Influenza
Conditions
Keywords
Adaptive Design, At Risk, H1N1, Synergy, TCAD
Brief summary
Seasonal influenza is responsible for many hospitalizations and deaths each year, despite effective antiviral treatments. Some individuals have medical conditions such as heart or lung diseases that make them particularly at risk of severe influenza infections that may result in hospitalization or death. Oseltamivir (Tamiflu) is used most often to treat flu, but there are still many hospitalizations, complications, and deaths even with treatment. This study evaluated the use of combination antivirals (amantadine, oseltamivir, and ribavirin) compared to oseltamivir alone in the treatment of influenza in an at-risk population.
Detailed description
Seasonal influenza is responsible for approximately 226,000 excess hospitalizations annually and despite effective antivirals causes significant morbidity and mortality (estimated 24,000-50,000 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 percent of the deaths with the 2009 H1N1 occurred among people younger than 65 years of age. The CDC has defined an at-risk population that accounts for the majority of hospitalization and morbidity associated with influenza. This study evaluated the use of combination antivirals as compared to oseltamivir alone in the treatment of influenza in an at-risk population. Subjects who met the CDC definition for being at-risk and that present with an influenza-like illness were screened for the study. Those subjects with a confirmatory test for influenza (rapid antigen or PCR) were randomized in a 1:1 manner to receive a blinded study treatment consisting of either the combination of amantadine, oseltamivir, and ribavirin or oseltamivir alone for 5 days. Clinical, virologic, and laboratory assessments on Days 1, 3, 7, 14, and 28 were used for both safety and efficacy analysis. Design: * Participants were screened with a physical examination and medical history, along with blood tests and throat swabs to confirm influenza infection. * Eligible participants were randomly assigned to take either oseltamivir alone (the current standard treatment for influenza) or to take oseltamivir, amantadine, and ribavirin. Participants had additional blood samples and throat swabs taken at the start of the study, and were shown how to complete a study diary at home. * Participants received a study medication kit containing the medication to take at home twice a day for 5 days. * Participants returned, with the medication kit, to the clinic on days 1 (the first day after the start of the study), 3, 7, 14, and 28. The first visit took 2 to 3 hours, but each subsequent visit took approximately 1 to 2 hours. Additional blood samples and throat swabs were taken at these visits. Pilot study: Due to the lack of reliable data concerning the AUC virologic endpoint, an external pilot study was conducted in the first 47 patients randomized to identify a primary endpoint and method of analysis, and to possibly modify the sample size. To ensure no effect on the type I error rate, data from these 47 patients were excluded from the primary and secondary efficacy analyses but were used in other analyses of secondary objectives.
Interventions
DRUGAmantadine, Ribavirin, Oseltamivir
Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.
DRUGOseltamivir
Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Enrollment (Screening) 1. Signed informed consent prior to initiation of any study procedures 2. Presence of an underlying medical condition(s) that might increase risk of complications from influenza 3. History of an influenza-like illness defined as: * One or more respiratory symptom (cough, sore throat, or nasal symptoms) AND * Either * Fever (subjective or documented \>38 degrees C) OR * 1 or more constitutional symptom (headache, malaise, myalgia, sweats/chills or fatigue) 4. Onset of illness no more than 96 hours before screening defined as when the subject experienced at least one respiratory symptom, constitutional symptom, or fever 5. Willingness to have samples stored Randomization 1. Signed informed consent 2. Presence of a medical condition(s) that had been associated with increased risk of complications from influenza * Age 65 years of age or older * Asthma * 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) \[though still able to provide informed consent per inclusion criteria #1\] * Chronic lung disease (such as COPD and cystic fibrosis) * Heart disease (such as congenital heart disease, congestive heart failure, and coronary artery disease) * Blood disorders (excluding genetic causes of anemia, as noted in the
Exclusion criteria
