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

• ClinicalTrials.gov Identifier: NCT00298233
• Recruitment Status: Completed
• First Posted: March 1, 2006
• Results First Posted: May 22, 2014
• Last Update Posted: June 6, 2014
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Wellcome Trust; World Health Organization; University of Oxford
• Information provided by (Responsible Party): Jeremy Farrar, Oxford University Clinical Research Unit, Vietnam

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Influenza; Avian Influenza; Severe Influenza	Drug: Oseltamivir	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 326 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, 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
• Study Start Date: February 2006
• Actual Primary Completion Date: January 2010
• Actual Study Completion Date: January 2010

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. Proportion of All Participants Negative for Viral RNA on Day 5 [ Time Frame: After 5 days of treatment ]
   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 :

1. Participants Meeting Criteria for Day 5 Clinical Failure [ Time Frame: After 5 days of treatment ]

   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.
2. In-hospital Mortality Rates [ Time Frame: After up to 10 days of treatment ]
   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.
3. Median Time (Days) Receipt of Oxygen [ Time Frame: Throughout study, 14 days ]
4. Median Time (Days) in ICU [ Time Frame: Throughout study, 14 days ]
5. Median Time (Days) on Ventilation [ Time Frame: Throughout study, 14 days ]
   Use of mechanical ventilation at any time for subjects with severe influenza and avian influenza.

Eligibility Criteria

• Ages Eligible for Study: 1 Year and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

Locations

Singapore

Changi General Hospital

Singapore, Singapore

National University Hospital, National University of Singapore

Singapore, Singapore

Tan Tock Seng Hospital

Singapore, Singapore

Thailand

Queen Sirikit National Institute of Child Health

Bangkok, Thailand

Siriraj Hospital Mahidol University

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

Children's Hospital #1

Ho Chi Minh City, Vietnam

Hospital for Tropical Diseases

Ho Chi Minh City, Vietnam

Pediatric Hospital #2

Ho Chi Minh City, Vietnam

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

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:

South East Asian Infectious Diseases Clinical Research Network - Protocol and support documents available 

Publications of Results:

South East Asia Infectious Disease Clinical Research Network. Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. BMJ. 2013 May 30;346:f3039. doi: 10.1136/bmj.f3039.

Other Publications:

Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis. 1995 Jan-Mar;1(1):7-15. Review.

Colman PM. Influenza virus neuraminidase: structure, antibodies, and inhibitors. Protein Sci. 1994 Oct;3(10):1687-96. Review.

de Jong MD, Bach VC, Phan TQ, Vo MH, Tran TT, Nguyen BH, Beld M, Le TP, Truong HK, Nguyen VV, Tran TH, Do QH, Farrar J. Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma. N Engl J Med. 2005 Feb 17;352(7):686-91.

• Responsible Party: Jeremy Farrar, Director, Oxford University Clinical Research Unit, Oxford University Clinical Research Unit, Vietnam
• ClinicalTrials.gov Identifier: NCT00298233
• Other Study ID Numbers: SEA 001; N01A050042 ( Other Grant/Funding Number: US NIH NIAID Contract )
• First Posted: March 1, 2006
• Results First Posted: May 22, 2014
• Last Update Posted: June 6, 2014
• Last Verified: May 2014

Keywords provided by Jeremy Farrar, Oxford University Clinical Research Unit, Vietnam:

Antibody Response; Antiviral Efficacy; Bird Flu; Severe Respiratory Distress; Viral Replication and Shedding

Additional relevant MeSH terms:

Influenza, Human; Influenza in Birds; Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Oseltamivir; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action