Evaluating the Use of Oseltamivir for the Treatment of Influenza in Adults

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01314911
• Collaborator: (none)
• Enrollment: 716
• Locations: 51
• Arms: 2
• Duration (Months): 79.6
• Patients Per Site: 14
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

People who are infected with the influenza virus may develop respiratory illnesses, such as pneumonia, or other life-threatening complications. Currently, there are four antiviral medications that are used to treat influenza. This study will examine one of these medications, oseltamivir, to examine how it affects the shedding of influenza virus in infected people.

Condition or Disease	Intervention/Treatment	Phase
Influenza, Human	Drug: Oseltamivir; Drug: Placebo	N/A

Detailed Description

Seasonal influenza is responsible for excess hospitalizations and, despite effective antivirals, causes significant morbidity and mortality (about 24,000 deaths each year in the United States alone). The influenza virus that emerged in 2009 (A/California/07/2009 H1N1) caused fewer deaths (12,000 flu-related deaths in the U.S.) but in contrast to seasonal flu, nearly 90% of the deaths with the 2009 H1N1 occurred among people younger than 65 years of age. Although there are four currently licensed anti-influenza medications (amantadine and rimantadine, oseltamivir, and zanamivir), previous studies have not demonstrated conclusively to what extent these medications affect influenza viral shedding. This study will evaluate whether oseltamivir modifies the viral shedding during the treatment of uncomplicated influenza in an adult population and also assess methods to detect viral replication in the upper respiratory tract.

Subjects who presented with an influenza-like illness without any risk factors for severe disease were screened for the study. Those with a confirmatory test for influenza (rapid antigen or polymerase chain reaction [PCR]) were randomized in a 1:1 manner to receive a blinded study treatment consisting of either the oseltamivir or placebo for 5 days. Clinical, virologic, and laboratory assessments on Days 1, 3, 7, and 28 were used for both safety and efficacy analysis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 716 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized Double-Blind Study Comparing Oseltamivir Versus Placebo for the Treatment of Influenza in Low Risk Adults
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Nov 18, 2017
• Actual Study Completion Date: Nov 18, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oseltamivir	Drug: Oseltamivir; Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Placebo Comparator: Placebo	Drug: Placebo; Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs at Day 3 -- Team Collected Samples [At Day 3]

   The central laboratory performed a qualitative PCR test on the NP sample from Day 0 team collected swap in order to confirm influenza infection and to determine the influenza type and subtype. For participants with a positive influenza test result at Day 0 from this qualitative PCR testing, the laboratory then performed qPCR testing of subsequent samples to quantify viral shedding.

Secondary Outcome Measures

1. Number of Participants by Virus Detection Status--Team Collected Samples [At Day 0, 3 and 7]

   Number of participants who had undetectable values (less than the limit of detection [LOD]), who had values between the LOD and the lower limit of quantification (LLOQ), and who had values ≥LLOQ

2. qPCR Viral Shedding -- Team Collected Samples [At Day 0, 3 and 7]

   Median, 25% and 75% percentile of the value of viral shedding (Results <LOD were imputed as the LOD value, and Results >= LOD, <LLOQ were imputed as the LLOQ value.)

3. Number Of Participants Shedding Virus -- Team Collected Samples [At day 3 and 7.]

   Number of participants with undetectable viral load at both Day 3 and Day 7; detectable at Day 3 and undetectable at Day 7; detectable at Day 7 (irrespective of whether or not detectable at Day 3).

4. Time to Alleviation of Influenza Clinical Symptoms [From treatment initiation to Day 28]

   The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Duration of clinical symptoms was defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms were grade 0 (absent) or 1 (mild). A measurement was considered to be the 8AM or 8PM assessment during Days 0 to 7 (so two measurements were obtained per day) and then the daily assessment thereafter. Time was calculated in half-days through to Day 7. If a subject's first two assessments on (baseline assessment and first subsequent diary card assessment) satisfied this criterion, then the duration was set to zero. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms evaluated.

5. Time to Absence of Fever [From treatment initiation to Day 28]

   Fever was considered present based on the diary cards if a subject reported a maximal temperature ≥38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Otherwise, fever was considered not present during the period since the diary card was previously completed, except that the evaluation was considered missing if either the temperature or the antipyretic drug use entry was not completed on the diary card. The duration of fever was defined as the time from Day 0 to the first of two successive assessments (through to Day 7) or to the first assessment (Day 8 onwards) at which no fever was present according to this definition.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with fever evaluated.

6. Time to Resolution of All Symptoms AND Fever [From treatment initiation to Day 28]

   The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Fever was considered present based on the diary cards if a subject reported a maximal temperature ≥38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Time to resolution of all clinical symptoms and fever is defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms are grade 0 (absent) or 1(mild) and no fever >=38.0 C or antipyretic drug is reported. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms and fever evaluated.