) * Endocrine disorders (such as diabetes mellitus) * Kidney disorders * Liver disorders * Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders) * Weakened immune system due to disease or medication (such as people with HIV/AIDS, or cancer, chronic steroids or other medications causing immune suppression) * BMI ≥ 40(kg/m²) 3. Onset of illness no more than 96 hours before screening defined as when the subject experienced at least one respiratory symptom, constitutional symptom, or fever 4. Positive test for influenza (either rapid antigen or PCR) \- Results from influenza testing obtained for clinical indications within 12 hours before screening/enrollment may be used if available. Randomization may proceed in cases of discrepant results (one positive and one negative) 5. One of the following to avoid pregnancy: * Females who were able to become pregnant (i.e., are not postmenopausal, have not undergone surgical sterilization, and are sexually active with men) must agree to use at least 2 effective forms of contraception from the date of informed consent through 6 months after the last dose of study drug. At least one of the methods of contraception should be a barrier method * Males who had not undergone surgical sterilization and are sexually active with women must agree to use condoms plus have a partner use at least one additional effective form of contraception from the date of informed consent through 6 months after the last dose of study drug 6. Willingness to have samples stored
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs | At Day 3 | The central laboratory performed a qualitative PCR test on the NP sample from Day 0 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
| Measure | Time frame | Description |
|---|---|---|
| qPCR Viral Shedding | 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.) |
| Number of Participants Shedding Virus | 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). |
| 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 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). A measurement is considered to be the 8AM or 8PM assessment during Days 0 to 7 (so two measurements are obtained per day) and then the daily assessment thereafter. Time will then be calculated in half-days through to Day 7. If a subject's first two assessments on (baseline assessment and first subsequent diary card assessment) satisfy this criterion, then the duration will be 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 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. |
| 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. |
| 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. |
| Number of Participants by Virus Detection Status | 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 |
| Time to Return of Physical Function to Pre-illness Leve | 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. |
| Percentage of Participants With Clinical Failure at Day 5 | From treatment initiation to Day 28 | Clinical failure at Day 5 is defined as the need for continued (non-study) antiviral use after Day 5. |
| Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza 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. |
| Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen | From treatment initiation to Day 28 | Percentage of participants who required new or increased use of supplemental oxygen |
| Percentage of Participants Who Required Hospitalization. | From treatment initiation to Day 28 | The percentage of participants hospitalized by 28 days was estimated from the Kaplan-Meier curves. |
| 28-day Mortality | From treatment initiation to Day 28 | Number of deaths |
| 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. |
Countries
Argentina, Australia, Mexico, Thailand, United States
Participant flow
Recruitment details
Outpatient or hospitalized participants at high risk for complications and morbidity, diagnosed with influenza by rapid antigen or PCR were recruited at 65 sites from 5 countries: 52 from the U.S., 2 from Australia, 3 from Mexico, and 4 each in Thailand and Argentina, between March 2011 to April 2016.
Pre-assignment details
Eight hundred eighty-one subjects were enrolled per protocol (signed consent). Two hundred fifty-one subjects were excluded during screening and did not participate in any other aspect of the trial. Three subjects were randomized improperly because they were given study drug kit prior to the randomization.
Participants by arm
| Arm | Count |
|---|---|
| Combination Therapy Drug: Amantadine, Ribavirin, Oseltamivir
Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg. | 314 |
| Oseltamivir Monotherapy Drug: Oseltamivir
Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg. | 312 |
| Total | 626 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 8 | 3 |
| Overall Study | Never Started Treatment | 0 | 4 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 3 | 1 |
| Overall Study | Taking Additional Antiviral Drug | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | Total | Combination Therapy | Oseltamivir Monotherapy |
|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 1 Participants | 4 Participants |
| Age, Categorical >=65 years | 128 Participants | 61 Participants | 67 Participants |
| Age, Categorical Between 18 and 65 years | 493 Participants | 252 Participants | 241 Participants |
| Age, Continuous | 49.5 years | 49.5 years | 49.5 years |
| Average Functional Status | 35 units on a scale | 35 units on a scale | 35 units on a scale |
