IRIS: Influenza Resistance Information Study

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00884117
• Collaborator: (none)
• Enrollment: 4,561
• Locations: 8
• Duration (Months): 82
• Patients Per Site: 570.1
• Patients Per Site Per Month: 7

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Drug: Oseltamivir

Study Design

• Study Type: Observational
• Actual Enrollment: 4561 participants
• Observational Model: Case-Only
• Time Perspective: Prospective
• Official Title: Influenza Resistance Information Study (IRIS)
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Participants Infected with Influenza 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; 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.; Other Names: Tamiflu

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Genotypic Resistance [Baseline (Day 1) and post-Baseline (Days 3, 6, 10)]

   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.)

2. Percentage of Participants Exhibiting Treatment-Emergent Resistance by Study Year Among Participants With H3N2 or H1N1pdm09 Infections [From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10) during Study Years 1, 2, 3, 4, 5, 6, 7]

   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.

Secondary Outcome Measures

1. Number of Participants With Viral RNA Detected by RT-PCR on Day 1 Among Adults Treated With Oseltamivir [Baseline (Day 1)]

2. Number of Participants With Viral RNA Detected by RT-PCR on Day 3 Among Adults Treated With Oseltamivir [Day 3]

3. Number of Participants With Viral RNA Detected by RT-PCR on Day 6 Among Adults Treated With Oseltamivir [Day 6]

4. Number of Participants With Viral RNA Detected by RT-PCR on Day 10 Among Adults Treated With Oseltamivir [Day 10]

5. Number of Participants With Viral RNA Detected by RT-PCR on Day 1 Among Children Treated With Oseltamivir [Baseline (Day 1)]

6. Number of Participants With Viral RNA Detected by RT-PCR on Day 3 Among Children Treated With Oseltamivir [Day 3]

7. Number of Participants With Viral RNA Detected by RT-PCR on Day 6 Among Children Treated With Oseltamivir [Day 6]

8. Number of Participants With Viral RNA Detected by RT-PCR on Day 10 Among Children Treated With Oseltamivir [Day 10]

9. Time to Non-Detection of Viral RNA [From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10)]

   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.

10. Time to Non-Detection of Viral RNA Among Participants With H3N2 Infections [From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10)]

    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.

11. Time to Non-Detection of Viral RNA Among Participants With H1N1pdm09 Infections [From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10)]

    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.

12. Time to Non-Detection of Viral RNA Among Participants With Influenza B Infections [From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10)]

    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.

13. Viral Load Among Adults Treated With Oseltamivir [Days 1, 3, 6, 10]

    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).

14. Viral Load Among Children Treated With Oseltamivir [Days 1, 3, 6, 10]

    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.

15. Percentage of Participants With Symptom Resolution on Day 6 Comparing Resistant and Susceptible Viruses [Day 6]

    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.

16. Percentage of Participants by Day of Viral RNA First Not Detected Comparing Resistant and Susceptible Viruses [Days 3, 6, 10]

    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.

17. Percentage of Participants With Resistant Versus Susceptible Viruses by Baseline Viral Load [Baseline (Day 1)]

    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.

18. Total Daily Symptom Score According to Global Assessment by the Investigator Among Adults Treated With Oseltamivir [Days 1, 6, 10]

    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.

19. Total Daily Symptom Score According to Global Assessment by the Investigator Among Children Treated With Oseltamivir [Days 1, 6, 10]

    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.

20. Body Temperature Among Adults Treated With Oseltamivir [Days 1, 10]

    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.

21. Change From Baseline in Body Temperature Among Adults Treated With Oseltamivir [Baseline (Day 1) to Day 10]

    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.

22. Body Temperature Among Children Treated With Oseltamivir [Days 1, 10]

    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.

