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

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02293863
• Collaborator: (none)
• Enrollment: 168
• Locations: 171
• Arms: 3
• Actual Duration (Months): 28.3
• Patients Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Drug: MHAA4549A; Drug: Oseltamivir; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 168 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Actual Study Start Date: Jan 14, 2015
• Actual Primary Completion Date: May 23, 2017
• Actual Study Completion Date: May 23, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A: MHAA4549A 3600 mg + Oseltamivir Participants will receive a single low IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Drug: MHAA4549A; Participants will receive a single dose of MHAA4549A by IV infusion on Day 1; Drug: Oseltamivir; 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.; Other Names: Tamiflu
Experimental: B: MHAA4549A 8400 mg + Oseltamivir Participants will receive a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Drug: MHAA4549A; Participants will receive a single dose of MHAA4549A by IV infusion on Day 1; Drug: Oseltamivir; 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.; Other Names: Tamiflu
Placebo Comparator: C: Placebo + Oseltamivir 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; 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.; Other Names: Tamiflu ; Drug: Placebo; Participants will receive a single IV dose of placebo matched to MHAA4549A on Day 1

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. Percentage of Participants Who Died Due to Any Cause [Days 14, 30 and 60]

5. 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).

6. 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.

7. 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.

8. Duration of Hospitalization [From randomization up to 60 days]

9. Duration of Intensive Care Unit (ICU) Stay [From randomization up to 60 days]

10. Percentage of Participants Using Antibiotics for Respiratory Infections [From randomization up to 60 days]

11. 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.

12. Percentage of Participants Readmitted to Hospital Due to Any Cause [Days 30 and 60]

13. Duration of Ventilation [From randomization up to 60 days]

14. 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).

15. 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)]

16. 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)]

17. 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)]

