A description of the DSMC was added. Since the study was open label, a sponsor-led DSMC was to oversee safety. A full review and summary of safety utilizing all collected safety assessments was to occur after each influenza season. Full procedures were to be described in the SAP.

Planned number of subjects updated from 72 to 130, of which ~100 subjects to be randomized to peramivir. IV peramivir to oral oseltamivir randomization ratios updated to 4:1 for each age cohort. Youngest subject age allowed into the study was changed from 2 years to 28 day; age cohort groupings updated accordingly. Age of subjects requiring assent changed from ≥14 to ≥7 years. Dose of IV peramivir updated to 600mg IV or 12 mg/kg depending on age. Oseltamivir dosing for subjects aged 28 days to <1 year was specified as weight-based, using an oral suspension of 3mg/kg BID ×5 days. RAT or PCR testing for influenza A/B removed from the screening procedure; Positive RAT or PCR influenza A test was removed from the inclusion criteria. Instead, inclusion criterion 2 specified that clinical signs & symptoms consistent with acute influenza infection OR a positive influenza RAT was required. Exclusion criterion 2 added; receipt of a live attenuated influenza infection within 14 days of presentation. Exclusion criterion 6 updated to include examples of exclusionary chronic diseases or illnesses. Dose adjustment for subjects with renal impairment was removed. Permitted concomitant medications updated regarding medications used for symptomatic treatment of influenza-related symptoms. Serum sample for future influenza antibody analysis added to the study procedures. Vital sign procedures specified that blood pressure was to be measured in children < 2 years of age only if clinically indicated. Procedures for assessing influenza symptoms were updated based on the allowable subject ages. Full procedures for DSMC safety oversight to be described in a DSMC charter, rather than the SAP. Informed consent procedures updated to specify that if the local IRB/IEC or state requirements limited the age of assent, then assent was to be obtained based on those requirements, but in all cases, assent was to be obtained for adolescents ≥ 14 years of age.

Lower age limit for inclusion criterion 1 changed from 28 days to birth. Overall number of subjects to be enrolled increased from 130 to 140. The age cohorts and treatments updated to include cohort ‘Birth to < 28 days’ to include up to 10 subjects receiving IV peramivir. The 2 to < 7 year-old cohort was split into 2 new cohorts: 2 to < 4 years (up to 10 subjects) and 4 to < 7 years (up to 30 subjects). Exclusion criteria updated to provide further clarification of subject eligibility. Justification added for dosing in neonates (0 to < 28 days): To maintain safe blood sampling levels for neonates, PK sampling limited to no more than two 1.0 mL samples for subjects who weigh <5 kg & the need for serum antibody testing limited to subjects who weigh <10 kg. Day 14 schedule of assessments description updated to clarify the need to perform repeat safety laboratory testing. To maintain appropriate fluid volume for children under the age of 12 months, the dilution of peramivir calculated using a subject’s age and weight. Clarification provided regarding the duration of collection of information on daily activity and eating patterns. Clarification provided regarding the timing of temperature taken at Baseline visit. Time cut-off for collection of AE reports changed from Day 7 to Day 14 following subject consent. To minimize blood loss for hospitalized subjects, text added regarding testing at local versus central laboratories. The descriptive statistical methodology and definitions updated to match the Statistical Analysis Plan for the study.

The peramivir IV dosing specification by age group was changed from 600 mg IV or 12 mg/kg IV depending on age to 600 mg IV for subjects ≥ 13 years, 12 mg/kg IV for subjects ≥ 6 months to ≤ 12 years, 8 mg/kg IV for subjects < 6 months. Prior to this amendment 4, the dose for all subjects ≤ 12 years of age was 12 mg/kg. The peramivir dilution protocol for children < 12 months of age was updated.

Inclusion criterion 3 and Exclusion criterion 6 changed from ‘onset of symptoms no more than 48 hours before presentation for screening for subjects < 2 years old’ to ‘onset of symptoms no more than 72 hours before presentation for screening for subjects < 2 years old’. Exclusion criterion 8 changed to allow subjects with identified risk factors. Exclusion criterion 9 changed from the specification of immunocompromised status to severe immunocompromised status. Sponsor Medical Officer’s contact information updated. Contact information for the submission of SAE report forms updated.