Influenza Resistance Information Study (IRIS)

• ClinicalTrials.gov Identifier: NCT00884117
• Recruitment Status: Completed
• First Posted: April 20, 2009
• Results First Posted: July 19, 2016
• Last Update Posted: October 19, 2016
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

Brief Summary:

This study will assist in the early detection of influenza resistant to antivirals and will monitor the clinical outcome of adults and children infected with influenza according to subtype and susceptibility. Participants clinically diagnosed with influenza will undergo a rapid diagnostic test and viral sampling at Baseline and on Days 3, 6, and 10. Participants will be clinically managed according to local guidelines and the decision to treat/not treat will be at the discretion of the Investigator.

Condition or disease	Intervention/treatment
Influenza	Drug: Oseltamivir

Study Design

• Study Type: Observational
• Actual Enrollment: 4561 participants
• Observational Model: Case-Only
• Time Perspective: Prospective
• Official Title: Influenza Resistance Information Study (IRIS)
• Study Start Date: January 2009
• Actual Primary Completion Date: November 2015
• Actual Study Completion Date: November 2015

Groups and Cohorts

Group/Cohort	Intervention/treatment
Participants Infected with Influenza; Participants with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness will be enrolled and followed for up to 10 days after informed consent for virological surveillance and assessment of clinical outcomes. Participants may receive treatment including oseltamivir, other treatment/medication, or no treatment.	Drug: Oseltamivir; Participants may receive treatment at the discretion of the investigator according to local practice standards, and there is no protocol-specified intervention. However, analyses will be presented separately for participants treated with oseltamivir during the course of the study.; Other Name: Tamiflu

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Genotypic Resistance [ Time Frame: Baseline (Day 1) and post-Baseline (Days 3, 6, 10) ]
   Samples were analyzed using reverse transcriptase-polymerase chain reaction (RT-PCR). Pre-defined mutations in viral ribonucleic acid (RNA) were noted, the presence of which was defined as genotypic resistance. The number of participants with genotypic resistance at Baseline was reported. The number of participants with genotypic resistance post-Baseline was determined by a collective count of all participants who had a resistance mutation at least once on Days 3, 6, and/or 10. (Hereafter, "H" stands for hemagglutinin and "N" stands for neuraminidase in abbreviations of viral subtype such as H1N1, H1N1pdm09, and H3N2.)
2. Percentage of Participants Exhibiting Treatment-Emergent Resistance by Study Year Among Participants With H3N2 or H1N1pdm09 Infections [ Time Frame: From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10) during Study Years 1, 2, 3, 4, 5, 6, 7 ]
   Pre-defined mutations in viral RNA were noted, the presence of which was defined as genotypic resistance. Treatment-emergent resistance was defined as the presence of genotypic or phenotypic resistance from a post-Baseline sample in the setting of a previously non-resistant Baseline sample. The percentage of participants with treatment-emergent resistance was reported by study year for participants with H3N2 or H1N1pdm09 infections. Only data with evaluable participants were reported.

Secondary Outcome Measures :

