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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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High-Dose Versus Standard-Dose Oseltamivir for the Treatment of Severe Influenza and Avian Influenza: A Phase II Double-Blind, Randomized Clinical Trial

Conditions
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Influenza, Avian Influenza, Severe Influenza

Intervention / Treatment
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* Drug: Oseltamivir


Participation Criteria
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Eligibility Criteria
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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: Need for hospitalization One of the following: New infiltrate on chest x-ray (or any infiltrate if no prior chest x-ray or not known) Severe tachypnea (more information on this criterion can be found in the protocol) Severe dyspnea Arterial oxygen saturation of 92% or less on room air by trans-cutaneous method 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 Illness (defined by onset of fever, respiratory symptoms, or constitutional symptoms) began within 10 days before study enrollment Avian influenza infection criteria: Nasal wash, nasopharyngeal aspirate, endotracheal aspirate, nasal swab, or throat swab that is RT-PCR positive influenza for H5 influenza 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

Ages Eligible for Study
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Minimum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Dose oseltamivir adult cohort<br>All participants >= 15 years will receive standard-dose oseltamivir (75 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days. | Drug: Oseltamivir<br>* Oseltamivir is a sialic acid analogue that potently and specifically inhibits the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Oseltamivir will be administered orally in standard formulations (capsules for adults and children at least 15 years of age; suspension for children younger than 15 years).<br>* Other names: Tamiflu;|
| Active Comparator: Double Dose oseltamivir Adult cohort<br>All participants >= 15 years will receive high-dose oseltamivir (150 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days. | Drug: Oseltamivir<br>* Oseltamivir is a sialic acid analogue that potently and specifically inhibits the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Oseltamivir will be administered orally in standard formulations (capsules for adults and children at least 15 years of age; suspension for children younger than 15 years).<br>* Other names: Tamiflu;|
| Active Comparator: Standard Dose Oseltamivir child cohort<br>All participants <15 years will receive standard-dose oseltamivir (75 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days. | Drug: Oseltamivir<br>* Oseltamivir is a sialic acid analogue that potently and specifically inhibits the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Oseltamivir will be administered orally in standard formulations (capsules for adults and children at least 15 years of age; suspension for children younger than 15 years).<br>* Other names: Tamiflu;|
| Active Comparator: Double Dose Oseltamivir child cohort<br>All Participants <15 years will receive high-dose oseltamivir (150 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days. | Drug: Oseltamivir<br>* Oseltamivir is a sialic acid analogue that potently and specifically inhibits the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Oseltamivir will be administered orally in standard formulations (capsules for adults and children at least 15 years of age; suspension for children younger than 15 years).<br>* Other names: Tamiflu;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of All Participants Negative for Viral RNA on Day 5 | 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. | After 5 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants Meeting Criteria for Day 5 Clinical Failure | 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. | After 5 days of treatment | 
| In-hospital Mortality Rates | 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. | After up to 10 days of treatment | 
| Median Time (Days) Receipt of Oxygen |  | Throughout study, 14 days | 
| Median Time (Days) in ICU |  | Throughout study, 14 days | 
| Median Time (Days) on Ventilation | Use of mechanical ventilation at any time for subjects with severe influenza and avian influenza. | Throughout study, 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antibody Response, Antiviral Efficacy, Bird Flu, Severe Respiratory Distress, Viral Replication and Shedding