23. Change From Baseline in Body Temperature Among Children Treated With Oseltamivir [Baseline (Day 1) to Day 10]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Chicago	Illinois	United States	60655
2		Westmead	New South Wales	Australia	2145
3		Bron		France	69677
4		Berlin		Germany	14052
5		Shatin		Hong Kong
6		Rotterdam		Netherlands	3000 CA
7		Sandnes		Norway	4313
8		Krakow		Poland	31-159

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00884117
• Other Study ID Numbers: NV20237; 2008-006149-24
• First Posted: Apr 20, 2009
• Last Update Posted: Oct 19, 2016
• Last Verified: Oct 1, 2016

• Additional relevant MeSH terms: Influenza, Human; Oseltamivir

Study Results

Participant Flow

Arm/Group Title	All Participants Infected With Influenza
Arm/Group Description	Participants with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled. During Years 1 to 5 of the overall study, otherwise healthy/non-immunocompromised adults and children greater than or equal to (≥) 1 year of age were considered as eligible. Following a protocol amendment, inclusion criteria for Years 6 and 7 were changed to only include healthy or immunocompromised children less than or equal to (≤) 12 years of age being treated with an influenza antiviral medication. Participants were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Period Title: Overall Study
STARTED	4561
COMPLETED	4312
NOT COMPLETED	249

Baseline Characteristics

Arm/Group Title	Otherwise Healthy Participants Infected With Influenza
Arm/Group Description	Otherwise healthy/non-immunocompromised participants with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled. During Years 1 to 5 of the overall study, adults and children ≥1 year of age were considered as eligible. Following a protocol amendment, inclusion criteria for Years 6 and 7 were changed to only include children ≤12 years of age being treated with an influenza antiviral medication. Participants were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Overall Participants	4553
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	19.5 (19.24)
Sex: Female, Male (Count of Participants)
Female	2331 51.2%
Male	2222 48.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Genotypic Resistance
Description	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.)
Time Frame	Baseline (Day 1) and post-Baseline (Days 3, 6, 10)

Outcome Measure Data

Analysis Population Description

All Laboratory-Confirmed Influenza Participants (ALCIP) Population: All with confirmed influenza by positive RT-PCR at Baseline. The "Number of Participants Analyzed" reflects the total of participants who provided evaluable data for their viral RNA subtype. The number who provided data for each viral RNA subtype in each timeframe (n) is shown.

Arm/Group Title	Otherwise Healthy Participants Infected With Influenza
Arm/Group Description	Otherwise healthy/non-immunocompromised participants with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled. During Years 1 to 5 of the overall study, adults and children ≥1 year of age were considered as eligible. Following a protocol amendment, inclusion criteria for Years 6 and 7 were changed to only include children ≤12 years of age being treated with an influenza antiviral medication. Participants were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	3725
Baseline, H1N1 Seasonal (n=47)	44 1%
Baseline, H1N1pdm09 (n=1240)	1 0%
Baseline, H3N2 (n=1432)	0 0%
Baseline, Influenza B (n=1006)	2 0%
Baseline, All Types/Subtypes (n=3725)	47 1%
Post-Baseline, H1N1 Seasonal (n=47)	0 0%
Post-Baseline, H1N1pdm09 (n=1240)	39 0.9%
Post-Baseline, H3N2 (n=1432)	18 0.4%
Post-Baseline, Influenza B (n=1006)	0 0%
Post-Baseline, All Types/Subtypes (n=3725)	57 1.3%

2. Primary Outcome

Title	Percentage of Participants Exhibiting Treatment-Emergent Resistance by Study Year Among Participants With H3N2 or H1N1pdm09 Infections
Description	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.
Time Frame	From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10) during Study Years 1, 2, 3, 4, 5, 6, 7

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects combined H3N2 or H1N1pdm09-infected participants across all study years who provided an analyzable post-Baseline sample for their viral RNA subtype. The number of participants who provided evaluable data for each viral RNA subtype in the specified timeframe (n) is shown in the table.

