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

Arandomized

double-blind

controlled

exploratory

study

comparing CS-8958 to oseltamivir phosphate in patients withinfluenza virus infection (Phase 2)
Investigators
Study Centre(s)Publication (reference)

Not published.

Studied Period
Phase of Development

Phase 2

Objectives

A 4-arm, randomized, double-blind comparative study in patientswith type A or B influenza virus infection was performed toevaluate the efficacy and safety of a single inhalation of CS-8958 5mg, 10 mg, or 20 mg, with oseltamivir phosphate as thecomparator.

Methodology

4-arm, multicenter, randomized, active control, double-blind,parallel comparative study

Number of Patients (planned

Planned number of patients : 280 subjects

and analyzed)(70 each in CS-8958 5 mg group, 10 mg group, and 20 mggroup, and oseltamivir phosphate group)
Full analysis set (FAS): 322 patients(CS-8958 5 mg group: 79 subjects, CS-8958 10 mg group: 83
subjects, CS-8958 20 mg group: 77 subjects, and oseltamivir
phosphate group: 83 subjects)

Diagnosis and Main Criteria

1) Patients diagnosed with influenza virus infection who met all offor Inclusion

the following inclusion criteria• Influenza virus-positive by an influenza rapid diagnostic kit• Body temperature (axillary) ≥ 37.5°C at the time of informed
consent• Study treatment could be started within 36 hours after the onsetof any influenza symptoms (eg fever [feeling of fever], headache,
myalgia/arthralgia, fatigue, chill/sweating, nasal symptoms, sorethroat, cough)2) Aged 20 to 64 years as of informed consent

Test Product, Dose and ModeCS-8958

of Administration

CS-8958 placebo
Patient received a single inhalation of CS-8958 5, 10, 20 mg orplacebo using a inhaler.

Duration of Treatment

Single dose (5 days for the control drug)

Reference Therapy, Dose andOseltamivir phosphate 75 mg capsule

Mode of Administration

Oseltamivir phosphate placebo capsule
Patient received 75 mg (as oseltamivir) or placebo orally twice
daily for 5 days.

Criteria for Evaluation

Primary Endpoint: Time to Resolution of Fever (36.9°C or Lower)
Secondary Endpoints: Time to alleviation of influenza illness

Statistical Method

Efficacy Analysis;Primary analysis: The median differences between the oseltamivir
phosphate group and each CS-8958 treatment group (the median ofthe CS-8958 treatment group − the median of the oseltamivir
phosphate group) in the time to resolution of fever and 95% CIs
were calculated. When the upper limit of 95% CI was less than 24hours, CS-8958 was to be considered to be an effective therapeutic
drug for influenza virus infection. The generalized Wilcoxon test
was performed using the oseltamivir phosphate group as a controlgroup.
Secondary analysis: The median differences between theoseltamivir phosphate group and each CS-8958 treatment groupin Time to alleviation of influenza illness and 95% CIs werecalculated. The generalized Wilcoxon test was performed using theoseltamivir phosphate group as a control group.
Safety Analysis;
Adverse Events: The number of subjects and the incidence bytreatment group were obtained for study drug-related adverse
events and all adverse events. Similar analysis was also performed
for each event and severity.

Summary - ConclusionEfficacy (primary endpoint):
The median of the primary endpoint “time to resolution of fever”
was 60.4 hours in the CS-8958 5 mg group, 54.6 hours in theCS-8958 10 mg group, 54.3 hours in the CS-8958 20 mg group,and 42.3 hours in the oseltamivir phosphate group. The mediandifferences (95% CI) between each CS-8958 treatment group andthe oseltamivir phosphate group were 18.1 hours (0.9 to 23.4) inthe CS-8958 5 mg group, 12.3 hours (−3.0 to 18.5) in the CS-8958
10 mg group, and 12.0 hours (−8.3 to 15.0) in the CS-8958 20 mggroup. The upper limit of 95% CI of the difference was less than
24 hours, although it was statistically significant in the CS-8958 5mg group.The medians of the secondary endpoint “time toalleviation of influenza illness” were 92.8 hours in the CS-8958 5mg group, 82.6 hours in the CS-8958 10 mg group, 81.8 hours inthe CS-8958 20 mg group, and 82.7 hours in the oseltamivir
phosphate group. The median differences (95% CIs) between each
CS-8958 treatment group and the oseltamivir phosphate groupwere 10.1 hours (−12.1 to 29.8) in the CS-8958 5 mg group, −0.2
hours (−16.9 to 22.4) in the CS-8958 10 mg group, and −0.9 hours(−22.3 to 17.7) in the CS-8958 20 mg group. Values of bothCS-8958 10 mg group and 20 mg group were comparable to that of
the oseltamivir phosphate group.
Safety:Adverse events occurred in 26.6% (21/79) of subjects in theCS-8958 5 mg group, 33.7% (28/83) in the CS-8958 10 mg group,
41.6% (32/77) in the CS-8958 20 mg group, and 33.7% (28/83) inthe oseltamivir phosphate group.
Date of ReportAugust 30, 2011