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

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ClinicalTrials.gov Identifier: NCT01314911
Recruitment Status : Completed
First Posted : March 15, 2011
Results First Posted : February 5, 2019
Last Update Posted : February 5, 2019
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Influenza, Human
Interventions Drug: Oseltamivir
Drug: Placebo
Enrollment 716
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 Details 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
Hide 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 [1] 273 274
Not Completed 5 6
Reason Not Completed
Lost to Follow-up             3             2
Withdrawal by Subject             1             3
Received Non-randomized Study Drug             0             1
Never Started Treatment             1             0
[1]
Data were locked on July 12, 2018 and were retrieved on August 14, 2018.
Arm/Group Title Oseltamivir Placebo Total
Hide 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 Number of Baseline Participants 277 279 556
Hide Baseline 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.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 277 participants 279 participants 556 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%
0
   0.0%
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 277 participants 279 participants 556 participants
37
(27 to 49)
35
(27 to 46)
36
(27 to 47)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 277 participants 279 participants 556 participants
Female
183
  66.1%
164
  58.8%
347
  62.4%
Male
94
  33.9%
115
  41.2%
209
  37.6%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 277 participants 279 participants 556 participants
Hispanic or Latino
11
   4.0%
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
   0.0%
1
   0.2%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race Number Analyzed 277 participants 279 participants 556 participants
Asian
193
  69.7%
192
  68.8%
385
  69.2%
White
74
  26.7%
76
  27.2%
150
  27.0%
Black or African American
7
   2.5%
11
   3.9%
18
   3.2%
Race not available to clinic
1
   0.4%
0
   0.0%
1
   0.2%
Subject does not know
1
   0.4%
0
   0.0%
1
   0.2%
Subject does not want to report
1
   0.4%
0
   0.0%
1
   0.2%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Argentina Number Analyzed 277 participants 279 participants 556 participants
4 8 12
United States Number Analyzed 277 participants 279 participants 556 participants
91 87 178
Thailand Number Analyzed 277 participants 279 participants 556 participants
182 184 366
Confirmed influenza infection status by central testing  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 277 participants 279 participants 556 participants
246
  88.8%
255
  91.4%
501
  90.1%
Influenza type/subtype by central testing  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 277 participants 279 participants 556 participants
Influenza A/H3N2
122
  44.0%
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
   0.0%
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  
Median (Full Range)
Unit of measure:  Hours
Number Analyzed 277 participants 279 participants 556 participants
29
(1 to 49)
27
(0 to 49)
28
(0 to 49)
Hours from randomization to treatment initiation  
Median (Full Range)
Unit of measure:  Hours
Number Analyzed 277 participants 279 participants 556 participants
1
(0 to 20)
1
(0 to 21)
1
(0 to 21)
Ever smoke tobacco  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 277 participants 279 participants 556 participants
35
  12.6%
33
  11.8%
68
  12.2%
Vaccination for season of enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 277 participants 279 participants 556 participants
34
  12.3%
23
   8.2%
57
  10.3%
BMI  
Median (Inter-Quartile Range)
Unit of measure:  Kg/m²
Number Analyzed 277 participants 279 participants 556 participants
24.8
(22.1 to 29.3)
24.7
(21.4 to 28.4)
24.7
(21.6 to 28.7)
Overall symptom score, excluding 'other'   [1] 
Median (Inter-Quartile Range)
Unit of measure:  Units on a scale
Number Analyzed 277 participants 279 participants 556 participants
13
(10 to 17)
13
(10 to 17)
13
(10 to 17)
[1]
Measure Description: Symptoms were scored on a 4-point scale : 0=absent, 1=mild, 2=moderate, 3=severe.Overall symptom score was the sum of available scores for each of the 11 symptoms assessed (so ignoring missing values). The possible range of the overall symptom score is therefore 0 (no symptoms) to 33 (severe for all 11 symptoms). Subjects with missing evaluations for all symptoms were given a missing overall symptom score.
Global assessment in the morning at Day 0  
Measure Type: Count of Participants
Unit of measure:  Participants
Subject feels as good today as before flu Number Analyzed 277 participants 279 participants 556 participants
13
   4.7%
6
   2.2%
19
   3.4%
Subject functions as well today as before flu Number Analyzed 277 participants 279 participants 556 participants
49
  17.7%
40
  14.3%
89
  16.0%
Functional status   [1] 
Median (Inter-Quartile Range)
Unit of measure:  Units on a scale
Pre-illness status Number Analyzed 277 participants 279 participants 556 participants
100
(90 to 100)
100
(95 to 100)
100
(95 to 100)
Day 0 status Number Analyzed 277 participants 279 participants 556 participants
65
(40 to 75)
65
(35 to 75)
65
(40 to 75)
[1]
Measure Description: Average functional status was calculated as the average of the ten items assessed (so ignoring missing values), scoring 0='yes, limited a lot', 50='yes, limited a little', 100='no, not limited at all'. The possible range of the functional status score is therefore 0 (worst possible status) to 100 (best possible status). Subjects with missing evaluations for all items were coded as missing.
