Influenza
Conditions
Brief summary
This is a randomized, double-blind, placebo-controlled study that will investigate the safety and clinical activity of a single intravenous (IV) dose of MHAA4549A in adult participants hospitalized with severe influenza A in combination with oseltamivir versus a comparator arm of placebo with oseltamivir.
Interventions
DRUGMHAA4549A
Participants will receive a single dose of MHAA4549A by IV infusion on Day 1
DRUGOseltamivir
Participants will receive oseltamivir capsule either 75 mg or 150 mg BID orally for minimum of 5 days. Dosage and administration should follow local prescribing information for oseltamivir.
DRUGPlacebo
Participants will receive a single IV dose of placebo matched to MHAA4549A on Day 1
Sponsors
Genentech, Inc.
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
* Diagnosis of influenza A where a Sponsor-approved influenza test is used as an aid in diagnosis. A Sponsor-approved influenza test includes: Influenza antigen test or Influenza polymerase chain reaction (PCR) test * One of the following markers of severity within 24 hours of admission: requirement for O2 supplementation to maintain SpO2 greater than (\>) 92 %; or requirement for Positive Pressure Ventilation (PPV) * A negative urine or serum pregnancy test for women of childbearing potential within 2 days prior to study treatment * Participants of reproductive potential must agree to use acceptable contraceptive measures as per the protocol as a minimum, and local guidelines, if more stringent
Exclusion criteria
* Pregnant or lactating women, or women who intend to become pregnant during the study * Hypersensitivity to monoclonal antibodies or any constituents (sodium succinate, sucrose, polysorbate 20) of study drug * Hypersensitivity to the active substance or to any excipients of oseltamivir * Investigational therapy within the 30 days prior to study treatment * Received prior therapy with any anti-influenza monoclonal antibody therapy (including MHAA4549A) within 8 months prior to study treatment * Current treatment (within 7 days of dosing) with probenecid, amantadine or rimantidine * Participants who have taken more than a total of 6 doses (3 doses for peramivir) of anti-influenza therapy (e.g., oseltamivir, zanamivir, laninamivir, peramivir) in the period from onset of symptoms and prior to study treatment * Admission \>48 hours prior to study treatment * Onset of influenza symptoms (including fever, chills, malaise, dry cough, loss of appetite, myalgias, coryza, or nausea) \>5 days prior to study treatment * Positive influenza B or influenza A + B infection within 2 weeks prior to study treatment * High probability of mortality in the next 48 hours as determined by the investigator * Participants requiring home or baseline oxygenation therapy * Participants with history of chronic lung disease with a documented SpO2 less than (\<) 95% off oxygen * Participants on chronic dose of corticosteroids exceeding 10 milligrams per day (mg/day) of prednisone or equivalent steroid dose for duration of greater than 14 days within 30 days of entry into study * Participants with the following significant immune suppression: bone marrow or solid organ transplant in the previous 12 months; cancer chemotherapy in the previous 12 months, HIV infection with most recent Cluster of Differentiation 4 (CD4) \<200 cells per milliliter (cells/mL), or other significant immune suppression as determined by the investigator in discussion with the Sponsor Medical Monitor * Participants on extracorporeal membrane oxygenation (ECMO) at time of randomization * Any disease or condition that would, in the opinion of the site investigator or Sponsor, place the participant at an unacceptable risk of injury or render the participant unable to meet the requirements of the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events | From randomization up to 60 days | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. |
| Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A | From randomization up to 60 days | Reported are the number of participants positive for ATAs at baseline, the number of participants with treatment-induced ATAs and the number of participants with treatment-enhanced ATAs. |
| Time to Normalization of Respiratory Function | From randomization up to 60 days | The time to normalization of respiratory function was defined as the time to removal of the participant from oxygen (O2) supplementation in order to maintain a blood oxygen saturation level (SpO2) equal to or greater than 95% as measured by pulse oximetry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Died Due to Any Cause | Days 14, 30 and 60 | — |
