SYNOPSIS
Name ofDaiichi Sankyo Co., Ltd.

Sponsor/Company
Name of Finished Product

LIXIANA TABLETS

Name of Active Ingredient

Edoxaban Tosilate Hydrate

Title of Study

PhaseIIIClinicalThromboembolism):

StudyJapanofand

DU-176b
Taiwan(VenousMulticenter

Randomized Double-blind Study of DU-176b in Patients
Undergoing Total Knee Arthroplasty with Enoxaparin as
an Active Control
Investigators

71 investigators

Study Centre(s)71 centers

Publication (reference)

N.A.

Studied Period
Phase of Development

Phase III

Objectives

To verify the non-inferiority of edoxaban to enoxaparin withregard to prevention of venous thromboembolism (VTE) inpatients undergoing total knee arthroplasty.

Methodology

Edoxaban administered at a dose of 30 mg once daily wasassessed

forefficacy

andsafety,comparedwithenoxaparin administered at a dose of 20 mg twice daily,
under a double-blind, double-dummy design. The durationof treatment was set as 11 to 14 days, venography of theoperated limb was performed within 24 hours after thecompletion of administration. The present study wasperformed as a Japan-Taiwan multicenter study.
Number of Patients

Planned: 520 subjects (260 subjects per group)(planned and analyzed)

Treatment: 703 subjects (edoxaban group 354 subjects;
enoxaparin group 349 subjects)
Analyzed: 594 subjects (edoxaban group, 299 subjects;
enoxaparin group, 295 subjects)

Diagnosis and Main

Patients who were scheduled for primary TKA (excludingCriteria for Inclusionbilateral TKA), Patients aged 20 to < 85 years

Test Product, Dose andAdministration of 1 tablet was performed at 6 to 24 hours

Mode of Administration,

after surgery, and 1 tablet/day was administered orally inBatch Number

the morning from the next day (administration interval:
Approximately 10 hours or longer).

Lot number: edoxaban (30 mg tablets) (DU176F1T07T01)
edoxaban placebo (DU176F1T07T06)
Duration of Treatment

The duration of treatment was set at 11 to 14 days.

Reference Therapy, Dose

Administration was started with 1 syringe at 24 to 36

andhours after surgery, and 1 syringe was administered

ModeofAdministration,Batch

Numbersubcutaneously twice daily from the next day(administration interval: Approximately 12 hours).
Lot number: Enoxaparin (2000 IU injection) (912004)
Enoxaparin placebo (910918)

Criteria for Evaluation(Efficacy Primary Endpoint)
The primary endpoint was the proportion of subjects with
one or more of the following thromboembolic events(incidence proportion of thromboembolic events) that
occurred during the period from the start ofadministration of the study drug until the performance ofvenography at the completion of administration.
•Asymptomatic deep vein thrombosis (DVT)(DVT evaluated by venography performed on the operated
lower limb after completing administration of the study
drug.)•Symptomatic and definitely diagnosed pulmonary
embolism (PE).
•Symptomatic DVT that was confirmed before theperformance of planned venography.
(Safety Primary Endpoint)
The occurrence of the following bleeding events, adverseevents (AEs), and adverse drug reactions (ADRs) during
the period from the start of administration of the study
drug until the day of the follow-up examination wasevaluated.
1) Incidence proportion of major bleeding.
2) Incidence proportion of major bleeding or clinically
relevant non-major bleeding.

Statistical Method(Analyses of the Primary Efficacy Endpoint)
As primary analyses, the following hypothesis testing wascarried out for the proportion of subjects with one or morethromboembolic events, defined as the primary endpoint,using Z test statistics.
Null hypothesis H01: The incidence proportion ofthromboembolic events in the edoxaban group (PDU)= The incidence proportion of thromboembolic events inthe enoxaparin group (PE) + Δ (5%)
Alternative hypothesis H11: PDU < PE + Δ (level ofsignificance, 0.025; one-sided).
If the null hypothesis H01 was rejected, the following
analysis had to be sequentially performed using the χ2 teststatistic.
Null hypothesis H02: PDU = PE
Alternative hypothesis H12: PDU ≠ PE (level of significance,
0.05; two-sided)(Analyses of the Primary Safety Endpoint)
The incidence proportion of major bleeding that occurred
during the treatment period (from the day ofadministration of the study drug to the next day of thecompletion of administration) and its 95% CI werecalculated for each treatment group. The difference
between the edoxaban and enoxaparin groups and its 95%
CI were also calculated, and a paired comparison between
the treatment groups was performed using the χ2 test.
Concerning the breakdown of major bleeding events, thenumber of subjects with individual events and theincidence proportion were calculated for each treatmentgroup. Similar analyses were performed fortreatment-related major bleeding during the treatment
period, as well as major bleeding and treatment-related
major bleeding during the period from the start ofadministration of the study drug to the day of thefollow-up examination. Similar analyses were also
performed for clinically relevant non-major bleeding,major bleeding or clinically relevant non-major bleeding,and bleeding events (major bleeding, clinically relevant
non-major bleeding, and minor bleeding).
Summary - Conclusion(Efficacy Primary Endpoint)

The primary efficacy outcome occurred in 22 of 299 (7.4%)
patients receiving edoxaban and 41 of 295 (13.9%) patients
receiving enoxaparin. (p < 0.001 for non-inferiority; p =0.010 for superiority).
(Safety Primary Endpoint)
The incidence of major or clinically relevant non-major
bleeding events was 6.2% (22/354) vs 3.7% (13/349) in theedoxaban and enoxaparin groups, respectively (p=0.129).
Major bleeding occurred in 1.1% of the edoxaban groupand 0.3% of the enoxaparin group (p=0.373).
(Conclusions)This trial demonstrated that oral edoxaban 30 mg once
daily has efficacy superior to enoxaparin in 2,000 IU twice
daily in the prevention of thromboembolic events following
TKA without a significant difference in incidence ofbleeding events.
Date of Report

25 July, 2014