Arm/Group Title	Children <1 Year of Age Treated With Oseltamivir	Children 1 to 5 Years of Age Treated With Oseltamivir	Children 6 to 12 Years of Age Treated With Oseltamivir	Children Treated With Oseltamivir	Adults Treated With Oseltamivir	Participants Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children less than (<) 1 year of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 6 and 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised children 1 to 5 years of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised children 6 to 12 years of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised adults and children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	20	473	438	931	713	1644
Year 1, H3N2 (n=0,1,1,2,2,4)	NA NaN	0 NaN	0 NaN	0 NaN	0 NaN	0 NaN
Year 2, H1N1pdm09 (n=0,54,81,135,108,243)	NA NaN	1.9 NaN	0 NaN	0.7 NaN	0.9 NaN	0.8 NaN
Year 2, H3N2 (n=0,0,0,0,22,22)	NA NaN	NA NaN	NA NaN	NA NaN	0 NaN	0 NaN
Year 3, H1N1pdm09 (n=0,58,30,88,148,236)	NA NaN	20.7 NaN	3.3 NaN	14.8 NaN	1.4 NaN	6.4 NaN
Year 3, H3N2 (n=0,37,43,80,122,202)	NA NaN	2.7 NaN	0 NaN	1.3 NaN	0.8 NaN	1.0 NaN
Year 4, H1N1pdm09 (n=0,6,6,12,16,28)	NA NaN	16.7 NaN	0 NaN	8.3 NaN	0 NaN	3.6 NaN
Year 4, H3N2 (n=0,19,17,36,67,103)	NA NaN	10.5 NaN	11.8 NaN	11.1 NaN	0 NaN	3.9 NaN
Year 5, H1N1pdm09 (n=0,29,8,37,41,78)	NA NaN	20.7 NaN	12.5 NaN	18.9 NaN	4.9 NaN	11.5 NaN
Year 5, H3N2 (n=0,82,80,162,187,349)	NA NaN	8.5 NaN	1.3 NaN	4.9 NaN	1.1 NaN	2.9 NaN
Year 6, H1N1pdm09 (n=11,33,25,69,0,69)	36.4 0.8%	6.1 NaN	4.0 NaN	10.1 NaN	NA NaN	10.1 NaN
Year 6, H3N2 (n=1,45,27,73,0,73)	0 0%	0 NaN	0 NaN	0 NaN	NA NaN	0 NaN
Year 7, H1N1pdm09 (n=0,15,5,20,0,20)	NA NaN	33.3 NaN	0 NaN	25.0 NaN	NA NaN	25.0 NaN
Year 7, H3N2 (n=8,94,115,217,0,217)	0 0%	1.1 NaN	0.9 NaN	0.9 NaN	NA NaN	0.9 NaN

3. Secondary Outcome

Title	Number of Participants With Viral RNA Detected by RT-PCR on Day 1 Among Adults Treated With Oseltamivir
Time Frame	Baseline (Day 1)

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at the Baseline visit.

Arm/Group Title	Adults Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	961
Total	961 21.1%
H1N1 Seasonal	12 0.3%
H3N2	419 9.2%
H1N1pdm09	323 7.1%
Influenza B	207 4.5%

4. Secondary Outcome

Title	Number of Participants With Viral RNA Detected by RT-PCR on Day 3 Among Adults Treated With Oseltamivir
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at the Day 3 visit. The number of participants who provided evaluable data for each viral RNA subtype at the Day 3 visit (n) is shown in the table.

Arm/Group Title	Adults Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	912
Total (n=912)	781 17.2%
H1N1 Seasonal (n=11)	10 0.2%
H3N2 (n=398)	341 7.5%
H1N1pdm09 (n=308)	258 5.7%
Influenza B (n=195)	172 3.8%

5. Secondary Outcome

Title	Number of Participants With Viral RNA Detected by RT-PCR on Day 6 Among Adults Treated With Oseltamivir
Time Frame	Day 6

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at the Day 6 visit. The number of participants who provided evaluable data for each viral RNA subtype at the Day 6 visit (n) is shown in the table.

Arm/Group Title	Adults Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	889
Total (n=889)	317 7%
H1N1 Seasonal (n=9)	4 0.1%
H3N2 (n=382)	144 3.2%
H1N1pdm09 (n=308)	110 2.4%
Influenza B (n=190)	59 1.3%

6. Secondary Outcome

Title	Number of Participants With Viral RNA Detected by RT-PCR on Day 10 Among Adults Treated With Oseltamivir
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at the Day 10 visit. The number of participants who provided evaluable data for each viral RNA subtype at the Day 10 visit (n) is shown in the table.