| Area Under Viral Load-Time Curve (AUEC ) of Influenza A Virus | Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60) | Influenza A viral load was measured by quantitative polymerase chain reaction (qPCR) in nasopharyngeal samples at multiple time points during the study. AUEC is the area under the viral load-time curve expressed as log10 (viral particles/milliliter x hour) = log10 (vp/mL x hour). |
| Peak Influenza A Viral Load | Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60) | Influenza A viral load was measured by qPCR in nasopharyngeal samples at multiple time points during the study. Reported here is the peak Influenza A viral load expressed as log10 vp/mL. |
| Duration of Viral Shedding | Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60) | Influenza A viral load was measured by qPCR in nasopharyngeal samples at multiple time points during the study. Reported here is the duration of viral shedding. |
| Duration of Hospitalization | From randomization up to 60 days | — |
| Duration of Intensive Care Unit (ICU) Stay | From randomization up to 60 days | — |
| Percentage of Participants Using Antibiotics for Respiratory Infections | From randomization up to 60 days | — |
| Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Days 1-7, 14 and 30 | The clinical status of participants was defined by five mutually exclusive categories: 1. Death; 2. In the Intensive Care Unit (ICU); 3. Non-ICU hospitalization, requiring supplemental oxygen (O2); 4. Non-ICU hospitalization, not requiring supplemental oxygen (O2); 5. Not hospitalized. |
| Percentage of Participants Readmitted to Hospital Due to Any Cause | Days 30 and 60 | — |
| Duration of Ventilation | From randomization up to 60 days | — |
| Area Under Serum Concentration-Time Curve From Time 0 to Infinity (AUC ) of MHAA4549A | 30 minutes (min) before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60) | AUC0-inf is reported as day\*microgram/milliliter (day\*mcg/mL). |
| Maximum Serum Concentration (Cmax ) of MHAA4549A | 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60) | — |
| Elimination Half-Life (Terminal t1/2) of MHAA4549A | 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60) | — |
| Observed Clearance (CL-obs) of MHAA4549A | 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60) | — |
| Observed Steady State Volume of Distribution (Vss_obs) of MHAA4549A | 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60) | — |
| Percentage of Participants With Secondary Complications of Influenza | From randomization up to 60 days | The following were considered secondary complications of influenza: pneumonia, including hospital-acquired pneumonia (HAP) and ventilation-acquired pneumonia (VAP), exacerbations of chronic lung disease, myocarditis, acute respiratory distress syndrome (ARDS), otitis media, or other related complications. |
| Percentage of Participants With Clinical Failure | 24 hours after end of infusion (infusion duration = approximately 120 minutes) up to Day 60 | Clinical failure after 24 hours post-infusion of study drug was defined as progression to increased O2 requirement defined by an increase in oxygen supplementation from low flow oxygen (i.e., 2-6 liters per minute \[L/min\]) to high flow oxygen (i.e., \> 6 L/min) or from oxygen supplementation alone to any positive pressure ventilation (PPV) or extracorporeal membrane oxygenation (ECMO), progression to ICU, prolonged ventilation or O2 support defined by \> 2 weeks, or death. |
| Percentage of Participants With Clinical Resolution of Abnormal Vital Signs | From randomization up to 60 days | Description: Clinical resolution of abnormal vital signs was defined as meeting three out of five of the following criteria: 1. SpO2 ≥ 95% without supplemental O2; 2. Respiratory rate \< 24 breaths per minute without supplemental O2; 3. Core temperature \< 37.2 Celsius (C) immediately prior to receipt of any antipyretic drug, and at least 6-8 hours from the last dose of antipyretic or core temperature \> 36 C in participants who are initially hypothermic; 4. Heart rate (HR) \< 100 beats/minute; 5. Systolic blood pressure (SBP) \>90 mmHg. Reported here is the percentage of participants who had clinical resolution of at least three out of five abnormal vital signs by the end of study. |
Countries
Belgium, Brazil, Bulgaria, Canada, Chile, Czechia, France, Germany, Hong Kong, Hungary, Israel, Italy, Mexico, Netherlands, New Zealand, Peru, Poland, Russia, South Africa, South Korea, Spain, Sweden, Taiwan, Ukraine, United Kingdom
