SYNOPSIS
Name of Sponsor/Company

Daiichi Sankyo Co., Ltd.

Name of Finished Product

GRACEVIT ® TABLETS, GRACEVIT ® FINE GRANULES

Name of Active Ingredient

Sitafloxacin

Title of Study

Phase 3 clinical study of DU-6859a in patients with respiratory tract
infection

Investigators

Dr. Hiroyuki Koba, and 42 other investigators

Study Centre(s)43 sites

Publication (reference)

None

Studied Period

Date of obtaining first consent: October 14, 2008
Date of last observation: February 12, 2010

Phase of Development

Phase 3Objectives

The aim of this study is to compare the safety, eradication rate ofpneumococci, and PK-PD parameter at 100 mg once daily to those at
50 mg twice daily.

Additionally, the bacteriological efficacy against

drug-resistant pneumococci is evaluated.
Methodology

Open-label, multicentre, randomized study

Number of Patients

Planned: 150 patients(planned and analyzed)

Analyzed:
We combined the data from the twice-daily 50 mg sitafloxacin
treatment group in this study with the results from the same
treatment group in the open study that was conducted in 2005 and2006.
Treatment group
Valid for analysis ofsafety
Valid for analysis ofefficacy
Valid for analysis ofStreptococcus
pneumoniae
Valid for analysis ofPK-PD

50 mg bidPreviousstudy

100 mgqd

This study

98

51

115

16692

4792

139

56

251641

53

24

1640

Diagnosis and Main Criteria

Diagnosis: Pneumococcal respiratory tract infections

for Inclusion

Inclusion:

Total1) Patients with age of 20 or older at the time of obtaining informedconsents.
2) Patients who provided proper sputum for cultivation of pathogenic
bacteria.

3) Patients who is suspected to be pneumococcal infection with atleast one of below**:(1) Neutrophils and Gram-positive diplococci can be seen in Gram
stained smears of airway secreta (sputum etc.).
(2) Urinary antigen detection test for Streptococcus pneumoniae ispositive.
** (1) is essential for the patients received antibacterial drug within 7days (14 days for azithromycin) from the start of therapy.
4) Patients who diagnosed as a mild or moderate infectious diseaseaccording to the guideline (Clinical evaluation methods for new
antimicrobial agents to treat respiratory infections: Report of theCommittee for the Respiratory System, Japan Society ofChemotherapy) on the day or the day before the start of therapy andfit for oral antibacterial drug therapy.
Test Product, Dose and100 mg QD group: Oral administration of DU-6859a at 100 mg, once

Mode of Administration,

daily

Batch Number

50 mg BID group: Oral administration of DU-6859a at 50 mg, twice
daily
DU-6859a lot No.: D6859F1S08T01A

Duration of Treatment

Seven days

Reference Therapy, DoseNoneand Mode ofAdministration, Batch
NumberCriteria for Evaluation

1) Incidence of adverse events and of adverse drug reactions2) Bacteriological response against S. pneumoniae and drug-resistant
S. pneumoniae
3) PK-PD parameter (fAUC0-24h/MIC, fCmax/MIC, ratio of patients
whose fCmax are over MPC, fTime inside MSW)

Statistical Method

As bacteriological response, incidence of adverse events, incidence ofadverse drug reactions, and the ratio of patients whose Cmax are overMPC, point estimation and the two-sided 95% confidence interval
were calculated for both groups. Summary statistics of another
PK-PD indices were calculated.

We combined the data from thetwice-daily 50 mg sitafloxacin treatment group in this study with theresults from the same treatment group in the open study that wasconducted in 2005 and 2006.

Summary - Conclusion

The eradication rate of S. pneumoniae was 98.2% (55/56) in 100 mg
QD group and 92.7% (38/41) in 50 mg BID group, respectively.
The eradication rate of multidrug-resistant S. pneumoniae was 97.7%(42/43) in 100 mg QD group and 94.6% (35/37) in 50 mg BID group.
The mean fAUC0-24h/MIC did not differ significantly between the100 mg QD group (103.24) and the 50 mg BID group (105.25). The
mean fCmax/MIC was higher in the 100 mg QD group (10.19) than inthe 50 mg BID group (6.53). Pathogen eradication rate was 98.9%(89/90) when fAUC0-24h/MIC was over 30. The eradication rate wasalso 98.9% (89/90) when fCmax/MIC was over 2.
The incidence of adverse drug reactions was 33.7% (33/98) in 100 mg
QD group and 40.4% (67/166) in 50 mg BID group.
No obvious differences in efficacy and safety were observed between
100 mg QD group and 50 mg BID group.

In case where asufficiently high Cmax needs to be ensured in view of the susceptibilityof pathogens to drug, once daily 100 mg treatment should be selected.
Date of Report

March 26, 2012