Clinical trial NCT02293863: A Study of MHAA4549A in Combination With Oseltamivir Versus Oseltamivir in Participants With Severe Influenza A Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Influenza
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2014-11-18
Enrollment: 168
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Adverse Events
timeFrame: From randomization up to 60 days
measure: Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A
timeFrame: From randomization up to 60 days
measure: Time to Normalization of Respiratory Function
timeFrame: From randomization up to 60 days
Secondary outcomes:
measure: Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome
timeFrame: Days 1-7, 14 and 30
measure: Percentage of Participants With Clinical Failure
timeFrame: 24 hours after end of infusion (infusion duration = approximately 120 minutes) up to Day 60
measure: Percentage of Participants With Clinical Resolution of Abnormal Vital Signs
timeFrame: From randomization up to 60 days
measure: Percentage of Participants Who Died Due to Any Cause
timeFrame: Days 14, 30 and 60
measure: Area Under Viral Load-Time Curve (AUEC ) of Influenza A Virus
timeFrame: Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60)
measure: Peak Influenza A Viral Load
timeFrame: Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60)
measure: Duration of Viral Shedding
timeFrame: Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60)
measure: Duration of Hospitalization
timeFrame: From randomization up to 60 days
measure: Duration of Intensive Care Unit (ICU) Stay
timeFrame: From randomization up to 60 days
measure: Percentage of Participants Using Antibiotics for Respiratory Infections
timeFrame: From randomization up to 60 days
measure: Percentage of Participants With Secondary Complications of Influenza
timeFrame: From randomization up to 60 days
measure: Percentage of Participants Readmitted to Hospital Due to Any Cause
timeFrame: Days 30 and 60
measure: Duration of Ventilation
timeFrame: From randomization up to 60 days
measure: Area Under Serum Concentration-Time Curve From Time 0 to Infinity (AUC ) of MHAA4549A
timeFrame: 30 minutes (min) before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
measure: Maximum Serum Concentration (Cmax ) of MHAA4549A
timeFrame: 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
measure: Elimination Half-Life (Terminal t1/2) of MHAA4549A
timeFrame: 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
measure: Observed Clearance (CL-obs) of MHAA4549A
timeFrame: 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
measure: Observed Steady State Volume of Distribution (Vss_obs) of MHAA4549A
timeFrame: 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: CHU St Pierre (St Pierre)
city: Bruxelles
country: Belgium
facility: Hospital Erasme; Neurologie
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Mont-godinne
country: Belgium
facility: CHU UCL Mont-Godinne
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericordia; de Belo Horizonte
state: MG
city: Passo Fundo
country: Brazil
facility: Hospital Sao Vicente de Paulo
state: RS
city: Campinas
country: Brazil
facility: PUC Campinas
state: SP
city: Sao Jose do Rio Preto
country: Brazil
facility: FUNFARME
state: SP
city: Sao Paulo
country: Brazil
facility: Hospital Alemao Oswaldo Cruz; Oncologia
state: SP
city: Vila Clementino
country: Brazil
facility: Hospital Edmundo Vasconcelos
state: SP
city: Gabrovo
country: Bulgaria
facility: MHAT "Dr. Tota Venkova"- Gabrovo
city: Plovdiv
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment "St. George"
city: Ruse
country: Bulgaria
facility: SHATPPD Dr. Dimitar Gramatikov, Ruse Ltd.
