Respiratory Virus Hospitalization Study (FLU 003 Plus)

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.

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.