SYNOPSIS
Name ofDaiichi Sankyo Co., Ltd.

Sponsor/Company
Name of Finished Product

LIXIANA TABLETS

Name of Active Ingredient

Edoxaban Tosilate Hydrate

Title of Study

DU-176b

Phase

IIbclinicalstudy(venousthromboembolism):
Japan and Taiwan multicenter randomized double-blind
dose-finding study using Enoxaparin as a reference inpatients undergoing total hip replacement.
Investigators

34 investigators

Study Centre(s)34 centers

Publication (reference)

Journal of Arthroplasty, DOI: 10.1016/j.arth.2014.05.029

Studied Period

6months
Initiation Date (first subject enrolled): 19 Jun 2008
Completion Date (last subject completed): 11 December
2008

Phase of Development

Phase IIb

Objectives

The objectives are to compare the efficacy and safety ofedoxaban at 15 mg and 30 mg once daily for 11 to 14 daysin a double-blind manner, and to examine the appropriate
dosage of edoxaban in patients undergoing total hip
replacement.
Enoxaparin was designated as a reference drug in order tounderstand the relationship between edoxaban andcommercially supplied drugs for the efficacy and safety.

Methodology

Edoxaban 15 mg and 30 mg once daily are compared indouble- blind manner and open- label enoxaparin isdesignated as a reference, in order to assess the efficacy
and safety of edoxaban at 15 mg and 30 mg once daily andto examine the appropriate dosage of edoxaban.
After being performed a total hip replacement, patientsare randomly assigned to edoxaban 15 mg once dailygroup, edoxaban 30 mg once daily group, or enoxaparingroup in a 1:1:1 ratio.
After the administration for 11 to 14 days, bilateralvenograms will be obtained.

Number of Patients

Planned: 210 subjects (70 subjects per group)(planned and analyzed)

Treatment: 261 subjects (edoxaban 15 mg group, 89subjects; edoxaban 30 mg group, 85 subjects; enoxaparingroup, 87 subjects)
Efficacy Analyzed: 224 subjects (edoxaban 15 mg group, 78subjects; edoxaban 30 mg group, 72 subjects; enoxaparingroup, 74 subjects)

Diagnosis and Main

Patients who were scheduled for primary THA (excludingCriteria for Inclusionbilateral THA), 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 (15 mg tablets) (S06036-2)
edoxaban placebo (S06036-3)
Lot number:edoxaban (30 mg tablets) (S06036-5)
edoxaban placebo (S06036-8)

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

Modeofhours after surgery, and 1 syringe was administered

Administration,

BatchandNumber

subcutaneously

twicedailyfromthenextday(administration interval: Approximately 12 hours).
Lot number:
Enoxaparin (2000 IU injection) (DU176b-B-J209-4)
Enoxaparin placebo (DU176b-B-J209-4)

Criteria for Evaluation(Efficacy Primary Endpoint)
Proportion of subjects with one or more of the following
thromboembolic events occur during the period fromcommencement of administration of the investigational
product to venography implementation at the completionof administration of the investigational product isevaluated as a primary endpoint of efficacy· Asymptomatic DVT(DVT evaluated by venography performed on both lower
limbs at the completion of administration of theinvestigational product)· Symptomatic PE that was conclusively diagnosed· Symptomatic DVT confirmed before implementation ofpredetermined.
(Safety Primary Endpoint)
As a primary endpoint of safety, the following bleeding
events observed during the period from commencement ofadministration of the investigational product to thefollow-up visit date are evaluated.
(1) Incidence rate of major bleeding(2) Incidence rate of clinically relevant non-major bleeding(3) Incidence rate of major bleeding or clinically relevant
non-major bleeding
Statistical Method(Analyses of the Primary Efficacy Endpoint)
For the proportion of subjects with one or more ofthromboembolicevents(=incidence

rateofthromboembolic events), the difference between edoxaban
15 mg group and edoxaban 30 mg group, and its 95%
confidence interval thereof are calculated.
In addition, the incidence rate of thromboembolic eventsby administration group and its 95% confidence interval
thereof are also calculated. As reference, the difference
between Enoxaparin group and each edoxaban group, andits 95% confidence interval thereof are also calculated.
(Analyses of the Primary Safety Endpoint)
The incidence rate of major bleeding are calculated byadministration group. The incidence rate of clinically
relevant non-major bleeding and its 95% confidence
interval thereof are calculated by administration group.
In addition, for the incidence rate of clinically relevant
non-major bleeding, the difference between groups and its
95% confidence interval thereof are calculated. The
incidence rate of major bleeding or clinically relevant
non-major bleeding, and its 95% confidence interval
thereof are calculated by administration group. Inaddition, for the incidence rate of major bleeding orclinically relevant non-major bleeding, the difference
between groups and its 95% confidence interval thereof
are calculated.
Summary - Conclusion

The incidence of thromboembolic events was 3.8% (3/78),
2.8% (2/72), and 4.1% (3/74) in 15 mg, 30 mg edoxaban,and enoxaparin groups, respectively. The thromboembolic
events were all distal asymptomatic DVT.
The incidence of major or clinically relevant non-majorbleeding was 2.2% (2/89) in the 15 mg edoxaban group,
1.2% (1/85) in the 30 mg edoxaban group and 2.3% (2/87)
in the enoxaparin group. There was one major bleeding
event in the 30 mg edoxaban group.
Of the biomarkers, D-dimer, F1+2, and soluble fibrin
levels were most decreased in the edoxaban 30 mg group
When both efficacy and safety are considered, the results
suggest that edoxaban 30 mg once daily is the appropriate
dosage regimen for prevention of thromboembolic eventsin patients undergoing THA.

Date of Report

25 July, 2014