1. Number of Participants With Viral RNA Detected by RT-PCR on Day 1 Among Adults Treated With Oseltamivir [ Time Frame: Baseline (Day 1) ]
2. Number of Participants With Viral RNA Detected by RT-PCR on Day 3 Among Adults Treated With Oseltamivir [ Time Frame: Day 3 ]
3. Number of Participants With Viral RNA Detected by RT-PCR on Day 6 Among Adults Treated With Oseltamivir [ Time Frame: Day 6 ]
4. Number of Participants With Viral RNA Detected by RT-PCR on Day 10 Among Adults Treated With Oseltamivir [ Time Frame: Day 10 ]
5. Number of Participants With Viral RNA Detected by RT-PCR on Day 1 Among Children Treated With Oseltamivir [ Time Frame: Baseline (Day 1) ]
6. Number of Participants With Viral RNA Detected by RT-PCR on Day 3 Among Children Treated With Oseltamivir [ Time Frame: Day 3 ]
7. Number of Participants With Viral RNA Detected by RT-PCR on Day 6 Among Children Treated With Oseltamivir [ Time Frame: Day 6 ]
8. Number of Participants With Viral RNA Detected by RT-PCR on Day 10 Among Children Treated With Oseltamivir [ Time Frame: Day 10 ]
9. Time to Non-Detection of Viral RNA [ Time Frame: From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10) ]
   Time to non-detection/viral clearance was the time between symptom onset and the day on which viral RNA was no longer detected, or the last visit date if the participant was not RNA-negative at that visit. Time to non-detection/viral clearance was estimated using Kaplan-Meier analysis and expressed in days.
10. Time to Non-Detection of Viral RNA Among Participants With H3N2 Infections [ Time Frame: From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10) ]
    Time to non-detection/viral clearance was the time between symptom onset and the day on which viral RNA was no longer detected, or the last visit date if the participant was not RNA-negative at that visit. Time to non-detection/viral clearance was estimated using Kaplan-Meier analysis and expressed in days.
11. Time to Non-Detection of Viral RNA Among Participants With H1N1pdm09 Infections [ Time Frame: From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10) ]
    Time to non-detection/viral clearance was the time between symptom onset and the day on which viral RNA was no longer detected, or the last visit date if the participant was not RNA-negative at that visit. Time to non-detection/viral clearance was estimated using Kaplan-Meier analysis and expressed in days.
12. Time to Non-Detection of Viral RNA Among Participants With Influenza B Infections [ Time Frame: From Baseline (Day 1) to Day 10 (assessed on Days 1, 3, 6, 10) ]
    Time to non-detection/viral clearance was the time between symptom onset and the day on which viral RNA was no longer detected, or the last visit date if the participant was not RNA-negative at that visit. Time to non-detection/viral clearance was estimated using Kaplan-Meier analysis and expressed in days.
13. Viral Load Among Adults Treated With Oseltamivir [ Time Frame: Days 1, 3, 6, 10 ]
    Viral load was determined for those with detectable virus above the lower limit of quantification (LLQ) of 1.82 for influenza A viruses and 1.99 for influenza B viruses. The viral load from each sample was averaged among all participants and expressed in log10 of the number of viral particles per milliliter (log10 vp/mL).
14. Viral Load Among Children Treated With Oseltamivir [ Time Frame: Days 1, 3, 6, 10 ]
    Viral load was determined for those with detectable virus above the LLQ of 1.82 for influenza A viruses and 1.99 for influenza B viruses. The viral load from each sample was averaged among all participants and expressed in log10 vp/mL.
15. Percentage of Participants With Symptom Resolution on Day 6 Comparing Resistant and Susceptible Viruses [ Time Frame: Day 6 ]
    Pre-defined mutations in viral RNA were noted, the presence of which was defined as genotypic resistance. Phenotypic resistance was defined as 50% inhibitory concentration (IC50) more than 10-fold higher than the median value for all viruses of the same subtype. Treatment-emergent resistance was defined as the presence of genotypic or phenotypic resistance from a post-Baseline sample in the setting of a previously non-resistant Baseline sample. Susceptible viruses were those that did not exhibit treatment-emergent resistance. The percentage of participants with mild or absent symptoms on Day 6 was reported and stratified by resistant and susceptible viruses.
16. Percentage of Participants by Day of Viral RNA First Not Detected Comparing Resistant and Susceptible Viruses [ Time Frame: Days 3, 6, 10 ]
    Pre-defined mutations in viral RNA were noted, the presence of which was defined as genotypic resistance. Phenotypic resistance was defined as IC50 more than 10-fold higher than the median value for all viruses of the same subtype. Treatment-emergent resistance was defined as the presence of genotypic or phenotypic resistance from a post-Baseline sample in the setting of a previously non-resistant Baseline sample. Susceptible viruses were those that did not exhibit treatment-emergent resistance. The percentage of participants by earliest post-Baseline test day on which viral RNA was not detected was reported and stratified by resistant and susceptible viruses.
17. Percentage of Participants With Resistant Versus Susceptible Viruses by Baseline Viral Load [ Time Frame: Baseline (Day 1) ]
    Pre-defined mutations in viral RNA were noted, the presence of which was defined as genotypic resistance. Phenotypic resistance was defined as IC50 more than 10-fold higher than the median value for all viruses of the same subtype. Treatment-emergent resistance was defined as the presence of genotypic or phenotypic resistance from a post-Baseline sample in the setting of a previously non-resistant Baseline sample. Susceptible viruses were those that did not exhibit treatment-emergent resistance. The mean viral load from each sample was expressed in log10 vp/mL and stratified by resistant and susceptible viruses.
18. Total Daily Symptom Score According to Global Assessment by the Investigator Among Adults Treated With Oseltamivir [ Time Frame: Days 1, 6, 10 ]
    Symptoms were assessed on Days 1, 6, and 10. The Investigator rated seven symptoms of fever, sore throat, nasal congestion, cough, aches/pains, headache, and fatigue on a scale of 0 (absent/no problem) to 3 (severe/major problem). The global score was calculated as a sum of all individual symptom scores. Global scores may range from 0 to 21, with higher scores indicating worse or more pronounced symptoms.
19. Total Daily Symptom Score According to Global Assessment by the Investigator Among Children Treated With Oseltamivir [ Time Frame: Days 1, 6, 10 ]
    Symptoms were assessed on Days 1, 6, and 10. The Investigator rated seven symptoms of fever, sore throat, nasal congestion, cough, aches/pains, headache, and energy/tiredness on a scale of 0 (absent/no problem) to 3 (severe/major problem). The global score was calculated as a sum of all individual symptom scores. Global scores may range from 0 to 21, with higher scores indicating worse or more pronounced symptoms.
20. Body Temperature Among Adults Treated With Oseltamivir [ Time Frame: Days 1, 10 ]
    Body temperature was measured by the Investigator using an oral or tympanic thermometer at Baseline and Day 10. Body temperature at each visit was averaged among all participants and expressed in degrees Celsius.
21. Change From Baseline in Body Temperature Among Adults Treated With Oseltamivir [ Time Frame: Baseline (Day 1) to Day 10 ]
    Body temperature was measured by the Investigator using an oral or tympanic thermometer at Baseline and Day 10. The change in body temperature between visits was averaged among all participants and expressed in degrees Celsius.
22. Body Temperature Among Children Treated With Oseltamivir [ Time Frame: Days 1, 10 ]
    Body temperature was measured by the Investigator using an oral or tympanic thermometer at Baseline and Day 10. Body temperature at each visit was averaged among all participants and expressed in degrees Celsius.
23. Change From Baseline in Body Temperature Among Children Treated With Oseltamivir [ Time Frame: Baseline (Day 1) to Day 10 ]
    Body temperature was measured by the Investigator using an oral or tympanic thermometer at Baseline and Day 10. The change in body temperature between visits was averaged among all participants and expressed in degrees Celsius.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Participants with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness will be enrolled.

