Clinical trial NCT01056185: Respiratory Virus Hospitalization Study (FLU 003 Plus)
Official title: An International Observational Study to Characterize Adults Who Are Hospitalized With Influenza or Other Targeted Respiratory Viruses
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Influenza
Novel Respiratory Virus-1 Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV)
Novel Respiratory Virus-2 Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)
Keywords: influenza
flu
swine flu
respiratory virus
hospitalization
MERS-CoV
SARS-CoV
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: National Institutes of Health (NIH)
name: Clinical & Translational Science Institute, University of Minnesota
First posted: 2010-01-26
Enrollment: 1000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Adult patients who are hospitalized with a diagnosis (confirmed or suspected) of influenza or a targeted non-influenza viral respiratory infection, as soon as possible after the suspected diagnosis is made. Participants may have already been admitted to the hospital at the study site or may have been previously seen at another hospital where the diagnosis of influenza or infection with a targeted respiratory virus was made.

Brief summary: Following the sudden and unexpected emergence of influenza A(H1N1)pdm09 (2009 H1N1) virus, this observational study was initiated to estimate rates of morbidity and mortality and to examine predictors of severity among participants with 2009 H1N1 infection. In 2011, as surveillance indicated that 2009 H1N1 virus was co-circulating with other seasonal influenza A and B viruses worldwide, the protocol was expanded to include other influenza A subtypes and influenza B viruses. The current version of the protocol (released in August 2013) further broadens the scope of this observational study. With the recognition that novel respiratory viruses other than novel influenza A viruses, e.g., Middle East Respiratory Syndrome Coronavirus (MERS-CoV), could become prevalent and of major public health importance, the objectives of this protocol have been expanded.

Detailed description: The purpose of this observational study is to describe the characteristics and outcomes over a 60-day follow-up period of participants with influenza virus infection (including influenza A subtypes such as H3N2 and 2009 H1N1, or influenza B), or a targeted non-influenza respiratory virus, who are hospitalized with severe illness and/or complications in geographically diverse locations.

Specific objectives related to influenza virus infection are to estimate the percentage of participants who go on to develop severe disease or complications that require hospitalization; to obtain information on risk factors for disease severity; and to establish a central repository of specimens for use in virus characterization, including subtyping, antigenic and genetic analyses, identification of signature mutations associated with antiviral drug resistance, mutational evolution, and additional reassortment.

Specific objectives related to novel non-influenza respiratory viruses of potential major public health importance are to characterize initial cases and their outcomes in order to develop more specific protocols that could inform the prevention and treatment of these new infections.

The information used from this study on participants with influenza and novel respiratory virus infections will be rapidly analyzed and shared broadly in order to guide policymakers and to design future studies.

Approximately 500 patients with influenza will be enrolled each year at an estimated 75 sites which are in geographically diverse locations across several continents.

Study Plan:

* Participants who meet the eligibility criteria will be enrolled at participating clinical sites.
* Patients with a diagnosis of influenza (confirmed or suspected), who are hospitalized with complications or severe disease, will be enrolled.
* At enrollment, consent is signed and information (demographics, medical history (including prior influenza and pneumococcal vaccination), medications (including antivirals) and treatments prescribed) will be recorded. A blood sample for serum and plasma will be obtained at enrollment, as well as an upper respiratory tract sample and lower respiratory tract sample, if appropriate. The respiratory specimens will be sent for central reverse transcriptase polymerase chain reaction (RT-PCR) testing for influenza.
* For participants who are still hospitalized, and not intubated, 5 to 7 days after enrollment an additional upper respiratory sample is obtained.
* Status will be re-assessed at approximately 28 days and 60 days after enrollment and another blood sample for serum and plasma will obtained at both time points.
* For participants who are mechanically ventilated additional upper and lower respiratory tract specimens will be obtained at specific timepoints.

In February 2012, the FLU 004 Genomics protocol v 1.0 was released to the field. In August 2013, v 2.0 of the protocol was released as INSIGHT Genomics. The protocol was expanded beyond the FLU 002 and FLU 003 studies to include all qualifying INSIGHT studies (list of qualifying studies is posted on the INSIGHT website, www.insight-trials.org). The purpose of this substudy is to obtain a whole blood sample from which DNA will be extracted to study polymorphisms in immune response genes and other genetic variants that may be associated with an increased risk of severe influenza.

Participating FLU 003 Plus sites are given the option to also participate in INSIGHT Genomics which requires a separate protocol registration. Participants, once consented to FLU 003 Plus, will be offered the option to also consent to INSIGHT Genomics which includes a single whole blood sample collection. Participation in FLU 003 Plus will not be compromised if a participant opts not to participate in INSIGHT Genomics.