Complications of influenza  
Measure Type: Count of Participants
Unit of measure:  Participants
Sinusitis Number Analyzed 277 participants 279 participants 556 participants
4
   1.4%
3
   1.1%
7
   1.3%
Otitis Media Number Analyzed 277 participants 279 participants 556 participants
0
   0.0%
1
   0.4%
1
   0.2%
Bronchitis/Bronchiolitis Number Analyzed 277 participants 279 participants 556 participants
4
   1.4%
2
   0.7%
6
   1.1%
Pneumonia Number Analyzed 277 participants 279 participants 556 participants
0
   0.0%
1
   0.4%
1
   0.2%
Using antibiotic for other reasons Number Analyzed 277 participants 279 participants 556 participants
6
   2.2%
5
   1.8%
11
   2.0%
Viral shedding by team-collected samples   [1] 
Median (Inter-Quartile Range)
Unit of measure:  Log10 copies/mL
Number Analyzed 246 participants 255 participants 501 participants
6.9
(5.8 to 7.6)
6.9
(5.9 to 7.6)
6.9
(5.8 to 7.6)
[1]
Measure Analysis Population Description: restricted to subjects with confirmed influenza in a study team collected swab on Day 0
Category of virus by team-collected samples   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 246 participants 255 participants 501 participants
>= LLOQ
237
  96.3%
245
  96.1%
482
  96.2%
>= LOD, < LLOQ
6
   2.4%
5
   2.0%
11
   2.2%
< LOD
3
   1.2%
5
   2.0%
8
   1.6%
[1]
Measure Description: LOD(limit of detection) /LLOQ(lower limit of quantification) for Influenza A and Influenza B by qPCR is 3.2/3.9 and 3.4/4.0, respectively.Results <LOD were imputed as LOD; results >=LOD and <LLOQ were imputed as LLOQ.
[2]
Measure Analysis Population Description: restricted to subjects with confirmed influenza in a study team collected swab on Day 0
Viral shedding by self-collected samples   [1] 
Median (Inter-Quartile Range)
Unit of measure:  Log10 copies/mL
Number Analyzed 246 participants 255 participants 501 participants
6.1
(4.9 to 6.9)
6.2
(5.4 to 6.9)
6.2
(5.2 to 6.9)
[1]
Measure Analysis Population Description: restricted to subjects with confirmed influenza in a study team collected swab on Day 0
Category of virus by self-collected samples   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 246 participants 255 participants 501 participants
>= LLOQ
217
  88.2%
225
  88.2%
442
  88.2%
>= LOD, < LLOQ
11
   4.5%
6
   2.4%
17
   3.4%
< LOD
17
   6.9%
23
   9.0%
40
   8.0%
Missing
1
   0.4%
1
   0.4%
2
   0.4%
[1]
Measure Description: LOD(limit of detection) /LLOQ(lower limit of quantification) for Influenza A and Influenza B by qPCR is 3.2/3.9 and 3.4/4.0, respectively.
[2]
Measure Analysis Population Description: restricted to subjects with confirmed influenza in a study team collected swab on Day 0
1.Primary Outcome
Title Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs at Day 3 -- Team Collected Samples
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 220 229
Measure Type: Count of Participants
Unit of Measure: Participants
99
  45.0%
131
  57.2%
Hide 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 [Not Specified]
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 246 255
Measure Type: Count of Participants
Unit of Measure: Participants
Day 0 >= LLOQ
237
  96.3%
245
  96.1%
>= LOD, < LLOQ
6
   2.4%
5
   2.0%
< LOD
3
   1.2%
5
   2.0%
Missing
0
   0.0%
0
   0.0%
Day 3 >= LLOQ
85
  34.6%
109
  42.7%
>= LOD, < LLOQ
24
   9.8%
36
  14.1%
< LOD
134
  54.5%
107
  42.0%
Missing
3
   1.2%
3
   1.2%
Day 7 >= LLOQ
16
   6.5%
21
   8.2%
>= LOD, < LLOQ
11
   4.5%
5
   2.0%
< LOD
214
  87.0%
224
  87.8%
Missing
5
   2.0%
5
   2.0%
3.Secondary Outcome
Title qPCR Viral Shedding -- Team Collected Samples
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 246 255
Median (Inter-Quartile Range)
Unit of Measure: log10 copies/mL
Day 0
6.85
(5.8 to 7.6)
6.9
(5.9 to 7.6)
Day 3
3.4
(3.2 to 4.5)
3.9
(3.2 to 4.9)
Day 7
3.2
(3.2 to 3.4)
3.2
(3.2 to 3.4)
4.Secondary Outcome
Title Number Of Participants Shedding Virus -- Team Collected Samples
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 246 255
Measure Type: Count of Participants
Unit of Measure: Participants
Undetectable at both Day 3 and 7
126
  51.2%
100
  39.2%
Detectable at Day 3 and undetectable at Day 7
87
  35.4%
124
  48.6%
Detectable at Day 7
27
  11.0%
26
  10.2%
Missing result at Day 3 and/or Day 7
6
   2.4%
5
   2.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0243
Comments P-value was not adjusted for multiple interim analyses.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
5.Secondary Outcome
Title Time to Alleviation of Influenza Clinical Symptoms
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 277 279
Median (95% Confidence Interval)
Unit of Measure: days
4
(3.5 to 4.5)
4
(3.5 to 4.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.41
Comments P-value was not adjusted for multiple interim analyses.
