Safety, PK and Effectiveness of IV Peramivir in Elderly and Higher Risk Subjects With Uncomplicated Influenza

Safety was evaluated through assessment of Adverse Events (AEs).

Time frame: 14 days

Change in influenza viral titers was defined as the time-weighted change from Baseline in log\_10 tissue culture infective dose\_50 (TCID50/mL) and was summarized for each treatment group.

Time frame: Change from baseline assessed on days 3, 7 and 14.

Population: The Intent To Treat Infected (ITTI) population included all subjects who were enrolled, received study drug, and had confirmed influenza A and/or B by PCR. Eight subjects were excluded due to a negative or missing BL titer.

Study personnel evaluated the subject at Screening and Days 3, 7, and 14 for the presence of clinical signs and/or symptoms of the following influenza-related complications: Sinusitis, Otitis media, Bronchitis & Pneumonia. Note that subjects with clinical signs and/or symptoms consistent with bacterial infections, including otitis media, bronchitis, sinusitis, and/or pneumonia at Screening, were not eligible for enrollment in this study. If an influenza-related complication was suspected, then a targeted physical examination was to be conducted to confirm the presence or absence of the influenza-related complication.

Time frame: 14 days

Population: Intent-to-treat infected (ITTI) population

Up to 3 plasma samples will be drawn, where possible: immediately following infusion, 30 mins to 1 hr post-infusion & 1 to 3 hrs post-infusion. Maximum concentration (Cmax), area under the concentration vs. time curve (AUC) from time 0 to 1 hour (AUC0-1), AUC from time 0 to 1.5 hours (AUC0-1.5), and AUC from time 0 to the last measurable time point (AUC0-last) were calculated in Phoenix® WinNonlin® v6.4. No summary statistics were reported due to the variation in the infusion time and sampling times.

Time frame: up to 3 hours post peramivir infusion

Population: 73 subjects from the ITT population had sufficient PK samples collected for inclusion in the peramivir PK analysis

Assessment of viral shedding in bilateral, mid-nasal swab specimens taken at baseline and then on Day 3, 7 and 14.

Time frame: 14 days

Population: Intent to treat infected (ITTI) population + ITT population with positive baseline influenza viral titers \[\> 0.5 log10 TCID50/mL\]. Eight subjects were excluded due to a negative or missing Baseline titer.

Time for fever resolution based on subject diary record of temperature recorded twice daily. A subject had resolution of fever if he/she had an oral temperature \< 37.4°C/99.4°F oral and no antipyretic medications were taken for at least 12 hours. The time to resolution of fever was estimated for each age group and overall using the Kaplan-Meier method with temperature and symptom relief medication information obtained from the Subject Diary data. Subjects who did not have resolution of fever were censored at the time of their last non-missing post-baseline temperature assessment.

Time frame: 14 days

Population: Intent to treat infected (ITTI) population. Subjects who did not have resolution of fever were censored at the time of their last non-missing post-baseline temperature assessment; this included 1 subject in the 'At Risk (\<65 years)' group. Twelve subjects were excluded from summaries due to missing data or events resolving prior to initiation of study drug.

Subjects were asked to provide an assessment of 7 influenza symptoms (cough, sore throat, nasal congestion, myalgia \[aches and pains\], headache, feverishness, and fatigue) on a 4-point severity scale (0, absent; 1, mild; 2, moderate; 3, severe) beginning at Screening then twice daily beginning on Day 1 through to Day 13, and prior to the subject's clinic visit on Day 14. Once all symptoms were scored a 0 or 1 for at least 48 hours, recordings were discontinued. The time to alleviation of symptoms, defined as the time from initiation of study drug until the start of the 21.5-hour period (24 hours less 10%), where all symptoms of influenza were recorded as none (0) or mild (1), was estimated overall and for each age group using the Kaplan-Meier method.

Time frame: 14 days

Population: Intent to treat infected (ITTI) population. Subjects who did not experience alleviation of symptoms were censored at the date of their last non-missing post-baseline assessment; this included 5 subjects in the 'At Risk (\<65 years)' group, 4 subjects in the 'Elderly (65-75 years)' group and 2 subjects in the 'Very Elderly (\>75 years)' group.

The ability to perform usual daily activities was assessed on a VAS (Visual Analogue Scale), where 0 indicates unable to perform usual activities at all and 10 indicates able to perform usual activities.. The time to return to usual activities was the number of days from initiation of study drug until the subject recorded a rating of 10 (able to perform all usual activities fully) on the VAS; this was estimated for each age group and overall using the Kaplan-Meier method.

Time frame: 14 days

Population: Subjects who did not return to normal activities were censored at the time of their last non-missing post-baseline assessment; this included 9 subjects in the 'At Risk (\<65 years)' group, 12 subjects in the 'Elderly (65-75 years)' group and 2 subjects in the 'Very Elderly (\>75 years)' group. Two subjects were excluded from summaries due to missing data or events resolving prior to initiation of study treatment.