18. 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)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CHU St Pierre (St Pierre)	Brussels		Belgium	1000
2	Hospital Erasme; Neurologie	Bruxelles		Belgium	1070
3	UZ Leuven Gasthuisberg	Leuven		Belgium	3000
4	CHU UCL Mont-Godinne	Mont-godinne		Belgium	5530
5	Santa Casa de Misericordia; de Belo Horizonte	Belo Horizonte	MG	Brazil	30150-221
6	Hospital Sao Vicente de Paulo	Passo Fundo	RS	Brazil	99010-080
7	PUC Campinas	Campinas	SP	Brazil	13060-904
8	FUNFARME	Sao Jose do Rio Preto	SP	Brazil	15090-000
9	Hospital Alemao Oswaldo Cruz; Oncologia	Sao Paulo	SP	Brazil	01323-020
10	Hospital Edmundo Vasconcelos	Vila Clementino	SP	Brazil	04038-905
11	MHAT "Dr. Tota Venkova"- Gabrovo	Gabrovo		Bulgaria	5300
12	University Multiprofile Hospital for Active Treatment "St. George"	Plovdiv		Bulgaria	4005
13	SHATPPD Dr. Dimitar Gramatikov, Ruse Ltd.	Ruse		Bulgaria	7002
14	Multiprofile Hospital for Active Treatment AKTA-MEDIKA EOOD	Sevlievo		Bulgaria	5400
15	MHAT Lyulin EAD, Department of internal diseases	Sofia		Bulgaria	1336
16	MHAT TOKUDA SOFIA/ICU-Intensive Care Unit	Sofia		Bulgaria	1407
17	5th Multifunctional Hospital for Active treatment	Sofia		Bulgaria	1606
18	Military Medical Academy- MHAT	Sofia		Bulgaria	1606
19	University Multiprofile Hospital for Active Treatment and Emergency Medicine N. I. Pirogov EAD	Sofia		Bulgaria	1606
20	MBAL St Marina Dep Pulmonology, ICU	Varna		Bulgaria	9010
21	Multiprofile District Hospital for Active Treatment Dr. Stefan Cherkezov AD	Veliko Tarnovo		Bulgaria	5000
22	Peter Lougheed Centre	Calgary	Alberta	Canada	T1Y 6J4
23	Alberta Health Services	Calgary	Alberta	Canada	T2N 4N2
24	Foothills Medical Centre	Calgary	Alberta	Canada	T2N 4Z6
25	Rockyview General Hospital	Calgary	Alberta	Canada	T2V 1P9
26	Royal Columbian Hospital	New Westminster	British Columbia	Canada	V3L 3W7
27	St. Paul's Hospital, Providence Health Care	Vancouver	British Columbia	Canada	V6Z 1Y6
28	Victoria General Hospital	Victora	British Columbia	Canada	V8Z 6R5
29	Royal Jubilee Hospital Victoria general Hospital	Victoria	British Columbia	Canada	V8R 1J8
30	Moncton Hospital	Moncton	New Brunswick	Canada	E1C 6Z8
31	LHSC - University Hospital; Research Pharmacy	London	Ontario	Canada	N6A 5A5
32	Lakeridge Health	Oshawa	Ontario	Canada	L1G 2B9
33	Ottawa Hospital Research Institute	Ottawa	Ontario	Canada	K1Y 4E9
34	The Ottawa Hospital - Civic Campus	Ottawa	Ontario	Canada	K1Y 4E9
35	Toronto East General	Toronto	Ontario	Canada	M4C 3E7
36	University Health Network	Toronto	Ontario	Canada	M5G 2N2
37	Toronto Western Hospital	Toronto	Ontario	Canada	M5T 2S8
38	Centre Hospitalier de la Universite Laval	Quebec City	Quebec	Canada	G1V 4G5
39	Pavillion Chul-Chuq	Sainte-foy	Quebec	Canada	G1V 4G2
40	Centre de santé et de services sociaux de Trois-Rivières	Trois-Rivieres	Quebec	Canada	G9A1Y1
41	Hospital Dr. Hernan Henriquez Aravena	Temuco		Chile	4781151
42	Clinica Renaca	Vina del Mar		Chile	2540364
43	The University Hospital Brno	Brno		Czechia	62500
44	Fakultni nemocnice Hradec Kralove	Hradec Kralove		Czechia	500 05
45	Anesthesia and Intensive Care Dept., Regional Hospital Liberec	Liberec		Czechia	460 63
46	University hospital Ostrava, Clinic of infectious medicine	Ostrava		Czechia	708 52
47	Fakultni nemocnice Kralovske Vinohrady, Klinika anesteziologie a resuscitace	Praha 10		Czechia	100 34
48	CH Victor Dupouy	Argenteuil		France	95107
49	Centre Hospitalier Universitaire de Clermont Ferrand	Clermont-ferrand		France	63000
50	Service de Réanimation médicale - Bocage Central	Dijon		France	21079
51	APHP Raymond Poincare	Garches		France	92380
52	CHD Vendée	La Roche Sur Yon		France	85025
53	CHRU Lille	Lille		France	59037
54	Réanimation Polyvalente, CHU Limoges	Limoges		France	87043
55	CHRU Nancy	Nancy		France	54035
56	Archet 1 university Hospital	Nice		France	6202
