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

Influenza Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02293863
• Other study ID #: GV29216
• Secondary ID: 2014-000461-43
• Status: Completed
• Phase: Phase 2
• Start date: January 14, 2015
• Est. completion date: May 23, 2017

Study information

• Verified date: May 2018
• Source: Genentech, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 168
• Est. completion date: May 23, 2017
• Est. primary completion date: May 23, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Influenza
• Influenza, Human

Intervention

Drug:
• MHAA4549A
Participants will receive a single dose of MHAA4549A by IV infusion on Day 1
• 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.
• Placebo
Participants will receive a single IV dose of placebo matched to MHAA4549A on Day 1

Locations

Country	Name	City	State
Belgium	CHU St Pierre (St Pierre)	Brussels
Belgium	Hospital Erasme; Neurologie	Bruxelles
Belgium	UZ Leuven Gasthuisberg	Leuven
Belgium	CHU UCL Mont-Godinne	Mont-godinne
Brazil	Santa Casa de Misericordia; de Belo Horizonte	Belo Horizonte	MG
Brazil	PUC Campinas	Campinas	SP
Brazil	Hospital Sao Vicente de Paulo	Passo Fundo	RS
Brazil	FUNFARME	Sao Jose do Rio Preto	SP
Brazil	Hospital Alemao Oswaldo Cruz; Oncologia	Sao Paulo	SP
Brazil	Hospital Edmundo Vasconcelos	Vila Clementino	SP
Bulgaria	MHAT "Dr. Tota Venkova"- Gabrovo	Gabrovo
Bulgaria	University Multiprofile Hospital for Active Treatment "St. George"	Plovdiv
Bulgaria	SHATPPD Dr. Dimitar Gramatikov, Ruse Ltd.	Ruse
Bulgaria	Multiprofile Hospital for Active Treatment AKTA-MEDIKA EOOD	Sevlievo
Bulgaria	5th Multifunctional Hospital for Active treatment	Sofia
Bulgaria	MHAT Lyulin EAD, Department of internal diseases	Sofia
Bulgaria	MHAT TOKUDA SOFIA/ICU-Intensive Care Unit	Sofia
Bulgaria	Military Medical Academy- MHAT	Sofia
Bulgaria	University Multiprofile Hospital for Active Treatment and Emergency Medicine N. I. Pirogov EAD	Sofia
Bulgaria	MBAL St Marina Dep Pulmonology, ICU	Varna
Bulgaria	Multiprofile District Hospital for Active Treatment Dr. Stefan Cherkezov AD	Veliko Tarnovo
Canada	Alberta Health Services	Calgary	Alberta
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	Peter Lougheed Centre	Calgary	Alberta
Canada	Rockyview General Hospital	Calgary	Alberta
Canada	LHSC - University Hospital; Research Pharmacy	London	Ontario
Canada	Moncton Hospital	Moncton	New Brunswick
Canada	Royal Columbian Hospital	New Westminster	British Columbia
Canada	Lakeridge Health	Oshawa	Ontario
Canada	Ottawa Hospital Research Institute	Ottawa	Ontario
Canada	The Ottawa Hospital - Civic Campus	Ottawa	Ontario
Canada	Centre Hospitalier de la Universite Laval	Quebec City	Quebec
Canada	Pavillion Chul-Chuq	Sainte-foy	Quebec
Canada	Toronto East General	Toronto	Ontario
Canada	Toronto Western Hospital	Toronto	Ontario
Canada	University Health Network	Toronto	Ontario
Canada	Centre de santé et de services sociaux de Trois-Rivières	Trois-Rivieres	Quebec
Canada	St. Paul's Hospital, Providence Health Care	Vancouver	British Columbia
Canada	Victoria General Hospital	Victora	British Columbia
Canada	Royal Jubilee Hospital Victoria general Hospital	Victoria	British Columbia
Chile	Hospital Dr. Hernan Henriquez Aravena	Temuco
Chile	Clinica Renaca	Vina del Mar
Czechia	The University Hospital Brno	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czechia	Anesthesia and Intensive Care Dept., Regional Hospital Liberec	Liberec