7. Time to Feeling as Good as Before the Onset of the Influenza Illness [From treatment initiation to Day 28]

   Time to feeling as good as before influenza is defined as time to the first of two successive 'yes' responses to the question of 'feeling as good as you did before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.

8. Time to Return to Pre-influenza Function [From treatment initiation to Day 28]

   Time to return to pre-influenza function is defined as the time from Day 0 to the first of two successive 'Yes' answers to the global assessment question 'Are you functioning as well as you were before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.

9. Time to Return of Physical Function to Pre-illness Level [From treatment initiation to Day 28]

   Time to return of physical function to pre-illness level was defined as the time from Day 0 to the first of two successive measurements at which the physical function score equals or is better than the pre-illness score (obtained by recall at enrollment). For subjects who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with physical function evaluated.

10. Number of Participants With Treatment Compliance Status [From treatment initiation to Day 5]

    For each of the 5 days of treatment, participants were asked whether they took all study drug for that day. All participants were assumed to have taken at least some study drug even if they had zero days with all study drug reported as taken. Missing reports for some or all days were imputed as not having taken all study drug for the days concerned.

11. Percentage of Participants Who Required Hospitalization. [From treatment initiation to Day 28]

    The percentage of participants hospitalized by 28 days was constructed by inverting an exact binomial test of the actual percentages (ignoring loss to follow-up).

12. Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications Requiring An Antibiotic Use, After Day 0. [From treatment initiation to Day 28]

    Participants were assessed for the signs/symptoms suggestive of one of the following complications: Sinusitis, Otitis Media ,Bronchitis / Bronchiolitis, Pneumonia and antibiotic use for reason other than above.

13. 28-day Mortality [From treatment initiation to Day 28]

    Number of deaths

14. Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs --Self Collected Samples [At Day 3]

    For participants with a positive influenza test result at Day 0 from qualitative PCR testing on the team collected sample, the laboratory then performed qPCR testing of self-collected samples to quantify viral shedding.

15. Number of Participants by Virus Detection Status --Self Collected Samples [At Day 0, Day 0 evening, Day 1, Day 1 evening, Day 2, Day 2 evening and Day 3]

    Number of participants who had undetectable values (less than the limit of detection [LOD]), who had values between the LOD and the lower limit of quantification (LLOQ), and who had values ≥LLOQ. Evening samples on Day 0, 1 and 2 were only required under protocol versions 1.0-4.0 and so were only collected for about 20% of participants.

16. qPCR Viral Shedding -- Self Collected Samples [At Day 0, Day 0 evening, Day 1, Day 1 evening, Day 2, Day 2 evening and Day 3]

    Median, 25% and 75% percentile of the value of viral shedding (Results <LOD were imputed as the LOD value, and Results >= LOD, <LLOQ were imputed as the LLOQ value.). Evening samples on Day 0, 1 and 2 were only required under protocol versions 1.0-4.0 and so were only collected for about 20% of participants.

17. Area Under The Curve (AUC) Of Viral Shedding For Self Collected Samples [From Day 0 to Day 3]

    This AUC was calculated using the trapezoidal rule and the units of measurement are (days*log10 copies/mL) with the fact that it was the level of virus above the LLOQ being considered. The calculation of AUC was undertaken using measurements from Day 0 to Day 3 which were collected under all versions of the protocol (i.e. evening measurements on Days 0, 1 and 2 were not used as these were collected for only about 20% of subjects). Missing values during follow-up were ignored. This is equivalent to imputing a missing value using linear interpolation between the preceding and succeeding available values. For the five subjects with missing values following a last available measurement which was above the LLOQ, the remaining values were assumed to be the mean of preceding value and LLOQ in calculating the AUC.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent prior to initiation of any study procedures

• History of an influenza-like illness defined as:

1. One or more respiratory symptom (cough, sore throat, or nasal symptoms)

• Onset of illness no more than 48 hours before screening, defined as when the participant experienced at least one respiratory symptom

• Willing to have samples stored

• Positive test for influenza (either rapid antigen or polymerase chain reaction [PCR]); randomization could proceed in cases of discrepant results (one positive and one negative)

Exclusion Criteria:

• Hospitalization at the time of screening

• Presence of a medical condition(s) that had been associated with increased risk of complications from influenza

1. Aged 65 years of age or older

2. Asthma

3. Neurological and neuro-developmental conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle, such as cerebral palsy, epilepsy [seizure disorders], stroke, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury)