Arm/Group Title	Adults Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	833
Total (n=833)	88 1.9%
H3N2 (n=362)	44 1%
H1N1pdm09 (n=283)	33 0.7%
Influenza B (n=188)	11 0.2%

7. Secondary Outcome

Title	Number of Participants With Viral RNA Detected by RT-PCR on Day 1 Among Children Treated With Oseltamivir
Time Frame	Baseline (Day 1)

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at the Baseline visit.

Arm/Group Title	Children Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	1283
Total	1283 28.2%
H3N2	583 12.8%
H1N1pdm09	371 8.1%
Influenza B	329 7.2%

8. Secondary Outcome

Title	Number of Participants With Viral RNA Detected by RT-PCR on Day 3 Among Children Treated With Oseltamivir
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at the Day 3 visit. The number of participants who provided evaluable data for each viral RNA subtype at the Day 3 visit (n) is shown in the table.

Arm/Group Title	Children Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	1238
Total (n=1238)	1050 23.1%
H3N2 (n=562)	453 9.9%
H1N1pdm09 (n=358)	315 6.9%
Influenza B (n=318)	282 6.2%

9. Secondary Outcome

Title	Number of Participants With Viral RNA Detected by RT-PCR on Day 6 Among Children Treated With Oseltamivir
Time Frame	Day 6

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at the Day 6 visit. The number of participants who provided evaluable data for each viral RNA subtype at the Day 6 visit (n) is shown in the table.

Arm/Group Title	Children Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	1250
Total (n=1250)	628 13.8%
H3N2 (n=567)	271 6%
H1N1pdm09 (n=362)	181 4%
Influenza B (n=321)	176 3.9%

10. Secondary Outcome

Title	Number of Participants With Viral RNA Detected by RT-PCR on Day 10 Among Children Treated With Oseltamivir
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at the Day 10 visit. The number of participants who provided evaluable data for each viral RNA subtype at the Day 10 visit (n) is shown in the table.

Arm/Group Title	Children Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	1228
Total (n=1228)	197 4.3%
H3N2 (n=560)	73 1.6%
H1N1pdm09 (n=351)	64 1.4%
Influenza B (n=317)	60 1.3%

11. Secondary Outcome

Title	Time to Non-Detection of Viral RNA
Description	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.
Time Frame	From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10)

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the number of participants who provided sufficient post-Baseline data.

Arm/Group Title	Children ≤5 Years of Age Treated With Oseltamivir	Children 6 to 12 Years of Age Treated With Oseltamivir	Adults Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children ≤5 years of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised children 6 to 12 years of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	637	644	949
Median (95% Confidence Interval) [days]	9.7	8.2	7.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza, Children 1 to 5 Years of Age Treated With Oseltamivir, Children 6 to 12 Years of Age Treated With Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Kruskal-Wallis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza, Children 1 to 5 Years of Age Treated With Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Pairwise Wilcoxon
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza, Children 6 to 12 Years of Age Treated With Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Pairwise Wilcoxon
	Comments

12. Secondary Outcome

Title	Time to Non-Detection of Viral RNA Among Participants With H3N2 Infections
Description	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.
Time Frame	From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10)

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the number of participants with H3N2 infection who provided sufficient post-Baseline data.

Arm/Group Title	Children ≤5 Years of Age Treated With Oseltamivir	Children 6 to 12 Years of Age Treated With Oseltamivir	Adults Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children ≤5 years of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised children 6 to 12 years of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	295	287	419
Median (95% Confidence Interval) [days]	9.5	8.0	8.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza, Children 1 to 5 Years of Age Treated With Oseltamivir, Children 6 to 12 Years of Age Treated With Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments
	Method	Kruskal-Wallis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza, Children 1 to 5 Years of Age Treated With Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Pairwise Wilcoxon
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Children 1 to 5 Years of Age Treated With Oseltamivir, Children 6 to 12 Years of Age Treated With Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Pairwise Wilcoxon
	Comments

13. Secondary Outcome

Title	Time to Non-Detection of Viral RNA Among Participants With H1N1pdm09 Infections
Description	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.
Time Frame	From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10)

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the number of participants with H1N1pdm09 infection who provided sufficient post-Baseline data.