57	HOPITAL COCHIN university hospital	Paris		France	75014
58	Réanimation médicale NHC	Strasbourg		France	67000
59	Hopital Universitaire Hautepierre	Strasbourg		France	67098
60	Service de réanimation médicale, Hôpital Bretonneau	Tours		France	37044
61	Universitätsklinikum Frankfurt Goethe Universität	Frankfurt		Germany	60590
62	Universitätsklinikum Heidelberg	Heidelberg		Germany	69120
63	Uniklinik Köln, Medizinischen Klinik I	Koeln		Germany	50931
64	Uniklinikum Mainz	Mainz		Germany	55131
65	Uniklinik Tübingen	Tuebingen		Germany	72076
66	University of Hong Kong	Hong Kong		Hong Kong
67	Pest Megyei Flor Ferenc Korhaz	Kistarcsa		Hungary	2084
68	Csolnoky Ferenc Kórház	Veszprém		Hungary	8200
69	Jávorszky Ödön Hospital	Vác		Hungary	2600
70	Zala County Hospital ICU	Zalaegerszeg		Hungary	8900
71	Haemek Medical Center	Afula		Israel	18101
72	Soroka University Medical Centre	Beer-Sheva		Israel	84101
73	Wolfson Medical Center	Holon		Israel	58100
74	Hadasit Medical Research Services and Development Ltd	Jerusalem		Israel	91999
75	Galilee Medical Center	Nahariya		Israel	22100
76	Nazareth EMMS Hospital	Nazareth		Israel	16100
77	Rabin Medical Center	Petah Tikva		Israel	4941492
78	Kaplan Medical Center	Rehovot		Israel	7661041
79	Tel-Aviv Sourasky Medical Center	Tel Aviv		Israel	64239
80	Chaim Sheba Medical Center	Tel Hashomer		Israel	52661
81	Ziv Medical Center	Zefat		Israel	1311001
82	University Division of Infective and Tropical Diseases, University of Brescia, Italy	Brescia	Basilicata	Italy
83	Clinic of Infectious Diseases	Bologna	Emilia-Romagna	Italy	40127
84	University Hospital Modena, Intensive Care Unit	Modena	Emilia-Romagna	Italy	41125
85	National Institute for Infectious Diseases "L. Spallanzani"	Rome	Lazio	Italy	149
86	Asst Di Cremona	Cremona	Lombardia	Italy	26100
87	Ospedale San Raffaele - Milano	Milano	Lombardia	Italy	20127
88	A.O.U. S. Giovanni di Dio e Ruggi d'Aragona	Salerno	Sardegna	Italy	84131
89	Pusan National University Hospital	Busan		Korea, Republic of	602-739
90	Gachon University Gil Hospital	Incheon		Korea, Republic of
91	Korea University Anam Hospital	Seoul		Korea, Republic of	02841
92	Korea University Guro Hospital	Seoul		Korea, Republic of	08308
93	Yonsei University Health System/Severance Hospital	Seoul		Korea, Republic of	120-752
94	Hallym university Kangnam Sacred Heart Hospital; Infectious devision	Seoul		Korea, Republic of	150-950
95	Wonju Severance Christian Hospital	Wonju		Korea, Republic of	220-701
96	Hospital Civil de Guadalajara Dr Juan I Menchaca	Guadalajara		Mexico	44280
97	Hospital Civil de Guadalajara Fray Antonio Alcalde	Guadalajara		Mexico	44280
98	Instituto Nacional de Ciencias; Medicas y Nutricion; Salvador Zubiran	Mexico, Distrito Federal		Mexico	14000
99	CEPREP; Hospital Universitario	Monterrey		Mexico	64460
100	Hospital General de Tijuana	Tijuana		Mexico	22320
101	Centro de Especialidades Medicas Del Estado de Veracruz Dr Rafael Lucio	Xalapa-enriquez		Mexico	91020
102	Jeroen Bosch Ziekenhuis	'S Hertogenbosch		Netherlands	5223 GZ
103	Gelre Ziekenhuizen Apeldoorn; Hospitals Pharmacy	Apeldoorn		Netherlands	7334 DV
104	LUMC	Leiden		Netherlands	2300 ZA
105	UMC Radboud Nijmegen	Nijmegen		Netherlands	6500 HB
106	Erasmus Medical Centre; Department of Virology L-359	Rotterdam		Netherlands	3000 CA
107	Ikazia Hospital	Rotterdam		Netherlands	3083AN
108	UMCU	Utrecht		Netherlands	3508 GA
109	Isala	Zwolle		Netherlands	8025 AB
110	Auckland City Hospital	Auckland		New Zealand	1124
111	Christchurch Hospital	Christchurch		New Zealand	8011
112	Tauranga Hospital	Tauranga		New Zealand	3143
113	Hospital Regional del Cusco	Cusco		Peru	84
114	Hospital Nacional Adolfo Guevara Velasco	Cuzco		Peru	84
115	Hospital Guillermo Almenara Irigoyen Hospital Guillermo Almenara Irigoyen Hospital Guillermo Almen	La Victoria		Peru	Lima 13
116	Clinica Internacional Sede Lima	LIma		Peru	Lima 01