| Complications of Influenza Bronchitis/Bronchiolitis Missing | 3 Participants | 3 Participants | 0 Participants |
| Complications of Influenza Bronchitis/Bronchiolitis No | 599 Participants | 301 Participants | 298 Participants |
| Complications of Influenza Bronchitis/Bronchiolitis Unable to assess | 2 Participants | 2 Participants | 0 Participants |
| Complications of Influenza Bronchitis/Bronchiolitis Yes | 22 Participants | 8 Participants | 14 Participants |
| Complications of Influenza Otitis Media Missing | 3 Participants | 3 Participants | 0 Participants |
| Complications of Influenza Otitis Media No | 615 Participants | 307 Participants | 308 Participants |
| Complications of Influenza Otitis Media Unable to assess | 2 Participants | 2 Participants | 0 Participants |
| Complications of Influenza Otitis Media Yes | 6 Participants | 2 Participants | 4 Participants |
| Complications of Influenza Pneumonia Missing | 3 Participants | 3 Participants | 0 Participants |
| Complications of Influenza Pneumonia No | 607 Participants | 304 Participants | 303 Participants |
| Complications of Influenza Pneumonia Unable to assess | 2 Participants | 2 Participants | 0 Participants |
| Complications of Influenza Pneumonia Yes | 14 Participants | 5 Participants | 9 Participants |
| Complications of Influenza Sinusitis Missing | 3 Participants | 3 Participants | 0 Participants |
| Complications of Influenza Sinusitis No | 596 Participants | 298 Participants | 298 Participants |
| Complications of Influenza Sinusitis Unable to assess | 2 Participants | 2 Participants | 0 Participants |
| Complications of Influenza Sinusitis Yes | 25 Participants | 11 Participants | 14 Participants |
| Complications of Influenza Using antibiotic for other reasons Missing | 3 Participants | 3 Participants | 0 Participants |
| Complications of Influenza Using antibiotic for other reasons No | 582 Participants | 291 Participants | 291 Participants |
| Complications of Influenza Using antibiotic for other reasons Unable to assess | 0 Participants | 0 Participants | 0 Participants |
| Complications of Influenza Using antibiotic for other reasons Yes | 41 Participants | 20 Participants | 21 Participants |
| Confirmed Influenza Infection Status By Central Testing No | 172 Participants | 84 Participants | 88 Participants |
| Confirmed Influenza Infection Status By Central Testing Yes | 454 Participants | 230 Participants | 224 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 113 Participants | 55 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 512 Participants | 258 Participants | 254 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Functional status Bathing/dressing self Limited a little = 50 | 155 Participants | 72 Participants | 83 Participants |
| Functional status Bathing/dressing self Limited a lot = 0 | 102 Participants | 48 Participants | 54 Participants |
| Functional status Bathing/dressing self Missing | 7 Participants | 4 Participants | 3 Participants |
| Functional status Bathing/dressing self Not limited at all = 100 | 362 Participants | 190 Participants | 172 Participants |
| Functional status Bending or kneeling Limited a little = 50 | 251 Participants | 118 Participants | 133 Participants |
| Functional status Bending or kneeling Limited a lot = 0 | 171 Participants | 89 Participants | 82 Participants |
| Functional status Bending or kneeling Missing | 7 Participants | 4 Participants | 3 Participants |
| Functional status Bending or kneeling Not limited at all = 100 | 197 Participants | 103 Participants | 94 Participants |
| Functional status Climbing 1 flight Limited a little = 50 | 275 Participants | 146 Participants | 129 Participants |
| Functional status Climbing 1 flight Limited a lot = 0 | 200 Participants | 97 Participants | 103 Participants |
| Functional status Climbing 1 flight Missing | 7 Participants | 4 Participants | 3 Participants |
| Functional status Climbing 1 flight Not limited at all = 100 | 144 Participants | 67 Participants | 77 Participants |
| Functional status Climbing stairs Limited a little = 50 | 202 Participants | 97 Participants | 105 Participants |
| Functional status Climbing stairs Limited a lot = 0 | 354 Participants | 182 Participants | 172 Participants |
| Functional status Climbing stairs Missing | 7 Participants | 4 Participants | 3 Participants |
| Functional status Climbing stairs Not limited at all = 100 | 63 Participants | 31 Participants | 32 Participants |
| Functional status Lifting groceries Limited a little = 50 | 243 Participants | 129 Participants | 114 Participants |
| Functional status Lifting groceries Limited a lot = 0 | 215 Participants | 99 Participants | 116 Participants |
| Functional status Lifting groceries Missing | 7 Participants | 4 Participants | 3 Participants |
| Functional status Lifting groceries Not limited at all = 100 | 161 Participants | 82 Participants | 79 Participants |
| Functional status Moderate activities Limited a little = 50 | 221 Participants | 114 Participants | 107 Participants |