Method Log Rank
Comments [Not Specified]
6.Secondary Outcome
Title Time to Absence of Fever
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 277 279
Median (95% Confidence Interval)
Unit of Measure: days
1
(0.5 to 1.0)
1
(0.5 to 1.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.88
Comments P-value was not adjusted for multiple interim analyses.
Method Log Rank
Comments [Not Specified]
7.Secondary Outcome
Title Time to Resolution of All Symptoms AND Fever
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 277 279
Median (95% Confidence Interval)
Unit of Measure: days
4.0
(3.5 to 4.5)
4.0
(3.5 to 4.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7461
Comments P-value was not adjusted for multiple interim analyses.
Method Log Rank
Comments [Not Specified]
8.Secondary Outcome
Title Time to Feeling as Good as Before the Onset of the Influenza Illness
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 277 279
Median (95% Confidence Interval)
Unit of Measure: days
6.0
(5.0 to 6.5)
6.0
(5.5 to 6.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1501
Comments P-value was not adjusted for multiple interim analyses.
Method Log Rank
Comments [Not Specified]
9.Secondary Outcome
Title Time to Return to Pre-influenza Function
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 277 279
Median (95% Confidence Interval)
Unit of Measure: days
3.5
(3.5 to 4.5)
5.0
(4.0 to 5.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3025
Comments P-value was not adjusted for multiple interim analyses.
Method Log Rank
Comments [Not Specified]
10.Secondary Outcome
Title Time to Return of Physical Function to Pre-illness Level
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 277 279
Median (95% Confidence Interval)
Unit of Measure: days
7.0
(6.0 to 8.0)
7.0
(6.0 to 7.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5466
Comments P-value was not adjusted for multiple interim analyses.
Method Log Rank
Comments [Not Specified]
11.Secondary Outcome
Title Number of Participants With Treatment Compliance Status
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 277 279
Measure Type: Count of Participants
Unit of Measure: Participants
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.
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 277 279
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
1.4
(0.4 to 3.7)
0.7
(0.1 to 2.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
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
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.
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 277 279
Measure Type: Number
Unit of Measure: percentage of participants
Sinusitis 3.2 1.8
Otitis Media 0.4 0.4
Bronchitis Bronchiolitis 2.5 2.2
Pneumonia 0.4 0.4
Antibiotic use 2.5 3.6
If have at least one Complication 7.2 6.8
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.8498
Comments P-value was not adjusted for multiple interim analyses.
Method Z test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.4
Confidence Interval (2-Sided) 95%
-3.8 to 4.7
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
Hide Description Number of deaths
Time Frame From treatment initiation to Day 28
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 277 279
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
15.Secondary Outcome
Title Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs --Self Collected Samples
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 219 227
Measure Type: Count of Participants
Unit of Measure: Participants
56
  25.6%
89
  39.2%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0021
Comments P-value was not adjusted for multiple interim analyses.