117	Hospital Nacional; Arzobispo Loayza	LIma		Peru	Lima 01
118	Hospital Nacional Hipolito; Unanue	Lima		Peru	Lima 10
119	Hospital Central Fuerza; Aerea del Peru	Lima		Peru	Lima 18
120	Hospital Maria Auxiliadora	Lima		Peru	Lima 29
121	Clínica San Gabriel	Lima		Peru	Lima 32
122	Clinica San Borja	Lima		Peru	Lima 41
123	Hospital de la Amistad Peru Corea II-2 Santa Rosa	Piura		Peru	20001
124	Clinica Divino Nino Jesus; Orden de Malta	San Juan de Miraflores		Peru	LIMA 29
125	Clinica Peruana Americana	Trujillo		Peru	13011
126	Wojewodzki Szpital Specjalistyczny	Lublin		Poland	20-718
127	Icu Spsk - 2	Szczecin		Poland	70-111
128	Oddział Anestezjologii i Intensywnej Terapii;Wojewódzki Szpital Zespolony im. L. Rydygiera	Toruń		Poland	87-100
129	Oddział Anestezjologii i Intensywnej Terapii Wojewódzki Specjalistyczny Szpital im dr Wł Biegańsk	Łódź		Poland	91-347
130	Municipal Clinical Hospital #8	Chelyabinsk		Russian Federation	454000
131	Municipal Healthcare Institution "City Hospital №2"	Engels		Russian Federation	413124
132	Medical Military Academy n.a S.M.Kirov	St.Petersburg		Russian Federation	194044
133	Paciific state medical university	Vladivostok		Russian Federation	690002
134	Milpark Hospital	Parktown West		South Africa	2196
135	Emmed Research	Pretoria		South Africa	0084
136	Clinical Projects Research	Worcester		South Africa	6850
137	Mutua de Terrassa	Terrassa	Barcelona	Spain	08221
138	Hospital Clinic	Barcelona	Cantabria	Spain	08036
139	Hospital de Mataro	Mataro	Cantabria	Spain	08304
140	Hospital Universitario Marques de Valdecilla	Santander	Cantabria	Spain	39008
141	Hospital Universitario Son Espases	Palma de Mallorca	Islas Baleares	Spain	07010
142	Hospital del Mar	Barcelona		Spain	08003
143	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
144	Bellvitge University Hospital	Barcelona		Spain	08907
145	Hospital Universitario San Cecilio	Granada		Spain	18012
146	Hosp. Clinico San Carlos	Madrid		Spain	28040
147	Hospital Univ. de Getafe.Servicio de Neurologia	Madrid		Spain	28905
148	Joan XXIII University Hospital	Tarragona		Spain	43005
149	Servicio de Medicina Intensiva Hospital Universitario la Fe	Valencia		Spain	46026
150	Sahlgrenska Universitetssjukhuset	Goteborg		Sweden	413 45
151	Uppsala University Hospital, Department of Infectious Diseases	Göteborg		Sweden	41650
152	Skånes Universitetssjukhus	Mamö		Sweden	205 02
153	Norrland Universitetssjukhus	Umeå		Sweden	901 85
154	Kaohsiung Medical University Hospital, Cancer Center	Kaohsiung		Taiwan	807
155	Far East Memorial Hospital	New Taipei		Taiwan	220
156	Wanfang Hospital	Taipei		Taiwan	116
157	Chang Gung Medical Foundation Linkou Branch	Taoyuan City		Taiwan	333
158	Kyiv City Clinical Hospital #4	Kyiv		Ukraine	03110
159	Kyiv City Clinical Hospital #9	Kyiv		Ukraine	04060
160	Municipal Institution City Clinical Infectious Diseases Hospital	Odesa		Ukraine	65023
161	Poltava Regional Clinical Infectious Hospital	Poltava		Ukraine	36011
162	Municipal Institution Central City Hospital #1 City of Zhytomyr	Zhytomyr		Ukraine	10002
163	Queen Elizabeth Hospital	Birmingham		United Kingdom	B15 2TH
164	Heart of England NHS Trust	Birmingham		United Kingdom	B9 5SS
165	Queen Elizabeth University Hospital	Glasgow		United Kingdom	G51 4TF
166	Leeds General Infirmary, Anaesthetic Department, D Floor	Leeds		United Kingdom	LS1 3EX
167	King College Hospital NHS Foundation Trust	London		United Kingdom	SE5 9RS
168	University College London Hospitals NHS Foundation Trust - University College Hospital	London		United Kingdom	WC1E 6AU
169	Southampton University Hospitals NHS Trust	Southampton		United Kingdom	SO16 6YD
170	University Hospitals of North Midlands NHS Trust-Royal Stoke University Hospital	Stoke-On-Trent		United Kingdom	ST4 6QG
171	Taunton and Somerset NHS Foundation Trust Musgrove Park Hospital	Taunton		United Kingdom	TA1 5DA

