High-Dose Vs. Standard-Dose Oseltamivir (Tamiflu) to Treat Severe Influenza and Avian Influenza - Full Text View

Sponsored by:	National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00298233

Purpose

This study will compare the standard dose of the anti-influenza drug Tamiflu with a higher dose of the drug to see if the higher dose is more effective in treating severe influenza or avian influenza (bird flu) infections. The National Institutes of Health (NIH) is one of several international sites for this study.

People 18 years of age and older with severe influenza infection requiring hospitalization or with avian influenza infections may be eligible for this study. Candidates are screened with a nasal swab, throat swab and nasal wash to look for virus. For the nasal wash, a small amount of salt water is squirted in the nose and removed by suction.

Participants are randomly assigned to receive either the standard dose or higher dose of Tamiflu. They take the medication twice a day for 5 days. Patients who are still very ill at 5 days and meet certain conditions are given the medicine for another 5 days. Patients are admitted to the hospital, in isolation, for the duration of treatment. In addition to treatment, patients have the following tests and procedures:

Nose and throat swabs, nasal wash, rectal swab, blood and urine tests and chest x-ray before starting treatment
Blood draws on study days 1, 3, 5 and 7
Nose and throat swabs every day for the first 5 days and on days 10, 14 and 28
Rectal swabs days every day for the first 5 days and on days 10, 14 and 28

Patients with bird flu are seen in the clinic at 2 and 6 months. A repeat blood test is done at 6 months.

...

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

MedlinePlus related topics: Bird Flu Flu

Drug Information available for: Immunoglobulins Globulin, Immune Oseltamivir Tamiflu

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Efficacy Study
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

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

Percentage of subjects with severe influenza that have no viral shedding at day 5 [ Time Frame: 5 days after study enrollment ] [ Designated as safety issue: No ]

Estimated Enrollment:	600
Study Start Date:	February 2006

Arms	Assigned Interventions
Severe Standard Dose: Active Comparator	Drug: Oseltamivir Oseltamivir is a sialic acid analogues that potently and specifically inhibit the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Subjects are enrolled into severe influenza cohort or avian influenza cohort based on type of infection and severity of disease. Within each cohort, subjects are randomized to high dose or standard dose oseltamivir.@@@@@@
Severe High Dose: Active Comparator	Drug: Oseltamivir Oseltamivir is a sialic acid analogues that potently and specifically inhibit the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Subjects are enrolled into severe influenza cohort or avian influenza cohort based on type of infection and severity of disease. Within each cohort, subjects are randomized to high dose or standard dose oseltamivir.@@@@@@
Avian Standard Dose: Active Comparator	Drug: Oseltamivir Oseltamivir is a sialic acid analogues that potently and specifically inhibit the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Subjects are enrolled into severe influenza cohort or avian influenza cohort based on type of infection and severity of disease. Within each cohort, subjects are randomized to high dose or standard dose oseltamivir.@@@@@@
Avian High Dose: Active Comparator	Drug: Oseltamivir Oseltamivir is a sialic acid analogues that potently and specifically inhibit the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Subjects are enrolled into severe influenza cohort or avian influenza cohort based on type of infection and severity of disease. Within each cohort, subjects are randomized to high dose or standard dose oseltamivir.@@@@@@

Detailed Description:

Human influenza is a serious disease causing an estimated 500,000-1,000,000 deaths worldwide each year. In addition, there have been increasing numbers of cases of avian influenza in the last several years, which may pose a threat of a future pandemic with a novel influenza virus.

Oseltamivir is one therapeutic agent available for human influenza, and would be considered standard therapy for treatment of avian influenza. Both severe human influenza and avian influenza have a higher mortality than uncomplicated human influenza, have higher viral replication, shed larger amounts of virus, and shed virus longer. Oseltamivir has been shown to decrease viral replication and shedding in uncomplicated influenza, but similar studies have not been performed in severe human and avian influenza.

The primary purpose of this protocol is to evaluate high-dose oseltamivir (twice the standard dose) as compared to standard-dose oseltamivir in the treatment of severe human or avian influenza with the hypothesis that high-dose will decrease viral replication and shedding, and therefore may confer a clinical or survival advantage. This protocol will also attempt to define differences in the clinical manifestation, the relationship between antiviral plasma concentrations and viral dynamics, and pathogenesis of human and avian influenza, which may help to improve the treatment of these diseases.