Method Z test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -13.6
Confidence Interval (2-Sided) 95%
-22.2 to -5.1
Estimation Comments [Not Specified]
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 246 255
Measure Type: Count of Participants
Unit of Measure: Participants
Day 0 >= LLOQ
217
  88.2%
225
  88.2%
>= LOD, < LLOQ
11
   4.5%
6
   2.4%
< LOD
17
   6.9%
23
   9.0%
Missing
1
   0.4%
1
   0.4%
Day 0 evening >= LLOQ
37
  15.0%
48
  18.8%
>= LOD, < LLOQ
4
   1.6%
1
   0.4%
< LOD
8
   3.3%
5
   2.0%
Missing
197
  80.1%
201
  78.8%
Day 1 >= LLOQ
138
  56.1%
147
  57.6%
>= LOD, < LLOQ
30
  12.2%
27
  10.6%
< LOD
75
  30.5%
76
  29.8%
Missing
3
   1.2%
5
   2.0%
Day 1 evening >= LLOQ
23
   9.3%
29
  11.4%
>= LOD, < LLOQ
4
   1.6%
9
   3.5%
< LOD
24
   9.8%
13
   5.1%
Missing
195
  79.3%
204
  80.0%
Day 2 >= LLOQ
70
  28.5%
92
  36.1%
>= LOD, < LLOQ
26
  10.6%
31
  12.2%
< LOD
146
  59.3%
129
  50.6%
Missing
4
   1.6%
3
   1.2%
Day 2 evening >= LLOQ
11
   4.5%
12
   4.7%
>= LOD, < LLOQ
6
   2.4%
4
   1.6%
< LOD
32
  13.0%
41
  16.1%
Missing
197
  80.1%
198
  77.6%
Day 3 >= LLOQ
39
  15.9%
65
  25.5%
>= LOD, < LLOQ
25
  10.2%
35
  13.7%
< LOD
178
  72.4%
149
  58.4%
Missing
4
   1.6%
6
   2.4%
17.Secondary Outcome
Title qPCR Viral Shedding -- Self Collected Samples
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 246 255
Median (Inter-Quartile Range)
Unit of Measure: log10 copies/mL
Day 0
6.1
(4.9 to 6.9)
6.2
(5.4 to 6.9)
Day 0 evening
5.5
(4.3 to 6.2)
6.0
(5.0 to 6.6)
Day 1
4.2
(3.4 to 5.5)
4.5
(3.4 to 5.9)
Day 1 evening
3.9
(3.2 to 7.2)
4.0
(3.4 to 5.6)
Day 2
3.4
(3.2 to 4.3)
3.4
(3.2 to 4.8)
Day 2 evening
3.2
(3.2 to 3.9)
3.2
(3.2 to 3.9)
Day 3
3.2
(3.2 to 3.9)
3.4
(3.2 to 4.0)
18.Secondary Outcome
Title Area Under The Curve (AUC) Of Viral Shedding For Self Collected Samples
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 245 254
Median (Inter-Quartile Range)
Unit of Measure: days*log10 copies/mL
12.5
(11.35 to 14.55)
13.18
(11.55 to 15.75)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.022
Comments P-value was not adjusted for multiple interim analyses.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
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
Hide 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 (%) Affected / at Risk (%)
Total   0/277 (0.00%)   0/279 (0.00%) 
Hide Serious Adverse Events
Oseltamivir Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   5/277 (1.81%)   2/279 (0.72%) 
Gastrointestinal disorders     
Vomiting  1  1/277 (0.36%)  0/279 (0.00%) 
General disorders     
Chest pain  1  0/277 (0.00%)  1/279 (0.36%) 
Infections and infestations     
Influenza  1  2/277 (0.72%)  1/279 (0.36%) 
Sinusitis  1  1/277 (0.36%)  0/279 (0.00%) 
Pregnancy, puerperium and perinatal conditions     
Abortion spontaneous  1  1/277 (0.36%)  0/279 (0.00%) 
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Oseltamivir Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   134/277 (48.38%)   153/279 (54.84%) 
Gastrointestinal disorders     
Nausea  1  65/277 (23.47%)  61/279 (21.86%) 
Diarrhoea  1  41/277 (14.80%)  47/279 (16.85%) 
Vomiting  1  35/277 (12.64%)  36/279 (12.90%) 
General disorders     
Pyrexia  1  31/277 (11.19%)  27/279 (9.68%) 
Fatigue  1  24/277 (8.66%)  26/279 (9.32%) 
Musculoskeletal and connective tissue disorders     
Myalgia  1  16/277 (5.78%)  21/279 (7.53%) 
Nervous system disorders     
Headache  1  28/277 (10.11%)  24/279 (8.60%) 
Dizziness  1  22/277 (7.94%)  15/279 (5.38%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  28/277 (10.11%)  32/279 (11.47%) 
Oropharyngeal pain  1  24/277 (8.66%)  25/279 (8.96%) 
Rhinorrhoea  1  26/277 (9.39%)  23/279 (8.24%) 
Nasal congestion  1  20/277 (7.22%)  16/279 (5.73%) 
Vascular disorders     
Hypertension  1  15/277 (5.42%)  20/279 (7.17%) 
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: John Beigel, M.D
Organization: Leidos Biomedical Research, Inc. is support to the National Institute of Allergy and Infectious Diseases (NIAID)
Phone: 301-451-9881
EMail: jbeigel@niaid.nih.gov
Layout table for additonal information
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 Submitted: March 3, 2011
First Posted: March 15, 2011
Results First Submitted: January 11, 2019
Results First Posted: February 5, 2019
Last Update Posted: February 5, 2019