Eligibility criteria: Inclusion Criteria:

* Be ≥ 18 years of age
* Have been admitted to hospital
* Have a signed informed consent by participant or surrogate/representative
* Have a local diagnosis (confirmed or suspected) of influenza, or of a targeted non-influenza viral respiratory infection\*, resulting in (or extending a previous) hospitalization

  * A list of targeted non-influenza respiratory viruses is maintained on the INSIGHT website.

Exclusion Criteria:

* Current imprisonment, or compulsory detention (involuntary incarceration) for treat of a psychiatric or physical illness.

Primary outcomes:
measure: Death
timeFrame: 60-day period following enrollment
Secondary outcomes:
measure: Recovery from influenza illness (including days lost from normal activities) duration of hospitalization, days in intensive care, days of mechanical ventilation, days of dialysis, pregnancy outcome
timeFrame: approximately 60 days
Other outcomes:
Locations:
city: San Diego
country: United States
facility: UCSD Antiviral Research Center
state: California
city: Washington
country: United States
facility: George Washington Medical Faculty Associates
state: District of Columbia
city: Washington
country: United States
facility: Washington DC VA Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Infectious Diseases Clinical Research
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Camden
country: United States
facility: Cooper University Hospital
state: New Jersey
city: Newark
country: United States
facility: New Jersey Medical School Adult Clinical Research Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Cornell ID-CRU
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Medical Center
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital
state: Ohio
city: Chattanooga
country: United States
facility: University of Tennessee College of Medicine
state: Tennessee
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: El Palomar
country: Argentina
facility: Hospital Nacional Profesor Alejandro Posadas
state: Buenos Aires
city: La Plata
country: Argentina
facility: Instituto Medico Platense
state: Buenos Aires
city: Pilar
country: Argentina
facility: Hospital Universitario Austral
state: Buenos Aires
city: Vicente Lopez
country: Argentina
facility: Hospital Profesor Bernardo Houssay
state: Buenos Aires
city: Rosario
country: Argentina
facility: Sanatorio Britanico
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: CEMIC
city: Buenos Aires
country: Argentina
facility: Hospital General de Agudos JM Ramos Mejia
city: Buenos Aires
country: Argentina
facility: Hospital Interzonal General de Agudos Dr. Diego Paroissien
city: Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Cordoba
country: Argentina
facility: Hospital Privado Centro Medico de Cordoba
city: Cordoba
country: Argentina
facility: Hospital Rawson
city: Darlinghurst
country: Australia
facility: St. Vincent's Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Brussels
country: Belgium
facility: Centre Hospitalier Universitaire St. Pierre (C.H.U. St. Pierre)
city: Santiago
country: Chile
facility: Clinica Alemana
city: Santiago
country: Chile
facility: Fundacion Arriaran
city: Aarhus
country: Denmark
facility: Arhus Universitetshospital, Skejby
city: Copenhagen
country: Denmark
facility: CHIP
city: Hvidovre
country: Denmark
facility: Hvidovre University Hospital, Department of Infectious Diseases
city: Odense
country: Denmark
facility: Odense University Hospital
city: Bonn
country: Germany
facility: Medizinische Universitatsklinik - Bonn, Immunologische Ambulanz CRS
city: Cologne
country: Germany
facility: Klinik I fur Innere Medizin der Universitat zu Koln, Studienburo fur Infektiologie u. HIV
city: Frankfurt
country: Germany
facility: Johann Wolfgang Goethe - University Hospital, Infektionsambulanz CRS
city: Athens
country: Greece
facility: 1st Dept of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital
city: Athens
country: Greece
facility: 1st Respiratory Medicine Dept, Athens Hosp for Diseases of the Chest "Sotiria Hospital"
city: Athens
country: Greece
facility: Evangelismos General Hospital
city: Athens
country: Greece
facility: Hippokration University General Hospital of Athens
city: Lima
country: Peru
facility: Hospital Nacional Arzobispo Loayza
