SYNOPSIS
Name of Sponsor/Company

Daiichi Sankyo Co., Ltd.

Name of Finished Product

INAVIRⓇ DRY POWDER INHALER 20mg

Name of Active IngredientLaninamivir Octanoate Hydrate（JAN）

Title of Study

A randomized, double-blind, placebo-controlled, multi-center
phase II study for the evaluation of efficacy and safety of CS-8958
in patients with influenza virus infection

Investigators
Study Centre(s)Publication (reference)

Not published.

Studied Period
Phase of Development

Phase II

Objectives

The primary objective of this study was to evaluate the efficacy
after a single dose of 10 mg or 20 mg of CS-8958 in patients withinfluenza virus A or B infection using the time to resolution offever after treatment as the primary endpoint.

Methodology

Randomized double-blind, placebo controlled, parallel group,
multi-center study of a single dose of CS-8958 at 10 mg or 20 mg

Number of Patients (plannedPlanned number of patients : 180 patientsand analyzed)

CS-8958 10 mg group, 60 patients; CS-8958 20 mg group,
60 patients ; Placebo group, 60 patients
Full analysis set (FAS):174 patients
CS-8958 10 mg group. 56 patients; CS-8958 20 mg group, 59
patients; Placebo group. 59 patients

Diagnosis and Main Criteria

Patients who met following criteria were enrolled.

for Inclusion

1. Male or female patients aged 18 to 64 years.
2. Outpatients.
3. Providing written informed consent.
4. Patients with a positive rapid diagnostic test result for influenza
virus A and/or B.
5. Patients with an ear temperature of ≥ 37.8°C.
6. Patients who presented the onset of influenza symptoms (fever,headache, myalgia/arthralgia, fatigue, chill/perspiration, nasal
symptom, sore throat, cough, etc.) within 36 hours.

Test Product, Dose and ModeCS-8958

of Administration

CS-8958 placebo
Patient received a single inhalation of CS-8958 10 mg, 20 mg orplacebo using a inhaler.
Duration of Treatment

Single dose

Reference Therapy, Dose andNone

Mode of Administration
Criteria for Evaluation

Primary Endpoint: Time to Resolution of Fever (≤ 37.2°C)
Secondary Endpoints: Time to alleviation of influenza illness

Statistical Method

Efficacy Analysis;Primary analysis: The time to resolution of fever was analyzed
using the generalized Wilcoxon test, and its 95% confidenceinterval for the difference of median time to resolution of fever
between treatment groups were estimated. And median time toresolution of fever, its 95% confidence interval, and other summary
statistics were calculated for each treatment group.
Secondary analysis:The difference in the median of the CS-8958
treatment groups and its 95% confidence interval was calculated,
and the generalized Wilcoxon test was conducted.
Safety Analysis;
Adverse Events: The number of patients and the incidence in eachtreatment group were obtained for study drug-related adverse
events and all adverse events. Similar analysis was also performed
for each event and severity.

Summary - Conclusion

Efficacy (primary endpoint):
Primary analysis:
The Kaplan-Meier plot was comparable between the treatmentgroups. The median of the primary endpoint “time to resolution offever” was 39.7 h in CS-8958 10 mg group, 38.5 h in CS-8958 20
mg group, and 41.0 h in placebo group, and there were no
statistically significant differences between each CS-8958 groupand the placebo group. The differences (95% confidence interval)of the median time to resolution of fever between each CS-8958
group and placebo group were -1.3 h (-13.5 to 7.5) in CS-8958 10mg group and -2.5 h (-12.2 to 9.8) in CS-8958 20 mg group.
Secondary analysis:
The median of the secondary endpoint “time to alleviation ofinfluenza illness” was 62.0 h in CS-8958 10 mg group, 49.9 h inCS-8958 20 mg group, and 84.0 h in placebo group, and there wereno statistically significant differences between each CS-8958 groupand the placebo group. The differences (95% confidence interval)of the median time to alleviation of influenza illness between theCS-8958 groups and placebo group were -22.0 h (-44.7 to 5.6) inCS-8958 10 mg group, and -34.1 h (-43.8 to 4.4) in CS-8958 20
mg group.Although there was no statistically significant difference,
all of the doses tested shortened the time to alleviation of influenza
illness when compared with placebo.
Safety:AEs occurred in 25.9% (15/58) of patients in CS-8958 10 mggroup, 21.7% (13/60) in CS-8958 20 mg group, and 22.6% (14/62)
in placebo group. No significant safety concerns were raisedin all CS-8958 groups.
Date of ReportAugust 30, 2011