SYNOPSIS
Name ofDaiichi Sankyo Co., Ltd.

Sponsor/Company
Name of Finished Product

LIXIANA TABLETS

Name of Active Ingredient

Edoxaban Tosilate Hydrate

Title of Study

Phase 3 clinical study of DU-176b (non-valvular atrialfibrillation) -A Japanese, multicenter, open-label study of
DU-176b in patients with non-valvular atrial fibrillationand severe renal impairment-

Investigators

13 investigators.

Study Centre(s)13 sites.

Publication (reference)

N.A.

Studied Period
Phase of Development

Phase III

Objectives

The study objective was to compare the safety andpharmacokinetics of edoxaban in non-valvular atrial
fibrillation (NVAF) patients with severe renal impairment(SRI, 15 mL/min ≤ creatinine clearance (CLCR) < 30mL/min [excluding patients on hemodialysis]) at a dose of
15 mg once daily for 12 weeks with those in NVAF
patients with normal renal function or mild renalimpairment (Normal/MiRI, 50 mL/min ≤ CLCR) at a dose of
30 mg or 60 mg once daily for 12 weeks.

Methodology

This study was a Japanese, multicenter, open-label,3-parallel-group study of edoxaban in NVAF patients withSRI or Normal/MiRI. Subjects with SRI (the SRI 15-mggroup) received 15 mg of edoxaban once daily. Subjects
with Normal/MiRI were randomized to low-dose (theNormal/MiRIlow-dosegroup)orhigh-dose(theNormal/MiRI high-dose group) of edoxaban in equal
numbers. Subjects in the Normal/MiRI low-dose group
received 30 mg of edoxaban once daily; subjects who had
any dose adjustment factor received 15 mg of edoxaban
once daily. Subjects in the Normal/MiRI high-dose group
received 60 mg of edoxaban once daily; subjects who had
any dose adjustment factor received 30 mg of edoxaban
once daily.

Number of Patients

Planned: 90 subjects (the SRI 15 mg group: 50 subjects;(planned and analyzed)

the Normal/MiRI low-dose group: 20 subjects; theNormal/MiRI high-dose group: 20 subjects)
Safety Analyzed: 93 subjects (the SRI 15 mg group: 50subjects; the Normal/MiRI low-dose group: 22 subjects; theNormal/MiRI high-dose group: 21 subjects)
Pharmacokinetic Analyzed: 90 subjects (the SRI 15 mggroup: 48 subjects; the Normal/MiRI low-dose group: 21subjects; the Normal/MiRI high-dose group: 21 subjects)

Diagnosis and Main

The study enrolled patients with NVAF and SRI (15Criteria for Inclusion

mL/min ≤ CLCR < 30 mL/min; CLCR calculated by theCockcroft-Gault formula), and patients with NVAF andNormal/MiRI (50 mL/min ≤ CLCR). All patients had atleast one of the risk factors for stroke (CHADS2 score of atleast 1 point), Patients aged 20 years or older

Test Product, Dose andOnce daily for 12 weeks.

Mode of Administration,

Lot number: 15 mg tablet DU176F1T08T01B, 30 mg tablet

Batch Number

DU176F1T07T02B

Duration of Treatment

12 weeks

Reference Therapy, DoseN.A.

ModeofAdministration,BatchandNumber

Criteria for Evaluation(Safety Endpoint)(1) Incidence of adjudicated major bleeding or clinicallyrelevant non-major bleeding(2) Incidence of any adjudicated bleeding events(3) Incidence of adjudicated major bleeding(4) Incidence of adjudicated clinically relevant non-majorbleeding(5) Incidence of adverse events(6) Incidence of adverse drug reactions(Pharmacokinetic Endpoints)(1) Plasma DU-176 concentration(2) Plasma D21-2393 concentration

Statistical Method(Analyses of the Safety Endpoint)
Incidences and 95% CIs were calculated by treatment

group(Analysis of Plasma Drug Concentrations)
Descriptive statistics of plasma drug (DU-176 orD21-2393) concentrations were calculated by treatmentgroup at each time point. Descriptive statistics of the ratioof the plasma D21-2393 concentration to the plasma
DU-176 concentration ratio were also calculated bytreatment group at each time point. Scatter plots showing
the plasma drug concentration-time profile were prepared.
Summary - Conclusion

This study demonstrated that the plasma concentrationsin the subjects with SRI (15 mL/min ≤ CLCR < 30 mL/min)receiving 15 mg of edoxaban overlapped considerably withthose concentrations in the subjects with Normal/MiRI (50mL/min ≤ CLCR) receiving the low dose (30 mg, or 15 mg
with dose adjustment) or high dose (60 mg, or 30 mg withdose adjustment) of edoxaban. It was also demonstrated
that administration of 15 mg of edoxaban for 12 weeks inpatients with SRI did not result in a marked increase inbleeding compared to the low dose or high dose ofedoxaban in patients with Normal/MiRI.

Date of Report

25 July, 2014