Criteria

Inclusion Criteria:

• Participants greater than or equal to (≥) 1 year of age with a positive diagnostic test of influenza and/or displaying symptoms suggestive of influenza-like illness (during Years 1 to 5)
• Participants less than or equal to (≤) 12 years of age with a positive diagnostic test of influenza and displaying symptoms suggestive of influenza-like illness and who are being or, according to local standard of care, will be treated with an influenza antiviral (during Years 6 and 7)

Exclusion Criteria:

• Allergy to any potential influenza therapy
• Living in the same household or residential/care home as another study participant

Contacts and Locations

Locations

United States, Illinois

Chicago, Illinois, United States, 60655

Australia, New South Wales

Westmead, New South Wales, Australia, 2145

France

Bron, France, 69677

Germany

Berlin, Germany, 14052

Hong Kong

Shatin, Hong Kong

Netherlands

Rotterdam, Netherlands, 3000 CA

Norway

Sandnes, Norway, 4313

Poland

Krakow, Poland, 31-159

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Roosenhoff R, Reed V, Kenwright A, Schutten M, Boucher CA, Monto A, Clinch B, Kumar D, Whitley R, Nguyen-Van-Tam JS, Osterhaus ADME, Fouchier RAM, Fraaij PLA. Viral Kinetics and Resistance Development in Children Treated with Neuraminidase Inhibitors: The Influenza Resistance Information Study (IRIS). Clin Infect Dis. 2020 Aug 22;71(5):1186-1194. doi: 10.1093/cid/ciz939.

Fraaij PL, Schutten M, Javouhey E, Burleigh L, Outlaw R, Kumar D, Boucher CA. Viral shedding and susceptibility to oseltamivir in hospitalized immunocompromised patients with influenza in the Influenza Resistance Information Study (IRIS). Antivir Ther. 2015;20(6):633-42. doi: 10.3851/IMP2957. Epub 2015 Apr 7.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00884117
• Other Study ID Numbers: NV20237; 2008-006149-24 ( EudraCT Number )
• First Posted: April 20, 2009
• Results First Posted: July 19, 2016
• Last Update Posted: October 19, 2016
• Last Verified: October 2016

Additional relevant MeSH terms:

Influenza, Human; 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