Rapid Empiric Treatment With Oseltamivir Study (RETOS)

This will be both a prospective, randomized, unblinded clinical study of hospitalized
patients with acute LRTI admitted in one of four institutions in Louisville, KY (rapid
empiric treatment with oseltamivir study[RETOS]) and a prospective observation study to
describe influenza LRTI (Flu LRTI study). All hospitalized patients with acute LRTI will be
invited to participate in one of the arms of study. If the admitting clinician does not order
oseltamivir or zanamivir at the time of hospital admission, the patient is eligible for
randomization into Group A (standard clinical care, including empiric antibiotics and
anti-influenza drugs at the clinician discretion) or Group B (oseltamivir administered to the
patient within 24 hours of admission, ideally within 8-12 hours of admission, plus empiric
antibiotics).

Patients will be enrolled from one of four hospitals, the University of Louisville Hospital,
Veterans Affairs Medical Center of Louisville, Norton Hospital of Louisville, and Jewish
Hospital of Louisville. Eligible patients will be identified primarily in the Emergency
Departments of all four hospitals and evaluated for inclusion/exclusion criteria after
hospital admission orders are written. Patients will be enrolled only during the influenza
season. For this study, the influenza season is defined as December 1st until May 1st, unless
surveillance data suggests that influenza viruses are circulating earlier or have stopped
circulating.

For all three study groups, diagnosis of influenza will be based on nucleic acid
amplification through polymerase chain reaction (PCR). At the time of enrollment into the
study, a nasopharyngeal swab will be obtained for PCR. The University of Louisville
Infectious Diseases Reference Laboratory has extensive experience using molecular techniques
for the diagnosis of respiratory pathogens and will test batched specimens at monthly
intervals. In addition, we will collect the results from tests done for routine care and
bacterial or virus isolates identified during routine care for further characterization.

The management of patients in Group A and Group B will be different only in regard to early
empiric anti-influenza therapy. All other aspects of the management of these patients will be
in compliance with national guideline recommendations from IDSA/ATS (2). Patients in Group A
may have antiviral therapy started later in hospitalization or not treated at all. The study
will not interfere with Group A patient care.

A 1:1 randomization ratio within the two study arms is planned for EOS. A pre-defined
randomization chart will be designed in order to have the randomization process
Internet-based. The randomization table will be accessible by the project manager as a back
up in the event that any problem occurs with the Internet or the computerized system.

We will attempt to begin oseltamivir within 8 - 12 hours after hospital admission, and no
later than 24 hours. The study nurse will facilitate receipt of early oseltamivir treatment
for the consented patient in collaboration with the hospital pharmacies. The time of
oseltamivir administration will be recorded for all enrolled patients.

Inclusion Criteria:

For oseltamivir and standard of care groups:

- 18 years of age or older

- No oseltamivir or zanamivir ordered in hospital admission orders

- Meets criteria for acute LRTI

- Signed informed consent.

Exclusion Criteria:

For oseltamivir and standard of care groups:

- Oseltamivir or zanamivir ordered in hospital admission orders

- Patients hospitalized for the LRTI for more than 24 hours before enrollment into the
trial.

- Patients with mental conditions who are unlikely to comply with the study protocol and
who cannot give informed consent and have no guardian or proxy.

- Patients who have had severe allergic reactions such as anaphylaxis or serious skin
reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, or erythema
multiforme to any component of oseltamivir (TAMIFLU).

- Prisoners