4,122
serious
Total, serious adverse events
801 / 4,118852 / 4,122

Outcome results

Primary

Symptomatic Recurrent VTE, i.e., the Composite of DVT, Non-fatal PE, and Fatal PE

Symptomatic recurrent Venous Thromboembolism (VTE), i.e., the composite of deep Vein Thrombosis (DVT), non-fatal Pulmonary Embolism (PE), and fatal PE occurring during the Overall Study Period. Overall Study Period defined as The time from the reference date (randomization date/initial dose of study drug date) to the last study follow-up visit.

Time frame: 12 months from time of randomization

Population: (mITT) modified Intent To Treat Analysis Set

ArmMeasureValue (NUMBER)
Heparin/Edoxaban TosylateSymptomatic Recurrent VTE, i.e., the Composite of DVT, Non-fatal PE, and Fatal PE130 number or participants with an event
Heparin/WarfarinSymptomatic Recurrent VTE, i.e., the Composite of DVT, Non-fatal PE, and Fatal PE146 number or participants with an event
Comparison: (LMW) heparin/edoxaban will be non-inferior to (LMW) heparin/warfarin in preventing recurrence of acute, symptomatic VTE following initial index event. (LMW) Heparin/edoxaban was considered non-inferior to the standard therapy (\[LMW\] heparin/warfarin) if the upper limit of the two-sided 95% confidence interval (CI) for the Hazard Ratio (\[LMW\] heparin/edoxaban to standard therapy) was less than 1.5. Events included in Overall study period if occurred on or after randomization date up to Day 365.p-value: <0.000195% CI: [0.703, 1.128]Regression, Cox
Secondary

Clinically Relevant Bleeding (i.e., Major or Clinically Relevant Non-major Bleeding) Occurring During Treatment

Clinically relevant bleeding (i.e., major or clinically relevant non-major bleeding) occurring during treatment plus 3 days after their last dose for that time period.

Time frame: 12 months from time of randomization

Population: Safety Analysis Set

ArmMeasureValue (NUMBER)
Heparin/Edoxaban TosylateClinically Relevant Bleeding (i.e., Major or Clinically Relevant Non-major Bleeding) Occurring During Treatment349 participants with an event
Heparin/WarfarinClinically Relevant Bleeding (i.e., Major or Clinically Relevant Non-major Bleeding) Occurring During Treatment423 participants with an event
Comparison: Safety Analysis set includes all randomized subjects who received at least one dose of study drug.~Null hypothesis (LMW) heparin/edoxaban will be comparable to (LMW) heparin/warfarin in preventing recurrence of major or clinically relevant non-major bleeding.p-value: 0.00495% CI: [0.705, 0.936]Regression, Cox
Secondary

The Composite Clinical Outcome of Symptomatic Recurrent VTE and All-cause Mortality

Time frame: 12 months from time of randomization

Population: mITT Analysis set

ArmMeasureValue (NUMBER)
Heparin/Edoxaban TosylateThe Composite Clinical Outcome of Symptomatic Recurrent VTE and All-cause Mortality228 number of participants with event
Heparin/WarfarinThe Composite Clinical Outcome of Symptomatic Recurrent VTE and All-cause Mortality228 number of participants with event
p-value: 0.993395% CI: [0.832, 1.2]Regression, Cox

Source: ClinicalTrials.gov · Data processed: Mar 30, 2026