Participant flow
Recruitment details
Enrolled in the study were 168 participants. The participant flow is reported for the safety population (158 participants), which included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Oseltamivir Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days. | 56 |
| MHAA4549A 3600 mg + Oseltamivir Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days. | 55 |
| MHAA4549A 8400 mg + Oseltamivir Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days. | 47 |
| Total | 158 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 4 | 6 | 4 |
| Overall Study | Lost to Follow-up | 2 | 2 | 2 |
| Overall Study | Reason Not Specified | 0 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 3 | 1 |
Baseline characteristics
| Characteristic | Total | MHAA4549A 8400 mg + Oseltamivir | MHAA4549A 3600 mg + Oseltamivir | Placebo + Oseltamivir |
|---|---|---|---|---|
| Age, Continuous | 60.7 years STANDARD_DEVIATION 18.2 | 59.8 years STANDARD_DEVIATION 17.9 | 56.5 years STANDARD_DEVIATION 18.2 | 65.7 years STANDARD_DEVIATION 17.5 |
| Race/Ethnicity, Customized American Indian or Alaska native | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 41 Participants | 8 Participants | 20 Participants | 13 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 99 Participants | 34 Participants | 28 Participants | 37 Participants |
| Race/Ethnicity, Customized Not Stated | 18 Participants | 5 Participants | 7 Participants | 6 Participants |
| Race/Ethnicity, Customized Unknown | 19 Participants | 5 Participants | 9 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 128 Participants | 39 Participants | 44 Participants | 45 Participants |
| Sex: Female, Male Female | 71 Participants | 22 Participants | 25 Participants | 24 Participants |
| Sex: Female, Male Male | 87 Participants | 25 Participants | 30 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 56 | 6 / 55 | 4 / 47 |
| other Total, other adverse events | 28 / 56 | 26 / 55 | 18 / 47 |
| serious Total, serious adverse events | 8 / 56 | 11 / 55 | 12 / 47 |
Outcome results
Primary
Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A
Reported are the number of participants positive for ATAs at baseline, the number of participants with treatment-induced ATAs and the number of participants with treatment-enhanced ATAs.
Time frame: From randomization up to 60 days
Population: Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received. Here, number analyzed are the participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Oseltamivir | Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A | Treatment-induced ATAs | 0 participants |
| Placebo + Oseltamivir | Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A | Positive for ATAs at baseline | 0 participants |
| Placebo + Oseltamivir | Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A | Treatment-enhanced ATAs | 0 participants |
| MHAA4549A 3600 mg + Oseltamivir | Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A | Treatment-induced ATAs | 0 participants |
| MHAA4549A 3600 mg + Oseltamivir | Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A | Positive for ATAs at baseline | 1 participants |
| MHAA4549A 3600 mg + Oseltamivir | Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A | Treatment-enhanced ATAs | 0 participants |
| MHAA4549A 8400 mg + Oseltamivir | Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A | Positive for ATAs at baseline | 1 participants |
| MHAA4549A 8400 mg + Oseltamivir | Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A | Treatment-enhanced ATAs | 0 participants |
| MHAA4549A 8400 mg + Oseltamivir | Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A | Treatment-induced ATAs | 0 participants |
Primary
Percentage of Participants With Adverse Events
An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: From randomization up to 60 days
Population: Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Oseltamivir | Percentage of Participants With Adverse Events | 80.4 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants With Adverse Events | 67.3 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants With Adverse Events | 74.5 percentage of participants |
Primary
Time to Normalization of Respiratory Function
The time to normalization of respiratory function was defined as the time to removal of the participant from oxygen (O2) supplementation in order to maintain a blood oxygen saturation level (SpO2) equal to or greater than 95% as measured by pulse oximetry.
