Efficacy Study of Early Versus Late Oseltamivir Administration for Treating and Preventing Influenza - Full Text View

Purpose

This study is a randomized, blinded, placebo-controlled clinical efficacy trial to assess the duration and severity of influenza symptoms, and duration of viral shedding, in influenza patients receiving oseltamivir early and late relative to placebo.

There are two main hypotheses in this study:

The duration of influenza symptoms, mean severity score, and duration of viral shedding are reduced in patients who initiate oseltamivir treatment late (48 to 119 hours) compared to those receiving no antiviral therapy.
Prior influenza vaccination (same season) reduces the duration of influenza symptoms and mean symptom severity in patients receiving oseltamivir after adjusting for age and timing of antiviral therapy (early versus late).

There are two secondary hypotheses:

The duration of influenza symptoms, mean severity score, and duration of viral shedding are reduced in patients with influenza who initiate oseltamivir treatment early (< 48 hours) versus late (48 to 119 hours).
The incidence of secondary complications is lower in patients initiating oseltamivir therapy late relative to those receiving no antiviral therapy.

Condition	Intervention
Influenza	Drug: Oseltamivir Drug: Placebo

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	Monitoring Influenza Severity on Tamiflu (MIST)

Resource links provided by NLM:

MedlinePlus related topics: Flu

Drug Information available for: Oseltamivir Oseltamivir phosphate

U.S. FDA Resources

Further study details as provided by Marshfield Clinic Research Foundation:

Primary Outcome Measures:

Duration of influenza illness [ Time Frame: Interval (in 12 hour blocks) from symptom onset until resolution (minimum 7 days, maximum 14 days) ] [ Designated as safety issue: No ]
Resolution is defined as occurring at the first of two consecutive reporting periods (24 hours) when all 8 symptoms are scored as mild or absent (and no decongestant or antitussive products were used during that interval). Duration of fever will be based on the interval to the first of two consecutive periods (24 hours) where the temperature is less than 37.8 degrees C (100.0 degrees F) and no fever reducers were used (acetaminophen or ibuprofen).

Secondary Outcome Measures:

Mean Illness Severity Score [ Time Frame: Calculated from initial enrollment (randomization) up to first period of symptom resolution (minimum of 7 days, maximum of 14 days) ] [ Designated as safety issue: No ]
Mean severity score will be calculated by first summing the symptom severity scores for all reporting periods from initial enrollment (randomization) up to (and including) the first period of symptom resolution, as defined above. The summed total will be divided by the number of reporting periods to yield the mean severity score for each participant. For each reporting period, the possible symptom scores will range from 0 (all symptoms absent) to 24 (all symptoms severe). For children less than 2 years old, the possible scores will range from 0 to 15.
Duration of viral shedding [ Time Frame: Interval (in days) from collection of the first sample yielding a positive influenza test to the last sample yielding a positive culture (maximum 14 days) ] [ Designated as safety issue: No ]
Secondary complications (new clinical diagnosis of acute otitis media, acute sinusitis or radiographically confirmed pneumonia)documented in medical record, or influenza-related hospital admission [ Time Frame: From 0 to 30 days after randomization ] [ Designated as safety issue: No ]
Episodes of pneumonia will require a physician diagnosis of pneumonia, antimicrobial treatment for pneumonia, and an opacity or infiltrate on chest radiograph (or CT) that was not known to be chronic.
Mean influenza well-being score (health, ability to perform usual activities and sleep quality) [ Time Frame: Interval from randomization up to and including first day of symptom resolution (minimum 7 days, maximum 14 days) ] [ Designated as safety issue: No ]
Mean influenza wellbeing score will be calculated by first summing the daily scores for overall health (0-9 points), ability to perform usual activities (0-9 points), and sleep quality (0-9 points) from initial enrollment (randomization) up to (and including) the first day of symptom resolution. This will be divided by the number of reporting days to yield the mean daily influenza wellbeing score for each person.