Arm/Group Title	Children ≤5 Years of Age Treated With Oseltamivir	Children 6 to 12 Years of Age Treated With Oseltamivir	Adults Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children ≤5 years of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised children 6 to 12 years of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	212	158	323
Median (95% Confidence Interval) [days]	9.9	8.0	8.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza, Children 1 to 5 Years of Age Treated With Oseltamivir, Children 6 to 12 Years of Age Treated With Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Kruskal-Wallis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza, Children 1 to 5 Years of Age Treated With Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Pairwise Wilcoxon
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza, Children 6 to 12 Years of Age Treated With Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Pairwise Wilcoxon
	Comments

14. Secondary Outcome

Title	Time to Non-Detection of Viral RNA Among Participants With Influenza B Infections
Description	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.
Time Frame	From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10)

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the number of participants with influenza B infection who provided sufficient post-Baseline data.

Arm/Group Title	Children ≤5 Years of Age Treated With Oseltamivir	Children 6 to 12 Years of Age Treated With Oseltamivir	Adults Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children ≤5 years of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised children 6 to 12 years of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	130	199	207
Median (95% Confidence Interval) [days]	9.8	10.0	7.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza, Children 1 to 5 Years of Age Treated With Oseltamivir, Children 6 to 12 Years of Age Treated With Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Kruskal-Wallis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza, Children 6 to 12 Years of Age Treated With Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Pairwise Wilcoxon
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Children 1 to 5 Years of Age Treated With Oseltamivir, Children 6 to 12 Years of Age Treated With Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Pairwise Wilcoxon
	Comments

15. Secondary Outcome

Title	Viral Load Among Adults Treated With Oseltamivir
Description	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).
Time Frame	Days 1, 3, 6, 10

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the highest total number of participants who provided evaluable data for their viral RNA subtype at any visit. The number of participants who provided evaluable data for each viral RNA subtype at the specified visit (n) is shown in the table.

Arm/Group Title	Adults Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	959
Day 1, Total (n=959)	5.8 (1.18)
Day 1, H1N1 Seasonal (n=12)	5.7 (1.22)
Day 1, H3N2 (n=417)	5.8 (1.23)
Day 1, H1N1pdm09 (n=323)	5.7 (1.15)
Day 1, Influenza B (n=207)	5.9 (1.09)
Day 3, Total (n=781)	4.2 (1.17)
Day 3, H1N1 Seasonal (n=10)	4.2 (1.34)
Day 3, H3N2 (n=341)	3.9 (1.15)
Day 3, H1N1pdm09 (n=258)	4.1 (1.07)
Day 3, Influenza B (n=172)	4.7 (1.19)
Day 6, Total (n=317)	3.3 (1.05)
Day 6, H1N1 Seasonal (n=4)	4.1 (0.48)
Day 6, H3N2 (n=144)	3.2 (1.06)
Day 6, H1N1pdm09 (n=110)	3.1 (0.93)
Day 6, Influenza B (n=59)	3.9 (1.04)
Day 10, Total (n=88)	3.0 (0.88)
Day 10, H3N2 (n=44)	2.9 (0.87)
Day 10, H1N1pdm09 (n=33)	2.8 (0.79)
Day 10, Influenza B (n=11)	3.7 (0.84)

16. Secondary Outcome

Title	Viral Load Among Children Treated With Oseltamivir
Description	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.
Time Frame	Days 1, 3, 6, 10

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the highest total number of participants who provided evaluable data for their viral RNA subtype at any visit. The number of participants who provided evaluable data for each viral RNA subtype at the specified visit (n) is shown in the table.

