Influenza A
Conditions
Brief summary
This is a Phase 2, randomized, double-blind, placebo-controlled single dose study in otherwise healthy adults with acute uncomplicated seasonal influenza A to assess the safety and tolerability, efficacy, and pharmacokinetics of MHAA4549A.
Interventions
DRUGMHAA4549A
MHAA4549A will be administered as a single dose by IV administration.
DRUGPlacebo
Placebo will be administered as a single dose by IV administration.
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 65 Years
Healthy volunteers
No
Inclusion criteria
* Otherwise healthy participants * Positive test for influenza A infection * No more than 72 hours elapsed between onset of influenza-like illness and start of study drug * Presence of at least one moderate or severe constitutional symptom such as headache, myalgia, fever, chills, fatigue, anorexia, or nausea PLUS one moderate or severe respiratory symptom such as cough, sore throat, or rhinorrhea * For women of childbearing potential: negative pregnancy test and agreement to use acceptable contraceptive methods for at least 120 days after study drug administration * For men: agreement to use acceptable contraceptive methods for at least 30 days after study drug administration
Exclusion criteria
* Creatinine clearance less than or equal to (\</=) 80 milliliters per minute (mL/min) * Any significant medical conditions or laboratory abnormalities * Clinical signs and symptoms consistent with otitis, bronchitis, sinusitis, or pneumonia or active bacterial infection * Use of antiviral therapy in the period from onset of influenza-like illness and prior to enrollment * Pregnancy at Screening or is currently pregnant or breastfeeding * Investigational therapy within 30 days or 5 half-lives prior to start of study drug, whichever is greater * Prior anti-influenza monoclonal antibody use * Receipt of a nasal influenza A vaccine within 14 days prior to Screening * Positive test for influenza B or influenza A+B within 2 weeks prior to study drug * History of significant tobacco use or drug/alcohol abuse * Chronic use of oral or inhaled corticosteroids within 30 days prior to Screening * Autoimmune disease, known immunodeficiency of any cause, or use of immunosuppressive medications * History of any chronic respiratory condition * Human immunodeficiency virus (HIV) with cluster of differentiation (CD) 4 count \</= 200 cells per milliliter (cells/mL) in the past 12 months * Serious infection requiring oral or IV antibiotics within 14 days prior to Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events (AEs) | Baseline to Day 100 | An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Hospitalization for Influenza-Related Complications | Baseline to Day 100 | — |
| Percentage of Participants Requiring Antibiotics for Secondary Bacterial Respiratory Infections | Baseline to Day 100 | Participants with antibiotic usage for secondary bacterial respiratory infections were identified by counting participants with AEs containing the terms, pneumonia, lung, myocarditis, ARDS (acute respiratory distress syndrome), otitis media, or respiratory. |
| Percentage of Participants With Complications of Influenza | Baseline to Day 100 | Participants with complications of influenza were identified by counting participants with AEs containing the terms, pneumonia, lung, myocarditis, ARDS (acute respiratory distress syndrome), otitis media, or respiratory. |
| Percentage of Participants With Influenza A Relapse/Reinfection | Baseline to Day 100 | — |
| Percentage of Participants Requiring Hospitalization for Influenza-Related Complications | Baseline to Day 100 | — |
| Maximum Serum Concentration (Cmax) of MHAA4549A | Up to Day 100 (collections scheduled pre-dose [0 hours]; 60 minutes post-dose; and on Days 3, 5, 7, 30, and 100 post-dose; infusion duration = 2 hours) | — |
| Time to Alleviation of Symptoms of Influenza A Infection | Baseline to Day 14 | Time to alleviation of all 7 symptoms (i.e., nasal congestion, sore throat, cough, aches, fatigue, headaches, chills/sweats) was assessed using a rating scale of 0 (none), 1 (mild), 2 (moderate), or 3 (severe) for each symptom. The outcome was defined in two ways: time to a total symptom score of \<=1 and time to a total symptom score of \<=7. Resolution had to be maintained for 24 hours without use of symptom relief medications. For participants who were enrolled with mild symptoms, the symptom score had to be reduced by one point during the study duration. |
| Percentage of Participants With Influenza-Related Deaths | Baseline to Day 100 | — |
| Area Under the Concentration-Time Curve (AUC) of MHAA4549A | Up to Day 100 (collections scheduled pre-dose [0 hours]; 60 minutes post-dose; and on Days 3, 5, 7, 30, and 100 post-dose; infusion duration = 2 hours) | The AUC is a measure of the plasma concentration of the drug over time. It is used to characterize drug absorption. AUC was measured in micrograms times hours per milliliter (mcg\*h/mL). |
Countries
Canada, New Zealand, South Africa, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 34 investigational sites in 6 countries including the United States (15 centers), South Africa (12 centers), Canada, Spain, New Zealand (2 centers in each country), and Great Britain (1 center).