Enrollment:	194
Study Start Date:	January 2008
Study Completion Date:	February 2011
Primary Completion Date:	February 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Active Drug Adults and adolescents weighing greater than 88 pounds will receive one 75 mg oseltamivir capsule twice daily, with or without food for a total of 5 days (10 doses). Participants one year of age and older up to a maximum weight of 88 pounds will receive a liquid form of study medication containing oseltamivir at a concentration of 15mg/ml. The dose will be based on weight: for weight <=33 lbs, dose=30 mg, volume per dose (15mg/mL)=2 mL two times per day x 5 days (10 doses); for weight 34-51 lbs, dose=45 mg, volume per dose (15mg/mL)=3 mL two times per day x 5 days (10 doses); for weight 52-88 lbs, dose=60 mg, volume per dose (15mg/mL)= 4 mL two times per day x 5 days (10 doses)	Drug: Oseltamivir Adults and adolescents weighing greater than 88 pounds will receive one 75 mg oseltamivir capsule twice daily, with or without food for a total of 5 days (10 doses). Participants one year of age and older up to a maximum weight of 88 pounds will receive a liquid form of study medication containing oseltamivir at a concentration of 15mg/ml. The dose will be based on weight: for weight <=33 lbs, dose=30 mg, volume per dose (15mg/mL)=2 mL two times per day x 5 days (10 doses); for weight 34-51 lbs, dose=45 mg, volume per dose (15mg/mL)=3 mL two times per day x 5 days (10 doses); for weight 52-88 lbs, dose=60 mg, volume per dose (15mg/mL)= 4 mL two times per day x 5 days (10 doses) Other Name: Tamiflu
Placebo Comparator: Placebo Identical placebo capsule twice daily for 5 days (10 doses). Participants one year of age and older up to a maximum of 88 pounds will receive a placebo syrup. The dose will be based on weight as follows: <=33 pounds,2 mL doses, two times per day; 34 - 51 pounds, 3 mL doses, two times per day; 52-88 pounds, 4 mL doses, two times per day.	Drug: Placebo Identical placebo capsule twice daily for 5 days (10 doses). Participants one year of age and older up to a maximum of 88 pounds will receive a placebo syrup. The dose will be based on weight as follows: <=33 pounds,2 mL doses, two times per day; 34 - 51 pounds, 3 mL doses, two times per day; 52-88 pounds, 4 mL doses, two times per day.

Arms

Assigned Interventions

Experimental: Active Drug

Adults and adolescents weighing greater than 88 pounds will receive one 75 mg oseltamivir capsule twice daily, with or without food for a total of 5 days (10 doses). Participants one year of age and older up to a maximum weight of 88 pounds will receive a liquid form of study medication containing oseltamivir at a concentration of 15mg/ml. The dose will be based on weight:

for weight <=33 lbs, dose=30 mg, volume per dose (15mg/mL)=2 mL two times per day x 5 days (10 doses); for weight 34-51 lbs, dose=45 mg, volume per dose (15mg/mL)=3 mL two times per day x 5 days (10 doses); for weight 52-88 lbs, dose=60 mg, volume per dose (15mg/mL)= 4 mL two times per day x 5 days (10 doses)

Drug: Oseltamivir

Adults and adolescents weighing greater than 88 pounds will receive one 75 mg oseltamivir capsule twice daily, with or without food for a total of 5 days (10 doses). Participants one year of age and older up to a maximum weight of 88 pounds will receive a liquid form of study medication containing oseltamivir at a concentration of 15mg/ml. The dose will be based on weight:

for weight <=33 lbs, dose=30 mg, volume per dose (15mg/mL)=2 mL two times per day x 5 days (10 doses); for weight 34-51 lbs, dose=45 mg, volume per dose (15mg/mL)=3 mL two times per day x 5 days (10 doses); for weight 52-88 lbs, dose=60 mg, volume per dose (15mg/mL)= 4 mL two times per day x 5 days (10 doses)

Other Name: Tamiflu

Placebo Comparator: Placebo

Identical placebo capsule twice daily for 5 days (10 doses). Participants one year of age and older up to a maximum of 88 pounds will receive a placebo syrup. The dose will be based on weight as follows: <=33 pounds,2 mL doses, two times per day; 34 - 51 pounds, 3 mL doses, two times per day; 52-88 pounds, 4 mL doses, two times per day.

Drug: Placebo

Identical placebo capsule twice daily for 5 days (10 doses). Participants one year of age and older up to a maximum of 88 pounds will receive a placebo syrup. The dose will be based on weight as follows: <=33 pounds,2 mL doses, two times per day; 34 - 51 pounds, 3 mL doses, two times per day; 52-88 pounds, 4 mL doses, two times per day.

Detailed Description:

In the past decade influenza has become increasingly recognized as a serious disease and pandemic threat. Elderly persons, young children, and individuals with chronic medical conditions have the greatest risk for complications or death from influenza infection. Neuraminidase inhibitors are currently licensed for the treatment and prevention of influenza if started early in the course of illness, but little is known regarding the effects of oseltamivir (one neuraminidase inhibitor) on illness severity when initiated later in the course of illness. Greater knowledge of the treatment effects is urgently needed for optimal management of seasonal influenza, and to maximize use of a limited stockpile of antiviral drugs in the event of an influenza pandemic.

Eligibility

Ages Eligible for Study:	1 Year to 79 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria:

Outpatient or inpatient encounter for acute respiratory illness less than 5 days (120 hours) duration.
Acute respiratory illness with feverishness OR cough.
Access to the internet or telephone at home. This is required because symptom severity reports will be submitted twice daily using either a secure web-based form or automated telephone entry. All phones in the Marshfield area have touchtone service, allowing automated data entry.

Exclusion criteria:

Institutional resident (including assisted living or skilled nursing facility).
Self-reported chronic liver or kidney disease. These conditions are listed as precautions in the oseltamivir manufacturer package insert (www.rocheusa.com/products/tamiflu/pi.pdf).
Pregnancy or breast-feeding. Oseltamivir is classified as pregnancy category C, and it is excreted in breast milk. The package insert states that the drug should be used only if the potential benefit justifies the potential risk to the fetus or breast-fed infant.
Prior hypersensitivity reaction to oseltamivir.
Dementia, impaired communication, or other reason for inability to provide informed consent.
Immunocompromised status, including HIV infection, neutropenia, systemic corticosteroid use, or use of other immunosuppressive drugs in the past 30 days. The manufacturer states that the efficacy of oseltamivir has not been established in immunocompromised patients.
Patient received 1 or more doses of influenza antiviral agents (oseltamivir, zanamivir, amantadine, rimantadine) or a prescription for one of these drugs prior to randomization.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00555893

Locations

United States, Wisconsin
Marshfield Clinic Research Foundation
Marshfield, Wisconsin, United States, 54449

Sponsors and Collaborators

Marshfield Clinic Research Foundation

Centers for Disease Control and Prevention

Investigators

Principal Investigator:

Edward Belongia, MD

Marshfield Clinic Research Foundation

More Information

No publications provided

Responsible Party:	Edward Belongia, Senior Research Scientist, Director Epidemiology Research Center, Marshfield Clinic Research Foundation, Marshfield Clinic Research Foundation
ClinicalTrials.gov Identifier:	NCT00555893 History of Changes
Other Study ID Numbers:	1 UO1 IP000124-01
Study First Received:	November 7, 2007
Last Updated:	December 6, 2012
Health Authority:	United States: Institutional Review Board

Keywords provided by Marshfield Clinic Research Foundation:

randomized
blinded
controlled
efficacy

Additional relevant MeSH terms:

Influenza, Human
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 May 22, 2013