4. Chronic lung disease (such as chronic obstructive pulmonary disease [COPD] or cystic fibrosis)

5. Heart disease (such as congenital heart disease, congestive heart failure, or coronary artery disease)

6. Blood disorders

7. Endocrine disorders (such as diabetes mellitus)

8. Kidney disorders

9. Liver disorders

10. Metabolic disorders (such as inherited metabolic disorders or mitochondrial disorders)

11. Weakened immune system due to disease or medication (such as people with HIV/AIDS or cancer, or use of chronic steroids or other medications causing immune suppression)

12. Pregnant or 4 weeks postpartum

13. Body mass index (BMI) greater than or equal to 40

• Breastfeeding

• Inability to take oral medication or a history of gastrointestinal malabsorption that would preclude the use of oral medication

• Received more than one dose of any antiviral influenza medication since onset of influenza symptoms

• Known end stage kidney dysfunction (e.g., creatinine clearance less than 30 mL/min)

• Known hypersensitivity to oseltamivir, peramivir, or zanamivir

• Received live attenuated influenza virus vaccine within 3 weeks prior to study entry

• Use of any investigational drug within 30 days or 5 half-lives (whichever was longer) prior to study entry

• Participated in other research protocols that required more than 100mL of blood to be drawn in a 4-week period that overlapped with this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	East Valley Family Physicians	Chandler	Arizona	United States	85224
2	WCCT Global, LLC	Costa Mesa	California	United States	92626
3	Paragon Rx Clinical	Garden Grove	California	United States	92840
4	University of Southern California	Los Angeles	California	United States	92103
5	University of California, San Diego	San Diego	California	United States	92103
6	Westlake Medical Research	Thousand Oaks	California	United States	91360
7	Advanced Rx Clinical Research Group	Westminster	California	United States	92683
8	University of Colorado	Aurora	Colorado	United States	80045
9	University of Florida	Gainesville	Florida	United States	32610-0186
10	Best Quality Research, Inc.	Hialeah	Florida	United States	33106
11	Medical Consulting Center	Miami	Florida	United States	33125
12	Suncoast Research Group, LLC	Miami	Florida	United States	33135
13	DMI Research, Inc.	Pinellas Park	Florida	United States	33782
14	Columbus Regional Research Institute	Columbus	Georgia	United States	31904
15	University of Iowa	Iowa City	Iowa	United States	52242
16	Research Integrity, LLC	Owensboro	Kentucky	United States	42303
17	Horizon Research Group of Opelousas, LLC	Eunice	Louisiana	United States	70535
18	Michael Seep, MD; Centex Studies	Lake Charles	Louisiana	United States	70601
19	National Institutes of Health, Laboratory of Immunoregulation	Bethesda	Maryland	United States	20892
20	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
21	Skyline Medical Center	Elkhorn	Nebraska	United States	68022
22	Prairie Fields Family Medicine	Fremont	Nebraska	United States	68025
23	Southwest Family Physicians	Omaha	Nebraska	United States	68124
24	Clinical Research Advantage, Inc.	Omaha	Nebraska	United States	68144
25	New Jersey Medical School	Newark	New Jersey	United States	07103
26	NYU School of Medicine	New York	New York	United States	10016
27	Mount Sinai Medical Center	New York	New York	United States	10029
28	University of Rochester Medical Center	Rochester	New York	United States	14642
29	Great Lakes Medical Research	Westfield	New York	United States	14787
30	Clinical Research Solutions	Middleburg Heights	Ohio	United States	44130
31	University of Pennsylvania, Division of Infectious Disease	Philadelphia	Pennsylvania	United States	19104
32	Frontier Clinical Research, LLC	Smithfield	Pennsylvania	United States	15478
33	Health Concepts	Rapid City	South Dakota	United States	57702
34	Clinical Research Solutions	Franklin	Tennessee	United States	37067
35	Clinical Research Solutions	Jackson	Tennessee	United States	38305
36	Clinical Research Solutions	Nashville	Tennessee	United States	37211
37	Clinical Research Solutions	Smyrna	Tennessee	United States	37167
38	University of Texas Tech Amarillo	Amarillo	Texas	United States	79106
39	University of Texas Health Science Center at Houston	Houston	Texas	United States	77030
40	Centex Studies	Houston	Texas	United States	77058
41	Texas Tech University Health Sciences Center	Lubbock	Texas	United States	79430
42	Village Health Partners	Plano	Texas	United States	75024
43	Bandera Family Health Care	San Antonio	Texas	United States	78249
44	Virginia Commonwealth University Medical Center	Richmond	Virginia	United States	23298
45	Hospital General de Agudos J. M. Ramos Mejía	Buenos Aires		Argentina
46	Hospital Municipal "Prof. Dr. Bernardo A. Houssay"	Buenos Aires		Argentina
47	Hospital Público Descentralizado Dr. Guillermo Rawson	Cordoba		Argentina	05000
48	The Bamrasnaradura Infectious Diseases Institute	Mueang Nonthaburi	Nonthaburi	Thailand	1100
49	The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT)	Bangkok		Thailand	10330
50	Siriraj Hospital	Bangkok		Thailand	10700
51	Khon Kaen University (Department of Medicine)	Khon Kaen		Thailand	40002

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: John Beigel, MD, Leidos Biomedical Research, Inc. in support of Clinical Research Section, LIR, NIAID, National Institutes of Health
• Study Chair: Michael Ison, MD, MS, Division of Infectious Disease, Feinberg School of Medicine, Northwestern University

Study Documents (Full-Text)

• Statistical Analysis Plan - Aug 3, 2016
• Study Protocol - Aug 3, 2016

More Information

Additional Information:

• The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009).