| Functional status Moderate activities Limited a lot = 0 | 338 Participants | 167 Participants | 171 Participants |
| Functional status Moderate activities Missing | 7 Participants | 4 Participants | 3 Participants |
| Functional status Moderate activities Not limited at all = 100 | 60 Participants | 29 Participants | 31 Participants |
| Functional status Vigorous activities Limited a little = 50 | 117 Participants | 58 Participants | 59 Participants |
| Functional status Vigorous activities Limited a lot = 0 | 476 Participants | 238 Participants | 238 Participants |
| Functional status Vigorous activities Missing | 7 Participants | 4 Participants | 3 Participants |
| Functional status Vigorous activities Not limited at all = 100 | 26 Participants | 14 Participants | 12 Participants |
| Functional status Walking > 1 mile Limited a little = 50 | 159 Participants | 81 Participants | 78 Participants |
| Functional status Walking > 1 mile Limited a lot = 0 | 401 Participants | 199 Participants | 202 Participants |
| Functional status Walking > 1 mile Missing | 7 Participants | 4 Participants | 3 Participants |
| Functional status Walking > 1 mile Not limited at all = 100 | 59 Participants | 30 Participants | 29 Participants |
| Functional status Walking a block Limited a little = 50 | 234 Participants | 123 Participants | 111 Participants |
| Functional status Walking a block Limited a lot = 0 | 209 Participants | 101 Participants | 108 Participants |
| Functional status Walking a block Missing | 7 Participants | 4 Participants | 3 Participants |
| Functional status Walking a block Not limited at all = 100 | 176 Participants | 86 Participants | 90 Participants |
| Functional status Walking blocks Limited a little = 50 | 191 Participants | 100 Participants | 91 Participants |
| Functional status Walking blocks Limited a lot = 0 | 346 Participants | 169 Participants | 177 Participants |
| Functional status Walking blocks Missing | 7 Participants | 4 Participants | 3 Participants |
| Functional status Walking blocks Not limited at all = 100 | 82 Participants | 41 Participants | 41 Participants |
| Global assessment Subject feels as good today as before flu Missing | 7 Participants | 4 Participants | 3 Participants |
| Global assessment Subject feels as good today as before flu No | 603 Participants | 301 Participants | 302 Participants |
| Global assessment Subject feels as good today as before flu Yes | 16 Participants | 9 Participants | 7 Participants |
| Global assessment Subject functions as well today as before flu Missing | 7 Participants | 4 Participants | 3 Participants |
| Global assessment Subject functions as well today as before flu No | 576 Participants | 287 Participants | 289 Participants |
| Global assessment Subject functions as well today as before flu Yes | 43 Participants | 23 Participants | 20 Participants |
| Influenza Diagnostic Test by Local Testing Isothermal nucleic acid amplification technology | 1 Participants | 0 Participants | 1 Participants |
| Influenza Diagnostic Test by Local Testing Rapid antigen test | 562 Participants | 281 Participants | 281 Participants |
| Influenza Diagnostic Test by Local Testing RT-PCR/PCR | 63 Participants | 33 Participants | 30 Participants |
| Influenza Type/Subtype By Central Testing Influenza A/H1N1 | 104 Participants | 55 Participants | 49 Participants |
| Influenza Type/Subtype By Central Testing Influenza A/H3N2 | 244 Participants | 126 Participants | 118 Participants |
| Influenza Type/Subtype By Central Testing Influenza B | 106 Participants | 49 Participants | 57 Participants |
| Influenza Type/Subtype By Central Testing Missing | 3 Participants | 1 Participants | 2 Participants |
| Influenza Type/Subtype By Central Testing Negative | 169 Participants | 83 Participants | 86 Participants |
| Medical Conditions >= 65 years No | 128 Participants | 63 Participants | 65 Participants |
| Medical Conditions >= 65 years Yes | 498 Participants | 251 Participants | 247 Participants |
| Medical Conditions Asthma No | 199 Participants | 100 Participants | 99 Participants |
| Medical Conditions Asthma Yes | 427 Participants | 214 Participants | 213 Participants |
| Medical Conditions Blood disorder No | 13 Participants | 8 Participants | 5 Participants |
| Medical Conditions Blood disorder Yes | 613 Participants | 306 Participants | 307 Participants |
| Medical Conditions BMI >= 40 No | 125 Participants | 74 Participants | 51 Participants |
| Medical Conditions BMI >= 40 Yes | 501 Participants | 240 Participants | 261 Participants |
| Medical Conditions Chronic Lung disease No | 38 Participants | 17 Participants | 21 Participants |
| Medical Conditions Chronic Lung disease Yes | 588 Participants | 297 Participants | 291 Participants |
| Medical Conditions Endocrine No | 175 Participants | 87 Participants | 88 Participants |
| Medical Conditions Endocrine Yes | 451 Participants | 227 Participants | 224 Participants |
| Medical Conditions Heart disease No | 69 Participants | 30 Participants | 39 Participants |
| Medical Conditions Heart disease Yes | 557 Participants | 284 Participants | 273 Participants |