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 16, 2016

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT02293863
• Other Study ID Numbers: GV29216; 2014-000461-43
• First Posted: Nov 18, 2014
• Last Update Posted: Jun 18, 2018
• Last Verified: May 1, 2018

• Additional relevant MeSH terms: Influenza, Human; Oseltamivir

Study Results

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.

Arm/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Period Title: Overall Study
STARTED	56	55	47
COMPLETED	47	42	38
NOT COMPLETED	9	13	9

Baseline Characteristics

Arm/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir	Total
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Total of all reporting groups
Overall Participants	56	55	47	158
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.7 (17.5)	56.5 (18.2)	59.8 (17.9)	60.7 (18.2)
Sex: Female, Male (Count of Participants)
Female	24 42.9%	25 45.5%	22 46.8%	71 44.9%
Male	32 57.1%	30 54.5%	25 53.2%	87 55.1%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	13 23.2%	20 36.4%	8 17%	41 25.9%
Not Hispanic or Latino	37 66.1%	28 50.9%	34 72.3%	99 62.7%
Not Stated	6 10.7%	7 12.7%	5 10.6%	18 11.4%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska native	1 1.8%	0 0%	1 2.1%	2 1.3%
Asian	4 7.1%	0 0%	2 4.3%	6 3.8%
Black or African American	1 1.8%	1 1.8%	0 0%	2 1.3%
White	45 80.4%	44 80%	39 83%	128 81%
Multiple	0 0%	1 1.8%	0 0%	1 0.6%
Unknown	5 8.9%	9 16.4%	5 10.6%	19 12%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.

Arm/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	56	55	47
Number [percentage of participants]	80.4 143.6%	67.3 122.4%	74.5 158.5%

2. Primary Outcome

Title	Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	56	55	47
Positive for ATAs at baseline	0 0%	1 1.8%	1 2.1%
Treatment-induced ATAs	0 0%	0 0%	0 0%
Treatment-enhanced ATAs	0 0%	0 0%	0 0%

3. Primary Outcome

Title	Time to Normalization of Respiratory Function
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	54	52	44
Median (80% Confidence Interval) [days]	4.28	2.78	2.65

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6050
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 80%; 0.83 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2028
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 80%; 0.85 to 1.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	54	52	44
Day 1: Death	0.0 0%	0.0 0%	0.0 0%
Day 1: In ICU	42.6 76.1%	38.5 70%	43.2 91.9%
Day 1: Non-ICU, requiring supplemental O2	57.4 102.5%	61.5 111.8%	52.3 111.3%
Day 1: Non-ICU, not requiring supplemental O2	0.0 0%	0.0 0%	4.5 9.6%
Day 1: Not hospitalized	0.0 0%	0.0 0%	0.0 0%
Day 2: Death	0.0 0%	0.0 0%	2.3 4.9%
Day 2: In ICU	42.6 76.1%	38.5 70%	38.6 82.1%
Day 2: Non-ICU, requiring supplemental O2	40.7 72.7%	51.9 94.4%	31.8 67.7%
Day 2: Non-ICU, not requiring supplemental O2	11.1 19.8%	7.7 14%	20.5 43.6%
Day 2: Not hospitalized	5.6 10%	1.9 3.5%	6.8 14.5%
Day 3: Death	0.0 0%	0.0 0%	2.3 4.9%
Day 3: In ICU	37.0 66.1%	32.7 59.5%	34.1 72.6%
Day 3: Non-ICU, requiring supplemental O2	31.5 56.3%	42.3 76.9%	27.3 58.1%
Day 3: Non-ICU, not requiring supplemental O2	20.4 36.4%	19.2 34.9%	25.0 53.2%
Day 3: Not hospitalized	11.1 19.8%	5.8 10.5%	11.4 24.3%
Day 4: Death	0.0 0%	0.0 0%	2.3 4.9%
Day 4: In ICU	35.2 62.9%	30.8 56%	29.5 62.8%
Day 4: Non-ICU, requiring supplemental O2	25.9 46.3%	21.2 38.5%	18.2 38.7%
Day 4: Non-ICU, not requiring supplemental O2	22.2 39.6%	36.5 66.4%	29.5 62.8%
Day 4: Not hospitalized	16.7 29.8%	11.5 20.9%	20.5 43.6%
Day 5: Death	0.0 0%	0.0 0%	2.3 4.9%
Day 5: In ICU	27.8 49.6%	26.9 48.9%	27.3 58.1%
Day 5: Non-ICU, requiring supplemental O2	25.9 46.3%	19.2 34.9%	18.2 38.7%
Day 5: Non-ICU, not requiring supplemental O2	24.1 43%	34.6 62.9%	27.3 58.1%
Day 5: Not hospitalized	22.2 39.6%	19.2 34.9%	25.0 53.2%
Day 6: Death	1.9 3.4%	1.9 3.5%	2.3 4.9%
Day 6: In ICU	22.2 39.6%	23.1 42%	22.7 48.3%
Day 6: Non-ICU, requiring supplemental O2	22.2 39.6%	15.4 28%	15.9 33.8%
Day 6: Non-ICU, not requiring supplemental O2	27.8 49.6%	34.6 62.9%	25.0 53.2%
Day 6: Not hospitalized	25.9 46.3%	25.0 45.5%	34.1 72.6%
Day 7: Death	1.9 3.4%	1.9 3.5%	2.3 4.9%
Day 7: In ICU	18.5 33%	21.2 38.5%	20.5 43.6%
Day 7: Non-ICU, requiring supplemental O2	24.1 43%	13.5 24.5%	15.9 33.8%
Day 7: Non-ICU, not requiring supplemental O2	14.8 26.4%	28.8 52.4%	25.0 53.2%
Day 7: Not hospitalized	40.7 72.7%	34.6 62.9%	36.4 77.4%
Day 14: Death	1.9 3.4%	3.8 6.9%	6.8 14.5%
Day 14: In ICU	5.6 10%	11.5 20.9%	9.1 19.4%
Day 14: Non-ICU, requiring supplemental O2	7.4 13.2%	3.8 6.9%	6.8 14.5%
Day 14: Non-ICU, not requiring supplemental O2	14.8 26.4%	3.8 6.9%	4.5 9.6%
Day 14: Not hospitalized	70.4 125.7%	76.9 139.8%	72.7 154.7%
Day 30: Death	5.6 10%	7.7 14%	9.1 19.4%
Day 30: In ICU	1.9 3.4%	3.8 6.9%	4.5 9.6%
Day 30: Non-ICU, requiring supplemental O2	5.6 10%	1.9 3.5%	4.5 9.6%
Day 30: Non-ICU, not requiring supplemental O2	1.9 3.4%	3.8 6.9%	0.0 0%
Day 30: Not hospitalized	85.2 152.1%	82.7 150.4%	81.8 174%

