Rapid Empiric Treatment With Oseltamivir Study (RETOS)



Status:Completed
Conditions:Influenza, Pneumonia
Therapuetic Areas:Immunology / Infectious Diseases, Pulmonary / Respiratory Diseases
Healthy:No
Age Range:18 - Any
Updated:11/8/2017
Start Date:November 2010
End Date:May 2016

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Title: Effectiveness of Empiric Antiviral Treatment for Hospitalized Community Acquired Pneumonia During the Influenza Season (U18)

Current guidelines recommend early initiation of empiric antibiotic therapy to cover typical
and atypical bacteria that may cause community-acquired pneumonia (CAP). Influenza antiviral
therapy in patients with suspected or confirmed influenza. However, many clinicians do not
suspect influenza among patients with CAP or other acute lower respiratory tract illness
(LRTI) and often do not test for influenza. Additionally, results from currently available
diagnostic tests for influenza may be delayed and several tests have low sensitivity and will
give false negative results. Thus, anti-influenza treatment for patients with hospitalized
influenza CAP and LRTI is frequently initiated late if at all. There is an association
between delayed time to administration of empiric antibiotic therapy with increased clinical
failure and mortality. As a result, empiric antibiotic therapy for patients with suspect CAP
is begun within 4 - 6 hours of hospitalization. This has recently been demonstrated for
delayed antiviral treatment as well. We hypothesize that, as happens with early empiric
antibiotics for bacterial CAP, a standardized approach of adding early empiric anti-influenza
therapy during the influenza season to hospitalized patients with suspect CAP and LRTI will
improve clinical outcomes of patients with influenza associated CAP and LRTI.

To test our hypothesis we plan a prospective, randomized, multicenter clinical trial of
hospitalized patients with acute LRTI, including suspect CAP, during . If early
anti-influenza medications were not included on the patients admission orders, patients will
be randomized to standard care, including empiric antibacterial therapy as recommended by
ATS/IDSA guidelines plus standard influenza diagnostics and treatment (Standard of care)
versus early initiation of empiric antiinfluenza therapy plus standard care, e.g. empiric
antibacterial (oseltamivir group). The primary study outcome will be development of clinical
failure and selected clinical outcomes during the 30 days after enrollment. Other clinical
outcomes that will be compared between study groups include time to clinical stability,
duration of hospitalization, development of cardiovascular events, re-hospitalization,
short-term mortality (30 days), and long-term mortality (1 year). The secondary study outcome
will be the cost-effectiveness of the intervention.

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
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Louisville, Kentucky 40207
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Louisville, Kentucky 40202
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Louisville, Kentucky 40202
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530 S Jackson St
Louisville, Kentucky 40202
502-562-3226
University of Louisville Hospital As the academic hospital at the heart of the Louisville Metro...
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Louisville, Kentucky 40206
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