Czechia	University hospital Ostrava, Clinic of infectious medicine	Ostrava
Czechia	Fakultni nemocnice Kralovske Vinohrady, Klinika anesteziologie a resuscitace	Praha 10
France	CH Victor Dupouy	Argenteuil
France	Centre Hospitalier Universitaire de Clermont Ferrand	Clermont-ferrand
France	Service de Réanimation médicale - Bocage Central	Dijon
France	APHP Raymond Poincare	Garches
France	CHD Vendée	La Roche Sur Yon
France	CHRU Lille	Lille
France	Réanimation Polyvalente, CHU Limoges	Limoges
France	CHRU Nancy	Nancy
France	Archet 1 university Hospital	Nice
France	HOPITAL COCHIN university hospital	Paris
France	Hopital Universitaire Hautepierre	Strasbourg
France	Réanimation médicale NHC	Strasbourg
France	Service de réanimation médicale, Hôpital Bretonneau	Tours
Germany	Universitätsklinikum Frankfurt Goethe Universität	Frankfurt
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Uniklinik Köln, Medizinischen Klinik I	Koeln
Germany	Uniklinikum Mainz	Mainz
Germany	Uniklinik Tübingen	Tuebingen
Hong Kong	University of Hong Kong	Hong Kong
Hungary	Pest Megyei Flor Ferenc Korhaz	Kistarcsa
Hungary	Jávorszky Ödön Hospital	Vác
Hungary	Csolnoky Ferenc Kórház	Veszprém
Hungary	Zala County Hospital ICU	Zalaegerszeg
Israel	Haemek Medical Center	Afula
Israel	Soroka University Medical Centre	Beer-Sheva
Israel	Wolfson Medical Center	Holon
Israel	Hadasit Medical Research Services and Development Ltd	Jerusalem
Israel	Galilee Medical Center	Nahariya
Israel	Nazareth EMMS Hospital	Nazareth
Israel	Rabin Medical Center	Petah Tikva
Israel	Kaplan Medical Center	Rehovot
Israel	Tel-Aviv Sourasky Medical Center	Tel Aviv
Israel	Chaim Sheba Medical Center	Tel Hashomer
Israel	Ziv Medical Center	Zefat
Italy	Clinic of Infectious Diseases	Bologna	Emilia-Romagna
Italy	University Division of Infective and Tropical Diseases, University of Brescia, Italy	Brescia	Basilicata
Italy	Asst Di Cremona	Cremona	Lombardia
Italy	Ospedale San Raffaele - Milano	Milano	Lombardia
Italy	University Hospital Modena, Intensive Care Unit	Modena	Emilia-Romagna
Italy	National Institute for Infectious Diseases "L. Spallanzani"	Rome	Lazio
Italy	A.O.U. S. Giovanni di Dio e Ruggi d'Aragona	Salerno	Sardegna
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Gachon University Gil Hospital	Incheon
Korea, Republic of	Hallym university Kangnam Sacred Heart Hospital; Infectious devision	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Yonsei University Health System/Severance Hospital	Seoul
Korea, Republic of	Wonju Severance Christian Hospital	Wonju
Mexico	Hospital Civil de Guadalajara Dr Juan I Menchaca	Guadalajara
Mexico	Hospital Civil de Guadalajara Fray Antonio Alcalde	Guadalajara
Mexico	Instituto Nacional de Ciencias; Medicas y Nutricion; Salvador Zubiran	Mexico, Distrito Federal
Mexico	CEPREP; Hospital Universitario	Monterrey
Mexico	Hospital General de Tijuana	Tijuana
Mexico	Centro de Especialidades Medicas Del Estado de Veracruz Dr Rafael Lucio	Xalapa-enriquez
Netherlands	Jeroen Bosch Ziekenhuis	'S Hertogenbosch
Netherlands	Gelre Ziekenhuizen Apeldoorn; Hospitals Pharmacy	Apeldoorn
Netherlands	LUMC	Leiden
Netherlands	UMC Radboud Nijmegen	Nijmegen
Netherlands	Erasmus Medical Centre; Department of Virology L-359	Rotterdam
Netherlands	Ikazia Hospital	Rotterdam
Netherlands	UMCU	Utrecht
Netherlands	Isala	Zwolle
New Zealand	Auckland City Hospital	Auckland
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Tauranga Hospital	Tauranga