Publications

• Monto AS. Vaccines and antiviral drugs in pandemic preparedness. Emerg Infect Dis. 2006 Jan;12(1):55-60.
• Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003 Jan 8;289(2):179-86.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT01314911
• Other Study ID Numbers: IRC 004; 11-I-0031; IRC004
• First Posted: Mar 15, 2011
• Last Update Posted: Feb 5, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): H1N1; Complications; PCR; Seasonal Influenza; Viral Shedding
• Additional relevant MeSH terms: Influenza, Human; Oseltamivir

Study Results

Participant Flow

Recruitment Details	Participants with an influenza-like illness and diagnosed with influenza by rapid antigen or PCR were recruited at 42 sites from 3 countries: 3 from Argentina, 4 from Thailand and 35 from the U.S., between January 2012 to October 2017.
Pre-assignment Detail	Seven hundred and sixteen subjects were enrolled per protocol (signed consent). Of these 716 subjects, three subjects were inadvertent enrollments, and one was a repeat enrollment of a subject who had been previously enrolled .One hundred fifty-four subjects were excluded during screening and did not participate in any other aspect of the trial.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Period Title: Overall Study
STARTED	278	280
COMPLETED	273	274
NOT COMPLETED	5	6

Baseline Characteristics

Arm/Group Title	Oseltamivir	Placebo	Total
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.	Total of all reporting groups
Overall Participants	277	279	556
Age (Count of Participants)
<=18 years	6 2.2%	6 2.2%	12 2.2%
Between 18 and 65 years	271 97.8%	273 97.8%	544 97.8%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	37	35	36
Sex: Female, Male (Count of Participants)
Female	183 66.1%	164 58.8%	347 62.4%
Male	94 33.9%	115 41.2%	209 37.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 4%	13 4.7%	24 4.3%
Not Hispanic or Latino	265 95.7%	266 95.3%	531 95.5%
Unknown or Not Reported	1 0.4%	0 0%	1 0.2%
Race/Ethnicity, Customized (Count of Participants)
Asian	193 69.7%	192 68.8%	385 69.2%
White	74 26.7%	76 27.2%	150 27%
Black or African American	7 2.5%	11 3.9%	18 3.2%
Race not available to clinic	1 0.4%	0 0%	1 0.2%
Subject does not know	1 0.4%	0 0%	1 0.2%
Subject does not want to report	1 0.4%	0 0%	1 0.2%
Region of Enrollment (participants) [Number]
Argentina	4 1.4%	8 2.9%	12 2.2%
United States	91 32.9%	87 31.2%	178 32%
Thailand	182 65.7%	184 65.9%	366 65.8%
Confirmed influenza infection status by central testing (Count of Participants)
Count of Participants [Participants]	246 88.8%	255 91.4%	501 90.1%
Influenza type/subtype by central testing (Count of Participants)
Influenza A/H3N2	122 44%	129 46.2%	251 45.1%
Influenza A/H1N1	39 14.1%	54 19.4%	93 16.7%
Influenza B	85 30.7%	71 25.4%	156 28.1%
Negative	30 10.8%	22 7.9%	52 9.4%
Co-infection	0 0%	1 0.4%	1 0.2%
Missing	1 0.4%	2 0.7%	3 0.5%
Hours from onset of influenza-like illness to screening (Hours) [Median (Full Range) ]
Median (Full Range) [Hours]	29	27	28
Hours from randomization to treatment initiation (hours) [Median (Full Range) ]
Median (Full Range) [hours]	1	1	1
Ever smoke tobacco (Count of Participants)
Count of Participants [Participants]	35 12.6%	33 11.8%	68 12.2%
Vaccination for season of enrollment (Count of Participants)
Count of Participants [Participants]	34 12.3%	23 8.2%	57 10.3%
BMI (kg/m²) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m²]	24.8	24.7	24.7
Overall symptom score, excluding 'other' (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	13	13	13
Global assessment in the morning at Day 0 (Count of Participants)
Subject feels as good today as before flu	13 4.7%	6 2.2%	19 3.4%
Subject functions as well today as before flu	49 17.7%	40 14.3%	89 16%
Functional status (units on a scale) [Median (Inter-Quartile Range) ]
Pre-illness status	100	100	100
Day 0 status	65	65	65
Complications of influenza (Count of Participants)
Sinusitis	4 1.4%	3 1.1%	7 1.3%
Otitis Media	0 0%	1 0.4%	1 0.2%
Bronchitis/Bronchiolitis	4 1.4%	2 0.7%	6 1.1%
Pneumonia	0 0%	1 0.4%	1 0.2%
Using antibiotic for other reasons	6 2.2%	5 1.8%	11 2%
Viral shedding by team-collected samples (log10 copies/mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [log10 copies/mL]	6.9	6.9	6.9
Category of virus by team-collected samples (Count of Participants)
>= LLOQ	237 85.6%	245 87.8%	482 86.7%
>= LOD, < LLOQ	6 2.2%	5 1.8%	11 2%
< LOD	3 1.1%	5 1.8%	8 1.4%
Viral shedding by self-collected samples (log10 copies/mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [log10 copies/mL]	6.1	6.2	6.2
Category of virus by self-collected samples (Count of Participants)
>= LLOQ	217 78.3%	225 80.6%	442 79.5%
>= LOD, < LLOQ	11 4%	6 2.2%	17 3.1%
< LOD	17 6.1%	23 8.2%	40 7.2%
Missing	1 0.4%	1 0.4%	2 0.4%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs at Day 3 -- Team Collected Samples
Description	The central laboratory performed a qualitative PCR test on the NP sample from Day 0 team collected swap in order to confirm influenza infection and to determine the influenza type and subtype. For participants with a positive influenza test result at Day 0 from this qualitative PCR testing, the laboratory then performed qPCR testing of subsequent samples to quantify viral shedding.
Time Frame	At Day 3

