A Study of Tamiflu (Oseltamivir) for Treatment of Influenza With a Focus on (H1N1) 2009 Flu Strain

Study Overview
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Brief Summary
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This randomized, double-blind, multi-center study of Tamiflu (Oseltamivir) will evaluate the efficacy against viral activity, the effectiveness in resolving the disease symptoms, and the safety and tolerability in patients with influenza. Patients with (H1N1) 2009 influenza strain or influenza A are eligible for this study. Patients will be randomized to one of four treatment regimens. Patients will receive oral doses of either 75 mg (adults) or 150 mg (adults) of study drug twice daily for 5 or 10 consecutive days. The dose will be body weight-adjusted for pediatric patients.

Official Title
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A Randomized, Multicenter Trial of Oseltamivir [Tamiflu] Doses of 75 mg for 5 or 10 Days Versus 150 mg for 5 or 10 Days to Evaluate the Effect on the Duration of Viral Shedding in Influenza Patients With Pandemic (H1N1) 2009

Conditions
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Influenza

Intervention / Treatment
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* Drug: Oseltamivir
* Drug: Oseltamivir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pediatric, adolescent and adult patients >/=1 year of age Fever >/=37.8 degrees C or at least one respiratory symptom (cough, coryza, sore throat, or rhinitis) Positive rapid diagnostic test for pandemic (H1N1) 2009 virus or influenza A in the 24 hours prior to the first dose of study drug </=96 hours between onset of influenza-like illness and first dose of oseltamivir Exclusion Criteria: Currently receiving any form of renal replacement therapy including hemodialysis, peritoneal dialysis, or hemofiltration History of chronic renal failure or clinical suspicion of renal failure at baseline Clinical evidence of hepatic compensation at the time of randomization Known HIV infection Vaccination with live attenuated influenza vaccine (LAIV) in the two weeks prior to first dose of study medication

