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

This study has been completed.
Sponsor:
Collaborators:
Wellcome Trust
World Health Organization
University of Oxford
Information provided by (Responsible Party):
Jeremy Farrar, Oxford University Clinical Research Unit, Vietnam
ClinicalTrials.gov Identifier:
NCT00298233
First received: March 1, 2006
Last updated: May 26, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Influenza
Avian Influenza
Severe Influenza
Drug: Oseltamivir
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: High-Dose Versus Standard-Dose Oseltamivir for the Treatment of Severe Influenza and Avian Influenza: A Phase II Double-Blind, Randomized Clinical Trial

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Proportion of All Participants Negative for Viral RNA on Day 5 [ Time Frame: After 5 days of treatment ] [ Designated as safety issue: No ]
    Proportion of all participants with no detectable viral RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) in a combined nasal and throat swab sample on day 5.


Secondary Outcome Measures:
  • Participants Meeting Criteria for Day 5 Clinical Failure [ Time Frame: After 5 days of treatment ] [ Designated as safety issue: No ]

    Proportion of participants that have clinical failure by day 5. Subjects that meet one of the following on Day 5 will be classified as a clinical failure:

    • Severe tachypnea (respiratory rate ≥ 30 for ages ≥12 years, rate ≥ 40 for ages 6 to 12 years, rate ≥45 for ages 3 to 6 years, rate ≥ 50 for ages 1 to 3 years)
    • Severe dyspnea (unable to speak full sentences, or use of accessory respiratory muscles)
    • Arterial oxygen saturation ≤92% on room air by trans-cutaneous method
    • Need for mechanical ventilation or intensive care unit (ICU) admission For the purpose of endpoint definition, death prior to or on Day 5 will also be considered a clinical failure at Day 5.

  • In-hospital Mortality Rates [ Time Frame: After up to 10 days of treatment ] [ Designated as safety issue: No ]
    Standard therapy with oseltamivir is five days. Those patients with persistent symptoms on day five were continued on the randomized dose for an additional five days and assessments were performed up to day 10.

  • Median Time (Days) Receipt of Oxygen [ Time Frame: Throughout study, 14 days ] [ Designated as safety issue: No ]
  • Median Time (Days) in ICU [ Time Frame: Throughout study, 14 days ] [ Designated as safety issue: No ]
  • Median Time (Days) on Ventilation [ Time Frame: Throughout study, 14 days ] [ Designated as safety issue: No ]
    Use of mechanical ventilation at any time for subjects with severe influenza and avian influenza.


Enrollment: 326
Study Start Date: February 2006
Study Completion Date: January 2010
Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Standard Dose oseltamivir adult cohort
All participants >= 15 years 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.
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
Active Comparator: Double Dose oseltamivir Adult cohort
All participants >= 15 years 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.
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
Active Comparator: Standard Dose Oseltamivir child cohort
All participants <15 years 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.
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
Active Comparator: Double Dose Oseltamivir child cohort
All Participants <15 years 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.
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

Detailed Description:

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 oseltamivir 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.

  Eligibility

Ages Eligible for Study:   1 Year and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 reverse transcriptase-polymerase chain reaction (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
  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: NCT00298233

Locations
Singapore
Changi General Hospital
Singapore, Singapore
National University Hospital, National University of Singapore
Singapore, Singapore
Tan Tock Seng Hospital
Singapore, Singapore
Thailand
Siriraj Hospital Mahidol University
Bangkok, Thailand
Queen Sirikit National Institute of Child Health
Bangkok, Thailand
Bamrasnaradura Infectious Disease Institute
Nonthaburi, Thailand
Chest Disease Institute
Nonthaburi, Thailand
Vietnam
National Hospital of Pediatrics
Hanoi, Vietnam
National Institute fof Infectious and Tropical Diseases
Hanoi, Vietnam
Pediatric Hospital #2
Ho Chi Minh City, Vietnam
Hospital for Tropical Diseases
Ho Chi Minh City, Vietnam
Children's Hospital #1
Ho Chi Minh City, Vietnam
Sponsors and Collaborators
Wellcome Trust
World Health Organization
University of Oxford
Investigators
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
  More Information

Additional Information:
Publications:
Responsible Party: Jeremy Farrar, Director, Oxford University Clinical Research Unit, Oxford University Clinical Research Unit, Vietnam
ClinicalTrials.gov Identifier: NCT00298233     History of Changes
Other Study ID Numbers: SEA 001, N01A050042
Study First Received: March 1, 2006
Results First Received: January 17, 2014
Last Updated: May 26, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Antibody Response
Antiviral Efficacy
Bird Flu
Severe Respiratory Distress
Viral Replication and Shedding

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

ClinicalTrials.gov processed this record on October 20, 2014