| Medical Conditions Kidney No | 14 Participants | 8 Participants | 6 Participants |
| Medical Conditions Kidney Yes | 612 Participants | 306 Participants | 306 Participants |
| Medical Conditions Liver disorder No | 10 Participants | 3 Participants | 7 Participants |
| Medical Conditions Liver disorder Yes | 616 Participants | 311 Participants | 305 Participants |
| Medical Conditions Metabolic No | 20 Participants | 12 Participants | 8 Participants |
| Medical Conditions Metabolic Yes | 606 Participants | 302 Participants | 304 Participants |
| Medical Conditions Neurological condition No | 36 Participants | 17 Participants | 19 Participants |
| Medical Conditions Neurological condition Yes | 590 Participants | 297 Participants | 293 Participants |
| Medical Conditions Weakened immune system No | 90 Participants | 44 Participants | 46 Participants |
| Medical Conditions Weakened immune system Yes | 536 Participants | 270 Participants | 266 Participants |
| Overall Symptom Score | 15 units on a scale | 15 units on a scale | 15 units on a scale |
| Positive Influenza Test by Local Testing | 626 Participants | 314 Participants | 312 Participants |
| Presence of fever Missing | 7 Participants | 4 Participants | 3 Participants |
| Presence of fever No | 432 Participants | 216 Participants | 216 Participants |
| Presence of fever Yes | 187 Participants | 94 Participants | 93 Participants |
| Quantitative PCR Viral Shedding | 6.5 log10 copies/mL | 6.4 log10 copies/mL | 6.7 log10 copies/mL |
| Race/Ethnicity, Customized American Indian | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 143 Participants | 70 Participants | 73 Participants |
| Race/Ethnicity, Customized Black or African American | 43 Participants | 18 Participants | 25 Participants |
| Race/Ethnicity, Customized Race not available to clinic | 42 Participants | 21 Participants | 21 Participants |
| Race/Ethnicity, Customized Subject does not know | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Subject does not want to report | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 392 Participants | 203 Participants | 189 Participants |
| Region of Enrollment Argentina | 22 participants | 12 participants | 10 participants |
| Region of Enrollment Australia | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Mexico | 35 participants | 17 participants | 18 participants |
| Region of Enrollment Thailand | 131 participants | 65 participants | 66 participants |
| Region of Enrollment United States | 436 participants | 220 participants | 216 participants |
| Result of Influenza Test By Local Testing Influenza A/H1N1 | 27 Participants | 13 Participants | 14 Participants |
| Result of Influenza Test By Local Testing Influenza A/H3N2 | 2 Participants | 1 Participants | 1 Participants |
| Result of Influenza Test By Local Testing Influenza A not typed | 360 Participants | 180 Participants | 180 Participants |
| Result of Influenza Test By Local Testing Influenza A unsubtypable | 51 Participants | 29 Participants | 22 Participants |
| Result of Influenza Test By Local Testing Influenza B | 155 Participants | 75 Participants | 80 Participants |
| Result of Influenza Test By Local Testing Influenza positive (unknown A or B) | 15 Participants | 10 Participants | 5 Participants |
| Result of Influenza Test By Local Testing Multiple types/subtypes | 16 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Female | 385 Participants | 187 Participants | 198 Participants |
| Sex: Female, Male Male | 241 Participants | 127 Participants | 114 Participants |
| Symptom Score Cough Absent | 32 Participants | 18 Participants | 14 Participants |
| Symptom Score Cough Mild | 154 Participants | 68 Participants | 86 Participants |
| Symptom Score Cough Missing | 8 Participants | 4 Participants | 4 Participants |
| Symptom Score Cough Moderate | 269 Participants | 139 Participants | 130 Participants |
| Symptom Score Cough Severe | 163 Participants | 85 Participants | 78 Participants |
| Symptom Score Diarrhea Absent | 484 Participants | 231 Participants | 253 Participants |
| Symptom Score Diarrhea Mild | 62 Participants | 36 Participants | 26 Participants |
| Symptom Score Diarrhea Missing | 9 Participants | 6 Participants | 3 Participants |
| Symptom Score Diarrhea Moderate | 46 Participants | 26 Participants | 20 Participants |
| Symptom Score Diarrhea Severe | 25 Participants | 15 Participants | 10 Participants |
| Symptom Score Fatigue Absent | 43 Participants | 28 Participants | 15 Participants |
| Symptom Score Fatigue Mild | 76 Participants | 33 Participants | 43 Participants |
| Symptom Score Fatigue Missing | 8 Participants | 4 Participants | 4 Participants |
| Symptom Score Fatigue Moderate | 222 Participants | 117 Participants | 105 Participants |
| Symptom Score Fatigue Severe | 277 Participants | 132 Participants | 145 Participants |
| Symptom Score Feverishness Absent | 132 Participants | 70 Participants | 62 Participants |
| Symptom Score Feverishness Mild | 129 Participants | 61 Participants | 68 Participants |