Peru	Hospital Regional del Cusco	Cusco
Peru	Hospital Nacional Adolfo Guevara Velasco	Cuzco
Peru	Hospital Guillermo Almenara Irigoyen Hospital Guillermo Almenara Irigoyen Hospital Guillermo Almen	La Victoria
Peru	Clinica Internacional Sede Lima	LIma
Peru	Clinica San Borja	Lima
Peru	Clínica San Gabriel	Lima
Peru	Hospital Central Fuerza; Aerea del Peru	Lima
Peru	Hospital Maria Auxiliadora	Lima
Peru	Hospital Nacional Hipolito; Unanue	Lima
Peru	Hospital Nacional; Arzobispo Loayza	LIma
Peru	Hospital de la Amistad Peru Corea II-2 Santa Rosa	Piura
Peru	Clinica Divino Nino Jesus; Orden de Malta	San Juan de Miraflores
Peru	Clinica Peruana Americana	Trujillo
Poland	Oddzial Anestezjologii i Intensywnej Terapii Wojewódzki Specjalistyczny Szpital im dr Wl Biegansk	Lódz
Poland	Wojewodzki Szpital Specjalistyczny	Lublin
Poland	Icu Spsk - 2	Szczecin
Poland	Oddzial Anestezjologii i Intensywnej Terapii;Wojewódzki Szpital Zespolony im. L. Rydygiera	Torun
Russian Federation	Municipal Clinical Hospital #8	Chelyabinsk
Russian Federation	Municipal Healthcare Institution "City Hospital ?2"	Engels
Russian Federation	Medical Military Academy n.a S.M.Kirov	St.Petersburg
Russian Federation	Paciific state medical university	Vladivostok
South Africa	Milpark Hospital	Parktown West
South Africa	Emmed Research	Pretoria
South Africa	Clinical Projects Research	Worcester
Spain	Bellvitge University Hospital	Barcelona
Spain	Hospital Clinic	Barcelona	Cantabria
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario San Cecilio	Granada
Spain	Hosp. Clinico San Carlos	Madrid
Spain	Hospital Univ. de Getafe.Servicio de Neurologia	Madrid
Spain	Hospital de Mataro	Mataro	Cantabria
Spain	Hospital Universitario Son Espases	Palma de Mallorca	Islas Baleares
Spain	Hospital Universitario Marques de Valdecilla	Santander	Cantabria
Spain	Joan XXIII University Hospital	Tarragona
Spain	Mutua de Terrassa	Terrassa	Barcelona
Spain	Servicio de Medicina Intensiva Hospital Universitario la Fe	Valencia
Sweden	Sahlgrenska Universitetssjukhuset	Goteborg
Sweden	Uppsala University Hospital, Department of Infectious Diseases	Göteborg
Sweden	Skånes Universitetssjukhus	Mamö
Sweden	Norrland Universitetssjukhus	Umeå
Taiwan	Kaohsiung Medical University Hospital, Cancer Center	Kaohsiung
Taiwan	Far East Memorial Hospital	New Taipei
Taiwan	Wanfang Hospital	Taipei
Taiwan	Chang Gung Medical Foundation Linkou Branch	Taoyuan City
Ukraine	Kyiv City Clinical Hospital #4	Kyiv
Ukraine	Kyiv City Clinical Hospital #9	Kyiv
Ukraine	Municipal Institution City Clinical Infectious Diseases Hospital	Odesa
Ukraine	Poltava Regional Clinical Infectious Hospital	Poltava
Ukraine	Municipal Institution Central City Hospital #1 City of Zhytomyr	Zhytomyr
United Kingdom	Heart of England NHS Trust	Birmingham
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	Queen Elizabeth University Hospital	Glasgow
United Kingdom	Leeds General Infirmary, Anaesthetic Department, D Floor	Leeds
United Kingdom	King College Hospital NHS Foundation Trust	London
United Kingdom	University College London Hospitals NHS Foundation Trust - University College Hospital	London
United Kingdom	Southampton University Hospitals NHS Trust	Southampton
United Kingdom	University Hospitals of North Midlands NHS Trust-Royal Stoke University Hospital	Stoke-On-Trent
United Kingdom	Taunton and Somerset NHS Foundation Trust Musgrove Park Hospital	Taunton

