High-Dose Versus Standard-Dose Oseltamivir to Treat Severe Influenza and Avian Influenza

• Proportion of All Participants Negative for Viral RNA on Day 5 [ Time Frame: After 5 days of treatment ] [ Designated as safety issue: No ]
  Proportion of all participants with no detectable viral RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) in a combined nasal and throat swab sample on day 5.
  
  

• Participants Meeting Criteria for Day 5 Clinical Failure [ Time Frame: After 5 days of treatment ] [ Designated as safety issue: No ]

  Proportion of participants that have clinical failure by day 5. Subjects that meet one of the following on Day 5 will be classified as a clinical failure:

  • Severe tachypnea (respiratory rate ≥ 30 for ages ≥12 years, rate ≥ 40 for ages 6 to 12 years, rate ≥45 for ages 3 to 6 years, rate ≥ 50 for ages 1 to 3 years)
  • Severe dyspnea (unable to speak full sentences, or use of accessory respiratory muscles)
  • Arterial oxygen saturation ≤92% on room air by trans-cutaneous method
  • Need for mechanical ventilation or intensive care unit (ICU) admission For the purpose of endpoint definition, death prior to or on Day 5 will also be considered a clinical failure at Day 5.
  
  
• In-hospital Mortality Rates [ Time Frame: After up to 10 days of treatment ] [ Designated as safety issue: No ]
  Standard therapy with oseltamivir is five days. Those patients with persistent symptoms on day five were continued on the randomized dose for an additional five days and assessments were performed up to day 10.
  
  
• Median Time (Days) Receipt of Oxygen [ Time Frame: Throughout study, 14 days ] [ Designated as safety issue: No ]
  
• Median Time (Days) in ICU [ Time Frame: Throughout study, 14 days ] [ Designated as safety issue: No ]
  
• Median Time (Days) on Ventilation [ Time Frame: Throughout study, 14 days ] [ Designated as safety issue: No ]
  Use of mechanical ventilation at any time for subjects with severe influenza and avian influenza.
  
  

Two main types of influenza virus--Types A and B--are responsible for the seasonal flu epidemics that occur each year. The influenza A viruses can be broken down into subtypes based on two proteins on the surface of the virus: hemagglutinin (H) and neuraminidase (N). The A subtypes usually found in humans are H1N1, H1N2, and H3N2. Other A subtypes are found primarily in animals. For example, the "avian influenza virus" refers to an influenza A virus that is found chiefly in birds.

Although avian influenza does not usually affect humans, increasing numbers of cases of human infection from avian influenza virus H5N1 have been reported in the last several years. Because all influenza viruses have the ability to modify, there is concern that this trend of increasing cases may pose a threat of a future pandemic with a new H5N1 virus that could spread easily from person to person.

The H5N1 virus that has caused human infection in Asia is resistant to amantadine and rimantadine, two antiviral medications commonly used for treating people with influenza. Another antiviral medication, oseltamivir, is currently used to treat people with uncomplicated human influenza. The purpose of this study is to compare standard-dose oseltamivir and high-does oseltamivir for treating people who are hospitalized with severe human influenza or avian influenza. The study will also attempt to identify how severe human influenza and avian influenza differ in the following factors: clinical manifestation, relationship between antiviral plasma concentrations and viral dynamics, and pathogenesis.

Upon meeting certain screening criteria, participants will be randomly assigned to receive oseltamivir either at a standard-dose level (75 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) or at a high-dose level (150 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function). Treatment will continue for 5 days, after which participants who meet clinical failure criteria will continue their assigned treatment for an additional 5 days. It is anticipated that participants will remain hospitalized through the course of treatment. On Day 0, which marks the first day of hospitalization, participants will undergo a medical review, physical examination, blood sampling, nasal swab, throat swab, anal swab, and chest x-ray. An endotracheal aspirate procedure and urine sampling may also be performed. During the hospital stay, most of the above procedures will be repeated regularly, and additional samples of lung fluid, cerebral spinal fluid, and pleural fluid may be obtained. On Day 5 and possibly on Day 10, participants will undergo a follow-up x-ray. If applicable, participants will attend outpatient study visits on Days 10, 14, and 28 for further evaluation; participants with avian influenza will also attend visits on Days 56 and 180.