| Symptom Score Feverishness Missing | 8 Participants | 4 Participants | 4 Participants |
| Symptom Score Feverishness Moderate | 209 Participants | 111 Participants | 98 Participants |
| Symptom Score Feverishness Severe | 148 Participants | 68 Participants | 80 Participants |
| Symptom Score Headache Absent | 115 Participants | 60 Participants | 55 Participants |
| Symptom Score Headache Mild | 157 Participants | 76 Participants | 81 Participants |
| Symptom Score Headache Missing | 7 Participants | 4 Participants | 3 Participants |
| Symptom Score Headache Moderate | 198 Participants | 99 Participants | 99 Participants |
| Symptom Score Headache Severe | 149 Participants | 75 Participants | 74 Participants |
| Symptom Score Muscle aches Absent | 74 Participants | 44 Participants | 30 Participants |
| Symptom Score Muscle aches Mild | 107 Participants | 51 Participants | 56 Participants |
| Symptom Score Muscle aches Missing | 7 Participants | 4 Participants | 3 Participants |
| Symptom Score Muscle aches Moderate | 199 Participants | 100 Participants | 99 Participants |
| Symptom Score Muscle aches Severe | 239 Participants | 115 Participants | 124 Participants |
| Symptom Score Nausea Absent | 395 Participants | 197 Participants | 198 Participants |
| Symptom Score Nausea Mild | 105 Participants | 54 Participants | 51 Participants |
| Symptom Score Nausea Missing | 10 Participants | 6 Participants | 4 Participants |
| Symptom Score Nausea Moderate | 73 Participants | 38 Participants | 35 Participants |
| Symptom Score Nausea Severe | 43 Participants | 19 Participants | 24 Participants |
| Symptom Score Rhinorrhea Absent | 131 Participants | 77 Participants | 54 Participants |
| Symptom Score Rhinorrhea Mild | 175 Participants | 79 Participants | 96 Participants |
| Symptom Score Rhinorrhea Missing | 10 Participants | 6 Participants | 4 Participants |
| Symptom Score Rhinorrhea Moderate | 180 Participants | 96 Participants | 84 Participants |
| Symptom Score Rhinorrhea Severe | 130 Participants | 56 Participants | 74 Participants |
| Symptom Score Sore throat Absent | 160 Participants | 80 Participants | 80 Participants |
| Symptom Score Sore throat Mild | 185 Participants | 94 Participants | 91 Participants |
| Symptom Score Sore throat Missing | 7 Participants | 4 Participants | 3 Participants |
| Symptom Score Sore throat Moderate | 193 Participants | 102 Participants | 91 Participants |
| Symptom Score Sore throat Severe | 81 Participants | 34 Participants | 47 Participants |
| Symptom Score Stuffy nose Absent | 148 Participants | 82 Participants | 66 Participants |
| Symptom Score Stuffy nose Mild | 130 Participants | 62 Participants | 68 Participants |
| Symptom Score Stuffy nose Missing | 8 Participants | 4 Participants | 4 Participants |
| Symptom Score Stuffy nose Moderate | 203 Participants | 107 Participants | 96 Participants |
| Symptom Score Stuffy nose Severe | 137 Participants | 59 Participants | 78 Participants |
| Symptom Score Vomiting Absent | 537 Participants | 268 Participants | 269 Participants |
| Symptom Score Vomiting Mild | 36 Participants | 18 Participants | 18 Participants |
| Symptom Score Vomiting Missing | 10 Participants | 6 Participants | 4 Participants |
| Symptom Score Vomiting Moderate | 28 Participants | 16 Participants | 12 Participants |
| Symptom Score Vomiting Severe | 15 Participants | 6 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 314 | 1 / 312 |
| other Total, other adverse events | 148 / 314 | 163 / 312 |
| serious Total, serious adverse events | 14 / 314 | 6 / 312 |
Outcome results
Primary
Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs
The central laboratory performed a qualitative PCR test on the NP sample from Day 0 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
Population: The population analyzed was restricted to the 407 participants who had a confirmed positive test for influenza by qPCR in the central laboratory testing and were not in the pilot study for IRC003. 13 participants (5 in the Combination Therapy and 8 in the Oseltamivir Monotherapy) had missing endpoint samples so were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs | 40 percentage of participants analyzed |
| Oseltamivir Monotherapy | Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs | 50 percentage of participants analyzed |
Comparison: Assuming that pooled percentage of participants with virus detectable by PCR at Day 3 is 50%, assuming that the Combination Therapy was better than the Oseltamivir Monotherapy and that the detectable rate in the Combination Therapy was 42.5% compared to 57.5% in the Oseltamivir Monotherapy (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.p-value: 0.04695% CI: [-19.8, -0.2]Z-test, 2-sided
Secondary
28-day Mortality
Number of deaths
Time frame: From treatment initiation to Day 28
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | 28-day Mortality | 0 participants |
| Oseltamivir Monotherapy | 28-day Mortality | 1 participants |
Secondary
Number of Participants by Virus Detection Status
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.