Arm/Group Title	Children Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	1283
Day 1, Total (n=1283)	5.8 (1.15)
Day 1, H3N2 (n=583)	5.6 (1.22)
Day 1, H1N1pdm09 (n=371)	5.7 (1.13)
Day 1, Influenza B (n=329)	6.1 (0.98)
Day 3, Total (n=1050)	4.5 (1.25)
Day 3, H3N2 (n=453)	4.1 (1.16)
Day 3, H1N1pdm09 (n=315)	4.3 (1.12)
Day 3, Influenza B (n=282)	5.2 (1.19)
Day 6, Total (n=628)	3.8 (1.18)
Day 6, H3N2 (n=271)	3.6 (1.19)
Day 6, H1N1pdm09 (n=181)	3.7 (1.21)
Day 6, Influenza B (n=176)	4.1 (1.08)
Day 10, Total (n=197)	3.3 (0.99)
Day 10, H3N2 (n=73)	3.1 (1.01)
Day 10, H1N1pdm09 (n=64)	3.1 (0.84)
Day 10, Influenza B (n=60)	3.6 (1.04)

17. Secondary Outcome

Title	Percentage of Participants With Symptom Resolution on Day 6 Comparing Resistant and Susceptible Viruses
Description	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.
Time Frame	Day 6

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants with wild-type infection status at Baseline who provided evaluable data at the Day 6 visit. The number of participants who provided evaluable data for each resistance status at the Day 6 visit (n) is shown in the table.

Arm/Group Title	Participants Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised adults and children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	1730
Total (n=1730)	61.2 1.3%
Resistant (n=59)	55.9 1.2%
Susceptible (n=1671)	61.4 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza
	Comments	Resistant versus Susceptible
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4464
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

18. Secondary Outcome

Title	Percentage of Participants by Day of Viral RNA First Not Detected Comparing Resistant and Susceptible Viruses
Description	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.
Time Frame	Days 3, 6, 10

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants with wild-type infection status at Baseline who provided evaluable data at the specified visit. The number of participants who provided evaluable data for each resistance status at the specified visit (n) is shown in the table.

Arm/Group Title	Participants Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised adults and children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	1682
Day 3, Total (n=1682)	15.3 0.3%
Day 3, Resistant (n=59)	0 0%
Day 3, Susceptible (n=1623)	15.8 0.3%
Day 6, Total (n=1682)	40.5 0.9%
Day 6, Resistant (n=59)	10.2 0.2%
Day 6, Susceptible (n=1623)	41.7 0.9%
Day 10, Total (n=1682)	30.4 0.7%
Day 10, Resistant (n=59)	59.3 1.3%
Day 10, Susceptible (n=1623)	29.4 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza
	Comments	Resistant versus Susceptible
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

19. Secondary Outcome

Title	Percentage of Participants With Resistant Versus Susceptible Viruses by Baseline Viral Load
Description	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.
Time Frame	Baseline (Day 1)

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants with wild-type infection status at Baseline who provided evaluable data. The number of participants who provided evaluable data for each resistance status at Baseline (n) is shown in the table.

Arm/Group Title	Participants Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised adults and children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	1802
Total, Resistant (n=1802)	3.2 0.1%
Total, Susceptible (n=1802)	96.8 2.1%
Viral Load <4.95, Resistant (n=452)	2.0 0%
Viral Load <4.95, Susceptible (n=452)	98.0 2.2%
Viral Load 4.95 to 5.89, Resistant (n=450)	3.8 0.1%
Viral Load 4.95 to 5.89, Susceptible (n=450)	96.2 2.1%
Viral Load 5.89 to 6.61, Resistant (n=457)	3.1 0.1%
Viral Load 5.89 to 6.61, Susceptible (n=457)	96.9 2.1%
Viral Load >6.61, Resistant (n=443)	3.8 0.1%
Viral Load >6.61, Susceptible (n=443)	96.2 2.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Otherwise Healthy Participants Infected With Influenza
	Comments	Resistant versus Susceptible
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2499
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

20. Secondary Outcome

Title	Total Daily Symptom Score According to Global Assessment by the Investigator Among Adults Treated With Oseltamivir
Description	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.
Time Frame	Days 1, 6, 10

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at the specified visit. The number of participants who provided evaluable data for each viral RNA subtype at the specified visit (n) is shown in the table.