Pre-assignment details
Randomization was stratified by onset of influenza-like illness (≤ 36 hours and \> 36 hours) and a permuted block randomization method was used to obtain an approximate 1:1:1 ratio of subjects in the 3600 mg MHAA4549A, 8400 mg MHAA4549A, and placebo strata.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received single-dose placebo by intravenous (IV) administration. | 43 |
| MHAA4549A 3600 mg Participants received single-dose MHAA4549A, 3600 milligrams (mg), by IV administration. | 41 |
| MHAA4549A 8400 mg Participants received single-dose MHAA4549A, 8400 mg, by IV administration. | 40 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | MHAA4549A 3600 mg | MHAA4549A 8400 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 39.3 years STANDARD_DEVIATION 10.8 | 36.5 years STANDARD_DEVIATION 12.5 | 35.0 years STANDARD_DEVIATION 13.6 | 37.0 years STANDARD_DEVIATION 12.4 |
| Race/Ethnicity, Customized Asian | 2 Participants | 4 Participants | 1 Participants | 7 Participants |
| Race/Ethnicity, Customized Black or African American | 13 Participants | 7 Participants | 15 Participants | 35 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 40 Participants | 38 Participants | 38 Participants | 116 Participants |
| Race/Ethnicity, Customized Not Stated | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 27 Participants | 26 Participants | 23 Participants | 76 Participants |
| Sex: Female, Male Female | 27 Participants | 22 Participants | 22 Participants | 71 Participants |
| Sex: Female, Male Male | 16 Participants | 19 Participants | 18 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 0 / 41 | 0 / 40 |
| other Total, other adverse events | 4 / 43 | 7 / 41 | 6 / 40 |
| serious Total, serious adverse events | 0 / 43 | 0 / 41 | 1 / 40 |
Outcome results
Primary
Percentage of Participants With Adverse Events (AEs)
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug.
Time frame: Baseline to Day 100
Population: The safety population included all participants randomized to treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Adverse Events (AEs) | 30.2 percentage of participants |
| MHAA4549A 3600 mg | Percentage of Participants With Adverse Events (AEs) | 39.0 percentage of participants |
| MHAA4549A 8400 mg | Percentage of Participants With Adverse Events (AEs) | 30.0 percentage of participants |
Secondary
Area Under the Concentration-Time Curve (AUC) of MHAA4549A
The AUC is a measure of the plasma concentration of the drug over time. It is used to characterize drug absorption. AUC was measured in micrograms times hours per milliliter (mcg\*h/mL).
Time frame: Up to Day 100 (collections scheduled pre-dose [0 hours]; 60 minutes post-dose; and on Days 3, 5, 7, 30, and 100 post-dose; infusion duration = 2 hours)
Population: Data were collected for this outcome measure.
Secondary
Duration of Hospitalization for Influenza-Related Complications
Time frame: Baseline to Day 100
Population: The intent-to-treat infected (ITTI) population included all randomized participants who had an influenza A infection confirmed by central polymerase chain reaction (PCR).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Duration of Hospitalization for Influenza-Related Complications | 0 days |
| MHAA4549A 3600 mg | Duration of Hospitalization for Influenza-Related Complications | 0 days |
| MHAA4549A 8400 mg | Duration of Hospitalization for Influenza-Related Complications | 0 days |
Secondary
Maximum Serum Concentration (Cmax) of MHAA4549A
Time frame: Up to Day 100 (collections scheduled pre-dose [0 hours]; 60 minutes post-dose; and on Days 3, 5, 7, 30, and 100 post-dose; infusion duration = 2 hours)
Population: The pharmacokinetic (PK)-evaluable population included all participants who received MHA4549A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Serum Concentration (Cmax) of MHAA4549A | 1050 mcg/mL | Standard Deviation 299 |
| MHAA4549A 3600 mg | Maximum Serum Concentration (Cmax) of MHAA4549A | 2190 mcg/mL | Standard Deviation 581 |
Secondary
Percentage of Participants Requiring Antibiotics for Secondary Bacterial Respiratory Infections
Participants with antibiotic usage for secondary bacterial respiratory infections were identified by counting participants with AEs containing the terms, pneumonia, lung, myocarditis, ARDS (acute respiratory distress syndrome), otitis media, or respiratory.