Time frame: From randomization up to 60 days
Population: Intent-to-treat infected (ITTi) population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Oseltamivir | Time to Normalization of Respiratory Function | 4.28 days |
| MHAA4549A 3600 mg + Oseltamivir | Time to Normalization of Respiratory Function | 2.78 days |
| MHAA4549A 8400 mg + Oseltamivir | Time to Normalization of Respiratory Function | 2.65 days |
p-value: 0.60580% CI: [0.83, 1.4]Wilcoxon (Mann-Whitney)
p-value: 0.202880% CI: [0.85, 1.51]Wilcoxon (Mann-Whitney)
Secondary
Area Under Serum Concentration-Time Curve From Time 0 to Infinity (AUC ) of MHAA4549A
AUC0-inf is reported as day\*microgram/milliliter (day\*mcg/mL).
Time frame: 30 minutes (min) before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
Population: Pharmacokinetic (PK)-evaluable population included all participants, who received MHAA4549A and from whom evaluable PK samples were obtained.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Oseltamivir | Area Under Serum Concentration-Time Curve From Time 0 to Infinity (AUC ) of MHAA4549A | 11400 day*mcg/mL | Standard Deviation 4530 |
| MHAA4549A 3600 mg + Oseltamivir | Area Under Serum Concentration-Time Curve From Time 0 to Infinity (AUC ) of MHAA4549A | 26700 day*mcg/mL | Standard Deviation 9810 |
Secondary
Area Under Viral Load-Time Curve (AUEC ) of Influenza A Virus
Influenza A viral load was measured by quantitative polymerase chain reaction (qPCR) in nasopharyngeal samples at multiple time points during the study. AUEC is the area under the viral load-time curve expressed as log10 (viral particles/milliliter x hour) = log10 (vp/mL x hour).
Time frame: Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60)
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization. Here, number analyzed are the participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Oseltamivir | Area Under Viral Load-Time Curve (AUEC ) of Influenza A Virus | 25.72 log10 (vp/mL x hour). | Standard Deviation 15.92 |
| MHAA4549A 3600 mg + Oseltamivir | Area Under Viral Load-Time Curve (AUEC ) of Influenza A Virus | 21.99 log10 (vp/mL x hour). | Standard Deviation 16.57 |
| MHAA4549A 8400 mg + Oseltamivir | Area Under Viral Load-Time Curve (AUEC ) of Influenza A Virus | 25.03 log10 (vp/mL x hour). | Standard Deviation 13.48 |
p-value: 0.240780% CI: [-6.41, -1.06]ANOVA
p-value: 0.833980% CI: [-3.49, 2.1]ANOVA
Secondary
Duration of Hospitalization
Time frame: From randomization up to 60 days
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Oseltamivir | Duration of Hospitalization | 8.95 days |
| MHAA4549A 3600 mg + Oseltamivir | Duration of Hospitalization | 7.65 days |
| MHAA4549A 8400 mg + Oseltamivir | Duration of Hospitalization | 6.69 days |
p-value: 0.880680% CI: [0.78, 1.32]Wilcoxon (Mann-Whitney)
p-value: 0.544780% CI: [0.8, 1.38]Wilcoxon (Mann-Whitney)
Secondary
Duration of Intensive Care Unit (ICU) Stay
Time frame: From randomization up to 60 days
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization. Here, number analyzed are the participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Oseltamivir | Duration of Intensive Care Unit (ICU) Stay | 4.66 days |
| MHAA4549A 3600 mg + Oseltamivir | Duration of Intensive Care Unit (ICU) Stay | 6.60 days |
| MHAA4549A 8400 mg + Oseltamivir | Duration of Intensive Care Unit (ICU) Stay | 5.29 days |
p-value: 0.417180% CI: [0.47, 1.03]Wilcoxon (Mann-Whitney)
p-value: 0.832280% CI: [0.61, 1.34]Wilcoxon (Mann-Whitney)
Secondary
Duration of Ventilation
Time frame: From randomization up to 60 days
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization. Here, number analyzed are the participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Oseltamivir | Duration of Ventilation | 4.11 days |
| MHAA4549A 3600 mg + Oseltamivir | Duration of Ventilation | 7.05 days |
| MHAA4549A 8400 mg + Oseltamivir | Duration of Ventilation | 5.89 days |
p-value: 0.782780% CI: [0.41, 1.07]Wilcoxon (Mann-Whitney)
p-value: 0.252280% CI: [0.36, 0.96]Wilcoxon (Mann-Whitney)
Secondary
Duration of Viral Shedding
Influenza A viral load was measured by qPCR in nasopharyngeal samples at multiple time points during the study. Reported here is the duration of viral shedding.
