This study has been designed as a randomized, double-blind, controlled, study to evaluate the efficacy and safety of two once daily intravenous peramivir regimens (200 mg and 400 mg) versus oral oseltamivir phosphate (75 mg twice daily) in hospitalized subjects with acute serious or potentially life threatening influenza. Study treatments will be provided for up to 5 consecutive days.

Inclusion Criteria:

• Age ≥18 years of age, male or female
• Able to provide informed consent, or for whom consent may be provided by guardian
• Presence of fever at time of screening of ≥38.0°C (≥ 100.0°F) taken orally, or ≥38.5°C (≥101.2°F) taken rectally. This requirement is waived if the subject has (1) a history of fever within 24 hours prior to screening and administered any antipyretic(s) in the 24 hours prior to screening, or (2) has no history of documented fever as defined above, but reports a symptom of feverishness at some time during 48 hours prior to screening
• Presence of at least 1 respiratory symptom (cough, sore throat, nasal congestion/symptoms) of any severity (mild, moderate, severe)
• Presence of at least 1 constitutional symptom (headache, myalgia, feverishness, malaise, fatigue) of any severity (mild, moderate, severe)
• Onset of illness no more than 72 hours before presentation. Time of onset of illness defined as either (1) the time when temperature (oral or rectal) was elevated (at least 1°C of elevation-oral temperature), OR (2) the time when the subject experienced the presence of at least 1 respiratory symptom AND the presence of at least 1 constitutional symptom
• Presence of 1 or more of the following factors in a subject willing to be hospitalized for inpatient observation and treatment:
• Age ≥60 years
• Presence of chronic obstructive pulmonary disease (COPD) or other chronic lung disease requiring daily pharmacotherapy
• History of congestive heart failure with or without medically significant recent change in cardiac status, but without signs or symptoms compatible with NYHA Class IV functional status
• Presence of diabetes mellitus, clinically stable or unstable
• Transcutaneous oxygen saturation <94% without supplemental oxygen for at least 5 minutes, or a medically significant decrease in oxygen saturation from an established baseline value
• Systolic blood pressure <90 mmHg
• Severity of illness that, in the Investigator's judgment, justifies hospitalization of the subject for supportive care
• Positive rapid antigen test (RAT) for influenza A and/or influenza B (using an approved test kit) or other test for influenza virus antigen performed in a clinical laboratory at the screening/enrollment evaluation
• Females of childbearing potential must report one of the following:
• Be surgically sterile or clinically post-menopausal
• Have been sexually abstinent 4 weeks prior to date of screening evaluation and be willing to remain abstinent through 4 weeks after study-drug administration for all perimenopausal women or women of child-bearing potential
• Use oral contraceptives or other form of hormonal birth control including hormonal vaginal rings or transdermal patches and have been using these for 3 months prior through 4 weeks after study-drug administration for all perimenopausal women or women of child-bearing potential
• Use an intra-uterine device (IUD), or adequate barrier contraception (or double-barrier method such as condom or diaphragm with spermicidal gel or foam) as birth control 4 weeks prior to date of screening evaluation through 4 weeks after study drug administration for all perimenopausal women or women of child-bearing potential

Exclusion Criteria:

• Immunized against influenza with live attenuated virus vaccine in the previous weeks
• Treatment with any dose(s) of rimantadine, amantadine, zanamivir, or oseltamivir in the previous 7 days
• Current clinical evidence of a recognized or suspected acute non-influenzal infectious illness with onset prior to Screening
• Serum creatinine laboratory result at Screening >1.6 mg/dL or a result >25% above the upper limit of normal for the laboratory performing the test
• History of clinically significant proteinuria (≥1000 mg/24 hrs)
• History of moderate or severe renal impairment and/or previous clinical laboratory data indicating an estimated creatinine clearance <50 mL/min during the previous 12 months
• Electrocardiogram (ECG) at Screening visit showing evidence of acute ischemia, or presence of a medically significant dysrhythmia
• Presence of cardiac signs or symptoms compatible with NYHA Class III or Class IV functional status for congestive heart failure or angina (see NYHA Appendix V)
• Presence of diagnosed COPD or other chronic lung condition requiring either continuous or intermittent oxygen therapy as an outpatient. Note: Subjects who are determined to require acute supplemental oxygen therapy at the time of Screening and/or at hospital admission may be enrolled, if exclusion criteria #13 or #14 are not applicable.
• History of organ transplantation during the previous 12 months
• Known HIV infection with most recent CD4+ T-cell count ≤350 cells/mL
• History of diagnosis of any type of cancer (hematologic or solid tumor), that has required chemotherapy or radiation therapy in the previous 12 months, excluding non-melanomatous localized skin cancer
• Presence of ongoing requirement for chronic mechanical ventilation, either via oral or nasotracheal intubation or via tracheostomy, or chronic or intermittent requirement for BiPAP (bilevel positive airway pressure) at screening. Note: Subjects who require intermittent CPAP treatment for sleep apnea (without oxygen supplementation) may be enrolled
• Subjects who require acute mechanical ventilatory support of any type at the time of screening.
• History of alcohol abuse or drug addiction during the previous 12 months
• Participation in a clinical study of an experimental medication or other treatment during the previous 4 weeks
• Previous treatment with intravenous or intramuscular peramivir
• Women who are pregnant (positive serum or urine pregnancy test), who are attempting to become pregnant, or who are breast-feeding
• Subjects who have been hospitalized due to a condition other than acute influenza and in whom influenza is diagnosed during hospitalization.