5. Secondary Outcome

Title	Percentage of Participants With Clinical Failure
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	54	52	44
Number (80% Confidence Interval) [percentage of participants]	14.8 26.4%	25.0 45.5%	22.7 48.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1905
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	10.19
	Confidence Interval	(2-Sided) 80%; -0.15 to 20.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3168
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	7.91
	Confidence Interval	(2-Sided) 80%; -2.64 to 18.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With Clinical Resolution of Abnormal Vital Signs
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	54	52	44
Number (80% Confidence Interval) [percentage of participants]	81.3 145.2%	73.3 133.3%	66.7 141.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6043
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	-7.92
	Confidence Interval	(2-Sided) 80%; -27.50 to 11.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3865
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	-14.58
	Confidence Interval	(2-Sided) 80%; -36.13 to 6.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Participants Who Died Due to Any Cause
Time Frame	Days 14, 30 and 60

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	54	52	44
Day 14	1.9 3.4%	3.8 6.9%	6.8 14.5%
Day 30	5.6 10%	7.7 14%	9.1 19.4%
Day 60	7.4 13.2%	9.6 17.5%	9.1 19.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments	Day 14
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5379
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	1.99
	Confidence Interval	(2-Sided) 80%; -5.57 to 9.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments	Day 14
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2189
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	4.97
	Confidence Interval	(2-Sided) 80%; -3.12 to 13.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments	Day 30
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6594
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	2.14
	Confidence Interval	(2-Sided) 80%; -6.04 to 10.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments	Day 30
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5013
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	3.54
	Confidence Interval	(2-Sided) 80%; -5.24 to 12.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments	Day 60
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6849
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	2.21
	Confidence Interval	(2-Sided) 80%; -6.28 to 10.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments	Day 60
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7633
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	1.68
	Confidence Interval	(2-Sided) 80%; -7.38 to 10.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Area Under Viral Load-Time Curve (AUEC ) of Influenza A Virus
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	48	46	39
Mean (Standard Deviation) [log10 (vp/mL x hour).]	25.72 (15.92)	21.99 (16.57)	25.03 (13.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2407
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.73
	Confidence Interval	(2-Sided) 80%; -6.41 to -1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8339
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.70
	Confidence Interval	(2-Sided) 80%; -3.49 to 2.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Peak Influenza A Viral Load
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	48	46	39
Mean (Standard Deviation) [log10 vp/mL]	5.70 (1.32)	5.37 (1.39)	5.28 (1.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2790
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 80%; -0.60 to -0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1909
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 80%; -0.70 to -0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Duration of Viral Shedding
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	54	52	44
Median (80% Confidence Interval) [days]	4.00	4.63	4.60