Population: 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 in the qualitative PCR evaluation at Day 0 from central laboratory testing.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Combination Therapy | Number of Participants by Virus Detection Status | Day 0 | >=LOD, <LLOQ | 4 Participants |
| Combination Therapy | Number of Participants by Virus Detection Status | Day 3 | <LOD | 134 Participants |
| Combination Therapy | Number of Participants by Virus Detection Status | Day 0 | Missing | 0 Participants |
| Combination Therapy | Number of Participants by Virus Detection Status | Day 3 | Missing | 9 Participants |
| Combination Therapy | Number of Participants by Virus Detection Status | Day 0 | >=LLOQ | 221 Participants |
| Combination Therapy | Number of Participants by Virus Detection Status | Day 7 | >=LLOQ | 19 Participants |
| Combination Therapy | Number of Participants by Virus Detection Status | Day 3 | >=LLOQ | 65 Participants |
| Combination Therapy | Number of Participants by Virus Detection Status | Day 7 | >=LOD, <LLOQ | 4 Participants |
| Combination Therapy | Number of Participants by Virus Detection Status | Day 0 | <LOD | 5 Participants |
| Combination Therapy | Number of Participants by Virus Detection Status | Day 3 | >=LOD, <LLOQ | 22 Participants |
| Combination Therapy | Number of Participants by Virus Detection Status | Day 7 | Missing | 14 Participants |
| Combination Therapy | Number of Participants by Virus Detection Status | Day 7 | <LOD | 193 Participants |
| Oseltamivir Monotherapy | Number of Participants by Virus Detection Status | Day 7 | Missing | 9 Participants |
| Oseltamivir Monotherapy | Number of Participants by Virus Detection Status | Day 0 | >=LLOQ | 200 Participants |
| Oseltamivir Monotherapy | Number of Participants by Virus Detection Status | Day 0 | >=LOD, <LLOQ | 9 Participants |
| Oseltamivir Monotherapy | Number of Participants by Virus Detection Status | Day 0 | <LOD | 15 Participants |
| Oseltamivir Monotherapy | Number of Participants by Virus Detection Status | Day 0 | Missing | 0 Participants |
| Oseltamivir Monotherapy | Number of Participants by Virus Detection Status | Day 3 | >=LLOQ | 87 Participants |
| Oseltamivir Monotherapy | Number of Participants by Virus Detection Status | Day 3 | >=LOD, <LLOQ | 25 Participants |
| Oseltamivir Monotherapy | Number of Participants by Virus Detection Status | Day 3 | <LOD | 104 Participants |
| Oseltamivir Monotherapy | Number of Participants by Virus Detection Status | Day 3 | Missing | 8 Participants |
| Oseltamivir Monotherapy | Number of Participants by Virus Detection Status | Day 7 | >=LLOQ | 24 Participants |
| Oseltamivir Monotherapy | Number of Participants by Virus Detection Status | Day 7 | >=LOD, <LLOQ | 7 Participants |
| Oseltamivir Monotherapy | Number of Participants by Virus Detection Status | Day 7 | <LOD | 184 Participants |
Secondary
Number of Participants Shedding Virus
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.
Population: 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 in the qualitative PCR evaluation at Day 0 from central laboratory testing.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Number of Participants Shedding Virus | Undetectable at both Day 3 and 7 | 126 Participants |
| Combination Therapy | Number of Participants Shedding Virus | Detectable at Day 3 and undetectable at Day 7 | 67 Participants |
| Combination Therapy | Number of Participants Shedding Virus | Detectable at Day 7 | 23 Participants |
| Combination Therapy | Number of Participants Shedding Virus | Missing result at Day 3 and/or Day 7 | 14 Participants |
| Oseltamivir Monotherapy | Number of Participants Shedding Virus | Missing result at Day 3 and/or Day 7 | 11 Participants |
| Oseltamivir Monotherapy | Number of Participants Shedding Virus | Undetectable at both Day 3 and 7 | 95 Participants |
| Oseltamivir Monotherapy | Number of Participants Shedding Virus | Detectable at Day 7 | 30 Participants |
| Oseltamivir Monotherapy | Number of Participants Shedding Virus | Detectable at Day 3 and undetectable at Day 7 | 88 Participants |
Secondary
Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza 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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Combination Therapy | Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | Otitis Media | 0.3 percentage of participants analyzed |
| Combination Therapy | Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | Pneumonia | 2.2 percentage of participants analyzed |
| Combination Therapy | Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | Sinustis | 4.5 percentage of participants analyzed |
| Combination Therapy | Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | Antibiotic use for other reasons | 8.6 percentage of participants analyzed |
| Combination Therapy | Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | Bronchitis Bronchiolitis | 5.7 percentage of participants analyzed |
| Combination Therapy | Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | At least one complication and/or use of antibiotic | 16.6 percentage of participants analyzed |
| Oseltamivir Monotherapy | Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | Bronchitis Bronchiolitis | 3.5 percentage of participants analyzed |
| Oseltamivir Monotherapy | Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | Sinustis | 4.5 percentage of participants analyzed |
| Oseltamivir Monotherapy | Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | Otitis Media | 1.0 percentage of participants analyzed |
| Oseltamivir Monotherapy | Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | At least one complication and/or use of antibiotic | 15.4 percentage of participants analyzed |
| Oseltamivir Monotherapy | Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | Pneumonia | 1.9 percentage of participants analyzed |
| Oseltamivir Monotherapy | Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | Antibiotic use for other reasons | 9.3 percentage of participants analyzed |
Secondary
Percentage of Participants Who Required Hospitalization.
