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 2/3 Study of CS-8958 in Pediatric Patients-A randomized double-blind controlled study of CS-8958
comparing with oseltamivir phosphate in patients with influenza
virus infection aged 9 years or younger -Investigators
Study Centre(s)Publication (reference)

Antimicrob Agents Chemother. 2010 Jun;54(6):2575-82.

Studied Period
Phase of Development

Phase 2, Phase 3Objectives

A 3-arm, randomized, double-blind comparative study in pediatricpatients (aged 9 years and under) with type A or B influenza virus
infection was performed to evaluate the efficacy and safety of asingle inhalation of CS-8958 20 mg or 40 mg, with oseltamivir
phosphate as a control.

Methodology

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

Number of Patients (planned

Number of Planned Subjects:180 subjects (60 subjectsand analyzed)each in CS-8958 20 mg group, 40 mg group, andoseltamivir phosphate group)Full analysis set (FAS):184 subjects (CS-8958 20 mg group: 61subjects, CS-8958 40 mg group: 61 subjects, and oseltamivir
phosphate group: 62 subjects)

Diagnosis and Main Criteria

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

following criteria:1) Influenza virus-positive by an influenza rapid diagnostic kit, anddiagnosed with influenza virus infection by the investigators
2) Body temperature (axillary) ≥ 38.0℃ at the time of informed
consent
3) Within 36 hours after the onset of any influenza symptoms (egfever [feeling of fever], nasal symptoms, cough) at the time of
informed consent
4) Aged ≤ 9 years as of the last study treatment
5) Patients the investigators considered able to inhale the study

drug using the inhaler
Test Product, Dose and Mode

CS-8958

of Administration

CS-8958 placebo
Patients inhaled a single dose of the following drugs using aninhaler: CS-8958 and CS-8958 placebo in the CS-8958 20 mggroup, and CS-8958 in the CS-8958 40 mg group, and CS-8958
placebo in the oseltamivir phosphate group.

Duration of Treatment

Single dose (5 days for the control group)

Reference Therapy, Dose andOseltamivir phosphate dry syrup

Mode of Administration

Oseltamivir phosphate placebo
Patients took oral oseltamivir phosphate placebo twice daily for 5days in the CS-8958 20 and 40 mg groups. In the oseltamivir
phosphate group, patients took oral oseltamivir phosphate drysyrup at a dose of 66.7 mg/kg (equivalent to 2 mg/kg ofoseltamivir) twice daily for 5 days.

Criteria for Evaluation

Time to alleviation of influenza illness

Statistical Method

Efficacy Analysis;Primary analysis: The median differences between each CS-8958
group and the oseltamivir phosphate group (CS-8958 group −oseltamivir phosphate group) were calculated. The 95% CIs werecalculated from generalized Wilcoxon test statistics. In addition,
the generalized Wilcoxon test was performed using the oseltamivir
phosphate group as a control.
Safety Analysis;
Adverse Events
The number of subjects with adverse events and their incidence
were presented by causal relationship (all/related) for eachtreatment group. Serious adverse events, severe adverse events anddiscontinuations due to adverse events were also summarized. The
number of subjects with each adverse event and the incidence werepresented by causal relationship (all/related) and by severity andcausal relationship (all/related) for each treatment group.

Summary - Conclusion

Efficacy (primary endpoint):
The median time to alleviation of influenza illness was 56.4 hours
in the CS-8958 20 mg group, 55.4 hours in the CS-8958 40 mggroup, and 87.3 hours in the oseltamivir phosphate group. The
median differences (95% CI) between each CS-8958 group and theoseltamivir phosphate group were −31.0 (−50.3 to −5.5) hours in
the 20 mg group and −31.9 (−43.4 to 0.5) hours in the 40 mggroup. The time to alleviation of influenza illness was significantly
shorter in the CS-8958 20 mg group than in the oseltamivir
phosphate group. Although it was not statistically significant, thetime to alleviation of influenza illness in the CS-8958 40 mg group
was also shorter than in the oseltamivir phosphate group.
Safety:The incidence of adverse events was 34.4% (21/61) in the CS-8958
20 mg group, 24.2% (15/62) in the CS-8958 40 mg group, 29.3%(36/123) in both CS-8958 groups, and 38.7% (24/62) in theoseltamivir phosphate group. There was no major difference in theincidence of adverse events between each CS-8958 group and theoseltamivir phosphate group.
Date of ReportAugust 30, 2011