Sponsors (1)

Lead Sponsor	Collaborator
Genentech, Inc.

Countries where clinical trial is conducted

Belgium,  Brazil,  Bulgaria,  Canada,  Chile,  Czechia,  France,  Germany,  Hong Kong,  Hungary,  Israel,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  New Zealand,  Peru,  Poland,  Russian Federation,  South Africa,  Spain,  Sweden,  Taiwan,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Adverse Events	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	From randomization up to 60 days
Primary	Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A	Reported are the number of participants positive for ATAs at baseline, the number of participants with treatment-induced ATAs and the number of participants with treatment-enhanced ATAs.	From randomization up to 60 days
Primary	Time to Normalization of Respiratory Function	The time to normalization of respiratory function was defined as the time to removal of the participant from oxygen (O2) supplementation in order to maintain a blood oxygen saturation level (SpO2) equal to or greater than 95% as measured by pulse oximetry.	From randomization up to 60 days
Secondary	Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome	The clinical status of participants was defined by five mutually exclusive categories: 1. Death; 2. In the Intensive Care Unit (ICU); 3. Non-ICU hospitalization, requiring supplemental oxygen (O2); 4. Non-ICU hospitalization, not requiring supplemental oxygen (O2); 5. Not hospitalized.	Days 1-7, 14 and 30
Secondary	Percentage of Participants With Clinical Failure	Clinical failure after 24 hours post-infusion of study drug was defined as progression to increased O2 requirement defined by an increase in oxygen supplementation from low flow oxygen (i.e., 2-6 liters per minute [L/min]) to high flow oxygen (i.e., > 6 L/min) or from oxygen supplementation alone to any positive pressure ventilation (PPV) or extracorporeal membrane oxygenation (ECMO), progression to ICU, prolonged ventilation or O2 support defined by > 2 weeks, or death.	24 hours after end of infusion (infusion duration = approximately 120 minutes) up to Day 60
Secondary	Percentage of Participants With Clinical Resolution of Abnormal Vital Signs	Description: Clinical resolution of abnormal vital signs was defined as meeting three out of five of the following criteria: 1. SpO2 = 95% without supplemental O2; 2. Respiratory rate < 24 breaths per minute without supplemental O2; 3. Core temperature < 37.2 Celsius (C) immediately prior to receipt of any antipyretic drug, and at least 6-8 hours from the last dose of antipyretic or core temperature > 36 C in participants who are initially hypothermic; 4. Heart rate (HR) < 100 beats/minute; 5. Systolic blood pressure (SBP) >90 mmHg. Reported here is the percentage of participants who had clinical resolution of at least three out of five abnormal vital signs by the end of study.	From randomization up to 60 days
Secondary	Percentage of Participants Who Died Due to Any Cause		Days 14, 30 and 60
Secondary	Area Under Viral Load-Time Curve (AUEC ) of Influenza A Virus	Influenza A viral load was measured by quantitative polymerase chain reaction (qPCR) in nasopharyngeal samples at multiple time points during the study. AUEC is the area under the viral load-time curve expressed as log10 (viral particles/milliliter x hour) = log10 (vp/mL x hour).	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)
Secondary	Peak Influenza A Viral Load	Influenza A viral load was measured by qPCR in nasopharyngeal samples at multiple time points during the study. Reported here is the peak Influenza A viral load expressed as log10 vp/mL.	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)
Secondary	Duration of Viral Shedding	Influenza A viral load was measured by qPCR in nasopharyngeal samples at multiple time points during the study. Reported here is the duration of viral shedding.	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)
Secondary	Duration of Hospitalization		From randomization up to 60 days
Secondary	Duration of Intensive Care Unit (ICU) Stay		From randomization up to 60 days
Secondary	Percentage of Participants Using Antibiotics for Respiratory Infections		From randomization up to 60 days
Secondary	Percentage of Participants With Secondary Complications of Influenza	The following were considered secondary complications of influenza: pneumonia, including hospital-acquired pneumonia (HAP) and ventilation-acquired pneumonia (VAP), exacerbations of chronic lung disease, myocarditis, acute respiratory distress syndrome (ARDS), otitis media, or other related complications.	From randomization up to 60 days
Secondary	Percentage of Participants Readmitted to Hospital Due to Any Cause		Days 30 and 60
Secondary	Duration of Ventilation		From randomization up to 60 days
Secondary	Area Under Serum Concentration-Time Curve From Time 0 to Infinity (AUC ) of MHAA4549A	AUC0-inf is reported as day*microgram/milliliter (day*mcg/mL).	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)