The percentage of participants hospitalized by 28 days was estimated from the Kaplan-Meier curves.
Time frame: From treatment initiation to Day 28
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Percentage of Participants Who Required Hospitalization. | 4.28 percentage of participants analyzed |
| Oseltamivir Monotherapy | Percentage of Participants Who Required Hospitalization. | 0.98 percentage of participants analyzed |
Secondary
Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen
Percentage of participants who required new or increased use of supplemental oxygen
Time frame: From treatment initiation to Day 28
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen | 1.91 percentage of participants analyzed |
| Oseltamivir Monotherapy | Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen | 1.6 percentage of participants analyzed |
Secondary
Percentage of Participants With Clinical Failure at Day 5
Clinical failure at Day 5 is defined as the need for continued (non-study) antiviral use after Day 5.
Time frame: From treatment initiation to Day 28
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Percentage of Participants With Clinical Failure at Day 5 | 7.0 percentage of participants analyzed |
| Oseltamivir Monotherapy | Percentage of Participants With Clinical Failure at Day 5 | 7.7 percentage of participants analyzed |
Secondary
qPCR Viral Shedding
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
Population: 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 in the qualitative PCR evaluation at Day 0 from central laboratory testing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Combination Therapy | qPCR Viral Shedding | Day 0 | 6.4 Log10 copies/mL |
| Combination Therapy | qPCR Viral Shedding | Day 3 | 3.4 Log10 copies/mL |
| Combination Therapy | qPCR Viral Shedding | Day 7 | 3.2 Log10 copies/mL |
| Oseltamivir Monotherapy | qPCR Viral Shedding | Day 0 | 6.7 Log10 copies/mL |
| Oseltamivir Monotherapy | qPCR Viral Shedding | Day 3 | 3.9 Log10 copies/mL |
| Oseltamivir Monotherapy | qPCR Viral Shedding | Day 7 | 3.2 Log10 copies/mL |
Secondary
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Time to Absence of Fever | 0.5 Days |
| Oseltamivir Monotherapy | Time to Absence of Fever | 0.5 Days |
Secondary
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 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). A measurement is considered to be the 8AM or 8PM assessment during Days 0 to 7 (so two measurements are obtained per day) and then the daily assessment thereafter. Time will then be calculated in half-days through to Day 7. If a subject's first two assessments on (baseline assessment and first subsequent diary card assessment) satisfy this criterion, then the duration will be 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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Time to Alleviation of Influenza Clinical Symptoms. | 4.5 Days |
| Oseltamivir Monotherapy | Time to Alleviation of Influenza Clinical Symptoms. | 4.0 Days |
Secondary
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Time to Feeling as Good as Before the Onset of the Influenza Illness | 7.5 Days |
| Oseltamivir Monotherapy | Time to Feeling as Good as Before the Onset of the Influenza Illness | 6.5 Days |
Secondary
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Time to Resolution of All Symptoms AND Fever | 4.5 Days |
| Oseltamivir Monotherapy | Time to Resolution of All Symptoms AND Fever | 4.5 Days |
Secondary
Time to Return of Physical Function to Pre-illness Leve
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Time to Return of Physical Function to Pre-illness Leve | 7.0 Days |
| Oseltamivir Monotherapy | Time to Return of Physical Function to Pre-illness Leve | 6.0 Days |
Secondary
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Time to Return to Pre-influenza Function | 7.0 Days |
| Oseltamivir Monotherapy | Time to Return to Pre-influenza Function | 6.0 Days |