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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
716
Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo.
Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs at Day 3 -- Team Collected Samples
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
Number of Participants by Virus Detection Status--Team Collected Samples
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
qPCR Viral Shedding -- Team Collected Samples
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
Number Of Participants Shedding Virus -- Team Collected Samples
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.
Time to Alleviation of Influenza Clinical Symptoms
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.
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East Valley Family Physicians
Chandler, Arizona, United States
WCCT Global, LLC
Costa Mesa, California, United States
Paragon Rx Clinical
Garden Grove, California, United States
University of Southern California
Los Angeles, California, United States
University of California, San Diego
San Diego, California, United States
Westlake Medical Research
Thousand Oaks, California, United States
Advanced Rx Clinical Research Group
Westminster, California, United States
University of Colorado
Aurora, Colorado, United States
University of Florida
Gainesville, Florida, United States
Best Quality Research, Inc.
Hialeah, Florida, United States
...and 41 more locations
Time frame: From treatment initiation to Day 28
Time to Absence of Fever
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
Time to Resolution of All Symptoms AND Fever
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
Time to Feeling as Good as Before the Onset of the Influenza Illness
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
Time to Return to Pre-influenza Function
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
Time to Return of Physical Function to Pre-illness Level
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
Number of Participants With Treatment Compliance Status
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
Percentage of Participants Who Required Hospitalization.
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
Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications Requiring An Antibiotic Use, After Day 0.
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
28-day Mortality
Number of deaths
Time frame: From treatment initiation to Day 28
Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs --Self Collected Samples
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
Number of Participants by Virus Detection Status --Self Collected Samples
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
qPCR Viral Shedding -- Self Collected Samples
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
Area Under The Curve (AUC) Of Viral Shedding For Self Collected Samples
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