Outcome Measure Data

Analysis Population Description

The population analyzed was restricted to the 455 participants who had a confirmed positive test (from team collected sample) for influenza by qPCR in the central laboratory testing and were not in the pilot study for IRC004. 6 participants (3 in each arm) had missing endpoint samples so were excluded from the analysis.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	220	229
Count of Participants [Participants]	99 35.7%	131 47%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Placebo
	Comments	Assuming that pooled percentage of participants with virus detectable by PCR at Day 3 is 50%, assuming that the Oseltamivir arm was better than the placebo arm and that the detectable rate in the Oseltamivir arm was 42.5% compared to 57.5% in the placebo arm (a 15% reduction), and assuming 10% subjects with missing qPCR at Day 3, in a two-sided, two-sample 0.05-level t- test with 546 participants combined across both arms, there was 90% power.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0097
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	Z-test, 2-sided
	Comments	Comparison of randomized arms was based on the normal approximation to the binomial distribution.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.2
	Confidence Interval	(2-Sided) 95%; -21.4 to -3.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.6
	Estimation Comments	The difference in percents was calculated as the percent detectable in the Oseltamivir arm minus the percent detectable in the Placebo arm.

2. Secondary Outcome

Title	Number of Participants by Virus Detection Status--Team Collected Samples
Description	Number of participants who had undetectable values (less than the limit of detection [LOD]), who had values between the LOD and the lower limit of quantification (LLOQ), and who had values ≥LLOQ
Time Frame	At Day 0, 3 and 7

Outcome Measure Data

Analysis Population Description

The population analyzed is the Primary Efficacy Population (PEP), which included all participants who were randomized properly, had received at least one dose of study drug, and had influenza virus isolated and typed(from team collected sample) in the qualitative PCR evaluation at Day 0 from central laboratory testing.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	246	255
>= LLOQ	237 85.6%	245 87.8%
>= LOD, < LLOQ	6 2.2%	5 1.8%
< LOD	3 1.1%	5 1.8%
Missing	0 0%	0 0%
>= LLOQ	85 30.7%	109 39.1%
>= LOD, < LLOQ	24 8.7%	36 12.9%
< LOD	134 48.4%	107 38.4%
Missing	3 1.1%	3 1.1%
>= LLOQ	16 5.8%	21 7.5%
>= LOD, < LLOQ	11 4%	5 1.8%
< LOD	214 77.3%	224 80.3%
Missing	5 1.8%	5 1.8%

3. Secondary Outcome

Title	qPCR Viral Shedding -- Team Collected Samples
Description	Median, 25% and 75% percentile of the value of viral shedding (Results <LOD were imputed as the LOD value, and Results >= LOD, <LLOQ were imputed as the LLOQ value.)
Time Frame	At Day 0, 3 and 7

Outcome Measure Data

Analysis Population Description

The population analyzed is the Primary Efficacy Population (PEP), which included all participants who were randomized properly, had received at least one dose of study drug, and had influenza virus isolated and typed (from team collected sample) in the qualitative PCR evaluation at Day 0 from central laboratory testing.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	246	255
Day 0	6.85	6.9
Day 3	3.4	3.9
Day 7	3.2	3.2

4. Secondary Outcome

Title	Number Of Participants Shedding Virus -- Team Collected Samples
Description	Number of participants with undetectable viral load at both Day 3 and Day 7; detectable at Day 3 and undetectable at Day 7; detectable at Day 7 (irrespective of whether or not detectable at Day 3).
Time Frame	At day 3 and 7.