Arm/Group Title	Adults Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	961
Day 1, Total (n=960)	12.3 (5.03)
Day 1, H1N1 Seasonal (n=12)	11.4 (6.02)
Day 1, H3N2 (n=419)	11.2 (5.41)
Day 1, H1N1pdm09 (n=323)	13.2 (4.28)
Day 1, Influenza B (n=206)	13.4 (4.76)
Day 6, Total (n=890)	3.7 (3.27)
Day 6, H1N1 Seasonal (n=9)	2.8 (2.91)
Day 6, H3N2 (n=383)	3.4 (3.03)
Day 6, H1N1pdm09 (n=307)	3.8 (3.28)
Day 6, Influenza B (n=191)	4.1 (3.66)
Day 10, Total (n=827)	2.0 (2.51)
Day 10, H3N2 (n=357)	2.1 (2.6)
Day 10, H1N1pdm09 (n=281)	1.9 (2.36)
Day 10, Influenza B (n=189)	2.1 (2.57)

21. Secondary Outcome

Title	Total Daily Symptom Score According to Global Assessment by the Investigator Among Children Treated With Oseltamivir
Description	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.
Time Frame	Days 1, 6, 10

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at the specified visit. The number of participants who provided evaluable data for each viral RNA subtype at the specified visit (n) is shown in the table.

Arm/Group Title	Children Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	1283
Day 1, Total (n=1283)	12.4 (3.92)
Day 1, H3N2 (n=583)	12.3 (3.77)
Day 1, H1N1pdm09 (n=371)	11.9 (4.02)
Day 1, Influenza B (n=329)	13.0 (3.98)
Day 6, Total (n=1252)	3.3 (2.83)
Day 6, H3N2 (n=567)	3.2 (2.57)
Day 6, H1N1pdm09 (n=364)	3.2 (2.60)
Day 6, Influenza B (n=321)	3.5 (3.44)
Day 10, Total (n=1228)	1.3 (1.59)
Day 10, H3N2 (n=562)	1.3 (1.59)
Day 10, H1N1pdm09 (n=350)	1.4 (1.54)
Day 10, Influenza B (n=316)	1.3 (1.63)

22. Secondary Outcome

Title	Body Temperature Among Adults Treated With Oseltamivir
Description	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.
Time Frame	Days 1, 10

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at the specified visit. The number of participants who provided evaluable data for each viral RNA subtype at the specified visit (n) is shown in the table.

Arm/Group Title	Adults Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	960
Day 1, Total (n=960)	38.0 (0.91)
Day 1, H1N1 Seasonal (n=12)	37.8 (1.10)
Day 1, H3N2 (n=418)	37.8 (0.89)
Day 1, H1N1pdm09 (n=323)	38.2 (0.88)
Day 1, Influenza B (n=207)	38.0 (0.90)
Day 10, Total (n=827)	36.6 (0.40)
Day 10, H3N2 (n=356)	36.6 (0.40)
Day 10, H1N1pdm09 (n=282)	36.6 (0.38)
Day 10, Influenza B (n=189)	36.6 (0.41)

23. Secondary Outcome

Title	Change From Baseline in Body Temperature Among Adults Treated With Oseltamivir
Description	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.
Time Frame	Baseline (Day 1) to Day 10

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at Baseline and Day 10. The number of participants who provided evaluable data for each viral RNA subtype at Baseline and Day 10 (n) is shown in the table.

Arm/Group Title	Adults Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised adults with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 5 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	826
Total (n=826)	-1.4 (0.96)
H3N2 (n=355)	-1.2 (0.94)
H1N1pdm09 (n=282)	-1.7 (0.93)
Influenza B (n=189)	-1.4 (0.95)

24. Secondary Outcome

Title	Body Temperature Among Children Treated With Oseltamivir
Description	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.
Time Frame	Days 1, 10

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at the specified visit. The number of participants who provided evaluable data for each viral RNA subtype at the specified visit (n) is shown in the table.

Arm/Group Title	Children Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	1282
Day 1, Total (n=1282)	38.3 (0.93)
Day 1, H3N2 (n=583)	38.3 (0.98)
Day 1, H1N1pdm09 (n=370)	38.3 (0.91)
Day 1, Influenza B (n=329)	38.2 (0.87)
Day 10, Total (n=1223)	36.7 (0.38)
Day 10, H3N2 (n=560)	36.6 (0.37)
Day 10, H1N1pdm09 (n=346)	36.7 (0.40)
Day 10, Influenza B (n=317)	36.6 (0.38)

25. Secondary Outcome

Title	Change From Baseline in Body Temperature Among Children Treated With Oseltamivir
Description	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.
Time Frame	Baseline (Day 1) to Day 10

Outcome Measure Data

Analysis Population Description

ALCIP Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for their viral RNA subtype at Baseline and Day 10. The number of participants who provided evaluable data for each viral RNA subtype at Baseline and Day 10 (n) is shown in the table.