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7413
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 80%; 0.77 to 1.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4763
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 80%; 0.99 to 1.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Duration of Hospitalization
Time Frame	From randomization up to 60 days

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	54	52	44
Median (80% Confidence Interval) [days]	8.95	7.65	6.69

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8806
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 80%; 0.78 to 1.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5447
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 80%; 0.80 to 1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Duration of Intensive Care Unit (ICU) Stay
Time Frame	From randomization up to 60 days

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	54	52	44
Median (80% Confidence Interval) [days]	4.66	6.60	5.29

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4171
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 80%; 0.47 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8322
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 80%; 0.61 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Percentage of Participants Using Antibiotics for Respiratory Infections
Time Frame	From randomization up to 60 days

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	54	52	44
Number (80% Confidence Interval) [percentage of participants]	13.0 23.2%	11.5 20.9%	11.4 24.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8240
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	-1.42
	Confidence Interval	(2-Sided) 80%; -10.61 to 7.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8111
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	-1.60
	Confidence Interval	(2-Sided) 80%; -11.48 to 8.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Percentage of Participants With Secondary Complications of Influenza
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	54	52	44
Number (80% Confidence Interval) [percentage of participants]	13.0 23.2%	15.4 28%	13.6 28.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7219
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	2.42
	Confidence Interval	(2-Sided) 80%; -6.96 to 11.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9225
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 80%; -9.29 to 10.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Percentage of Participants Readmitted to Hospital Due to Any Cause
Time Frame	Days 30 and 60

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	54	52	44
Number (80% Confidence Interval) [percentage of participants]	1.9 3.4%	3.8 6.9%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5379
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	1.99
	Confidence Interval	(2-Sided) 80%; -5.57 to 9.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3667
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in event rates
	Estimated Value	-1.85
	Confidence Interval	(2-Sided) 80%; -9.88 to 6.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Duration of Ventilation
Time Frame	From randomization up to 60 days

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Oseltamivir	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	54	52	44
Median (80% Confidence Interval) [days]	4.11	7.05	5.89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 3600 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7827
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 80%; 0.41 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Oseltamivir, MHAA4549A 8400 mg + Oseltamivir
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2522
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 80%; 0.36 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Area Under Serum Concentration-Time Curve From Time 0 to Infinity (AUC ) of MHAA4549A
Description	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)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-evaluable population included all participants, who received MHAA4549A and from whom evaluable PK samples were obtained.

Arm/Group Title	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	38	31
Mean (Standard Deviation) [day*mcg/mL]	11400 (4530)	26700 (9810)

18. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	38	31
Mean (Standard Deviation) [mcg/mL]	916 (294)	2220 (556)

19. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	38	31
Mean (Standard Deviation) [day]	19.0 (4.91)	17.8 (3.88)

20. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	38	31
Mean (Standard Deviation) [mL/day]	288 (158)	350 (130)

21. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MHAA4549A 3600 mg + Oseltamivir	MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.	Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
Measure Participants	38	31
Mean (Standard Deviation) [mL]	6410 (3170)	7450 (2270)