Outcome Measure Data

Analysis Population Description

The population analyzed is the Primary Efficacy Population (PEP), which included all participants who were randomized properly, had received at least one dose of study drug, and had influenza virus isolated and typed (from team collected sample) in the qualitative PCR evaluation at Day 0 from central laboratory testing.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	246	255
Undetectable at both Day 3 and 7	126 45.5%	100 35.8%
Detectable at Day 3 and undetectable at Day 7	87 31.4%	124 44.4%
Detectable at Day 7	27 9.7%	26 9.3%
Missing result at Day 3 and/or Day 7	6 2.2%	5 1.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0243
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Time to Alleviation of Influenza Clinical Symptoms
Description	The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Duration of clinical symptoms was defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms were grade 0 (absent) or 1 (mild). A measurement was considered to be the 8AM or 8PM assessment during Days 0 to 7 (so two measurements were obtained per day) and then the daily assessment thereafter. Time was calculated in half-days through to Day 7. If a subject's first two assessments on (baseline assessment and first subsequent diary card assessment) satisfied this criterion, then the duration was set to zero. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms evaluated.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	277	279
Median (95% Confidence Interval) [days]	4	4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.41
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	Log Rank
	Comments

6. Secondary Outcome

Title	Time to Absence of Fever
Description	Fever was considered present based on the diary cards if a subject reported a maximal temperature ≥38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Otherwise, fever was considered not present during the period since the diary card was previously completed, except that the evaluation was considered missing if either the temperature or the antipyretic drug use entry was not completed on the diary card. The duration of fever was defined as the time from Day 0 to the first of two successive assessments (through to Day 7) or to the first assessment (Day 8 onwards) at which no fever was present according to this definition.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with fever evaluated.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	277	279
Median (95% Confidence Interval) [days]	1	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	Log Rank
	Comments

7. Secondary Outcome

Title	Time to Resolution of All Symptoms AND Fever
Description	The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Fever was considered present based on the diary cards if a subject reported a maximal temperature ≥38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Time to resolution of all clinical symptoms and fever is defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms are grade 0 (absent) or 1(mild) and no fever >=38.0 C or antipyretic drug is reported. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms and fever evaluated.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which includes all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	277	279
Median (95% Confidence Interval) [days]	4.0	4.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7461
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	Log Rank
	Comments

8. Secondary Outcome

Title	Time to Feeling as Good as Before the Onset of the Influenza Illness
Description	Time to feeling as good as before influenza is defined as time to the first of two successive 'yes' responses to the question of 'feeling as good as you did before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	277	279
Median (95% Confidence Interval) [days]	6.0	6.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1501
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	Log Rank
	Comments

9. Secondary Outcome

Title	Time to Return to Pre-influenza Function
Description	Time to return to pre-influenza function is defined as the time from Day 0 to the first of two successive 'Yes' answers to the global assessment question 'Are you functioning as well as you were before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	277	279
Median (95% Confidence Interval) [days]	3.5	5.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3025
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	Log Rank
	Comments

10. Secondary Outcome

Title	Time to Return of Physical Function to Pre-illness Level
Description	Time to return of physical function to pre-illness level was defined as the time from Day 0 to the first of two successive measurements at which the physical function score equals or is better than the pre-illness score (obtained by recall at enrollment). For subjects who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with physical function evaluated.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	277	279
Median (95% Confidence Interval) [days]	7.0	7.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5466
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	Log Rank
	Comments

11. Secondary Outcome

Title	Number of Participants With Treatment Compliance Status
Description	For each of the 5 days of treatment, participants were asked whether they took all study drug for that day. All participants were assumed to have taken at least some study drug even if they had zero days with all study drug reported as taken. Missing reports for some or all days were imputed as not having taken all study drug for the days concerned.
Time Frame	From treatment initiation to Day 5

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	277	279
0 day with all study drug reported as taken	1 0.4%	2 0.7%
1 day with all study drug reported as taken	2 0.7%	2 0.7%
3 days with all study drug reported as taken	2 0.7%	1 0.4%
4 days with all study drug reported as taken	2 0.7%	1 0.4%
5 days with all study drug reported as taken	270 97.5%	273 97.8%

12. Secondary Outcome

Title	Percentage of Participants Who Required Hospitalization.
Description	The percentage of participants hospitalized by 28 days was constructed by inverting an exact binomial test of the actual percentages (ignoring loss to follow-up).
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	277	279
Number (95% Confidence Interval) [percentage of participants]	1.4 0.5%	0.7 0.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5311
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	two-sample binomial exact test
	Comments	The two-sample binomial exact test was performed in PROC STATXACT.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -1.4 to 3.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in percents was calculated as the percent in the Oseltamivir arm minus the percent in the placebo arm.

