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Rapid Empiric Treatment With Oseltamivir Study (RETOS) (RETOS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01248715
Recruitment Status : Completed
First Posted : November 25, 2010
Results First Posted : September 6, 2017
Last Update Posted : June 5, 2023
Centers for Disease Control and Prevention
Information provided by (Responsible Party):
University of Louisville

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Influenza Pneumonia Drug: oseltamivir Phase 4

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1107 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Title: Effectiveness of Empiric Antiviral Treatment for Hospitalized Community Acquired Pneumonia During the Influenza Season (U18)
Study Start Date : November 2010
Actual Primary Completion Date : May 2016
Actual Study Completion Date : May 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Oseltamivir

Arm Intervention/treatment
Experimental: Oseltamirvir
These patients will receive early oseltamivir plus current, standard empiric antibacterial therapy.
Drug: oseltamivir
These patients will receive early (within 8-12 hours of admission, no later than 24 hours after admission) oseltamivir plus current, standard empiric antibacterial therapy based on national recommendations from the IDSA/ATS guidelines for management of hospitalized patients with CAP (2). Anti-influenza therapy will be given using oseltamivir at a dose of 75 mg twice daily. The oseltamivir dose will be adjusted in patients with renal insufficiency according to the package insert. Duration of antiviral therapy will be for a minimum of 5 days for patients with evidence of early clinical improvement and prolonged depending on clinical stability
Other Name: Tamiflu

No Intervention: Standard of care
These patients will be treated with the current, standard care, including currently recommended antibiotics or antiviral therapy based on national recommendations from the IDSA/ATS guidelines for management of hospitalized patients with CAP and ACIP antiviral use guidelines for hospitalized patients with confirmed of suspect influenza, per clinician discretion. In addition these patients with have a NP swab collected for influenza PCR testing and clinical information will be extracted from the medical record.

Primary Outcome Measures :
  1. Number of Participants With Clinical Failure (Failure to Reach Clinical Stability) [ Time Frame: 7 days ]
    Number of subject that showed lack of clinical improvement within 7 days. Criteria for clinical improvement include no fever; white blood cell count decreases, or increases in the case of leukopenia, to more than 10% from the prior day; the evaluation of signs and symptoms of CAP to define when the patient is subjectively better, and the patient is able to tolerate food by mouth.

  2. Number of Participants to Transfer to ICU After 24 h [ Time Frame: 24 h ]
    Number of subjects that were transfered to an intensive care unit (ICU) after 24 hours of hospitalization. A patient transferred to ICU within 24 hours of admission was considered as a direct admission to ICU and not meeting criteria for clinical failure.

  3. Number of Participants That Required Re-hospitalization [ Time Frame: 30 days ]
    Participants that were re-hospitalized within 30 days after enrollment.

  4. Number of Participants That Had Short-term Mortality [ Time Frame: 30 days ]
    Number of subjects who died within 30 days of enrollment

Secondary Outcome Measures :
  1. Days to Reach Clinical Stability [ Time Frame: 30 days ]
    Time to clinical improvement. The criteria for clinical improvement were followed during the first week from the day of admission and defined as follows: a) improvement of signs and symptoms of LRTI reported by patient b) afebrile for at least 8 hours, c) decrease in white blood cell count to more than 10% from the prior day, and d) able to tolerate oral feeding. A patient was considered clinically improved on the day that these four criteria were all met.

  2. Length of Hospital Stay [ Time Frame: through study completion, up to 30 days ]
    Duration of hospitalization calculated as the day of discharge minus the day of admission.

  3. Number of Participants With Hospital Mortality. [ Time Frame: through study completion, up to 30 days ]
    Number of subjects who died while hospitalized

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01248715

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United States, Kentucky
Jewish Hospital
Louisville, Kentucky, United States, 40202
Norton Hospital
Louisville, Kentucky, United States, 40202
University of Louisville Hospital
Louisville, Kentucky, United States, 40202
Rex Robley VA Medical Center
Louisville, Kentucky, United States, 40206
Baptist Hospital East
Louisville, Kentucky, United States, 40272
Sponsors and Collaborators
University of Louisville
Centers for Disease Control and Prevention
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Principal Investigator: Julio A Ramirez, MD University of Louisville
Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: University of Louisville Identifier: NCT01248715    
Other Study ID Numbers: RETOS
First Posted: November 25, 2010    Key Record Dates
Results First Posted: September 6, 2017
Last Update Posted: June 5, 2023
Last Verified: June 2023
Keywords provided by University of Louisville:
pneumonia, bacterial
pneumonia, viral
respiratory tract infections
oseltamivir, therapeutic use
Additional relevant MeSH terms:
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Influenza, Human
Respiratory Tract Infections
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Diseases
Lung Diseases
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action