city: Sevlievo
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment AKTA-MEDIKA EOOD
city: Sofia
country: Bulgaria
facility: MHAT Lyulin EAD, Department of internal diseases
city: Sofia
country: Bulgaria
facility: MHAT TOKUDA SOFIA/ICU-Intensive Care Unit
city: Sofia
country: Bulgaria
facility: 5th Multifunctional Hospital for Active treatment
city: Sofia
country: Bulgaria
facility: Military Medical Academy- MHAT
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment and Emergency Medicine N. I. Pirogov EAD
city: Varna
country: Bulgaria
facility: MBAL St Marina Dep Pulmonology, ICU
city: Veliko Tarnovo
country: Bulgaria
facility: Multiprofile District Hospital for Active Treatment Dr. Stefan Cherkezov AD
city: Calgary
country: Canada
facility: Peter Lougheed Centre
state: Alberta
city: Calgary
country: Canada
facility: Alberta Health Services
state: Alberta
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Calgary
country: Canada
facility: Rockyview General Hospital
state: Alberta
city: New Westminster
country: Canada
facility: Royal Columbian Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St. Paul's Hospital, Providence Health Care
state: British Columbia
city: Victora
country: Canada
facility: Victoria General Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Royal Jubilee Hospital Victoria general Hospital
state: British Columbia
city: Moncton
country: Canada
facility: Moncton Hospital
state: New Brunswick
city: London
country: Canada
facility: LHSC - University Hospital; Research Pharmacy
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital - Civic Campus
state: Ontario
city: Toronto
country: Canada
facility: Toronto East General
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Toronto
country: Canada
facility: Toronto Western Hospital
state: Ontario
city: Quebec City
country: Canada
facility: Centre Hospitalier de la Universite Laval
state: Quebec
city: Sainte-foy
country: Canada
facility: Pavillion Chul-Chuq
state: Quebec
city: Trois-Rivieres
country: Canada
facility: Centre de santé et de services sociaux de Trois-Rivières
state: Quebec
city: Temuco
country: Chile
facility: Hospital Dr. Hernan Henriquez Aravena
city: Vina del Mar
country: Chile
facility: Clinica Renaca
city: Brno
country: Czechia
facility: The University Hospital Brno
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Liberec
country: Czechia
facility: Anesthesia and Intensive Care Dept., Regional Hospital Liberec
city: Ostrava
country: Czechia
facility: University hospital Ostrava, Clinic of infectious medicine
city: Praha 10
country: Czechia
facility: Fakultni nemocnice Kralovske Vinohrady, Klinika anesteziologie a resuscitace
city: Argenteuil
country: France
facility: CH Victor Dupouy
city: Clermont-ferrand
country: France
facility: Centre Hospitalier Universitaire de Clermont Ferrand
city: Dijon
country: France
facility: Service de Réanimation médicale - Bocage Central
city: Garches
country: France
facility: APHP Raymond Poincare
city: La Roche Sur Yon
country: France
facility: CHD Vendée
city: Lille
country: France
facility: CHRU Lille
city: Limoges
country: France
facility: Réanimation Polyvalente, CHU Limoges
city: Nancy
country: France
facility: CHRU Nancy
city: Nice
country: France
facility: Archet 1 university Hospital
city: Paris
country: France
facility: HOPITAL COCHIN university hospital
city: Strasbourg
country: France
facility: Réanimation médicale NHC
city: Strasbourg
country: France
facility: Hopital Universitaire Hautepierre
city: Tours
country: France
facility: Service de réanimation médicale, Hôpital Bretonneau
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt Goethe Universität
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Koeln
country: Germany
facility: Uniklinik Köln, Medizinischen Klinik I
city: Mainz
country: Germany
facility: Uniklinikum Mainz
city: Tuebingen
country: Germany
facility: Uniklinik Tübingen
city: Hong Kong
country: Hong Kong
facility: University of Hong Kong
city: Kistarcsa
country: Hungary
