Rapid Empiric Treatment With Oseltamivir Study (RETOS)

This study is enrolling participants by invitation only.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Louisville
ClinicalTrials.gov Identifier:
NCT01248715
First received: November 23, 2010
Last updated: June 24, 2013
Last verified: June 2013
  Purpose

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 Intervention Phase
Influenza
Pneumonia
Drug: oseltamivir
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Title: Effectiveness of Empiric Antiviral Treatment for Hospitalized Community Acquired Pneumonia During the Influenza Season (U18)

Resource links provided by NLM:


Further study details as provided by University of Louisville:

Primary Outcome Measures:
  • Clinical Failure [ Time Frame: 7 days ] [ Designated as safety issue: No ]

    Any of the following:

    1. 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. Need for intensive care admission.


Secondary Outcome Measures:
  • Cost-effectiveness [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    We will measure (1) all costs associated with administering antibiotic use and anti-influenza use, (2) costs of hospital stay (measured as average cost per day), (3) length of stay in the hospital, (3) cost of all diagnostic tests performed, and (4) rate of clinical failure. Combined with the within-trial data an estimate of the incremental cost-effectiveness ratio according to a traditional decision analytic model will be calculated. Estimation of cost will adhere to current standards. Rate of clinical failure will be calculated from the within trial data

  • Long-term mortality [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Death within 1 year of enrollments

  • Short-term mortality [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Death within 30 days of enrollment

  • Re-hospitalization [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Re-hospitalization within 30 days after enrollment.


Estimated Enrollment: 1000
Study Start Date: November 2010
Estimated Study Completion Date: May 2014
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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: Flu LRTI Substudy
Subject diagnosed with lower respiratory tract illness (LRTI) and given antiviral by physician before study enrollment.
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.

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). If the admitting clinician orders oseltamivir or zanamivir the patient is not eligible for randomization but is eligible for enrollment into an observational study that will describe the clinical course and outcomes of patients with influenza LRTI (Group C).

The primary Aim for the influenza LRTI study (Group C) is to describe hospitalized patients with LRTI who were suspected to have influenza at the time of admission, including the proportion w PCR confirmation, and selected clinical outcomes and clinical failure.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

For Flu LRTI substudy:

  • 18 years of age or older
  • 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

For Flu LRTI substudy:

  • Patients hospitalized for LRTI for more than 48 hours before enrollment.
  • 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.
  • Prisoners
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01248715

Locations
United States, Kentucky
University of Louisville Hospital
Louisville, Kentucky, United States, 40202
Norton Hospital
Louisville, Kentucky, United States, 40202
Jewish 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
Investigators
Principal Investigator: Julio A Ramirez, MD University of Louisville
  More Information

Additional Information:
Publications:
Responsible Party: University of Louisville
ClinicalTrials.gov Identifier: NCT01248715     History of Changes
Other Study ID Numbers: RETOS
Study First Received: November 23, 2010
Last Updated: June 24, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Louisville:
pneumonia, bacterial
pneumonia, viral
respiratory tract infections
oseltamivir, therapeutic use

Additional relevant MeSH terms:
Influenza, Human
Pneumonia
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Lung Diseases
Antiviral Agents
Oseltamivir
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 20, 2014