Rapid Empiric Treatment With Oseltamivir Study (RETOS)

NCT01248715 | Completed Phase 4 Results DMC

• 1 other identifier: RETOS
• Study Type: interventional
• Target: 1,107
• Locations: 1 country
• Sites: 5

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.

Conditions

Influenza; Pneumonia

Keywords

pneumonia, bacterial; pneumonia, viral; respiratory tract infections; oseltamivir, therapeutic use

Outcome Measures

Primary Outcomes (4)

• Number of Participants With Clinical Failure (Failure to Reach Clinical Stability)

  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.

  7 days

• Number of Participants to Transfer to ICU After 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.

  24 h

• Number of Participants That Required Re-hospitalization

  Participants that were re-hospitalized within 30 days after enrollment.

  30 days

• Number of Participants That Had Short-term Mortality

  Number of subjects who died within 30 days of enrollment

  30 days

Secondary Outcomes (3)

• Days to Reach Clinical Stability

  30 days

• Length of Hospital Stay

  through study completion, up to 30 days

• Number of Participants With Hospital Mortality.

  through study completion, up to 30 days

Study Arms (2)

Oseltamirvir

EXPERIMENTAL

These patients will receive early oseltamivir plus current, standard empiric antibacterial therapy.

Drug: oseltamivir

Standard of care

NO INTERVENTION

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.

Interventions

oseltamivir DRUG

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

Also known as: Tamiflu

Oseltamirvir

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For oseltamivir and standard of care groups:
• years of age or older
• No oseltamivir or zanamivir ordered in hospital admission orders
• Meets criteria for acute LRTI
• Signed informed consent.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Louisville: lead
• Centers for Disease Control and Prevention: collaborator

Study Sites (5)

Jewish Hospital

Louisville, Kentucky, 40202, United States

Location

Norton Hospital

Louisville, Kentucky, 40202, United States

Location

University of Louisville Hospital

Louisville, Kentucky, 40202, United States

Location

Rex Robley VA Medical Center

Louisville, Kentucky, 40206, United States

Location

Baptist Hospital East

Louisville, Kentucky, 40272, United States

Location

Related Publications (4)

• Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007 Mar 1;44 Suppl 2(Suppl 2):S27-72. doi: 10.1086/511159. No abstract available.

  PMID: 17278083 BACKGROUND

• Wiemken TL, Furmanek SP, Carrico RM, Peyrani P, Hoft D, Fry AM, Ramirez JA. Effectiveness of oseltamivir treatment on clinical failure in hospitalized patients with lower respiratory tract infection. BMC Infect Dis. 2021 Oct 27;21(1):1106. doi: 10.1186/s12879-021-06812-2.

  PMID: 34702188 DERIVED

• Wiemken TL, Jala VR, Kelley RR, Peyrani P, Mattingly WA, Arnold FW, Cabral PW, Cavallazzi R, Haribabu B, Ramirez JA. The upper respiratory tract microbiome of hospitalised patients with community-acquired pneumonia of unknown aetiology: a pilot study. Pneumonia (Nathan). 2015 Dec 1;6:83-89. doi: 10.15172/pneu.2015.6/682. eCollection 2015.

  PMID: 31641582 DERIVED

• Ramirez J, Peyrani P, Wiemken T, Chaves SS, Fry AM. A Randomized Study Evaluating the Effectiveness of Oseltamivir Initiated at the Time of Hospital Admission in Adults Hospitalized With Influenza-Associated Lower Respiratory Tract Infections. Clin Infect Dis. 2018 Aug 16;67(5):736-742. doi: 10.1093/cid/ciy163.

  PMID: 29659754 DERIVED

Related Links

• National Center for Health Statistics

MeSH Terms

Conditions

Influenza, Human; Pneumonia; Pneumonia, Bacterial; Pneumonia, Viral; Respiratory Tract Infections

Interventions

Oseltamivir

Condition Hierarchy (Ancestors)

Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons

Limitations and Caveats

The primary limitation of our study that we were not able to reach the number of patients that were estimated in the sample size calculation.

Results Point of Contact

• Title: Dr. Paula Peyrani
• Organization: University Louisville

paula.peyrani@louisville.edu

502-852-3905

Study Officials

• Julio A Ramirez, MD

  University of Louisville

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 23, 2010
• First Posted: November 25, 2010
• Study Start: November 1, 2010
• Primary Completion: May 1, 2016
• Study Completion: May 1, 2016
• Last Updated: June 15, 2023
• Results First Posted: September 6, 2017

Record last verified: 2023-06

Locations

US (5)