Eligibility

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

Criteria

-INCLUSION CRITERIA:

Age greater than or equal to 1 year

AND
At least one respiratory symptom:
- Cough
- Dyspnea (shortness of breath)
- Sore throat
AND
Have evidence of severe influenza and avian influenza as defined below (A or B)

A. Evidence of severe influenza infection:

- 1. Need for hospitalization (as determined by investigator or clinician)

AND

2. One of the following: (all criteria as judged by the investigator)
New infiltrate on chest X-ray (or any infiltrate if no prior chest X-ray or not known)
Severe tachypnea (respiratory rate greater than or equal to 30 for ages greater than or equal to 12 years, rate greater than or equal to 40 for ages 6 to 12 years, rate greater than or equal to 45 for ages 3 to 6 years, rate greater than or equal to 50 for ages 1 to 3 years)
Severe dyspnea (unable to speak full sentences, or use of accessory respiratory muscles)
Arterial oxygen saturation less than or equal to 92% on room air by trans-cutaneous method

AND

3. Positive diagnostic testing for influenza defined as (one of the following)
Rapid influenza antigen (Ag) positive (A or B)
Qualitative RT-PCR positive for influenza (any)

AND

- 4. Illness (onset of fever, respiratory symptoms, or constitutional symptoms) began within the 10 days prior to enrollment

B. Evidence of avian influenza infection

Nasal wash, nasopharyngeal aspirate, endotracheal aspirate, nasal swab, or throat swab that is RT-PCR positive influenza for H5 influenza

AND
Illness (onset of fever, respiratory symptoms, or constitutional symptoms) began within the 14 days prior to enrollment

EXCLUSION CRITERIA (any of the following):

Pregnancy or urine beta-hCG positive.
Females who are actively breast feeding.
Receipt of more than 72 hours of oseltamivir (six doses) within the last 14 days.
Receipt of oseltamivir at higher than standard doses (75 mg bid, or equivalent dose adjusted for age, weight and creatinine clearance) within the last 14 days or during this 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 with the information immediately available.
Creatinine Clearance (estimated by serum Cr) less than 10 ml/min.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00298233

Contacts

Contact: Patient Recruitment and Public Liaison Office	(800) 411-1222	prpl@mail.cc.nih.gov
Contact: TTY	1-866-411-1010

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892
Indonesia
Persahabatan Hospital	Recruiting
Jakarta, Indonesia
Sulianto Saroso Hospital	Recruiting
Jakarta, Indonesia
Rumah Sakit Hasan Sadikan	Recruiting
Bandung, Indonesia
Singapore
Tan Tock Seng Hospital	Recruiting
Singapore, Singapore
Singapore General Hospital	Recruiting
Singapore, Singapore
National University Hospital, National University of Singapore	Recruiting
Singapore, Singapore
Changi General Hospital	Recruiting
Singapore, Singapore
Thailand
Queen Sirikit National Institute of Child Health	Recruiting
Bangkok, Thailand
Bamrasnaradura Infectious Disease Hospital	Recruiting
Nonthaburi, Thailand
Siriraj Hospital Mahidol University	Recruiting
Bangkok, Thailand
Chest Disease Institute	Recruiting
Nonthaburi, Thailand
Vietnam
National Institute fof Infectious and Tropical Diseases	Recruiting
Hanoi, Vietnam
National Hospital of Pediatrics	Recruiting
Hanoi, Vietnam
Children's Hospital #1	Recruiting
Ho Chi Minh City, Vietnam
Pediatric Hospital #2	Recruiting
Ho Chi Minh City, Vietnam
Hospital for Tropical Diseases	Recruiting
Ho Chi Minh City, Vietnam

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

More Information

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

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:	( RCHSPB )
Study ID Numbers:	060106, 06-I-0106
Study First Received:	March 1, 2006
Last Updated:	November 8, 2008
ClinicalTrials.gov Identifier:	NCT00298233
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Antibody Response
Antiviral Efficacy
Bird Flu
Severe Respiratory Distress

Viral Replication and Shedding
Influenza
Avian Influenza
Bird Flu

Study placed in the following topic categories:

Virus Diseases
Antibodies
Respiratory Tract Diseases
Respiratory Tract Infections
Influenza, Human

Influenza in Birds
Orthomyxoviridae Infections
Immunoglobulins
Oseltamivir

Additional relevant MeSH terms:

Anti-Infective Agents
RNA Virus Infections
Molecular Mechanisms of Pharmacological Action
Therapeutic Uses

Enzyme Inhibitors
Antiviral Agents
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 16, 2009