13. Secondary Outcome

Title	Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications Requiring An Antibiotic Use, After Day 0.
Description	Participants were assessed for the signs/symptoms suggestive of one of the following complications: Sinusitis, Otitis Media ,Bronchitis / Bronchiolitis, Pneumonia and antibiotic use for reason other than above.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug. The categories in the table are not mutually exclusive (because some participants had multiple complications) and the last row of the table summarizes all incidents.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	277	279
Sinusitis	3.2 1.2%	1.8 0.6%
Otitis Media	0.4 0.1%	0.4 0.1%
Bronchitis Bronchiolitis	2.5 0.9%	2.2 0.8%
Pneumonia	0.4 0.1%	0.4 0.1%
Antibiotic use	2.5 0.9%	3.6 1.3%
If have at least one Complication	7.2 2.6%	6.8 2.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Placebo
	Comments	This test compared the difference in percentages of participants with at least one complication between two randomized arms.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8498
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	Z test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -3.8 to 4.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in percents was calculated as the percent in the Oseltamivir arm minus the percent in the placebo arm.

14. Secondary Outcome

Title	28-day Mortality
Description	Number of deaths
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	277	279
Count of Participants [Participants]	0 0%	0 0%

15. Secondary Outcome

Title	Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs --Self Collected Samples
Description	For participants with a positive influenza test result at Day 0 from qualitative PCR testing on the team collected sample, the laboratory then performed qPCR testing of self-collected samples to quantify viral shedding.
Time Frame	At Day 3

Outcome Measure Data

Analysis Population Description

The population analyzed was restricted to the 455 participants who had a confirmed positive test (from team collected sample) for influenza in the central laboratory testing and were not in the pilot study for IRC004. 9 participants (4 in the Oseltamivir arm and 5 in the Placebo arm) had missing endpoint samples so were excluded from the analysis.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	219	227
Count of Participants [Participants]	56 20.2%	89 31.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	Z test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.6
	Confidence Interval	(2-Sided) 95%; -22.2 to -5.1
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		The difference in percents was calculated as the percent with detectable in the Oseltamivir arm minus the percent with detectable in the placebo arm.

16. Secondary Outcome

Title	Number of Participants by Virus Detection Status --Self Collected Samples
Description	Number of participants who had undetectable values (less than the limit of detection [LOD]), who had values between the LOD and the lower limit of quantification (LLOQ), and who had values ≥LLOQ. Evening samples on Day 0, 1 and 2 were only required under protocol versions 1.0-4.0 and so were only collected for about 20% of participants.
Time Frame	At Day 0, Day 0 evening, Day 1, Day 1 evening, Day 2, Day 2 evening and Day 3

Outcome Measure Data

Analysis Population Description

The population analyzed is the Primary Efficacy Population (PEP), which included all participants who were randomized properly, had received at least one dose of study drug, and had influenza virus isolated and typed (from team collected sample) in the qualitative PCR evaluation at Day 0 from central laboratory testing.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	246	255
>= LLOQ	217 78.3%	225 80.6%
>= LOD, < LLOQ	11 4%	6 2.2%
< LOD	17 6.1%	23 8.2%
Missing	1 0.4%	1 0.4%
>= LLOQ	37 13.4%	48 17.2%
>= LOD, < LLOQ	4 1.4%	1 0.4%
< LOD	8 2.9%	5 1.8%
Missing	197 71.1%	201 72%
>= LLOQ	138 49.8%	147 52.7%
>= LOD, < LLOQ	30 10.8%	27 9.7%
< LOD	75 27.1%	76 27.2%
Missing	3 1.1%	5 1.8%
>= LLOQ	23 8.3%	29 10.4%
>= LOD, < LLOQ	4 1.4%	9 3.2%
< LOD	24 8.7%	13 4.7%
Missing	195 70.4%	204 73.1%
>= LLOQ	70 25.3%	92 33%
>= LOD, < LLOQ	26 9.4%	31 11.1%
< LOD	146 52.7%	129 46.2%
Missing	4 1.4%	3 1.1%
>= LLOQ	11 4%	12 4.3%
>= LOD, < LLOQ	6 2.2%	4 1.4%
< LOD	32 11.6%	41 14.7%
Missing	197 71.1%	198 71%
>= LLOQ	39 14.1%	65 23.3%
>= LOD, < LLOQ	25 9%	35 12.5%
< LOD	178 64.3%	149 53.4%
Missing	4 1.4%	6 2.2%

