High-Dose Versus Standard-Dose Oseltamivir to Treat Severe Influenza and Avian Influenza

This study has been completed.
Sponsor:
Collaborators:
Wellcome Trust
Global Influenza Program World Health Organization
University of Oxford
Information provided by:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00298233
First received: March 1, 2006
Last updated: March 18, 2010
Last verified: October 2009

March 1, 2006
March 18, 2010
February 2006
January 2010   (final data collection date for primary outcome measure)
Percentage of participants with severe influenza that have no viral shedding at Day 5, as assessed by negative RT-PCR for viral RNA in nose and throat swabs [ Time Frame: 5 days after study enrollment ] [ Designated as safety issue: No ]
Not Provided
Complete list of historical versions of study NCT00298233 on ClinicalTrials.gov Archive Site
  • Clinical endpoints [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Virologic endpoints [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Exploratory endpoints [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Not Provided
Not Provided
Not Provided
 
High-Dose Versus Standard-Dose Oseltamivir to Treat Severe Influenza and Avian Influenza
High-Dose Versus Standard-Dose Oseltamivir for the Treatment of Severe Influenza and Avian Influenza: A Phase II Double-Blind, Randomized Clinical Trial

Influenza, also known as the flu, is a contagious respiratory illness caused by influenza viruses. The illness can range in severity, from mild to severe to even death, and it causes an estimated 500,000 to 1,000,000 deaths worldwide each year. In the last several years, there have been increasing numbers of human cases of avian influenza, or bird flu. This trend may pose a threat of a future pandemic--worldwide outbreak of disease--with an avian influenza virus that can easily spread from person to person. Oseltamivir is an antiviral medication that is used to treat people with uncomplicated human influenza, and it may be effective in treating people with either severe human influenza or avian influenza. The purpose of this international study is to compare standard-dose oseltamivir versus high-dose oseltamivir for treating people who are hospitalized with severe human influenza or avian influenza.

Two main types of influenza virus--Types A and B--are responsible for the seasonal flu epidemics that occur each year. The influenza A viruses can be broken down into subtypes based on two proteins on the surface of the virus: hemagglutinin (H) and neuraminidase (N). The A subtypes usually found in humans are H1N1, H1N2, and H3N2. Other A subtypes are found primarily in animals. For example, the "avian influenza virus" refers to an influenza A virus that is found chiefly in birds.

Although avian influenza does not usually affect humans, increasing numbers of cases of human infection from avian influenza virus H5N1 have been reported in the last several years. Because all influenza viruses have the ability to modify, there is concern that this trend of increasing cases may pose a threat of a future pandemic with a new H5N1 virus that could spread easily from person to person.

The H5N1 virus that has caused human infection in Asia is resistant to amantadine and rimantadine, two antiviral medications commonly used for treating people with influenza. Another antiviral medication, oseltamivir, is currently used to treat people with uncomplicated human influenza. The purpose of this study is to compare standard-dose oseltamvir and high-does oseltamivir for treating people who are hospitalized with severe human influenza or avian influenza. The study will also attempt to identify how severe human influenza and avian influenza differ in the following factors: clinical manifestation, relationship between antiviral plasma concentrations and viral dynamics, and pathogenesis.

Upon meeting certain screening criteria, participants will be randomly assigned to receive oseltamivir either at a standard-dose level (75 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) or at a high-dose level (150 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function). Treatment will continue for 5 days, after which participants who meet clinical failure criteria will continue their assigned treatment for an additional 5 days. It is anticipated that participants will remain hospitalized through the course of treatment. On Day 0, which marks the first day of hospitalization, participants will undergo a medical review, physical examination, blood sampling, nasal swab, throat swab, anal swab, and chest x-ray. An endotracheal aspirate procedure and urine sampling may also be performed. During the hospital stay, most of the above procedures will be repeated regularly, and additional samples of lung fluid, cerebral spinal fluid, and pleural fluid may be obtained. On Day 5 and possibly on Day 10, participants will undergo a follow-up x-ray. If applicable, participants will attend outpatient study visits on Days 10, 14, and 28 for further evaluation; participants with avian influenza will also attend visits on Days 56 and 180.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
  • Influenza
  • Avian Influenza
  • Severe Influenza
  • Drug: Oseltamivir
    Oseltamivir is a sialic acid analogue that potently and specifically inhibits the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Oseltamivir will be administered orally in standard formulations (capsules for adults and children at least 15 years of age; suspension for children younger than 15 years).
    Other Name: Tamiflu
  • Drug: Placebo oseltamivir
    Placebo will be administered orally (capsules for adults and children at least 15 years of age; suspension for children younger than 15 years).
  • Active Comparator: Standard Dose for Severe Influenza
    Participants will receive standard-dose oseltamivir (75 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days.
    Interventions:
    • Drug: Oseltamivir
    • Drug: Placebo oseltamivir
  • Active Comparator: High Dose for Severe Influenza
    Participants will receive high-dose oseltamivir (150 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days.
    Intervention: Drug: Oseltamivir
  • Active Comparator: Standard Dose for Avian Influenza
    Participants will receive standard-dose oseltamivir (75 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days.
    Interventions:
    • Drug: Oseltamivir
    • Drug: Placebo oseltamivir
  • Active Comparator: High Dose for Avian Influenza
    Participants will receive high-dose oseltamivir (150 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days.
    Intervention: Drug: Oseltamivir

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
321
January 2010
January 2010   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • At least one of the following respiratory symptoms: cough, dyspnea, sore throat
  • Evidence of severe influenza or avian influenza, as defined below
  • Severe influenza infection criteria:

    1. Need for hospitalization
    2. One of the following:

      1. New infiltrate on chest x-ray (or any infiltrate if no prior chest x-ray or not known)
      2. Severe tachypnea (more information on this criterion can be found in the protocol)
      3. Severe dyspnea
      4. Arterial oxygen saturation of 92% or less on room air by trans-cutaneous method
    3. Positive diagnostic testing for influenza, as defined by either rapid influenza antigen (Ag) positive (A or B) or qualitative RT-PCR positive for any influenza
    4. Illness (defined by onset of fever, respiratory symptoms, or constitutional symptoms) began within 10 days before study enrollment
  • Avian influenza infection criteria:

    1. Nasal wash, nasopharyngeal aspirate, endotracheal aspirate, nasal swab, or throat swab that is RT-PCR positive influenza for H5 influenza
    2. Illness (defined by onset of fever, respiratory symptoms, or constitutional symptoms) began within 14 days before study enrollment

Exclusion Criteria:

  • Received more than 72 hours of oseltamivir (six doses) within 14 days
  • Received oseltamivir at higher than standard doses within the last 14 days or during current acute illness, whichever is longer
  • History of allergy or severe intolerance of oseltamivir, as determined by the investigator
  • Alternate explanation for the clinical findings, as determined by the investigator and with the information immediately available
  • Creatine clearance less than 10 ml/minute
  • Pregnant or breastfeeding
Both
1 Year and older
No
Contact information is only displayed when the study is recruiting subjects
Indonesia,   Singapore,   Thailand,   Vietnam
 
NCT00298233
SEA 001, SEA 001
Yes
RCHSPB, National Institutes of Health
National Institute of Allergy and Infectious Diseases (NIAID)
  • Wellcome Trust
  • Global Influenza Program World Health Organization
  • University of Oxford
Principal Investigator: Tawee Chotpitayasunohdh, MD Queen Sirikit National Institute of Child Health, Bangkok, Thailand
Principal Investigator: Tran Tinh Hien, MD Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
National Institute of Allergy and Infectious Diseases (NIAID)
October 2009

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP