Influenza Resistance Information Study

Study Overview
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Brief Summary
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This study will assist in the early detection of influenza resistant to antivirals and will monitor the clinical outcome of adults and children infected with influenza according to subtype and susceptibility. Participants clinically diagnosed with influenza will undergo a rapid diagnostic test and viral sampling at Baseline and on Days 3, 6, and 10. Participants will be clinically managed according to local guidelines and the decision to treat/not treat will be at the discretion of the Investigator.

Official Title
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Influenza Resistance Information Study (IRIS)

Conditions
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Influenza

Intervention / Treatment
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* Drug: Oseltamivir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants greater than or equal to (≥) 1 year of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness (during Years 1 to 5) Participants less than or equal to (≤) 12 years of age with a positive diagnostic test of influenza and displaying symptoms suggestive of influenza-like illness and who are being or, according to local standard of care, will be treated with an influenza antiviral (during Years 6 and 7) Exclusion Criteria: Allergy to any potential influenza therapy Living in the same household or residential/care home as another study participant
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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Participants Infected with Influenza<br>Participants with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness will be enrolled and followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes. Participants may receive treatment including oseltamivir, other treatment/medication, or no treatment. | Drug: Oseltamivir<br>* Participants may receive treatment at the discretion of the investigator according to local practice standards, and there is no protocol-specified intervention. However, analyses will be presented separately for participants treated with oseltamivir during the course of the study.<br>* Other names: Tamiflu;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Genotypic Resistance | Samples were analyzed using reverse transcriptase-polymerase chain reaction (RT-PCR). Pre-defined mutations in viral ribonucleic acid (RNA) were noted, the presence of which was defined as genotypic resistance. The number of participants with genotypic resistance at Baseline was reported. The number of participants with genotypic resistance post-Baseline was determined by a collective count of all participants who had a resistance mutation at least once on Days 3, 6, and/or 10. (Hereafter, H stands for hemagglutinin and N stands for neuraminidase in abbreviations of viral subtype such as H1N1, H1N1pdm09, and H3N2.) | Baseline (Day 1) and post-Baseline (Days 3, 6, 10) | 
| Percentage of Participants Exhibiting Treatment-Emergent Resistance by Study Year Among Participants With H3N2 or H1N1pdm09 Infections | Pre-defined mutations in viral RNA were noted, the presence of which was defined as genotypic resistance. Treatment-emergent resistance was defined as the presence of genotypic or phenotypic resistance from a post-Baseline sample in the setting of a previously non-resistant Baseline sample. The percentage of participants with treatment-emergent resistance was reported by study year for participants with H3N2 or H1N1pdm09 infections. Only data with evaluable participants were reported. | From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10) during Study Years 1, 2, 3, 4, 5, 6, 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Viral RNA Detected by RT-PCR on Day 1 Among Adults Treated With Oseltamivir |  | Baseline (Day 1) | 
| Number of Participants With Viral RNA Detected by RT-PCR on Day 3 Among Adults Treated With Oseltamivir |  | Day 3 | 
| Number of Participants With Viral RNA Detected by RT-PCR on Day 6 Among Adults Treated With Oseltamivir |  | Day 6 | 
| Number of Participants With Viral RNA Detected by RT-PCR on Day 10 Among Adults Treated With Oseltamivir |  | Day 10 | 
| Number of Participants With Viral RNA Detected by RT-PCR on Day 1 Among Children Treated With Oseltamivir |  | Baseline (Day 1) | 
| Number of Participants With Viral RNA Detected by RT-PCR on Day 3 Among Children Treated With Oseltamivir |  | Day 3 | 
| Number of Participants With Viral RNA Detected by RT-PCR on Day 6 Among Children Treated With Oseltamivir |  | Day 6 | 
| Number of Participants With Viral RNA Detected by RT-PCR on Day 10 Among Children Treated With Oseltamivir |  | Day 10 | 
| Time to Non-Detection of Viral RNA | Time to non-detection/viral clearance was the time between symptom onset and the day on which viral RNA was no longer detected, or the last visit date if the participant was not RNA-negative at that visit. Time to non-detection/viral clearance was estimated using Kaplan-Meier analysis and expressed in days. | From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10) | 
| Time to Non-Detection of Viral RNA Among Participants With H3N2 Infections | Time to non-detection/viral clearance was the time between symptom onset and the day on which viral RNA was no longer detected, or the last visit date if the participant was not RNA-negative at that visit. Time to non-detection/viral clearance was estimated using Kaplan-Meier analysis and expressed in days. | From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10) | 
| Time to Non-Detection of Viral RNA Among Participants With H1N1pdm09 Infections | Time to non-detection/viral clearance was the time between symptom onset and the day on which viral RNA was no longer detected, or the last visit date if the participant was not RNA-negative at that visit. Time to non-detection/viral clearance was estimated using Kaplan-Meier analysis and expressed in days. | From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10) | 
| Time to Non-Detection of Viral RNA Among Participants With Influenza B Infections | Time to non-detection/viral clearance was the time between symptom onset and the day on which viral RNA was no longer detected, or the last visit date if the participant was not RNA-negative at that visit. Time to non-detection/viral clearance was estimated using Kaplan-Meier analysis and expressed in days. | From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10) | 
| Viral Load Among Adults Treated With Oseltamivir | Viral load was determined for those with detectable virus above the lower limit of quantification (LLQ) of 1.82 for influenza A viruses and 1.99 for influenza B viruses. The viral load from each sample was averaged among all participants and expressed in log10 of the number of viral particles per milliliter (log10 vp/mL). | Days 1, 3, 6, 10 | 
| Viral Load Among Children Treated With Oseltamivir | Viral load was determined for those with detectable virus above the LLQ of 1.82 for influenza A viruses and 1.99 for influenza B viruses. The viral load from each sample was averaged among all participants and expressed in log10 vp/mL. | Days 1, 3, 6, 10 | 
| Percentage of Participants With Symptom Resolution on Day 6 Comparing Resistant and Susceptible Viruses | Pre-defined mutations in viral RNA were noted, the presence of which was defined as genotypic resistance. Phenotypic resistance was defined as 50% inhibitory concentration (IC50) more than 10-fold higher than the median value for all viruses of the same subtype. Treatment-emergent resistance was defined as the presence of genotypic or phenotypic resistance from a post-Baseline sample in the setting of a previously non-resistant Baseline sample. Susceptible viruses were those that did not exhibit treatment-emergent resistance. The percentage of participants with mild or absent symptoms on Day 6 was reported and stratified by resistant and susceptible viruses. | Day 6 | 
| Percentage of Participants by Day of Viral RNA First Not Detected Comparing Resistant and Susceptible Viruses | Pre-defined mutations in viral RNA were noted, the presence of which was defined as genotypic resistance. Phenotypic resistance was defined as IC50 more than 10-fold higher than the median value for all viruses of the same subtype. Treatment-emergent resistance was defined as the presence of genotypic or phenotypic resistance from a post-Baseline sample in the setting of a previously non-resistant Baseline sample. Susceptible viruses were those that did not exhibit treatment-emergent resistance. The percentage of participants by earliest post-Baseline test day on which viral RNA was not detected was reported and stratified by resistant and susceptible viruses. | Days 3, 6, 10 | 
| Percentage of Participants With Resistant Versus Susceptible Viruses by Baseline Viral Load | Pre-defined mutations in viral RNA were noted, the presence of which was defined as genotypic resistance. Phenotypic resistance was defined as IC50 more than 10-fold higher than the median value for all viruses of the same subtype. Treatment-emergent resistance was defined as the presence of genotypic or phenotypic resistance from a post-Baseline sample in the setting of a previously non-resistant Baseline sample. Susceptible viruses were those that did not exhibit treatment-emergent resistance. The mean viral load from each sample was expressed in log10 vp/mL and stratified by resistant and susceptible viruses. | Baseline (Day 1) | 
| Total Daily Symptom Score According to Global Assessment by the Investigator Among Adults Treated With Oseltamivir | Symptoms were assessed on Days 1, 6, and 10. The Investigator rated seven symptoms of fever, sore throat, nasal congestion, cough, aches/pains, headache, and fatigue on a scale of 0 (absent/no problem) to 3 (severe/major problem). The global score was calculated as a sum of all individual symptom scores. Global scores may range from 0 to 21, with higher scores indicating worse or more pronounced symptoms. | Days 1, 6, 10 | 
| Total Daily Symptom Score According to Global Assessment by the Investigator Among Children Treated With Oseltamivir | Symptoms were assessed on Days 1, 6, and 10. The Investigator rated seven symptoms of fever, sore throat, nasal congestion, cough, aches/pains, headache, and energy/tiredness on a scale of 0 (absent/no problem) to 3 (severe/major problem). The global score was calculated as a sum of all individual symptom scores. Global scores may range from 0 to 21, with higher scores indicating worse or more pronounced symptoms. | Days 1, 6, 10 | 
| Body Temperature Among Adults Treated With Oseltamivir | Body temperature was measured by the Investigator using an oral or tympanic thermometer at Baseline and Day 10. Body temperature at each visit was averaged among all participants and expressed in degrees Celsius. | Days 1, 10 | 
| Change From Baseline in Body Temperature Among Adults Treated With Oseltamivir | Body temperature was measured by the Investigator using an oral or tympanic thermometer at Baseline and Day 10. The change in body temperature between visits was averaged among all participants and expressed in degrees Celsius. | Baseline (Day 1) to Day 10 | 
| Body Temperature Among Children Treated With Oseltamivir | Body temperature was measured by the Investigator using an oral or tympanic thermometer at Baseline and Day 10. Body temperature at each visit was averaged among all participants and expressed in degrees Celsius. | Days 1, 10 | 
| Change From Baseline in Body Temperature Among Children Treated With Oseltamivir | Body temperature was measured by the Investigator using an oral or tympanic thermometer at Baseline and Day 10. The change in body temperature between visits was averaged among all participants and expressed in degrees Celsius. | Baseline (Day 1) to Day 10 |