High-Dose Versus Standard-Dose Oseltamivir to Treat Severe Influenza and Avian Influenza
High-Dose Versus Standard-Dose Oseltamivir to Treat Severe Influenza and Avian Influenza
Influenza, also known as the flu, is a contagious respiratory illness caused by influenza
 viruses. The illness can range in severity, from mild to severe to even death, and it causes
 an estimated 500,000 to 1,000,000 deaths worldwide each year. In the last several years,
 there have been increasing numbers of human cases of avian influenza, or bird flu. This trend
 may pose a threat of a future pandemic--worldwide outbreak of disease--with an avian
 influenza virus that can easily spread from person to person. Oseltamivir is an antiviral
 medication that is used to treat people with uncomplicated human influenza, and it may be
 effective in treating people with either severe human influenza or avian influenza. The
 purpose of this international study is to compare standard-dose oseltamivir versus high-dose
 oseltamivir for treating people who are hospitalized with severe human influenza or 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.
Inclusion Criteria:

 -  At least one of the following respiratory symptoms: cough, dyspnea, sore throat

 -  Evidence of severe influenza or avian influenza, as defined below

 -  Severe influenza infection criteria:

 1. Need for hospitalization

 2. One of the following:

 1. New infiltrate on chest x-ray (or any infiltrate if no prior chest x-ray or
 not known)

 2. Severe tachypnea (more information on this criterion can be found in the
 protocol)

 3. Severe dyspnea

 4. Arterial oxygen saturation of 92% or less on room air by trans-cutaneous
 method

 3. Positive diagnostic testing for influenza, as defined by either rapid influenza
 antigen (Ag) positive (A or B) or qualitative reverse transcriptase-polymerase
 chain reaction (RT-PCR) positive for any influenza

 4. Illness (defined by onset of fever, respiratory symptoms, or constitutional
 symptoms) began within 10 days before study enrollment

 -  Avian influenza infection criteria:

 1. Nasal wash, nasopharyngeal aspirate, endotracheal aspirate, nasal swab, or throat
 swab that is RT-PCR positive influenza for H5 influenza

 2. Illness (defined by onset of fever, respiratory symptoms, or constitutional
 symptoms) began within 14 days before study enrollment

 Exclusion Criteria:

 -  Received more than 72 hours of oseltamivir (six doses) within 14 days

 -  Received oseltamivir at higher than standard doses within the last 14 days or during
 current acute illness, whichever is longer

 -  History of allergy or severe intolerance of oseltamivir, as determined by the
 investigator

 -  Alternate explanation for the clinical findings, as determined by the investigator and
 with the information immediately available

 -  Creatine clearance less than 10 ml/minute

 -  Pregnant or breastfeeding