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oseltamivir standard dose 5 days<br>Adults and children 13 years and older received 75 mg oseltamivir and a placebo capsule twice daily for 5 days. Children aged 1 - 12 years received a weight-based dose (from 30 to 75 mg) oseltamivir suspension and placebo suspension orally twice daily for 5 days. Participants received matching placebo for the second 5 days of treatment. | Drug: Oseltamivir<br>* Oseltamivir capsules for participants ≥ 13 years.<br>* Other names: Tamiflu;Drug: Oseltamivir<br>* Pediatric suspension for participants aged ≤ 12 years.<br>* Other names: Tamiflu;Drug: Placebo<br>* Matching placebo provided as capsules and as a suspension.<br>|
| Experimental: Oseltamivir standard dose 10 days<br>Adults and children 13 years and older received 75 mg oseltamivir and a placebo capsule twice daily for 10 days. Children aged 1 - 12 years received a weight-based dose (from 30 to 75 mg) oseltamivir suspension and placebo suspension orally twice daily for 10 days. | Drug: Oseltamivir<br>* Oseltamivir capsules for participants ≥ 13 years.<br>* Other names: Tamiflu;Drug: Oseltamivir<br>* Pediatric suspension for participants aged ≤ 12 years.<br>* Other names: Tamiflu;Drug: Placebo<br>* Matching placebo provided as capsules and as a suspension.<br>|
| Experimental: Oseltamivir high dose 5 days<br>Adults and children 13 years and older received 150 mg (2 x 75 mg) oseltamivir capsules twice daily for 5 days. Children aged 1 - 12 years received a weight-based dose (from 60 to 150 mg) oseltamivir suspension orally twice daily for 5 days. Participants received matching placebo for the second 5 days of treatment. | Drug: Oseltamivir<br>* Oseltamivir capsules for participants ≥ 13 years.<br>* Other names: Tamiflu;Drug: Oseltamivir<br>* Pediatric suspension for participants aged ≤ 12 years.<br>* Other names: Tamiflu;Drug: Placebo<br>* Matching placebo provided as capsules and as a suspension.<br>|
| Experimental: Oseltamivir high dose 10 days<br>Adults and children 13 years and older received 150 mg (2 x 75 mg) oseltamivir capsules twice daily for 10 days. Children aged 1- 12 years received a weight-based dose (from 60 to 150 mg) oseltamivir suspension orally twice daily for 10 days. | Drug: Oseltamivir<br>* Oseltamivir capsules for participants ≥ 13 years.<br>* Other names: Tamiflu;Drug: Oseltamivir<br>* Pediatric suspension for participants aged ≤ 12 years.<br>* Other names: Tamiflu;Drug: Placebo<br>* Matching placebo provided as capsules and as a suspension.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Cessation of Viral Shedding | The time to cessation of viral shedding was measured by viral culture and defined as the time from treatment initiation to the time of the first negative culture with no subsequent positive cultures. Any patient with a positive culture at the last sample time was censored at that time point. Median time to cessation was estimated from the Kaplan-Meier curve. | Day 1 to Day 40 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Viral Shedding by Clinic Visit as Measured by Viral Culture | Viral shedding was measured by viral culture from samples obtained from nasal and throat swabs and performed by the central laboratory. | Baseline and Days 3, 6, 8, 11, 15 and 40 | 
| Percentage of Participants With Viral Shedding by Clinic Visit as Measured by Reverse Transcriptase Polymerase Chain Reaction | Viral shedding was measured by reverse transcriptase polymerase chain reaction (RT-PCR) from samples obtained from nasal and throat swabs and performed by the central laboratory. | Baseline and Days 3, 6, 8, 11, 15 and 40 | 
| Change From Baseline in Influenza Titer Measured by Viral Culture | Influenza virus titer measured by viral culture and expressed on a Log10 scale of the 50% Tissue Culture Infective Dose (TCID50; amount of virus required to kill 50% of inoculated tissue culture cells). | Baseline, Days 2 through 15 | 
| Number of Participants With Development of Oseltamivir-Resistant Influenza Virus | The last positive viral isolate from each patient was tested for reduced sensitivity to oseltamivir. Phenotypic assay was performed to determine the susceptibility of the last positive viral isolate from each patient. If required, a genotypic assay to determine the contribution of both the neuraminidase (NA) and hemagglutinin (HA) genes to decreased susceptibility was also performed. | 40 days | 
| Time to Resolution of Fever | Temperature was recorded by the patient in a diary twice daily for 10 days and once daily thereafter. Fever was defined as a body temperature greater than or including 37.8 degrees Celsius (or ≥ 100.04 Fahrenheit). Time to resolution of fever was defined as the total number of hours from the first dose of study medication to the first time at which temperature is ≤ 37.2 degrees Celsius and lasts at least 21.5 hours. Patients who were still febrile at the end of the study period were censored at that time. | Day 1 through Day 40 | 
| Time to Alleviation of All Clinical Symptoms - Children | Daily influenza-like symptoms (such as poor appetite, irritability, low energy, nasal congestion, runny nose etc) were recorded in a diary on a scale from 0 (no problem) to 3 (major problem). A patient is considered free of all clinical influenza symptoms if all symptoms were checked as 'no problem' or 'minor problem' (i.e., symptom score ≤1). Time to alleviation of all clinical symptoms was defined as the number of hours from the first dose to the first time the patient had alleviation of all symptoms. Patients without alleviation of symptoms were censored at the last available assessment. | Day 1 to Day 40 | 
| Time to Alleviation of All Clinical Symptoms - Adults | Daily influenza-like symptoms (such as nasal congestion, sore throat, cough, aches and pains, fatigue, headache, chills) were recorded in a diary on a scale from 0 (absent) to 3 (severe). A patient is considered free of all clinical influenza symptoms if all symptoms were checked as 'absent' or 'mild' (i.e., symptom score ≤1). Time to alleviation of all clinical symptoms was defined as the number of hours from the first dose to the first time the patient had alleviation of all symptoms. Patients without alleviation of symptoms were censored at the last available assessment. | Day 1 to Day 40 | 
| Number of Participants Who Developed Secondary Illnesses During the Study | The number of participants who developed secondary illnesses due to influenza, including four pre-defined adverse events: otitis media, bronchitis, pneumonia, or sinusitis at any time during the study. | Day 1 through Day 40 | 
| Number of Participants Who Developed Secondary Illnesses That Were Treated With Antibiotics | The number of participants who developed secondary illnesses due to influenza, including otitis media, bronchitis, pneumonia, or sinusitis at any time during the study which were treated with antibiotics. | Day 1 through Day 40 |