facility: Pest Megyei Flor Ferenc Korhaz
city: Veszprém
country: Hungary
facility: Csolnoky Ferenc Kórház
city: Vác
country: Hungary
facility: Jávorszky Ödön Hospital
city: Zalaegerszeg
country: Hungary
facility: Zala County Hospital ICU
city: Afula
country: Israel
facility: Haemek Medical Center
city: Beer-Sheva
country: Israel
facility: Soroka University Medical Centre
city: Holon
country: Israel
facility: Wolfson Medical Center
city: Jerusalem
country: Israel
facility: Hadasit Medical Research Services and Development Ltd
city: Nahariya
country: Israel
facility: Galilee Medical Center
city: Nazareth
country: Israel
facility: Nazareth EMMS Hospital
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
city: Rehovot
country: Israel
facility: Kaplan Medical Center
city: Tel Aviv
country: Israel
facility: Tel-Aviv Sourasky Medical Center
city: Tel Hashomer
country: Israel
facility: Chaim Sheba Medical Center
city: Zefat
country: Israel
facility: Ziv Medical Center
city: Brescia
country: Italy
facility: University Division of Infective and Tropical Diseases, University of Brescia, Italy
state: Basilicata
city: Bologna
country: Italy
facility: Clinic of Infectious Diseases
state: Emilia-Romagna
city: Modena
country: Italy
facility: University Hospital Modena, Intensive Care Unit
state: Emilia-Romagna
city: Rome
country: Italy
facility: National Institute for Infectious Diseases "L. Spallanzani"
state: Lazio
city: Cremona
country: Italy
facility: Asst Di Cremona
state: Lombardia
city: Milano
country: Italy
facility: Ospedale San Raffaele - Milano
state: Lombardia
city: Salerno
country: Italy
facility: A.O.U. S. Giovanni di Dio e Ruggi d'Aragona
state: Sardegna
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System/Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Hallym university Kangnam Sacred Heart Hospital; Infectious devision
city: Wonju
country: Korea, Republic of
facility: Wonju Severance Christian Hospital
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara Dr Juan I Menchaca
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara Fray Antonio Alcalde
city: Mexico, Distrito Federal
country: Mexico
facility: Instituto Nacional de Ciencias; Medicas y Nutricion; Salvador Zubiran
city: Monterrey
country: Mexico
facility: CEPREP; Hospital Universitario
city: Tijuana
country: Mexico
facility: Hospital General de Tijuana
city: Xalapa-enriquez
country: Mexico
facility: Centro de Especialidades Medicas Del Estado de Veracruz Dr Rafael Lucio
city: 'S Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuizen Apeldoorn; Hospitals Pharmacy
city: Leiden
country: Netherlands
facility: LUMC
city: Nijmegen
country: Netherlands
facility: UMC Radboud Nijmegen
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Centre; Department of Virology L-359
city: Rotterdam
country: Netherlands
facility: Ikazia Hospital
city: Utrecht
country: Netherlands
facility: UMCU
city: Zwolle
country: Netherlands
facility: Isala
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Tauranga
country: New Zealand
facility: Tauranga Hospital
city: Cusco
country: Peru
facility: Hospital Regional del Cusco
city: Cuzco
country: Peru
facility: Hospital Nacional Adolfo Guevara Velasco
city: La Victoria
country: Peru
facility: Hospital Guillermo Almenara Irigoyen Hospital Guillermo Almenara Irigoyen Hospital Guillermo Almen
city: LIma
country: Peru
facility: Clinica Internacional Sede Lima
city: LIma
country: Peru
facility: Hospital Nacional; Arzobispo Loayza
city: Lima
country: Peru
facility: Hospital Nacional Hipolito; Unanue
city: Lima
country: Peru
facility: Hospital Central Fuerza; Aerea del Peru
city: Lima
country: Peru
facility: Hospital Maria Auxiliadora
city: Lima
country: Peru
facility: Clínica San Gabriel
city: Lima
country: Peru
facility: Clinica San Borja
city: Piura
country: Peru
facility: Hospital de la Amistad Peru Corea II-2 Santa Rosa
city: San Juan de Miraflores
country: Peru
facility: Clinica Divino Nino Jesus; Orden de Malta
city: Trujillo
country: Peru
facility: Clinica Peruana Americana
