SYNOPSIS
Name ofDaiichi Sankyo Co., Ltd.

Sponsor/Company
Name of Finished Product

LIXIANA TABLETS

Name of Active Ingredient

Edoxaban Tosilate Hydrate

Title of Study

A Phase IIb, Randomized, Double-blind,
Placebo-controlled, Parallel-group, Dose-ranging,Multi-center Study in Patients Undergoing Total Knee
Replacement

Investigators

63 investigators

Study Centre(s)63 sites

Publication (reference)

Journal of Thrombosis and Haemostasis, 8: 2458–2468

Studied Period

1 year and 3 months
Initiation Date (first subject enrolled): 3 July 2006
Completion Date (last subject completed): 19 September2007

Phase of Development

Phase II

Objectives

To assess the dose-response relationship of the efficacy ofedoxaban for the prevention of deep vein thrombosis(DVT) and pulmonary embolism (PE) in patients
undergoing total knee replacement (TKR), as well as its
safety, in a randomized, double-blind, placebo-controlled,dose-ranging study.

Methodology

Study design: Multicenter, randomized, double-blind,placebo-controlled, parallel 5-group, dose-ranging
study of edoxaban at the 4 dose levels of 5 mg/day,
15 mg/day, 30 mg/day, and 60 mg/day
Duration of treatment: Oral treatment for 11 to 14 days

Number of Patients

Planned: 500 subjects (100 subjects per group)(planned and analyzed)

Treatment: 520 subjects (edoxaban 5 mg group: 103
subjects; 15 mg group: 106 subjects; 30 mg group: 103
subjects; 60 mg group: 106 subjects; Placebo group: 102subjects)
Analyzed: 445 subjects (edoxaban 5 mg group: 88 subjects;
15 mg group: 92 subjects; 30 mg group: 88 subjects; 60 mggroup: 88 subjects; Placebo group: 89 subjects)

Diagnosis and Main

Patients who were scheduled for primary TKR (excludingCriteria for Inclusionbilateral TKR), Patients aged 20 to < 85 years

Test Product, Dose andFour tablets were orally administered once daily,

Mode of Administration,

treatment was started within 6 to 24 hr after surgery, andBatch Number

was given in the morning, in principle, from the following
day onwards.
Lot number : 5 mg tablet S05042-1 , 15 mg
tablet S04045-5

Duration of Treatment

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

Reference Therapy, DoseFour tablets were orally administered once daily,

andModeoftreatment was started within 6 to 24 hr after surgery, andAdministration,Batch

was given in the morning, in principle, from the following

Numberday onwards.
Lot number: S04045-6

Criteria for Evaluation(Efficacy Primary Endpoint)
The primary efficacy endpoint was the proportion ofsubjects who experienced at least one of thethromboembolic events listed below during the period fromthe start of treatment with the study drug to thevenography at the end of the study treatment.
(1) Lower extremity DVT confirmed by bilateralvenography at the end of study treatment(2) Definite diagnosis of symptomatic PE(3) Symptomatic DVT confirmed before the venography atthe end of study treatment(Safety Primary Endpoint)
The primary safety endpoints were those listed below
during the period fromthe start of study treatment to the day of the follow-up
examination.
(1) Incidence of major bleeding(2) Incidence of clinically relevant non-major bleeding

Statistical Method(Analyses of the Primary Efficacy Endpoint)
As the primary analysis, the dose-response relationship in
the incidence ([Number of subjects with events / Numberof subjects assessed] × 100, the same hereinafter) of
thromboembolic event (at least one of either DVT,

symptomatic PE, or symptomatic DVT) was verified using
the Cochran-Armitage test, and the difference between theplacebo group and each edoxaban group was verified using
the Shirley-Williams multiple comparison.
(Analyses of the Primary Safety Endpoint)
For the incidence of major bleeding, the difference between
the placebo group and each edoxaban group was calculatedwith the 95% CI, and paired comparisons between theplacebo group and each edoxaban group were performed
using the χ2 test. To examine the dose-response
relationship, the incidence was analyzed using theCochran-Armitage test. Paired comparisons among theedoxaban groups were also performed using the χ2 test.
The incidence of major bleeding and the 95% CI werecalculated by treatment group. These analyses were also
performedfor

theincidence

ofclinicallyrelevant

non-major bleeding, and the total of major bleeding andclinically relevant non-major bleeding.
Summary - Conclusion

In the FAS, the incidence of thromboembolic events (atleast one of either DVT, symptomatic PE, or symptomaticDVT) was 48.3% (43/89) in the placebo group, 29.5%(26/88) in the edoxaban 5 mg group, 26.1% (24/92) in the15 mg group, 12.5% (11/88) in the 30 mg group, and 9.1%(8/88)

in

the

thromboembolic

60mgevents

group.

The

decreased

incidence

withofincreasingedoxaban dose, and a dose-response relationship for theeffect of edoxaban in VTE prevention was verified inpatients undergoing TKR (Cochran-Armitage test; P <0.001). The results also verified the superiority of eachedoxabanregimentoplaceboinheincidenceofthromboembolic events, which was achieved even in the 5mg group (Shirley-Williams multiple comparison; P =0.005).
The incidence of all-causality major bleeding was 1.0%(1/102) in the placebo group and 0.9% (1/106) in theedoxaban 60 mg group, with no major bleeding in the 5mg, 15 mg, or 30 mg group. No dose-response relationshipon the incidence was observed (Cochran-Armitage test, P =0.494).
The incidence of all-causality clinically relevant non-major
bleeding was 3.9% (4/102) in the placebo group, 2.9%(3/103) in the edoxaban 5 mg group, 4.7% (5/106) in the 15mg group, 3.9% (4/103) in the 30 mg group, and 3.8%(4/106) in the 60 mg group. No dose-response relationshipon the incidence was observed (Cochran-Armitage test, P =0.456).
Based on these results, it was concluded that theappropriate

dosageregimenof edoxaban

for VTE

prevention in patients undergoing TKR was 30 mg once
daily.
Date of Report

25 July, 2014