Clinical trial NCT00298233: High-Dose Versus Standard-Dose Oseltamivir to Treat Severe Influenza and Avian Influenza
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Influenza
Avian Influenza
Severe Influenza
Keywords: Antibody Response
Antiviral Efficacy
Bird Flu
Severe Respiratory Distress
Viral Replication and Shedding
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Wellcome Trust
name: World Health Organization
name: University of Oxford
First posted: 2006-03-01
Enrollment: 326
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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

Primary outcomes:
measure: Proportion of All Participants Negative for Viral RNA on Day 5
timeFrame: After 5 days of treatment
Secondary outcomes:
measure: Participants Meeting Criteria for Day 5 Clinical Failure
timeFrame: After 5 days of treatment
measure: In-hospital Mortality Rates
timeFrame: After up to 10 days of treatment
measure: Median Time (Days) Receipt of Oxygen
timeFrame: Throughout study, 14 days
measure: Median Time (Days) in ICU
timeFrame: Throughout study, 14 days
measure: Median Time (Days) on Ventilation
timeFrame: Throughout study, 14 days
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: Changi General Hospital
city: Singapore
country: Singapore
facility: National University Hospital, National University of Singapore
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Bangkok
country: Thailand
facility: Queen Sirikit National Institute of Child Health
city: Bangkok
country: Thailand
facility: Siriraj Hospital Mahidol University
city: Nonthaburi
country: Thailand
facility: Bamrasnaradura Infectious Disease Institute
city: Nonthaburi
country: Thailand
facility: Chest Disease Institute
city: Hanoi
country: Vietnam
facility: National Hospital of Pediatrics
city: Hanoi
country: Vietnam
facility: National Institute fof Infectious and Tropical Diseases
city: Ho Chi Minh City
country: Vietnam
facility: Children's Hospital #1
city: Ho Chi Minh City
country: Vietnam
facility: Hospital for Tropical Diseases
city: Ho Chi Minh City
country: Vietnam
facility: Pediatric Hospital #2
Study officials:
affiliation: Queen Sirikit National Institute of Child Health, Bangkok, Thailand
name: Tawee Chotpitayasunohdh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
name: Tran Tinh Hien, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis. 1995 Jan-Mar;1(1):7-15. doi: 10.3201/eid0101.950102.
citation: Colman PM. Influenza virus neuraminidase: structure, antibodies, and inhibitors. Protein Sci. 1994 Oct;3(10):1687-96. doi: 10.1002/pro.5560031007.
citation: 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. doi: 10.1056/NEJMoa044307.
citation: 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.