Trial Comparing High Versus Standard Dose Oseltamivir in Severe Influenza Infection in ICU
Information source: University of Manitoba
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Influenza A Virus
Intervention: Oseltamivir (Drug)
Phase: Phase 2
Status: Terminated
Sponsored by: University of Manitoba Official(s) and/or principal investigator(s): Anand Kumar, MD, Principal Investigator, Affiliation: University of Manitoba
Summary
Primary Objectives:
The primary objective of the trial is to compare the antiviral efficacy of a 10 day course
of standard (75 mg bid) and high-dose (225 mg bid) oseltamivir (or equivalent doses in
mild-moderate renal failure) in the treatment of severe influenza infections.
The hypothesis is that high dose oseltamivir will increase the proportion of patients with
negative reverse transcriptase (RT)-PCR detection of influenza viral RNA (and viral culture,
at selected sites) at Day 5 post-treatment.
An important secondary objective of the trial, which reflects the main clinical objective,
is to determine the difference in the numbers of ventilator days between the standard-dose
and high-dose groups
Clinical Details
Official title: A Randomized, Double-Blinded Controlled Trial Comparing High vs Standard Dose Oseltamivir in Severe, Influenza Infection in ICU. "ROSII Study"
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Negative reverse transcriptase (RT)-PCR detection of viral RNA in nasopharyngeal and tracheal aspirate (intubated) or oropharyngeal (non-intubated) samples at Day 5 among patients who require ICU admission due to respiratory distress.
Secondary outcome: Ventilator days up to 60 d (main clinical endpoint),
Detailed description:
Primary Objectives:
The primary objective of the trial is to compare the antiviral efficacy of a 10 day course
of standard (75 mg bid) and high-dose (225 mg bid) oseltamivir (or equivalent doses in
mild-moderate renal failure) in the treatment of severe influenza infections.
The hypothesis is that high dose oseltamivir will increase the proportion of patients with
negative reverse transcriptase (RT)-PCR detection of influenza viral RNA (and viral culture,
at selected sites) at Day 5 post-treatment.
An important secondary objective of the trial, which reflects the main clinical objective,
is to determine the difference in the numbers of ventilator days between the standard-dose
and high-dose groups.
Secondary Objectives:
- Laboratory objectives:
1. Assess viral RNA load and clearance from nasopharyngeal and tracheal aspirate
(intubated) or oropharyngeal (non-intubated) samples by RT-PCR on days 1, 3, 5, 7,
10, 14 and 28 days
2. Determine viral clearance by culture from nasopharyngeal and tracheal aspirate
(intubated) or oropharyngeal (non-intubated) samples on days 1, 3, 5, 7, 10, 14
and 28 days at select hospital sites with culture capability
3. Assess the pharmacokinetics of oseltamivir carboxylate and phosphate on Day 3 in
suspected H1N1 patients with respiratory distress and/or critical illness
requiring ICU care
4. Characterize the inflammatory cytokine response on Day 1-3, 5, 7, 10, 14, 21 and
28 days to severe influenza stratified by standard-dose versus high-dose
oseltamivir therapy.
5. Assess leukocyte gene expression at day 1, 3, 5, 10 and 21 days using high
throughput RNA assessment techniques
6. Examine urine for biomarkers of disease and severe disease
- Clinical and Safety Objectives:
1. Determine the difference in the number of ventilator days in the standard-dose and
high-dose groups
2. Determine tolerability of high-dose versus standard-dose oseltamivir as assessed
by the number of serious, atypical and drug-related adverse events that are
possibly or probably related to oseltamivir
3. Assess other secondary efficacy variables including survival duration, hospital
free days to day 60, ICU free days to day 60, and shock (ie vasopressor) and renal
failure free (ie not requiring hemodialysis; ultrafiltration acceptable) days to
day 28 in relation to high vs standard dose oseltamivir therapy
4. Assess 60 day mechanical ventilation and ICU-free days stay in relation to high vs
standard dose oseltamivir therapy
5. Determine clinical criteria used by clinicians when electing to continue or
re-initiate oseltamivir therapy beyond 10 study day treatment course
Tertiary Objectives: Exploratory Analyses
- Laboratory Objectives:
1. Assess the relationship between pharmacokinetic variables on day 3 and measures of
viral clearance
2. Assess the frequency and genetic basis of antiviral resistance to oseltamivir
during and after therapy
3. Determine possible host genetic factors including HLA type that predispose to
severe influenza
- Clinical and Safety Objectives:
1. Determine differences in development and persistence of adverse clinical signs
(fever, heart rate, hypotension), requirement for and duration of organ support
(supplemental oxygen, vasopressor/inotropes, continuous renal replacement therapy)
and occurrence and resolution of organ failure by Sequential Organ Failure
Assessment (SOFA) score at days 7, 10, 14 and 28 as a consequence of high-dose
versus standard-dose oseltamivir
2. Determine impact of oseltamivir dosing on frequency of progression to mechanical
ventilation among non-ventilated patients
Eligibility
Minimum age: 12 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Patients age 12 and older and 45 kg or more
2. Suspected or confirmed influenza (Appendix A)
3. Requirement for ICU admission due to respiratory distress or critical illness defined
as one of:
1. Inspired oxygen need of >50% for at least 4 hours (For FiO2 for non-intubated
patients see Appendix B)
2. mechanical ventilation
3. Patient is receiving inotrope or vasopressor
4. Negative b-HCG test or negative bedside urine test pending a confirmatory b-HCG test
for pregnancy in women of childbearing age (12-60 years of age) will allow study
entry
Exclusion Criteria:
1. Inability to obtain consent
2. Patients receiving more than two doses of 150 mg or higher oseltamivir in 36 hours
before study entry
3. Patients having received more than 3 doses of 75 mg oseltamivir immediately in 36
hours before study entry
4. Age less than 12 years, or age <16 and weight less than 45 kg
5. Unlikely to absorb enteral study drug (e. g. patients with partial or complete
mechanical bowel obstruction, intestinal ischemia, infarction, and short bowel
syndrome)
6. Known allergy or hypersensitivity to oseltamivir
7. Pregnancy or breast feeding
8. Previous enrollment in current study
9. Concurrent involvement in an RCT examining an antiviral agent including other
neuraminidase inhibitors, interferon-a and/or ribavirin
10. Chronic renal failure requiring chronic hemodialysis
11. Severe chronic liver disease (Child-Pugh Score 11-15)
12. Anticipated death within 24 hours as judged by attending physician or local PI
13. Patient carrying "do not intubate" order (a "no CPR" or "no defibrillate" or "no
chest compressions" order alone is allowed)
Locations and Contacts
Winnipeg Regional Health Authority; Health Sciences Centre, Winnipeg, Manitoba R3E 0Z3, Canada
Additional Information
Starting date: November 2009
Last updated: June 9, 2011
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