Trial Outcomes & Findings for A Study of MHAA4549A in Combination With Oseltamivir Versus Oseltamivir in Participants With Severe Influenza A Infection (NCT NCT02293863)

Last Updated: 2018-06-18

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

168 participants

Primary outcome timeframe

From randomization up to 60 days

Results posted on

2018-06-18

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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.	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.	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.
Overall Study STARTED	56	55	47
Overall Study COMPLETED	47	42	38
Overall Study NOT COMPLETED	9	13	9

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	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.
Overall Study Death	4	6	4
Overall Study Lost to Follow-up	2	2	2
Overall Study Withdrawal by Subject	3	3	1
Overall Study Reason Not Specified	0	2	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo + Oseltamivir n=56 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=55 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=47 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Total n=158 Participants Total of all reporting groups
Age, Continuous	65.7 years STANDARD_DEVIATION 17.5 • n=5 Participants	56.5 years STANDARD_DEVIATION 18.2 • n=7 Participants	59.8 years STANDARD_DEVIATION 17.9 • n=5 Participants	60.7 years STANDARD_DEVIATION 18.2 • n=4 Participants
Sex: Female, Male Female	24 Participants n=5 Participants	25 Participants n=7 Participants	22 Participants n=5 Participants	71 Participants n=4 Participants
Sex: Female, Male Male	32 Participants n=5 Participants	30 Participants n=7 Participants	25 Participants n=5 Participants	87 Participants n=4 Participants
Race/Ethnicity, Customized Hispanic or Latino	13 Participants n=5 Participants	20 Participants n=7 Participants	8 Participants n=5 Participants	41 Participants n=4 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	37 Participants n=5 Participants	28 Participants n=7 Participants	34 Participants n=5 Participants	99 Participants n=4 Participants
Race/Ethnicity, Customized Not Stated	6 Participants n=5 Participants	7 Participants n=7 Participants	5 Participants n=5 Participants	18 Participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaska native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race/Ethnicity, Customized Asian	4 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	6 Participants n=4 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race/Ethnicity, Customized White	45 Participants n=5 Participants	44 Participants n=7 Participants	39 Participants n=5 Participants	128 Participants n=4 Participants
Race/Ethnicity, Customized Multiple	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Unknown	5 Participants n=5 Participants	9 Participants n=7 Participants	5 Participants n=5 Participants	19 Participants n=4 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=56 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=55 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=47 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Percentage of Participants With Adverse Events	80.4 percentage of participants	67.3 percentage of participants	74.5 percentage of participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=56 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=55 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=47 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A Positive for ATAs at baseline	0 participants	1 participants	1 participants
Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A Treatment-induced ATAs	0 participants	0 participants	0 participants
Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A Treatment-enhanced ATAs	0 participants	0 participants	0 participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=54 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=52 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=44 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Time to Normalization of Respiratory Function	4.28 days Interval 3.06 to 6.6	2.78 days Interval 2.52 to 4.2	2.65 days Interval 1.58 to 4.52