Arm/Group Title	Children Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
Measure Participants	1222
Total (n=1222)	-1.6 (0.98)
H3N2 (n=560)	-1.6 (1.02)
H1N1pdm09 (n=345)	-1.5 (0.97)
Influenza B (n=317)	-1.6 (0.91)

Adverse Events

Time Frame	From Baseline (Day 1) to Day 10; assessed on Days 1, 3, 6, 10
Adverse Event Reporting Description	AEHP Population.
Arm/Group Title	Participants Treated With Oseltamivir		Participants Not Treated With Oseltamivir
Arm/Group Description	Otherwise healthy/non-immunocompromised adults and children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants receiving antiviral treatment with oseltamivir (according to local practice standards) were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.		Otherwise healthy/non-immunocompromised adults and children with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness were enrolled during Years 1 to 7 of the overall study. Participants not receiving oseltamivir, including no treatment or other antiviral treatment, were followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes.
All Cause Mortality
	Participants Treated With Oseltamivir		Participants Not Treated With Oseltamivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Participants Treated With Oseltamivir		Participants Not Treated With Oseltamivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/2578 (0.9%)		11/1975 (0.6%)
Cardiac disorders
Cardiac arrest	1/2578 (0%)		0/1975 (0%)
Myocardial infarction	1/2578 (0%)		0/1975 (0%)
General disorders
Non-cardiac chest pain	0/2578 (0%)		1/1975 (0.1%)
Oedema peripheral	1/2578 (0%)		0/1975 (0%)
Infections and infestations
Pneumonia	5/2578 (0.2%)		1/1975 (0.1%)
Bronchitis	0/2578 (0%)		2/1975 (0.1%)
Bronchiolitis	1/2578 (0%)		0/1975 (0%)
Bronchopneumonia	1/2578 (0%)		0/1975 (0%)
Cellulitis	1/2578 (0%)		0/1975 (0%)
Gastroenteritis	1/2578 (0%)		0/1975 (0%)
Gastrointestinal infection	1/2578 (0%)		0/1975 (0%)
Pneumonia staphylococcal	1/2578 (0%)		0/1975 (0%)
Pyelonephritis	0/2578 (0%)		1/1975 (0.1%)
Respiratory tract infection	0/2578 (0%)		1/1975 (0.1%)
Scarlet fever	1/2578 (0%)		0/1975 (0%)
Sepsis	1/2578 (0%)		0/1975 (0%)
Sinusitis	0/2578 (0%)		1/1975 (0.1%)
Staphylococcal infection	1/2578 (0%)		0/1975 (0%)
Tonsillitis	1/2578 (0%)		0/1975 (0%)
Tracheitis	0/2578 (0%)		1/1975 (0.1%)
Injury, poisoning and procedural complications
Cardiac pacemaker malfunction	0/2578 (0%)		1/1975 (0.1%)
Metabolism and nutrition disorders
Dehydration	1/2578 (0%)		0/1975 (0%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	0/2578 (0%)		1/1975 (0.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/2578 (0.1%)		2/1975 (0.1%)
Respiratory distress	2/2578 (0.1%)		0/1975 (0%)
Epistaxis	1/2578 (0%)		0/1975 (0%)
Pneumothorax	1/2578 (0%)		0/1975 (0%)
Respiratory failure	1/2578 (0%)		0/1975 (0%)
Other (Not Including Serious) Adverse Events
	Participants Treated With Oseltamivir		Participants Not Treated With Oseltamivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2578 (0%)		0/1975 (0%)

Limitations/Caveats

This was a non-randomized, observational study and many comparisons were not powered to detect a true statistically significant difference between groups. Inferential analyses should be interpreted with caution.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.