Time frame: Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60)
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization. Here, number analyzed are the participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Oseltamivir | Duration of Viral Shedding | 4.00 days |
| MHAA4549A 3600 mg + Oseltamivir | Duration of Viral Shedding | 4.63 days |
| MHAA4549A 8400 mg + Oseltamivir | Duration of Viral Shedding | 4.60 days |
p-value: 0.741380% CI: [0.77, 1.32]Wilcoxon (Mann-Whitney)
p-value: 0.476380% CI: [0.99, 1.77]Wilcoxon (Mann-Whitney)
Secondary
Elimination Half-Life (Terminal t1/2) of MHAA4549A
Time frame: 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
Population: PK-evaluable population included all participants, who received MHAA4549A and from whom evaluable PK samples were obtained.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Oseltamivir | Elimination Half-Life (Terminal t1/2) of MHAA4549A | 19.0 day | Standard Deviation 4.91 |
| MHAA4549A 3600 mg + Oseltamivir | Elimination Half-Life (Terminal t1/2) of MHAA4549A | 17.8 day | Standard Deviation 3.88 |
Secondary
Maximum Serum Concentration (Cmax ) of MHAA4549A
Time frame: 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
Population: PK-evaluable population included all participants, who received MHAA4549A and from whom evaluable PK samples were obtained.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Oseltamivir | Maximum Serum Concentration (Cmax ) of MHAA4549A | 916 mcg/mL | Standard Deviation 294 |
| MHAA4549A 3600 mg + Oseltamivir | Maximum Serum Concentration (Cmax ) of MHAA4549A | 2220 mcg/mL | Standard Deviation 556 |
Secondary
Observed Clearance (CL-obs) of MHAA4549A
Time frame: 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
Population: PK-evaluable population included all participants, who received MHAA4549A and from whom evaluable PK samples were obtained.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Oseltamivir | Observed Clearance (CL-obs) of MHAA4549A | 288 mL/day | Standard Deviation 158 |
| MHAA4549A 3600 mg + Oseltamivir | Observed Clearance (CL-obs) of MHAA4549A | 350 mL/day | Standard Deviation 130 |
Secondary
Observed Steady State Volume of Distribution (Vss_obs) of MHAA4549A
Time frame: 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
Population: PK-evaluable population included all participants, who received MHAA4549A and from whom evaluable PK samples were obtained.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Oseltamivir | Observed Steady State Volume of Distribution (Vss_obs) of MHAA4549A | 6410 mL | Standard Deviation 3170 |
| MHAA4549A 3600 mg + Oseltamivir | Observed Steady State Volume of Distribution (Vss_obs) of MHAA4549A | 7450 mL | Standard Deviation 2270 |
Secondary
Peak Influenza A Viral Load
Influenza A viral load was measured by qPCR in nasopharyngeal samples at multiple time points during the study. Reported here is the peak Influenza A viral load expressed as log10 vp/mL.
Time frame: Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60)
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization. Here, number analyzed are the participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Oseltamivir | Peak Influenza A Viral Load | 5.70 log10 vp/mL | Standard Deviation 1.32 |
| MHAA4549A 3600 mg + Oseltamivir | Peak Influenza A Viral Load | 5.37 log10 vp/mL | Standard Deviation 1.39 |
| MHAA4549A 8400 mg + Oseltamivir | Peak Influenza A Viral Load | 5.28 log10 vp/mL | Standard Deviation 1.71 |
p-value: 0.27980% CI: [-0.6, -0.07]ANOVA
p-value: 0.190980% CI: [-0.7, -0.15]ANOVA
Secondary
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome
The clinical status of participants was defined by five mutually exclusive categories: 1. Death; 2. In the Intensive Care Unit (ICU); 3. Non-ICU hospitalization, requiring supplemental oxygen (O2); 4. Non-ICU hospitalization, not requiring supplemental oxygen (O2); 5. Not hospitalized.
Time frame: Days 1-7, 14 and 30
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: Not hospitalized | 11.1 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: In ICU | 42.6 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: Not hospitalized | 25.9 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: Death | 0.0 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: Not hospitalized | 70.4 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: Non-ICU, not requiring supplemental O2 | 27.8 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: In ICU | 35.2 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: Death | 0.0 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: Non-ICU, requiring supplemental O2 | 22.2 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: Non-ICU, requiring supplemental O2 | 25.9 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: Death | 0.0 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: In ICU | 22.2 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: Non-ICU, not requiring supplemental O2 | 22.2 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: Non-ICU, not requiring supplemental O2 | 14.8 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: Death | 1.9 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: Not hospitalized | 16.7 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: In ICU | 42.6 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: Not hospitalized | 22.2 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: Death | 0.0 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: Non-ICU, requiring supplemental O2 | 5.6 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: Non-ICU, not requiring supplemental O2 | 24.1 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: In ICU | 27.8 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: Non-ICU, requiring supplemental O2 | 7.4 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: Non-ICU, requiring supplemental O2 | 25.9 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: Non-ICU, requiring supplemental O2 | 40.7 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: Non-ICU, requiring supplemental O2 | 57.4 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: In ICU | 5.6 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: Non-ICU, not requiring supplemental O2 | 11.1 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: Non-ICU, not requiring supplemental O2 | 1.9 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: Death | 1.9 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: Not hospitalized | 5.6 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: In ICU | 1.9 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: Not hospitalized | 40.7 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: Death | 0.0 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: Non-ICU, not requiring supplemental O2 | 0.0 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: Non-ICU, not requiring supplemental O2 | 14.8 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: In ICU | 37.0 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: Not hospitalized | 85.2 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: Non-ICU, requiring supplemental O2 | 24.1 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: Non-ICU, requiring supplemental O2 | 31.5 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: Death | 5.6 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: In ICU | 18.5 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: Non-ICU, not requiring supplemental O2 | 20.4 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: Not hospitalized | 0.0 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: Death | 1.9 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: Non-ICU, not requiring supplemental O2 | 3.8 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: Non-ICU, not requiring supplemental O2 | 3.8 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: Death | 0.0 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: In ICU | 38.5 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: Non-ICU, requiring supplemental O2 | 61.5 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: Non-ICU, not requiring supplemental O2 | 0.0 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: Not hospitalized | 0.0 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: Death | 0.0 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: In ICU | 38.5 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: Non-ICU, requiring supplemental O2 | 51.9 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: Non-ICU, not requiring supplemental O2 | 7.7 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: Not hospitalized | 1.9 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: Death | 0.0 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: In ICU | 32.7 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: Non-ICU, requiring supplemental O2 | 42.3 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: Non-ICU, not requiring supplemental O2 | 19.2 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: Not hospitalized | 5.8 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: Death | 0.0 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: In ICU | 30.8 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: Non-ICU, requiring supplemental O2 | 21.2 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: Non-ICU, not requiring supplemental O2 | 36.5 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: Not hospitalized | 11.5 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: Death | 0.0 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: In ICU | 26.9 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: Non-ICU, requiring supplemental O2 | 19.2 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: Non-ICU, not requiring supplemental O2 | 34.6 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: Not hospitalized | 19.2 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: Death | 1.9 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: In ICU | 23.1 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: Non-ICU, requiring supplemental O2 | 15.4 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: Non-ICU, not requiring supplemental O2 | 34.6 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: Not hospitalized | 25.0 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: Death | 1.9 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: In ICU | 21.2 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: Non-ICU, requiring supplemental O2 | 13.5 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: Non-ICU, not requiring supplemental O2 | 28.8 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: Not hospitalized | 34.6 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: Death | 3.8 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: In ICU | 11.5 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: Non-ICU, requiring supplemental O2 | 3.8 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: Not hospitalized | 76.9 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: Death | 7.7 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: In ICU | 3.8 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: Non-ICU, requiring supplemental O2 | 1.9 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: Not hospitalized | 82.7 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: Not hospitalized | 11.4 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: Not hospitalized | 81.8 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: Not hospitalized | 34.1 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: Non-ICU, not requiring supplemental O2 | 25.0 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: Not hospitalized | 72.7 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: Death | 2.3 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: Non-ICU, requiring supplemental O2 | 27.3 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: Non-ICU, not requiring supplemental O2 | 4.5 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: In ICU | 20.5 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: In ICU | 34.1 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: Non-ICU, not requiring supplemental O2 | 0.0 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: Non-ICU, requiring supplemental O2 | 15.9 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 3: Death | 2.3 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: Death | 9.1 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: Non-ICU, not requiring supplemental O2 | 25.0 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: Not hospitalized | 6.8 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: Non-ICU, requiring supplemental O2 | 52.3 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 7: Not hospitalized | 36.4 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: Non-ICU, not requiring supplemental O2 | 20.5 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: Death | 0.0 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: Death | 6.8 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: Non-ICU, requiring supplemental O2 | 31.8 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: In ICU | 4.5 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: In ICU | 9.1 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: In ICU | 27.3 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: In ICU | 38.6 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: Non-ICU, requiring supplemental O2 | 18.2 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: Death | 2.3 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: In ICU | 43.2 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: Non-ICU, not requiring supplemental O2 | 27.3 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: Not hospitalized | 20.5 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: Non-ICU, requiring supplemental O2 | 6.8 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 5: Not hospitalized | 25.0 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: Non-ICU, not requiring supplemental O2 | 29.5 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 2: Death | 2.3 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: Death | 2.3 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: Non-ICU, requiring supplemental O2 | 18.2 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 30: Non-ICU, requiring supplemental O2 | 4.5 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: In ICU | 22.7 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: In ICU | 29.5 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 14: Non-ICU, not requiring supplemental O2 | 4.5 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: Non-ICU, requiring supplemental O2 | 15.9 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 4: Death | 2.3 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 1: Not hospitalized | 0.0 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome | Day 6: Non-ICU, not requiring supplemental O2 | 25.0 percentage of participants |
Secondary
Percentage of Participants Readmitted to Hospital Due to Any Cause
Time frame: Days 30 and 60
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Oseltamivir | Percentage of Participants Readmitted to Hospital Due to Any Cause | 1.9 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants Readmitted to Hospital Due to Any Cause | 3.8 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants Readmitted to Hospital Due to Any Cause | 0 percentage of participants |
p-value: 0.537980% CI: [-5.57, 9.56]Cochran-Mantel-Haenszel
p-value: 0.366780% CI: [-9.88, 6.18]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Using Antibiotics for Respiratory Infections
Time frame: From randomization up to 60 days
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Oseltamivir | Percentage of Participants Using Antibiotics for Respiratory Infections | 13.0 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants Using Antibiotics for Respiratory Infections | 11.5 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants Using Antibiotics for Respiratory Infections | 11.4 percentage of participants |
p-value: 0.82480% CI: [-10.61, 7.76]Cochran-Mantel-Haenszel
p-value: 0.811180% CI: [-11.48, 8.28]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Died Due to Any Cause
Time frame: Days 14, 30 and 60
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Oseltamivir | Percentage of Participants Who Died Due to Any Cause | Day 30 | 5.6 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants Who Died Due to Any Cause | Day 14 | 1.9 percentage of participants |
| Placebo + Oseltamivir | Percentage of Participants Who Died Due to Any Cause | Day 60 | 7.4 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants Who Died Due to Any Cause | Day 30 | 7.7 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants Who Died Due to Any Cause | Day 14 | 3.8 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants Who Died Due to Any Cause | Day 60 | 9.6 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants Who Died Due to Any Cause | Day 14 | 6.8 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants Who Died Due to Any Cause | Day 60 | 9.1 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants Who Died Due to Any Cause | Day 30 | 9.1 percentage of participants |
Comparison: Day 14p-value: 0.537980% CI: [-5.57, 9.56]Cochran-Mantel-Haenszel
Comparison: Day 14p-value: 0.218980% CI: [-3.12, 13.05]Cochran-Mantel-Haenszel
Comparison: Day 30p-value: 0.659480% CI: [-6.04, 10.31]Cochran-Mantel-Haenszel
Comparison: Day 30p-value: 0.501380% CI: [-5.24, 12.31]Cochran-Mantel-Haenszel
Comparison: Day 60p-value: 0.684980% CI: [-6.28, 10.69]Cochran-Mantel-Haenszel
Comparison: Day 60p-value: 0.763380% CI: [-7.38, 10.74]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Clinical Failure
Clinical failure after 24 hours post-infusion of study drug was defined as progression to increased O2 requirement defined by an increase in oxygen supplementation from low flow oxygen (i.e., 2-6 liters per minute \[L/min\]) to high flow oxygen (i.e., \> 6 L/min) or from oxygen supplementation alone to any positive pressure ventilation (PPV) or extracorporeal membrane oxygenation (ECMO), progression to ICU, prolonged ventilation or O2 support defined by \> 2 weeks, or death.
Time frame: 24 hours after end of infusion (infusion duration = approximately 120 minutes) up to Day 60
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Oseltamivir | Percentage of Participants With Clinical Failure | 14.8 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants With Clinical Failure | 25.0 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants With Clinical Failure | 22.7 percentage of participants |
p-value: 0.190580% CI: [-0.15, 20.52]Cochran-Mantel-Haenszel
p-value: 0.316880% CI: [-2.64, 18.47]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Clinical Resolution of Abnormal Vital Signs
Description: Clinical resolution of abnormal vital signs was defined as meeting three out of five of the following criteria: 1. SpO2 ≥ 95% without supplemental O2; 2. Respiratory rate \< 24 breaths per minute without supplemental O2; 3. Core temperature \< 37.2 Celsius (C) immediately prior to receipt of any antipyretic drug, and at least 6-8 hours from the last dose of antipyretic or core temperature \> 36 C in participants who are initially hypothermic; 4. Heart rate (HR) \< 100 beats/minute; 5. Systolic blood pressure (SBP) \>90 mmHg. Reported here is the percentage of participants who had clinical resolution of at least three out of five abnormal vital signs by the end of study.
Time frame: From randomization up to 60 days
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Oseltamivir | Percentage of Participants With Clinical Resolution of Abnormal Vital Signs | 81.3 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants With Clinical Resolution of Abnormal Vital Signs | 73.3 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants With Clinical Resolution of Abnormal Vital Signs | 66.7 percentage of participants |
p-value: 0.604380% CI: [-27.5, 11.66]Cochran-Mantel-Haenszel
p-value: 0.386580% CI: [-36.13, 6.97]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Secondary Complications of Influenza
The following were considered secondary complications of influenza: pneumonia, including hospital-acquired pneumonia (HAP) and ventilation-acquired pneumonia (VAP), exacerbations of chronic lung disease, myocarditis, acute respiratory distress syndrome (ARDS), otitis media, or other related complications.
Time frame: From randomization up to 60 days
Population: ITTi population included all randomized participants who were confirmed to be influenza A infected, with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Oseltamivir | Percentage of Participants With Secondary Complications of Influenza | 13.0 percentage of participants |
| MHAA4549A 3600 mg + Oseltamivir | Percentage of Participants With Secondary Complications of Influenza | 15.4 percentage of participants |
| MHAA4549A 8400 mg + Oseltamivir | Percentage of Participants With Secondary Complications of Influenza | 13.6 percentage of participants |
p-value: 0.721980% CI: [-6.96, 11.8]Cochran-Mantel-Haenszel
p-value: 0.922580% CI: [-9.29, 10.64]Cochran-Mantel-Haenszel