Adverse Events

Time Frame	From randomization up to 60 days
Adverse Event Reporting Description	Safety Population included all randomized participants who received study drug, with participants grouped according to the treatment actually received.
Arm/Group Title	Placebo + Oseltamivir		MHAA4549A 3600 mg + Oseltamivir		MHAA4549A 8400 mg + Oseltamivir
Arm/Group Description	Participants received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.		Participants received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.		Participants received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
All Cause Mortality
	Placebo + Oseltamivir		MHAA4549A 3600 mg + Oseltamivir		MHAA4549A 8400 mg + Oseltamivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/56 (7.1%)		6/55 (10.9%)		4/47 (8.5%)
Serious Adverse Events
	Placebo + Oseltamivir		MHAA4549A 3600 mg + Oseltamivir		MHAA4549A 8400 mg + Oseltamivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/56 (14.3%)		11/55 (20%)		12/47 (25.5%)
Blood and lymphatic system disorders
Anaemia	1/56 (1.8%)		0/55 (0%)		0/47 (0%)
Cardiac disorders
Acute myocardial infarction	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
Atrial fibrillation	1/56 (1.8%)		0/55 (0%)		0/47 (0%)
Cardio-respiratory arrest	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
Myocardial ischaemia	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
Gastrointestinal disorders
Abdominal wall haematoma	0/56 (0%)		0/55 (0%)		1/47 (2.1%)
Intestinal ischaemia	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
Upper gastrointestinal haemorrhage	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
General disorders
Multiple organ dysfunction syndrome	0/56 (0%)		1/55 (1.8%)		1/47 (2.1%)
Ulcer	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
Infections and infestations
Pneumonia	1/56 (1.8%)		3/55 (5.5%)		3/47 (6.4%)
Septic shock	2/56 (3.6%)		1/55 (1.8%)		0/47 (0%)
Bronchitis	0/56 (0%)		0/55 (0%)		1/47 (2.1%)
Pneumonia bacterial	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
Tonsillitis	0/56 (0%)		0/55 (0%)		1/47 (2.1%)
Injury, poisoning and procedural complications
Suture rupture	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
Traumatic intracranial haemorrhage	1/56 (1.8%)		0/55 (0%)		0/47 (0%)
Metabolism and nutrition disorders
Hypomagnesaemia	1/56 (1.8%)		0/55 (0%)		0/47 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
Nervous system disorders
Intensive care unit acquired weakness	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
Ischaemic stroke	1/56 (1.8%)		0/55 (0%)		0/47 (0%)
Renal and urinary disorders
Acute kidney injury	1/56 (1.8%)		0/55 (0%)		1/47 (2.1%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/56 (0%)		1/55 (1.8%)		2/47 (4.3%)
Acute respiratory distress syndrome	0/56 (0%)		1/55 (1.8%)		1/47 (2.1%)
Acute pulmonary oedema	1/56 (1.8%)		0/55 (0%)		0/47 (0%)
Aspiration	1/56 (1.8%)		0/55 (0%)		0/47 (0%)
Dyspnoea	0/56 (0%)		0/55 (0%)		1/47 (2.1%)
Pneumomediastinum	0/56 (0%)		0/55 (0%)		1/47 (2.1%)
Pulmonary congestion	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
Respiratory distress	1/56 (1.8%)		0/55 (0%)		0/47 (0%)
Respiratory failure	0/56 (0%)		0/55 (0%)		1/47 (2.1%)
Surgical and medical procedures
Extubation	0/56 (0%)		0/55 (0%)		1/47 (2.1%)
Vascular disorders
Haemorrhage	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
Hypotension	0/56 (0%)		0/55 (0%)		1/47 (2.1%)
Hypovolaemic shock	0/56 (0%)		1/55 (1.8%)		0/47 (0%)
Other (Not Including Serious) Adverse Events
	Placebo + Oseltamivir		MHAA4549A 3600 mg + Oseltamivir		MHAA4549A 8400 mg + Oseltamivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/56 (50%)		26/55 (47.3%)		18/47 (38.3%)
Blood and lymphatic system disorders
Anaemia	3/56 (5.4%)		3/55 (5.5%)		2/47 (4.3%)
Cardiac disorders
Atrial fibrillation	3/56 (5.4%)		4/55 (7.3%)		2/47 (4.3%)
Gastrointestinal disorders
Diarrhoea	7/56 (12.5%)		3/55 (5.5%)		0/47 (0%)
Nausea	4/56 (7.1%)		4/55 (7.3%)		1/47 (2.1%)
Constipation	2/56 (3.6%)		4/55 (7.3%)		2/47 (4.3%)
Vomiting	3/56 (5.4%)		2/55 (3.6%)		2/47 (4.3%)
General disorders
Pyrexia	2/56 (3.6%)		4/55 (7.3%)		2/47 (4.3%)
Metabolism and nutrition disorders
Hypokalaemia	4/56 (7.1%)		2/55 (3.6%)		4/47 (8.5%)
Hypophosphataemia	4/56 (7.1%)		2/55 (3.6%)		2/47 (4.3%)
Hyperglycaemia	1/56 (1.8%)		3/55 (5.5%)		2/47 (4.3%)
Hyperkalaemia	1/56 (1.8%)		1/55 (1.8%)		3/47 (6.4%)
Hypoglycaemia	1/56 (1.8%)		3/55 (5.5%)		1/47 (2.1%)
Nervous system disorders
Headache	2/56 (3.6%)		2/55 (3.6%)		3/47 (6.4%)
Psychiatric disorders
Agitation	4/56 (7.1%)		3/55 (5.5%)		1/47 (2.1%)
Renal and urinary disorders
Haematuria	3/56 (5.4%)		5/55 (9.1%)		0/47 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/56 (1.8%)		1/55 (1.8%)		3/47 (6.4%)
Vascular disorders
Hypertension	7/56 (12.5%)		1/55 (1.8%)		4/47 (8.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.