Influenza, Human
Conditions
Keywords
Influenza, Neuraminidase inhibitor
Brief summary
The primary objective of this study is to confirm the efficacy of CS-8958 administered as a single inhaled low dose or single inhaled high dose by showing non-inferiority to oseltamivir phosphate using the time to alleviation of influenza illness. For safety evaluation, between-group comparisons will be made with regard to incidence of adverse events and other safety measures. In a secondary objective, the optimum dosage of CS-8958 for this indication will be evaluated based on the efficacy and safety of single inhaled low or high dose.
Interventions
DRUGCS-8958
CS-8958 powder 20 mg to be inhaled one time. Oseltamivir phosphate placebo capsules 2 times per day for 5 days
CS-8958 placebo powder to be inhaled one time. Oseltamivir phosphate oral capsules taken twice daily for 5 days.
Sponsors
Daiichi Sankyo Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of influenza * Axillary temperature of \> or = to 37.5 degrees C
Exclusion criteria
* Infection by bacteria species and/or virus other than influenza virus * Chronic respiratory disease * Renal dysfunction
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Alleviation of Influenza Illness | 15 days | The time to illness alleviation which was defined as the time from the initiation of trial treatment to the beginning of the first 21.5-h period in which all influenza symptoms were absent or mild. Patients recorded their severity of influenza symptoms (headache, myalgia/arthralgia, fatigue, chills/sweats, nasal symptom, sore throat, and cough) 4 times daily for 15 days. Patients whose influenza symptoms had not been alleviated at the time of their withdrawal from the study or at the end of the observation period were censored. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time for Body Temperature to Return to Normal | 15 days | Time for return to normal axillary temperature was was defined as the time until the beginning of the first 21.5-hour period in which the axillary temperature returned to 36.9°C. Patients recorded their axillary temperature 4 times daily for 15 days. Patients whose axillary temperature had not been returned to 36.9°C at the time of their withdrawal from the study or at the end of the observation period were censored. |
Countries
China, Japan, South Korea, Taiwan
Participant flow
Recruitment details
This multicenter, double-blind,randomized, active-controlled trial was conducted from November 2008 through March 2009 at 117 institutions in Japan, Taiwan, Korea, and China (Hong Kong).
Pre-assignment details
Full analysis set (FAS) was defined as the set of subjects who had a positive test result using the influenza rapid diagnostic kit, received at least 1 dose of the study drug, and had valid efficacy data. The data for the baseline characteristics is provided for this analysis set, not for all participants who entered the trial.
Participants by arm
| Arm | Count |
|---|---|
| CS-8958 High Dose 40 mg CS-8958 powder to be inhaled - high-dose arm | 334 |
| CS-8958 Low Dose 20 mg CS-8958 powder to be inhaled - low-dose arm | 326 |
| Oseltamivir 75 mg oseltamivir phosphate oral capsules | 336 |
| Total | 996 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 4 | 1 |
| Overall Study | Protocol Violation | 7 | 2 | 12 |
| Overall Study | Withdrawal by Subject | 5 | 2 | 3 |
Baseline characteristics
| Characteristic | CS-8958 Low Dose 20 mg | Total | CS-8958 High Dose 40 mg | Oseltamivir 75 mg |
|---|---|---|---|---|
| Age, Continuous | 35.6 years STANDARD_DEVIATION 11.7 | 35.0 years STANDARD_DEVIATION 11.5 | 34.9 years STANDARD_DEVIATION 11.5 | 34.7 years STANDARD_DEVIATION 11.3 |
| Laboratory confirmed influenza Negative | 7 Participants | 26 Participants | 8 Participants | 11 Participants |
| Laboratory confirmed influenza Virus A/H1N1 | 215 Participants | 645 Participants | 218 Participants | 212 Participants |
| Laboratory confirmed influenza Virus A/H3N2 | 102 Participants | 322 Participants | 108 Participants | 112 Participants |
| Laboratory confirmed influenza Virus B | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 326 Participants | 996 Participants | 334 Participants | 336 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 2 participants | 7 participants | 3 participants | 2 participants |
| Region of Enrollment Japan | 256 participants | 785 participants | 263 participants | 266 participants |
| Region of Enrollment Korea, Republic of | 7 participants | 18 participants | 6 participants | 5 participants |
| Region of Enrollment Taiwan | 61 participants | 186 participants | 62 participants | 63 participants |
| Sex: Female, Male Female | 164 Participants | 477 Participants | 155 Participants | 158 Participants |
| Sex: Female, Male Male | 162 Participants | 519 Participants | 179 Participants | 178 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 63 / 337 | 54 / 326 | 63 / 336 |
| serious Total, serious adverse events | 0 / 337 | 0 / 326 | 2 / 336 |
Outcome results
Primary
Time to Alleviation of Influenza Illness
The time to illness alleviation which was defined as the time from the initiation of trial treatment to the beginning of the first 21.5-h period in which all influenza symptoms were absent or mild. Patients recorded their severity of influenza symptoms (headache, myalgia/arthralgia, fatigue, chills/sweats, nasal symptom, sore throat, and cough) 4 times daily for 15 days. Patients whose influenza symptoms had not been alleviated at the time of their withdrawal from the study or at the end of the observation period were censored.
