Evaluation of the Efficacy and Safety of Peramivir in Subjects With Uncomplicated Acute Influenza.

A Phase II, Multicenter, Randomized, Double-Mask, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Intramuscular Peramivir in Subjects With Uncomplicated Acute Influenza.

This is a study for patients with flu who also have a fever as well as other flu symptoms. Patients must have had symptoms for less than 48 hours in order to participate. Patients will have two out of three chances of getting an active study treatment and the other third will receive a placebo (dummy drug). Nobody will know who gets the active drug and who gets the inactive drug. All patients will get supplies to treat symptoms of flu. Patients will need to be seen 5 more times after they are enrolled in the study.

Peramivir is a neuraminidase inhibitor that was previously shown to be effective in the treatment of human experimental influenza using an oral formulation. Parenteral formulations of peramivir (for intramuscular and intravenous injection) entered clinical development at the time of this Phase 2 study. A series of Phase 1 studies in human volunteers was completed that provided safety and pharmacokinetic results that supported the initiation of this Phase 2 multinational, randomized, double-mask study that compared the antiviral efficacy and safety of peramivir administered intramuscularly versus placebo in adults with uncomplicated acute influenza. Because of the unique pharmacokinetic and pharmacodynamic properties of peramivir - a long terminal half life in plasma and an extended duration of binding to the neuraminidase enzyme - subjects were randomized in a 1:1:1 ratio to receive a single dose of one of three treatments: peramivir 150 mg, peramivir 300 mg, and placebo. Study drug was administered as one 2-mL intramuscular injection in each gluteal muscle (total of 4 mL, injected in divided doses). This multinational study was originally to be conducted at approximately 80 sites in the US and Canada. When enrollment during the North American influenza season of 2006-2007 did not achieve the target, the study was extended to sites in Australia, New Zealand, South Africa, and Hong Kong.

Inclusion Criteria:

• Age ≥18 years

• Presence of fever at time of screening of ≥38.0 ºC (≥100.4 ºF) taken orally, or ≥38.5 ºC (≥101.2 ºF) taken rectally. However, this requirement is waived if the subject has a history of fever within the 24 hours prior to screening and has been administered antipyretic(s) in the 6 hours prior to screening.

• Presence of at least one respiratory symptom (cough, sore throat, or nasal symptoms) of any severity (mild, moderate, or severe)

• Presence of at least one constitutional symptom (headache, malaise, myalgia, sweats and/or chills, or fatigue) of any severity (mild, moderate, or severe)

• Onset of illness no more than 48 hours before presentation. Note: Time of onset of illness is defined as either (1) the time when the temperature (either oral or rectal) was first measured as elevated (at least one ºC of elevation-oral temperature), OR (2) the time when the subject experienced the presence of at least one respiratory symptom AND the presence of at least one constitutional symptom.

• Rapid Antigen Test (RAT) performed on an adequate specimen collected from an anterior nasal swab is positive. A negative initial RAT may be repeated within one hour of obtaining a negative result. A second negative RAT result will exclude the subject from evaluation for enrollment.

• Females of childbearing potential must report one of the following:

  • Be surgically sterile
  • 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
  • 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
  • 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.

Exclusion Criteria:

• Women who are breast-feeding
• History of diagnosed chronic obstructive pulmonary disease or diagnosis of severe persistent asthma
• History of chronic renal impairment requiring hemodialysis or known or suspected to have moderate or severe renal impairment (actual or estimated creatinine clearance <50 mL/min)
• History of congestive heart failure requiring daily pharmacotherapy with symptoms consistent with New York Heart Association Class II, III, or IV within the past 12 months
• Immunocompromised status due to illness or previous organ transplant
• Current use of systemic immunosuppressive medications (except inhaled corticosteroids)
• Use of rimantadine, amantadine, zanamivir, or oseltamivir in the past 7 days
• Immunized against influenza with live attenuated virus vaccine (FluMist®) in the previous 21 days
• Clinical evidence of active bacterial infection at any body site requiring therapy with oral or systemic antibiotics
• Clinically significant signs of acute respiratory distress
• Clinically significant signs of acute cardiac disease
• Screening ECG which suggests acute ischemia or presence of medically significant dysrhythmia
• Presence of a chronic disease or illness(es) with either clinical or historical evidence of recent exacerbation of such disease(s) or illness(es) or lack of control of such disease(s) or illness(es)
• History of hepatitis B, hepatitis C, or human immunodeficiency virus infection
• History of alcohol abuse or drug addiction within 1 year prior to admission in the study
• Participation in a study of any investigational drug within the last 30 days
• Positive urine pregnancy test