city: Lima
country: Peru
facility: Hospital Nacional Guillermo Almenara Irigoyen
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital La Paz
city: Madrid
country: Spain
facility: Hospital Universitario Gregorio Mara�on
city: Madrid
country: Spain
facility: Hospital Universitario Infanta Leonor
city: Vitoria-Gasteiz
country: Spain
facility: Hospital Txagorritxu
city: Bangkok
country: Thailand
facility: Chulalongkorn University Hospital
city: Khon Kaen
country: Thailand
facility: Khon Kaen University, Srinagarind Hospital
city: Nonthaburi
country: Thailand
facility: Bamrasnaradura Institute
city: Slough
country: United Kingdom
facility: Heatherwood and Wexham Park Hospitals NHS Foundation Trust
state: Berkshire
city: Brighton
country: United Kingdom
facility: Brighton and Sussex University Hospitals NHS Trust
state: East Sussex
city: Headington
country: United Kingdom
facility: Churchill Hospital
state: Oxford
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospital NHS Foundation Trust
state: South Yorkshire
city: Bradford
country: United Kingdom
facility: Bradford Teaching Hospitals NHS Foundation Trust
state: West Yorkshire
city: Leeds
country: United Kingdom
facility: St James's University Hospital
state: West Yorkshire
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle General Hospital
Study officials:
affiliation: University of Minnesota - Dept Biostatistics
name: Cavan Reilly, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team; Dawood FS, Jain S, Finelli L, Shaw MW, Lindstrom S, Garten RJ, Gubareva LV, Xu X, Bridges CB, Uyeki TM. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med. 2009 Jun 18;360(25):2605-15. doi: 10.1056/NEJMoa0903810. Epub 2009 May 7.
citation: World Health Organization (WHO), www.who.int/, accessed 26 August 2013
citation: Guery B, Poissy J, el Mansouf L, Sejourne C, Ettahar N, Lemaire X, Vuotto F, Goffard A, Behillil S, Enouf V, Caro V, Mailles A, Che D, Manuguerra JC, Mathieu D, Fontanet A, van der Werf S; MERS-CoV study group. Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission. Lancet. 2013 Jun 29;381(9885):2265-72. doi: 10.1016/S0140-6736(13)60982-4. Epub 2013 May 30.
citation: Drosten C, Seilmaier M, Corman VM, Hartmann W, Scheible G, Sack S, Guggemos W, Kallies R, Muth D, Junglen S, Muller MA, Haas W, Guberina H, Rohnisch T, Schmid-Wendtner M, Aldabbagh S, Dittmer U, Gold H, Graf P, Bonin F, Rambaut A, Wendtner CM. Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection. Lancet Infect Dis. 2013 Sep;13(9):745-51. doi: 10.1016/S1473-3099(13)70154-3. Epub 2013 Jun 17.
citation: World Health Organization (WHO), Severe Acute Respiratory Syndrome (SARS), www.who.int/csr/sars/, accessed 26 August 2013
citation: Wendt CH, Castro-Pearson S, Proper J, Pett S, Griffin TJ, Kan V, Carbone J, Koulouris N, Reilly C, Neaton JD; INSIGHT FLU003 Plus Study Group. Metabolite profiles associated with disease progression in influenza infection. PLoS One. 2021 Apr 2;16(4):e0247493. doi: 10.1371/journal.pone.0247493. eCollection 2021.
citation: Simonsen L, Higgs E, Taylor RJ, Wentworth D, Cozzi-Lepri A, Pett S, Dwyer DE, Davey R, Lynfield R, Losso M, Morales K, Glesby MJ, Weckx J, Carey D, Lane C, Lundgren J; INSIGHT FLU002 and FLU003 Study Groups. Using Clinical Research Networks to Assess Severity of an Emerging Influenza Pandemic. Clin Infect Dis. 2018 Jul 18;67(3):341-349. doi: 10.1093/cid/ciy088.
citation: Pett SL, Kunisaki KM, Wentworth D, Griffin TJ, Kalomenidis I, Nahra R, Montejano Sanchez R, Hodgson SW, Ruxrungtham K, Dwyer D, Davey RT, Wendt CH; INSIGHT FLU003 Plus Study Group. Increased Indoleamine-2,3-Dioxygenase Activity Is Associated With Poor Clinical Outcome in Adults Hospitalized With Influenza in the INSIGHT FLU003Plus Study. Open Forum Infect Dis. 2017 Oct 25;5(1):ofx228. doi: 10.1093/ofid/ofx228. eCollection 2018 Jan.
citation: Lynfield R, Davey R, Dwyer DE, Losso MH, Wentworth D, Cozzi-Lepri A, Herman-Lamin K, Cholewinska G, David D, Kuetter S, Ternesgen Z, Uyeki TM, Lane HC, Lundgren J, Neaton JD; INSIGHT Influenza Study Group. Outcomes of influenza A(H1N1)pdm09 virus infection: results from two international cohort studies. PLoS One. 2014 Jul 8;9(7):e101785. doi: 10.1371/journal.pone.0101785. eCollection 2014.