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=54 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=52 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=44 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 1: Death	0.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 1: In ICU	42.6 percentage of participants	38.5 percentage of participants	43.2 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 1: Non-ICU, requiring supplemental O2	57.4 percentage of participants	61.5 percentage of participants	52.3 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 1: Non-ICU, not requiring supplemental O2	0.0 percentage of participants	0.0 percentage of participants	4.5 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 1: Not hospitalized	0.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 2: Death	0.0 percentage of participants	0.0 percentage of participants	2.3 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 2: In ICU	42.6 percentage of participants	38.5 percentage of participants	38.6 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 2: Non-ICU, requiring supplemental O2	40.7 percentage of participants	51.9 percentage of participants	31.8 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 2: Non-ICU, not requiring supplemental O2	11.1 percentage of participants	7.7 percentage of participants	20.5 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 2: Not hospitalized	5.6 percentage of participants	1.9 percentage of participants	6.8 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 3: In ICU	37.0 percentage of participants	32.7 percentage of participants	34.1 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 3: Non-ICU, requiring supplemental O2	31.5 percentage of participants	42.3 percentage of participants	27.3 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 3: Non-ICU, not requiring supplemental O2	20.4 percentage of participants	19.2 percentage of participants	25.0 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 4: Death	0.0 percentage of participants	0.0 percentage of participants	2.3 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 4: In ICU	35.2 percentage of participants	30.8 percentage of participants	29.5 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 4: Non-ICU, requiring supplemental O2	25.9 percentage of participants	21.2 percentage of participants	18.2 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 4: Non-ICU, not requiring supplemental O2	22.2 percentage of participants	36.5 percentage of participants	29.5 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 4: Not hospitalized	16.7 percentage of participants	11.5 percentage of participants	20.5 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 5: Death	0.0 percentage of participants	0.0 percentage of participants	2.3 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 5: In ICU	27.8 percentage of participants	26.9 percentage of participants	27.3 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 5: Non-ICU, requiring supplemental O2	25.9 percentage of participants	19.2 percentage of participants	18.2 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 5: Non-ICU, not requiring supplemental O2	24.1 percentage of participants	34.6 percentage of participants	27.3 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 5: Not hospitalized	22.2 percentage of participants	19.2 percentage of participants	25.0 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 6: Death	1.9 percentage of participants	1.9 percentage of participants	2.3 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 6: Non-ICU, not requiring supplemental O2	27.8 percentage of participants	34.6 percentage of participants	25.0 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 6: Not hospitalized	25.9 percentage of participants	25.0 percentage of participants	34.1 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 7: Death	1.9 percentage of participants	1.9 percentage of participants	2.3 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 7: In ICU	18.5 percentage of participants	21.2 percentage of participants	20.5 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 7: Non-ICU, requiring supplemental O2	24.1 percentage of participants	13.5 percentage of participants	15.9 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 7: Non-ICU, not requiring supplemental O2	14.8 percentage of participants	28.8 percentage of participants	25.0 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 14: Death	1.9 percentage of participants	3.8 percentage of participants	6.8 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 14: In ICU	5.6 percentage of participants	11.5 percentage of participants	9.1 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 14: Non-ICU, requiring supplemental O2	7.4 percentage of participants	3.8 percentage of participants	6.8 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 14: Not hospitalized	70.4 percentage of participants	76.9 percentage of participants	72.7 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 30: Death	5.6 percentage of participants	7.7 percentage of participants	9.1 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 30: In ICU	1.9 percentage of participants	3.8 percentage of participants	4.5 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 30: Non-ICU, requiring supplemental O2	5.6 percentage of participants	1.9 percentage of participants	4.5 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 30: Non-ICU, not requiring supplemental O2	1.9 percentage of participants	3.8 percentage of participants	0.0 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 30: Not hospitalized	85.2 percentage of participants	82.7 percentage of participants	81.8 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 3: Death	0.0 percentage of participants	0.0 percentage of participants	2.3 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 3: Not hospitalized	11.1 percentage of participants	5.8 percentage of participants	11.4 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 6: In ICU	22.2 percentage of participants	23.1 percentage of participants	22.7 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 6: Non-ICU, requiring supplemental O2	22.2 percentage of participants	15.4 percentage of participants	15.9 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 7: Not hospitalized	40.7 percentage of participants	34.6 percentage of participants	36.4 percentage of participants
Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome Day 14: Non-ICU, not requiring supplemental O2	14.8 percentage of participants	3.8 percentage of participants	4.5 percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=54 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=52 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=44 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Percentage of Participants With Clinical Failure	14.8 percentage of participants Interval 8.82 to 22.95	25.0 percentage of participants Interval 17.22 to 34.32	22.7 percentage of participants Interval 14.63 to 32.84

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=54 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=52 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=44 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Percentage of Participants With Clinical Resolution of Abnormal Vital Signs	81.3 percentage of participants Interval 62.88 to 92.9	73.3 percentage of participants Interval 53.6 to 87.82	66.7 percentage of participants Interval 44.1 to 84.58

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=54 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=52 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=44 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Percentage of Participants Who Died Due to Any Cause Day 30	5.6 percentage of participants Interval 2.06 to 11.95	7.7 percentage of participants Interval 3.4 to 14.79	9.1 percentage of participants Interval 4.02 to 17.35
Percentage of Participants Who Died Due to Any Cause Day 60	7.4 percentage of participants Interval 3.27 to 14.26	9.6 percentage of participants Interval 4.75 to 17.11	9.1 percentage of participants Interval 4.02 to 17.35
Percentage of Participants Who Died Due to Any Cause Day 14	1.9 percentage of participants Interval 0.19 to 7.01	3.8 percentage of participants Interval 1.03 to 9.91	6.8 percentage of participants Interval 2.53 to 14.56

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=48 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=46 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=39 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Area Under Viral Load-Time Curve (AUEC ) of Influenza A Virus	25.72 log10 (vp/mL x hour). Standard Deviation 15.92	21.99 log10 (vp/mL x hour). Standard Deviation 16.57	25.03 log10 (vp/mL x hour). Standard Deviation 13.48

SECONDARY outcome

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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=48 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=46 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=39 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Peak Influenza A Viral Load	5.70 log10 vp/mL Standard Deviation 1.32	5.37 log10 vp/mL Standard Deviation 1.39	5.28 log10 vp/mL Standard Deviation 1.71

SECONDARY outcome

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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=54 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=52 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=44 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Duration of Viral Shedding	4.00 days Interval 3.66 to 5.6	4.63 days Interval 3.63 to 4.97	4.60 days Interval 3.57 to 5.53

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=54 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=52 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=44 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Duration of Hospitalization	8.95 days Interval 5.9 to 10.29	7.65 days Interval 6.94 to 8.02	6.69 days Interval 6.0 to 8.86

SECONDARY outcome

Timeframe: From randomization up to 60 days

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=54 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=52 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=44 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Duration of Intensive Care Unit (ICU) Stay	4.66 days Interval 3.91 to 7.1	6.60 days Interval 4.82 to 10.53	5.29 days Interval 3.25 to 6.58

