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Efficacy Study of Early Versus Late Oseltamivir Administration for Treating and Preventing Influenza

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00555893
Recruitment Status : Completed
First Posted : November 9, 2007
Results First Posted : January 14, 2015
Last Update Posted : October 16, 2018
Sponsor:
Collaborator:
Centers for Disease Control and Prevention
Information provided by (Responsible Party):
Edward Belongia, Marshfield Clinic Research Foundation

Tracking Information
First Submitted Date  ICMJE November 7, 2007
First Posted Date  ICMJE November 9, 2007
Results First Submitted Date  ICMJE January 7, 2015
Results First Posted Date  ICMJE January 14, 2015
Last Update Posted Date October 16, 2018
Study Start Date  ICMJE January 2008
Actual Primary Completion Date February 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 7, 2015)
Duration of Influenza Illness [ Time Frame: Interval (in 12 hour blocks) from time of randomization until resolution (minimum 7 days, maximum 14 days) ]
Resolution is defined as occurring at the start of the first 24-hour period in which the total symptom score was less than or equal to 2 with no symptom rated higher than mild. Time to resolution was calculated from the time of randomization to symptom resolution in 12 hour increments.
Original Primary Outcome Measures  ICMJE
 (submitted: November 7, 2007)
Duration of Influenza Illness [ Time Frame: Interval (in 12 hour blocks) from symptom onset until resolution ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 15, 2018)
  • 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) ]
    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.
  • Viral Shedding on Day 3-4 of Treatment [ Time Frame: 3-4 days after treatment initiation ]
    Proportion of participants with positive PCR on day 3-4 of treatment
  • Secondary Complications (Otitis Media, Sinusitis, Pneumonia, Hospital Admission) [ Time Frame: 30 days from symptom onset ]
  • Mean Influenza Well-being Score [ Time Frame: Randomization to resolution ]
    Mean influenza wellbeing score is 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 is divided by the number of reporting days to yield the mean daily influenza wellbeing score for each person. Minimum score is 0 and maximum is 27. Higher scores indicate better outcome.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 7, 2007)
  • Mean Illness Severity Score [ Time Frame: Calculated from initial enrollment (randomization) up to first period of symptom resolution ]
  • 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 ]
  • Secondary Attack Rate (number of influenza episodes confirmed by polymerase chain reaction in household members of index cases, divided by the total number of household members at-risk) [ Time Frame: Household members with symptom onset on days 2 through 7 after index case randomization ]
  • Antiviral effectiveness for reducing infectiousness (based on symptomatic, laboratory-confirmed influenza infections in household contacts) [ Time Frame: Days 2 through 7 after index case randomization ]
  • Secondary complications (new clinical diagnosis of acute otitis media, acute sinusitis or pneumonia)documented in medical record, or influenza-related hospital admission [ Time Frame: From 0 to 28 days after randomization ]
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy Study of Early Versus Late Oseltamivir Administration for Treating and Preventing Influenza
Official Title  ICMJE Monitoring Influenza Severity on Tamiflu (MIST)
Brief Summary

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:

  1. 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.
  2. 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:

  1. 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).
  2. The incidence of secondary complications is lower in patients initiating oseltamivir therapy late relative to those receiving no antiviral therapy.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Influenza
Intervention  ICMJE
  • 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
  • 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.
Study Arms  ICMJE
  • 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)

    Intervention: Drug: Oseltamivir
  • 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.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 12, 2012)
194
Original Estimated Enrollment  ICMJE
 (submitted: November 7, 2007)
400
Actual Study Completion Date  ICMJE February 2011
Actual Primary Completion Date February 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  1. Outpatient or inpatient encounter for acute respiratory illness less than 5 days (120 hours) duration.
  2. Acute respiratory illness with feverishness OR cough.
  3. 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:

  1. Institutional resident (including assisted living or skilled nursing facility).
  2. 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).
  3. 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.
  4. Prior hypersensitivity reaction to oseltamivir.
  5. Dementia, impaired communication, or other reason for inability to provide informed consent.
  6. 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.
  7. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 79 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00555893
Other Study ID Numbers  ICMJE 1U01IP000124-01( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Edward Belongia, Marshfield Clinic Research Foundation
Study Sponsor  ICMJE Marshfield Clinic Research Foundation
Collaborators  ICMJE Centers for Disease Control and Prevention
Investigators  ICMJE
Principal Investigator: Edward Belongia, MD Marshfield Clinic Research Foundation
PRS Account Marshfield Clinic Research Foundation
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP