A Study of MHAA4549A in Combination With Oseltamivir Versus Oseltamivir in Participants With Severe Influenza A Infection

Study Overview
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Brief Summary
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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.

Conditions
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Influenza

Intervention / Treatment
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* Drug: MHAA4549A
* Drug: Oseltamivir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: MHAA4549A 3600 mg + Oseltamivir<br>Participants will receive a single low IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days. | Drug: MHAA4549A<br>* Participants will receive a single dose of MHAA4549A by IV infusion on Day 1<br>Drug: Oseltamivir<br>* 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.<br>* Other names: Tamiflu;|
| Experimental: B: MHAA4549A 8400 mg + Oseltamivir<br>Participants will receive a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days. | Drug: MHAA4549A<br>* Participants will receive a single dose of MHAA4549A by IV infusion on Day 1<br>Drug: Oseltamivir<br>* 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.<br>* Other names: Tamiflu;|
| Placebo Comparator: C: Placebo + Oseltamivir<br>Participants will receive a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy (75 or 150 mg BID) for minimum of 5 days. | Drug: Oseltamivir<br>* 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.<br>* Other names: Tamiflu;Drug: Placebo<br>* Participants will receive a single IV dose of placebo matched to MHAA4549A on Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From randomization up to 60 days | 
| 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. | From randomization up to 60 days | 
| 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. | From randomization up to 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Days 1-7, 14 and 30 | 
| 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. | 24 hours after end of infusion (infusion duration = approximately 120 minutes) up to Day 60 | 
| 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. | From randomization up to 60 days | 
| 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 | 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). | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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 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. | From randomization up to 60 days | 
| 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 | AUC0-inf is reported as day*microgram/milliliter (day*mcg/mL). | 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) | 
| 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) |