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 Phase 2 Study of Repeated Administration of CS-8958− A randomized double-blind controlled exploratory study
comparing repeated administration of CS-8958 to oseltamivir
phosphate in patients with influenza virus infection −Investigators
Study Centre(s)Publication (reference)

Not published.

Studied Period
Phase of Development

Phase IIObjectives

A 2-group, randomized, double-blind, comparative study inpatients with type A or B influenza virus infection wasperformed to evaluate the efficacy and safety of a double
inhalation of CS-8958 20 mg with oseltamivir phosphateas the comparator.

Methodology

2-group,multicenter,randomized,activecontrol,double-blind, parallel comparative study
Number of Patients (planned

Planned number of patients : 140 subjects

and analyzed)(70 subjects in the CS-8958 group, 70 subjects in theoseltamivir phosphate group)
Full analysis set (FAS): 187 subjects(93 subjects in the CS-8958 group, 94 subjects in the oseltamivirphosphate group)

Diagnosis and Main Criteria

Patients with type A or B influenza virus infection who met all offor Inclusion

the following inclusion criteria were eligible to participate in thestudy.
1)

Influenza virus-positive by an influenza rapid diagnostic kit,
and diagnosed with influenza virus infection by theinvestigators

2)

Body temperature (axillary) ≥ 37.5°C at the time of informed
consent

3)

Within 36 hours after the onset of any influenza symptoms(fever [feeling of fever], headache, myalgia/arthralgia,
fatigue, chill/sweating, nasal symptoms, sore throat, cough) atthe time of informed consent4)

Aged ≥ 20 years as of informed consent

Test Product, Dose and ModeCS-8958

of Administration

CS-8958 placebo
Subjects in the CS-8958 groups received CS-8958 20 mg byinhalation once daily for 2 days using an inhaler.

Duration of Treatment

2 days (5 days for the control drug)

Reference Therapy, Dose andOseltamivir phosphate 75 mg capsule

Mode of Administration

Oseltamivir phosphate placebo capsule
Subjects in the oseltamivir phosphate group received 75 mg (asoseltamivir) orally twice daily for 5 days.

Criteria for Evaluation

Primary Endpoint: Time to Alleviation of Influenza Illness

Statistical Method

Efficacy Analysis;Primary analysis: The difference in the median time to alleviationof influenza illness between the CS-8958 group and the oseltamivir
phosphate group (CS-8958 group − oseltamivir phosphate group)
was calculated, and the 95% confidence interval (CI) was thencalculated based on the generalized Wilcoxon test statistics. A
generalized Wilcoxon test was performed with the oseltamivir
phosphate group as the comparator.
Safety Analysis;
Adverse Events: The number of subjects with adverse events andthe incidence of adverse events were presented by causal
relationship (all/drug-related) for each treatment group. Serious
adverse events, severe adverse events, and adverse events leading
to discontinuation were summarized in the same manner. The
number of subjects with individual adverse events and theincidence of individual adverse events were also presented bycausal relationship (all/drug-related) as well as by severity andcausal relationship (all/drug-related) for each treatment group.

Summary - Conclusion

Efficacy (primary endpoint):
The Kaplan-Meier plot of the time to alleviation of influenza
illness, which was the primary endpoint, showed a tendency
toward shorter time to resolution in the CS-8958 group than in theoseltamivir phosphate group. The median time to alleviation ofinfluenza illness was 86.0 hours in the CS-8958 group and 87.4
hours in the oseltamivir phosphate group. The difference in themedian time to alleviation of influenza illness between theCS-8958 group and the oseltamivir phosphate group (95% CI) was−1.4 (−27.6 to 7.3) hours; the time to alleviation of influenza
illness was comparable between the CS-8958 group and theoseltamivir phosphate group.
In the comparison of the time to alleviation of influenza illness
between the CS-8958 group and the oseltamivir phosphate groupusing Cox regression, which was performed as the secondary
analysis of the primary endpoint, the hazard ratio (95% CI) of theCS-8958 group to the oseltamivir phosphate group was 1.292(0.939 to 1.779). No statistically significant difference was foundbetween the CS-8958 group and the oseltamivir phosphate group.
Safety:The incidence of adverse events was 20.4% (19/93) in the CS-8958
group and 22.3% (21/94) in the oseltamivir phosphate group, andwas comparable between the CS-8958 group and the oseltamivir
phosphate group.
Date of ReportAugust 30, 2011