17. Secondary Outcome

Title	qPCR Viral Shedding -- Self Collected Samples
Description	Median, 25% and 75% percentile of the value of viral shedding (Results <LOD were imputed as the LOD value, and Results >= LOD, <LLOQ were imputed as the LLOQ value.). Evening samples on Day 0, 1 and 2 were only required under protocol versions 1.0-4.0 and so were only collected for about 20% of participants.
Time Frame	At Day 0, Day 0 evening, Day 1, Day 1 evening, Day 2, Day 2 evening and Day 3

Outcome Measure Data

Analysis Population Description

The population analyzed is the Primary Efficacy Population (PEP), which included all participants who were randomized properly, had received at least one dose of study drug, and had influenza virus isolated and typed (from team collected sample) in the qualitative PCR evaluation at Day 0 from central laboratory testing.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	246	255
Day 0	6.1	6.2
Day 0 evening	5.5	6.0
Day 1	4.2	4.5
Day 1 evening	3.9	4.0
Day 2	3.4	3.4
Day 2 evening	3.2	3.2
Day 3	3.2	3.4

18. Secondary Outcome

Title	Area Under The Curve (AUC) Of Viral Shedding For Self Collected Samples
Description	This AUC was calculated using the trapezoidal rule and the units of measurement are (days*log10 copies/mL) with the fact that it was the level of virus above the LLOQ being considered. The calculation of AUC was undertaken using measurements from Day 0 to Day 3 which were collected under all versions of the protocol (i.e. evening measurements on Days 0, 1 and 2 were not used as these were collected for only about 20% of subjects). Missing values during follow-up were ignored. This is equivalent to imputing a missing value using linear interpolation between the preceding and succeeding available values. For the five subjects with missing values following a last available measurement which was above the LLOQ, the remaining values were assumed to be the mean of preceding value and LLOQ in calculating the AUC.
Time Frame	From Day 0 to Day 3

Outcome Measure Data

Analysis Population Description

The population analyzed is the Primary Efficacy Population (PEP). The two subjects with missing values at Day 0 (one in each randomized arm) were excluded from this analysis.

Arm/Group Title	Oseltamivir	Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Measure Participants	245	254
Median (Inter-Quartile Range) [days*log10 copies/mL]	12.5	13.18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	Adverse events were collected throughout the conduct of the study; from Day 0 to Day 28
Adverse Event Reporting Description	All worsening symptoms were evaluated as potential adverse events.If a diagnosis was clinically evident (or subsequently determined), the diagnosis, rather than the individual signs and symptoms or lab abnormalities, were recorded as the AE. All worsening laboratory values were also evaluated as potential adverse events. The DAIDS AE Grading Table (V1.0) was used.
Arm/Group Title	Oseltamivir		Placebo
Arm/Group Description	Oseltamivir: Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.		Placebo: Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
All Cause Mortality
	Oseltamivir		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/277 (0%)		0/279 (0%)
Serious Adverse Events
	Oseltamivir		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/277 (1.8%)		2/279 (0.7%)
Gastrointestinal disorders
Vomiting	1/277 (0.4%)		0/279 (0%)
General disorders
Chest pain	0/277 (0%)		1/279 (0.4%)
Infections and infestations
Influenza	2/277 (0.7%)		1/279 (0.4%)
Sinusitis	1/277 (0.4%)		0/279 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/277 (0.4%)		0/279 (0%)
Other (Not Including Serious) Adverse Events
	Oseltamivir		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	134/277 (48.4%)		153/279 (54.8%)
Gastrointestinal disorders
Nausea	65/277 (23.5%)		61/279 (21.9%)
Diarrhoea	41/277 (14.8%)		47/279 (16.8%)
Vomiting	35/277 (12.6%)		36/279 (12.9%)
General disorders
Pyrexia	31/277 (11.2%)		27/279 (9.7%)
Fatigue	24/277 (8.7%)		26/279 (9.3%)
Musculoskeletal and connective tissue disorders
Myalgia	16/277 (5.8%)		21/279 (7.5%)
Nervous system disorders
Headache	28/277 (10.1%)		24/279 (8.6%)
Dizziness	22/277 (7.9%)		15/279 (5.4%)
Respiratory, thoracic and mediastinal disorders
Cough	28/277 (10.1%)		32/279 (11.5%)
Oropharyngeal pain	24/277 (8.7%)		25/279 (9%)
Rhinorrhoea	26/277 (9.4%)		23/279 (8.2%)
Nasal congestion	20/277 (7.2%)		16/279 (5.7%)
Vascular disorders
Hypertension	15/277 (5.4%)		20/279 (7.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.