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=54 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=52 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=44 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Percentage of Participants Using Antibiotics for Respiratory Infections	13.0 percentage of participants Interval 7.36 to 20.84	11.5 percentage of participants Interval 6.17 to 19.37	11.4 percentage of participants Interval 5.63 to 20.06

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=54 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=52 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=44 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Percentage of Participants With Secondary Complications of Influenza	13.0 percentage of participants Interval 7.36 to 20.84	15.4 percentage of participants Interval 9.17 to 23.79	13.6 percentage of participants Interval 7.32 to 22.71

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=54 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=52 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=44 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Percentage of Participants Readmitted to Hospital Due to Any Cause	1.9 percentage of participants Interval 0.19 to 7.01	3.8 percentage of participants Interval 1.03 to 9.91	0 percentage of participants Interval 0.0 to 5.1

SECONDARY outcome

Timeframe: From randomization up to 60 days

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=54 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=52 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=44 Participants Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Duration of Ventilation	4.11 days Interval 2.72 to 5.32	7.05 days Interval 1.92 to 13.12	5.89 days Interval 4.13 to 13.07

SECONDARY outcome

Timeframe: 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.

AUC0-inf is reported as day\*microgram/milliliter (day\*mcg/mL).

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=38 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=31 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	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.
Area Under Serum Concentration-Time Curve From Time 0 to Infinity (AUC ) of MHAA4549A	11400 day*mcg/mL Standard Deviation 4530	26700 day*mcg/mL Standard Deviation 9810	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=38 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=31 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	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.
Maximum Serum Concentration (Cmax ) of MHAA4549A	916 mcg/mL Standard Deviation 294	2220 mcg/mL Standard Deviation 556	—

SECONDARY outcome

Population: PK-evaluable population included all participants, who received MHAA4549A and from whom evaluable PK samples were obtained.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=38 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=31 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	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.
Elimination Half-Life (Terminal t1/2) of MHAA4549A	19.0 day Standard Deviation 4.91	17.8 day Standard Deviation 3.88	—

SECONDARY outcome

Population: PK-evaluable population included all participants, who received MHAA4549A and from whom evaluable PK samples were obtained.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=38 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=31 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	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.
Observed Clearance (CL-obs) of MHAA4549A	288 mL/day Standard Deviation 158	350 mL/day Standard Deviation 130	—

SECONDARY outcome

Population: PK-evaluable population included all participants, who received MHAA4549A and from whom evaluable PK samples were obtained.

Outcome measures

Outcome measures
Measure	Placebo + Oseltamivir n=38 Participants Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=31 Participants Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	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.
Observed Steady State Volume of Distribution (Vss_obs) of MHAA4549A	6410 mL Standard Deviation 3170	7450 mL Standard Deviation 2270	—

Adverse Events

Placebo + Oseltamivir

Serious events: 8 serious events

Other events: 28 other events

Deaths: 4 deaths

MHAA4549A 3600 mg + Oseltamivir

Serious events: 11 serious events

Other events: 26 other events

Deaths: 6 deaths

MHAA4549A 8400 mg + Oseltamivir

Serious events: 12 serious events

Other events: 18 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo + Oseltamivir n=56 participants at risk Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 3600 mg + Oseltamivir n=55 participants at risk Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	MHAA4549A 8400 mg + Oseltamivir n=47 participants at risk Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Gastrointestinal disorders Constipation	3.6% 2/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	7.3% 4/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	4.3% 2/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Gastrointestinal disorders Vomiting	5.4% 3/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	3.6% 2/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	4.3% 2/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Metabolism and nutrition disorders Hypokalaemia	7.1% 4/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	3.6% 2/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	8.5% 4/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Metabolism and nutrition disorders Hypophosphataemia	7.1% 4/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	3.6% 2/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	4.3% 2/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Metabolism and nutrition disorders Hyperglycaemia	1.8% 1/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	5.5% 3/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	4.3% 2/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Metabolism and nutrition disorders Hyperkalaemia	1.8% 1/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	1.8% 1/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	6.4% 3/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Metabolism and nutrition disorders Hypoglycaemia	1.8% 1/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	5.5% 3/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	2.1% 1/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Vascular disorders Hypertension	12.5% 7/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	1.8% 1/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	8.5% 4/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Cardiac disorders Atrial fibrillation	5.4% 3/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	7.3% 4/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	4.3% 2/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Blood and lymphatic system disorders Anaemia	5.4% 3/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	5.5% 3/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	4.3% 2/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
General disorders Pyrexia	3.6% 2/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	7.3% 4/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	4.3% 2/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Gastrointestinal disorders Diarrhoea	12.5% 7/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	5.5% 3/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	0.00% 0/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Gastrointestinal disorders Nausea	7.1% 4/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	7.3% 4/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	2.1% 1/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Psychiatric disorders Agitation	7.1% 4/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	5.5% 3/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	2.1% 1/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Renal and urinary disorders Haematuria	5.4% 3/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	9.1% 5/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	0.00% 0/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Nervous system disorders Headache	3.6% 2/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	3.6% 2/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	6.4% 3/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.8% 1/56 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	1.8% 1/55 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.	6.4% 3/47 • From randomization up to 60 days Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.