Time frame: 15 days
Population: Full analysis set (FAS) was defined as the set of subjects who had a positive test result using the influenza rapid diagnostic kit, received at least 1 dose of the study drug, and had valid efficacy data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CS-8958 High Dose 40 mg | Time to Alleviation of Influenza Illness | 73.0 hours |
| CS-8958 Low Dose 20 mg | Time to Alleviation of Influenza Illness | 85.8 hours |
| Oseltamivir 75 mg | Time to Alleviation of Influenza Illness | 73.6 hours |
Comparison: This trial was designed to confirm the efficacy of laninamivir octanoate by showing that the median time to illness alleviation in patients treated with laninamivir octanoate was not \>18 hours longer than that in patients treated with oseltamivir. Sample size of 300 patients in each group was determined to achieve a power of at least 80% to show noninferiority at both dose levels of laninamivir octanoate with use of a Monte Carlo simulation.p-value: 0.74895% CI: [-9.9, 6.9]Generalized Wilcoxon Test
Comparison: Null hypothesis was that there was no difference in the time to illness alleviationp-value: 0.03895% CI: [-18.2, -0.4]Generalized Wilcoxon Test
Comparison: This trial was designed to confirm the efficacy of laninamivir octanoate by showing that the median time to illness alleviation in patients treated with laninamivir octanoate was not \>18 hours longer than that in patients treated with oseltamivir. Sample size of 300 patients in each group was determined to achieve a power of at least 80% to show noninferiority at both dose levels of laninamivir octanoate with use of a Monte Carlo simulation.p-value: 0.10495% CI: [-1.5, 17.2]Generalized Wilcoxon test
Secondary
Time for Body Temperature to Return to Normal
Time for return to normal axillary temperature was was defined as the time until the beginning of the first 21.5-hour period in which the axillary temperature returned to 36.9°C. Patients recorded their axillary temperature 4 times daily for 15 days. Patients whose axillary temperature had not been returned to 36.9°C at the time of their withdrawal from the study or at the end of the observation period were censored.
Time frame: 15 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CS-8958 High Dose 40 mg | Time for Body Temperature to Return to Normal | 55.3 hours |
| CS-8958 Low Dose 20 mg | Time for Body Temperature to Return to Normal | 58.0 hours |
| Oseltamivir 75 mg | Time for Body Temperature to Return to Normal | 54.7 hours |
Comparison: Null hypothesis was that there was no difference in the time for return to normal axillary temperature.p-value: 0.31895% CI: [-2.8, 9.1]Generalized Wilcoxon test
Comparison: Null hypothesis was that there was no difference in the time for return to normal axillary temperature.p-value: 0.98195% CI: [-5.8, 5.7]Generalized Wilcoxon test
Comparison: Null hypothesis was that there was no difference in the time for return to normal axillary temperature.p-value: 0.34495% CI: [-9.1, 3.1]Generalized Wilcoxon test