Time frame: Baseline to Day 100
Population: The intent-to-treat infected (ITTI) population included all randomized participants who had an influenza A infection confirmed by central PCR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Requiring Antibiotics for Secondary Bacterial Respiratory Infections | 3.0 percentage of participants |
| MHAA4549A 3600 mg | Percentage of Participants Requiring Antibiotics for Secondary Bacterial Respiratory Infections | 0 percentage of participants |
| MHAA4549A 8400 mg | Percentage of Participants Requiring Antibiotics for Secondary Bacterial Respiratory Infections | 0 percentage of participants |
p-value: 0.303180% CI: [-12.25, 6.19]Cochran-Mantel-Haenszel
p-value: 0.332480% CI: [-12.82, 6.76]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Requiring Hospitalization for Influenza-Related Complications
Time frame: Baseline to Day 100
Population: The intent-to-treat infected (ITTI) population included all randomized participants who had an influenza A infection confirmed by central polymerase chain reaction (PCR).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Requiring Hospitalization for Influenza-Related Complications | 0 percentage of participants |
| MHAA4549A 3600 mg | Percentage of Participants Requiring Hospitalization for Influenza-Related Complications | 0 percentage of participants |
| MHAA4549A 8400 mg | Percentage of Participants Requiring Hospitalization for Influenza-Related Complications | 0 percentage of participants |
Secondary
Percentage of Participants With Complications of Influenza
Participants with complications of influenza were identified by counting participants with AEs containing the terms, pneumonia, lung, myocarditis, ARDS (acute respiratory distress syndrome), otitis media, or respiratory.
Time frame: Baseline to Day 100
Population: ITTI population included all randomized participants who had an influenza A infection confirmed by central PCR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Complications of Influenza | 3.0 percentage of participants |
| MHAA4549A 3600 mg | Percentage of Participants With Complications of Influenza | 0 percentage of participants |
| MHAA4549A 8400 mg | Percentage of Participants With Complications of Influenza | 0 percentage of participants |
p-value: 0.303180% CI: [-12.25, 6.19]Cochran-Mantel-Haenszel
p-value: 0.332480% CI: [-12.82, 6.76]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Influenza A Relapse/Reinfection
Time frame: Baseline to Day 100
Population: ITTI population included all randomized participants who had an influenza A infection confirmed by central PCR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Influenza A Relapse/Reinfection | 0 percentage of participants |
| MHAA4549A 3600 mg | Percentage of Participants With Influenza A Relapse/Reinfection | 0 percentage of participants |
| MHAA4549A 8400 mg | Percentage of Participants With Influenza A Relapse/Reinfection | 0 percentage of participants |
Secondary
Percentage of Participants With Influenza-Related Deaths
Time frame: Baseline to Day 100
Population: The safety population included all participants randomized to treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Influenza-Related Deaths | 0 percentage of participants |
| MHAA4549A 3600 mg | Percentage of Participants With Influenza-Related Deaths | 0 percentage of participants |
| MHAA4549A 8400 mg | Percentage of Participants With Influenza-Related Deaths | 0 percentage of participants |
Secondary
Time to Alleviation of Symptoms of Influenza A Infection
Time to alleviation of all 7 symptoms (i.e., nasal congestion, sore throat, cough, aches, fatigue, headaches, chills/sweats) was assessed using a rating scale of 0 (none), 1 (mild), 2 (moderate), or 3 (severe) for each symptom. The outcome was defined in two ways: time to a total symptom score of \<=1 and time to a total symptom score of \<=7. Resolution had to be maintained for 24 hours without use of symptom relief medications. For participants who were enrolled with mild symptoms, the symptom score had to be reduced by one point during the study duration.
Time frame: Baseline to Day 14
Population: ITTI population included all randomized participants who had an influenza A infection confirmed by central PCR. Data are reported for evaluable participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time to Alleviation of Symptoms of Influenza A Infection | Total Symptom Score of <=1 | 117.30 hours |
| Placebo | Time to Alleviation of Symptoms of Influenza A Infection | Total Symptom Score of <=7 | 44.50 hours |
| MHAA4549A 3600 mg | Time to Alleviation of Symptoms of Influenza A Infection | Total Symptom Score of <=1 | 153.80 hours |
| MHAA4549A 3600 mg | Time to Alleviation of Symptoms of Influenza A Infection | Total Symptom Score of <=7 | 74.18 hours |
| MHAA4549A 8400 mg | Time to Alleviation of Symptoms of Influenza A Infection | Total Symptom Score of <=1 | 145.82 hours |
| MHAA4549A 8400 mg | Time to Alleviation of Symptoms of Influenza A Infection | Total Symptom Score of <=7 | 65.59 hours |
Comparison: Total Symptom Score of \<=1p-value: 0.785880% CI: [0.62, 1.37]Wilcoxon
Comparison: Total Symptom Score of \<=1p-value: 0.51780% CI: [0.59, 1.36]Wilcoxon
Comparison: Total Symptom Score of \<=7p-value: 0.031280% CI: [0.45, 0.89]Wilcoxon
Comparison: Total Symptom Score of \<=7p-value: 0.204480% CI: [0.53, 1.04]Wilcoxon