city: Lublin
country: Poland
facility: Wojewodzki Szpital Specjalistyczny
city: Szczecin
country: Poland
facility: Icu Spsk - 2
city: Toruń
country: Poland
facility: Oddział Anestezjologii i Intensywnej Terapii;Wojewódzki Szpital Zespolony im. L. Rydygiera
city: Łódź
country: Poland
facility: Oddział Anestezjologii i Intensywnej Terapii Wojewódzki Specjalistyczny Szpital im dr Wł Biegańsk
city: Chelyabinsk
country: Russian Federation
facility: Municipal Clinical Hospital #8
city: Engels
country: Russian Federation
facility: Municipal Healthcare Institution "City Hospital №2"
city: St.Petersburg
country: Russian Federation
facility: Medical Military Academy n.a S.M.Kirov
city: Vladivostok
country: Russian Federation
facility: Paciific state medical university
city: Parktown West
country: South Africa
facility: Milpark Hospital
city: Pretoria
country: South Africa
facility: Emmed Research
city: Worcester
country: South Africa
facility: Clinical Projects Research
city: Terrassa
country: Spain
facility: Mutua de Terrassa
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Clinic
state: Cantabria
city: Mataro
country: Spain
facility: Hospital de Mataro
state: Cantabria
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
state: Cantabria
city: Palma de Mallorca
country: Spain
facility: Hospital Universitario Son Espases
state: Islas Baleares
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Bellvitge University Hospital
city: Granada
country: Spain
facility: Hospital Universitario San Cecilio
city: Madrid
country: Spain
facility: Hosp. Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Univ. de Getafe.Servicio de Neurologia
city: Tarragona
country: Spain
facility: Joan XXIII University Hospital
city: Valencia
country: Spain
facility: Servicio de Medicina Intensiva Hospital Universitario la Fe
city: Goteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Göteborg
country: Sweden
facility: Uppsala University Hospital, Department of Infectious Diseases
city: Mamö
country: Sweden
facility: Skånes Universitetssjukhus
city: Umeå
country: Sweden
facility: Norrland Universitetssjukhus
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Hospital, Cancer Center
city: New Taipei
country: Taiwan
facility: Far East Memorial Hospital
city: Taipei
country: Taiwan
facility: Wanfang Hospital
city: Taoyuan City
country: Taiwan
facility: Chang Gung Medical Foundation Linkou Branch
city: Kyiv
country: Ukraine
facility: Kyiv City Clinical Hospital #4
city: Kyiv
country: Ukraine
facility: Kyiv City Clinical Hospital #9
city: Odesa
country: Ukraine
facility: Municipal Institution City Clinical Infectious Diseases Hospital
city: Poltava
country: Ukraine
facility: Poltava Regional Clinical Infectious Hospital
city: Zhytomyr
country: Ukraine
facility: Municipal Institution Central City Hospital #1 City of Zhytomyr
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Birmingham
country: United Kingdom
facility: Heart of England NHS Trust
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary, Anaesthetic Department, D Floor
city: London
country: United Kingdom
facility: King College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust - University College Hospital
city: Southampton
country: United Kingdom
facility: Southampton University Hospitals NHS Trust
city: Stoke-On-Trent
country: United Kingdom
facility: University Hospitals of North Midlands NHS Trust-Royal Stoke University Hospital
city: Taunton
country: United Kingdom
facility: Taunton and Somerset NHS Foundation Trust Musgrove Park Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Lim JJ, Nilsson AC, Silverman M, Assy N, Kulkarni P, McBride JM, Deng R, Li C, Yang X, Nguyen A, Horn P, Maia M, Castro A, Peck MC, Galanter J, Chu T, Newton EM, Tavel JA. A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial of MHAA4549A, a Monoclonal Antibody, plus Oseltamivir in Patients Hospitalized with Severe Influenza A Virus Infection. Antimicrob Agents Chemother. 2020 Jun 23;64(7):e00352-20. doi: 10.1128/AAC.00352-20. Print 2020 Jun 23.