SYNOPSIS
Name of Sponsor/Company

Daiichi Sankyo Co., Ltd.

Name of Finished Product

INAVIRⓇ DRY POWDER INHALER 20 mg

Name of Active IngredientLaninamivir Octanoate Hydrate（JAN）

Title of Study

A Phase 3 Study of CS-8958 (Postexposure Prophylaxis)－A randomized, double-blind, placebo-controlled study toconfirm efficacy in the prevention of influenza virus infection－

Investigators
Study Centre(s)Publication (reference)

Not published.

Studied Period
Phase of Development

Phase 3Objectives

A randomized, double-blind, placebo-controlled, comparative
study was conducted to investigate the efficacy of 1 inhaledtreatment a week (2 inhaled treatments total) of CS-8958 20 mg or
40 mg for the prevention of influenza virus infection in household
members of patients with influenza A or B virus infection.
The primary efficacy endpoint was the proportion of participants
with clinical influenza virus infection, and the objective was toevaluate superiority of CS-8958 to placebo. For safety, theincidence of adverse events was compared between the treatmentgroups.
The optimal clinical dose was investigated on the basis of theresults of the efficacy and safety of inhaled treatments of CS-8958
20 mg or 40 mg.

Methodology

A multicenter, randomized, double-blind, , parallel-group,placebo-controlled, comparative study

Number of Patients (plannedPlanned:and analyzed)

600 participants (200 in the CS-8958 20 mg group, 200 in theCS-8958 40 mg group, and 200 in the placebo group)
Analyzed:
Full analysis set (FAS): 610 participants (207 in the CS-8958
20 mg group, 205 in the CS-8958 40 mg group, and 198 in theplacebo group)

Diagnosis and Main Criteria

Index patients:for Inclusion

1) Positive result on the influenza rapid diagnostic test2) No household members with influenza A or B virus infection inthe 4 weeks prior to informed consent
Participants:
1) Household member of a patient with influenza A or B virus
infection2) Negative result on the influenza rapid diagnostic test3) Body temperature (axillary) at informed consent ≤ 36.9°C4) No symptoms that cannot be distinguished frominfluenza(headache, myalgia/arthralgia, fatigue,chills/perspiration, nasal symptoms, sore throat, or cough) at
informed consent
5) Investigator has determined that the individual will be able touse the provided inhaler
Test Product, Dose and Mode

CS-8958-20TC (containing 20 mg as CS-8958)

of Administration, Batch

CS-8958-20PTC (placebo, externally indistinguishable from theNumberCS-8958)
In the CS-8958 20 mg group: Participants inhaled one
CS-8958-20TC and one CS-8958-PTC per week, and a total of twotimes. In the CS-8958 40 mg group: Participants inhaled twoCS-8958-20TC per week, and a total of two times. In the placebogroup, Participants inhaled two CS-8958-PTC per week, and a totalof two times.

Duration of Treatment

Once a week for 2 weeks, and a total of 2 times

Reference Therapy, Dose and-ModeofAdministration,

Batch Number
Criteria for Evaluation

Primary Endpoint:
Proportion of participants with clinical influenza virus infection
A participant with clinical influenza virus infection was defined
as having a clinical influenza virus infection when a positive
virus test result was obtained, body temperature was 37.5°C or
more, and at least 2 of the 7 influenza symptoms (headache,myalgia/arthralgia, fatigue, chills/perspiration, nasal symptoms,sore throat, and cough) were observed.

Statistical Method

Primary analysis (efficacy):
The CS-8958 20 mg group and 40 mg group were compared withthe placebo group using the Fisher exact test. A significance levelof 5%, 2-sided, was used, and the Holm method was used formultiplicity adjustment. In addition, the relative risk comparedwith the placebo group as well as their 95% confidence intervals(CIs) were calculated.
Safety analysis:
The numbers and proportions of participants with all-cause anddrug-related adverse events were calculated by treatment group.
Summary - Conclusion

The proportion of participants with clinical influenza virus
infection was 4.8% (10 of 207) in the CS-8958 20 mg group, 4.9%(10 of 205) in the CS-8958 40 mg group, and 8.6% (17 of 198) inthe placebo group. Although the proportion was lower in both theCS-8958 20 mg group and the CS-8958 40 mg group than in theplacebo group, the differences were not statistically significant (P= 0.1633 [CS-8958 20 mg group], P = 0.1643 [CS-8958 40 mggroup] by the Fisher exact test). The relative risk reduction (95%CI) compared to placebo was 43.7% (−19.9 to 73.6) in theCS-8958 20 mg group and 43.2% (−21.0 to 73.3) in the CS-8958
40 mg group.
The incidence of adverse events was similar among all thetreatment groups, and no major safety concerns were noted ineither of the CS-8958 group.
The aforementioned results suggested that CS-8958 is effective forthe prevention of influenza virus infection in household membersof patients with influenza virus infection; however, superiority toplacebo could not be confirmed, and it was concluded that furtherstudy to evaluate appropriate dosage for the prophylaxis ofinfluenza virus infection would be necessary.

Date of Report

Sep, 2014